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Introduction

One of the main lines of development in modern medicine and pharmacology is design of the methods for target delivery of pharmaceutical preparations into the damaged area of a body. This approach enables researchers to (i) increase the dose of a preparation present in the damaged organ; (ii) achieve prolonged action of a drug; (iii) exclude or considerably reduce possibility of toxic action of a drug on healthy organs and tissues. As a rule, conventional treatment involves introduction of a preparation into systemic blood circulation, whereupon the substance is distributed by blood in the organism of a patient. Therefore, in order to reach sufficiently high (i.e., therapeutically effective) concentration of a drug in the damaged area, it is necessary to introduce intentionally high amounts of this drug [1, 2]. The situation is also complicated by the fact that the majority of pharmaceutical preparations possess considerable toxicity; besides, in many cases, multiple administrations (courses of therapy) are necessary. In particular, a major problem of treatment of patients with oncological diseases is related to high or extremely high toxicity of modern chemotherapy drugs [3, 4]. Therefore, development of systems and methods for target drug delivery is an especially important and actual task.

In general, the process of target delivery of medicinal preparations proceeds as follows: (i) the drug-containing carrier is introduced into systemic blood circulation; (ii) the carrier circulates within an organism and is selectively accumulated in the damaged area; (iii) low doses of a drug preparation are gradually released from the carrier [1, 2, 5, 6]. However, the main disadvantage of this approach consists in the inability of carriers to be accumulated in a selected zone. Upon introducing into blood, carriers are distributed in the organism similarly to the conventional drugs [7]. An alternative procedure involves regional administration (for example, injecting drugs directly into the damaged area). This approach allows one to achieve predominant localization of carriers in the target provided that administration is performed with high accuracy.

Drug carriers are commonly designed on the basis of porous (hollow) micro- or nanospheres [8, 9]; however, particles without internal free volume can also be used (including liposomes, polymeric, oxide, metal particles, and the particles based on biocompatible non-toxic salts) [1, 2, 10-14]. Protective shells of various polymers are used to shield carriers and the enclosed drugs from the active internal media of an organism, and to provide prolongation of drug release. The polymers used to create these shells can be divided into two basic groups: synthetic (poly(acrylic acid) [15], polystyrene sulfonate [16], poly(ethylene oxide) [17]) and natural (carboxymethyl chitosan [18], alginate [19], hyaluronic acid [20], and dextran sulfate [21]).

The drug carriers used in the present work were based on porous microparticles of calcium carbonate (СаСО₃) covered with a layer of sodium salt of dextran sulfate; these objects meet the biological safety requirements and can be found in living organisms [22]. Spherical СаСО₃ porous vaterites (cores) were synthesized. Porous vaterite is one of three calcium carbonate polymorphs; other СаСО₃ modifications (cubic calcites and elongated aragonite crystals) do not possess porosity [23].

There are only few research papers concerning in vivo behavior of the СаСО₃-based drug carriers. In several works [21, 24], СаСО₃ vaterites containing various medicinal preparations were introduced to rats perorally and transdermally; their structures were studied after exposure to rat body for a certain time. The vaterites present in blood and plasma were destructed already in several hours after peroral administration [21, 25]. In the case of transdermal administration, vaterites underwent gradual bioresorption for one week without any morphological transformations [24]. In our earlier works, behavior of native СаСО₃-based carriers (without protective shells) in rat muscular tissue has been investigated [26]. It has been demonstrated that in 3 days after implantation of СаСО₃ cores into muscular tissue, structural transformation of calcium carbonate (from vaterite into aragonite) occurred; then, aragonite crystals were rapidly resorbed. In 2 weeks after operation, only traces of aragonite were found in tissues, and in 4 weeks, muscular tissue regained its normal state. No toxic action of the carriers on the surrounding tissues and the whole organism was revealed throughout the experiment.

We have found no papers describing in vivo behavior of СаСО₃-based carriers covered with dextran sulfate shells in muscular tissue.

The aim of the present work was to study in vivo behavior of porous spherical СаСО₃ vaterites (covered with protective shells of sodium salt of dextran sulfate) as components of target drug delivery systems in rat muscular tissue.

Materials and methods

Preparation of objects. Porous spherical vaterites (СаСО₃) were obtained by co-precipitation according to the technique described elsewhere [8] with several modifications [27]; namely, equal volumes of 1 M aqueous solutions of СаСl₂ × 2H₂O and Na₂CO₃ were poured together at stirring with an RW 20 anchor-type stirrer at 1 000 rpm. The mixture was stirred for 30 s. The suspension formed in 15 min was filtered with a Schott glass filter (#16); the precipitate was washed thrice with distilled water, then with aqueous solutions of acetone of increasing concentrations (30, 60, and 100%). The product was dried in thermostat at 40-50°С until a constant weight was reached. Diameters of the obtained cores varied from 1 to 4 μm. Then the cores were coated with polyanionic sodium salt of dextran sulfate (DexS) with ММ=9-20 kDa (Sigma Aldrich, USA). Calcium carbonate cores (50 mg) were added to 0.001 wt.% aqueous solution of DexS (10 mL). The suspension was stirred using a Multi Bio RS-24 rotor (Biosan, Latvia) for 1 h; the solid fraction was filtered off using a Schott glass filter (#16), washed thrice with distilled water and dried at 20°C.

Scanning electron microscopy. The samples were studied with the aid of a Supra 55VP scanning electron microscope (Carl Zeiss, Germany) using secondary electron imaging. Before measurements, the samples were covered with thin platinum layer.

Experiments with animals. The in vivo experiments involved 25 white 3-month-old male rats of Wistar strain (5 animals per each series of experiments). Weight of the animals varied from 200 to 250 g. For the study of in vivo bioresorption, СаСО₃ cores covered with DexS were sterilized in autoclave at 110°C for 1 h. Each weighed amount of СаСО₃ (10 mg) was hermetically packed in aluminum foil. The animals were operated under general anesthesia (intraperitoneal injections of Zoletil 100 dissolved in 20 mL of physiological solution and Rometar (20 mg/mL), 0.1 and 0.015 mL of solutions per 0.1 kg of animal body mass, respectively). The samples were placed into thigh great adductor muscle (musculus adductor magnus) of one hind extremity (one sample per animal). Then the wounds in extremities were sutured layer by layer using atraumatic needles and Prolene 4-0 suture. After outer suturing, the rats were caged individually, were fed standard diet, and had free access to water. All animals were active after surgery; no inflammation in the implantation area was observed, which is indicative of the absence of detrimental effects of implantation.

Morphological studies of СаСО₃ vaterites covered with DexS implanted in rat muscle tissue. In 3 days, 1, 2, 4 and 12 weeks after operation, samples of muscle tissue containing СаСО₃ covered with DexS were removed from animals, fixed with 10% neutral formalin in phosphate buffer (рН=7.4) for not less than 24 hrs, dehydrated using a series of ethanol solutions with increasing concentrations, and enclosed in paraffin blocks according to the standard histological technique. The paraffin cuts (5 μm in width) transverse to muscular fibers were obtained with the use of an Accu-Cut SRT 200 microtome (Sakura, Japan) and stained with Mayer hematoxylin and eosin (BioVitrum, Russia). The connective tissue was visualized according to the Mallory method (BioVitrum, Russia). Microscopic analysis was performed using a Leica DM750 light microscope (Germany) with a 10× ocular and 4, 10, 40, and 100× objectives. Images were recorded with an ICC50 camera (Leica, Germany).

Results and discussion

Fig. 1 presents SEM images of surfaces of СаСО₃ cores covered with DexS. It is seen that the cores are homogeneous in size; the average diameter of the majority of particles varies from 1 to 4 μm. The core surface is rough; nanometer-sized pores are observed. This structure is convenient for medicinal applications: the loaded substances can freely penetrate into the internal volume of a core, and prolonged release in the damaged area is facilitated. Besides, due to high porosity, transport of high amounts of a preparation is possible, which also contributes to therapeutic effect.

СаСО₃ cores covered with DexS in muscular tissue in 3 days after implantation. In 3 days after operation, in 1 of 5 operated animals, round plicated cavity was observed visually; this cavity contained transparent viscous liquid (apparently, DexS) and was surrounded by a thin СаСО₃ rim. High amount of leukocytes was found in the formed cavities (mainly neutrophiles and eosinophiles). In 4 of 5 cases, no cavities were revealed, and СаСО₃ was localized in muscular tissue in the form of round aggregates and whitish streaks (Fig. 2a). Histological studies showed that calcium carbonate was mainly present in the form of elongated crystals 40-120 μm long and 10-20 μm wide assembled in bundles and surrounded by rather wide cellular shaft. This “mound” or wall consisted of loose lying cells (mainly macrophages, little amounts of segment-nuclear leukocytes (neutrophiles, eosinophiles), single lymphocytes, and few fibroblasts (Fig. 3 a, b)). The vessels surrounding this cellular mound were varicose and plethoric; erythrocyte sludges (stacks of aggregated erythrocytes) were observed. Pronounced edema appeared between muscle fibers near implantation site. High amounts of macrophages were found in endomysium; the vessels were dramatically exaggerated and plethoric. No necrotic damage was revealed in the surrounding tissues.

The proposed mechanism of formation of cavities in muscular tissue involves the reaction between СаСО₃ cores and carbonic acid (the product of interaction between carbon dioxide and water, which is present in intercellular fluid). Carbon dioxide, in turn, is formed in the process of cellular respiration; however, it is mainly released by cells in the form of carbonic acid. The acid and the products of its dissociation exist in equilibrium. In addition, carbonic acid is included into the bicarbonate buffer system of blood plasma and intercellular fluid, which accounts for more than 50% of total buffer capacity [28]. The reaction between carbonic acid and СаСО₃ cores gives calcium hydrocarbonate Са(HСО₃)₂, an unstable compound, which dissolves well in water. Decrease in carbonic acid concentration in the reaction zone leads to beginning of decomposition of the salt to СаСО₃, carbon dioxide and water already at 15-20°C [29].

The average body temperature of rats is 38°C. Decrease in carbonic acid concentration in the implantation zone is caused by formation of a connective tissue capsule, which forms an impenetrable boundary between the reaction zone and intercellular fluid (containing buffer systems and products of muscle cell respiration). Consequently, СаСО₃ precipitates in the form of crystals (and not in the form of cores), and carbon dioxide that is released during decomposition forms a cavity. The most probable morphological modification of the appearing crystals is aragonite, which is formed at similar temperatures [30]. The main reaction equations can be written as follows:
СаСО₃ + CO₂ + H₂O → Са(HСО₃)₂,
or: СаСО₃ + H₂CO₃ → Са(HСО₃)₂;
Са(HСО₃)₂ → СаСО₃↓ + CO₂ ↑+ H₂O

The above reactions can proceed repeatedly and cease gradually as the interacting compounds are absorbed by the surrounding tissues and removed from the reaction zone.

СаСО₃ cores covered with DexS in muscular tissue in 1 week after implantation. In one week after operation, round cavities were detected in the implantation site in all cases; their sizes were larger than those formed in 3 days (Fig. 2 b). These cavities were also filled with a transparent viscous liquid; no СаСО₃ particles were visible. Microscopy studies revealed low amounts of calcium carbonate crystals accumulated at the periphery, on the inner surface of cavities. High amounts of cellular detritus and neutrophiles were present in the cavities (Fig. 3c). The cavities were surrounded with macrophage wall and a wide connective tissue capsule, in which fibroblasts were localized between young loose collagen fibers; macrophages, single segment-nuclear leukocytes and lymphocytes were also revealed. Many macrophages and lymphocytes penetrated into the cavity and were located inside it. The vessels in the forming capsule were exaggerated and plethoric; erythrocyte sludges were visible in some of them. Muscular tissue around the cavity was edematous; increased amounts of macrophages and lymphocytes were present in endomysium. The vessels in connective tissue interlayers were dramatically expanded and plethoric. No necrotic damage in the surrounding tissues was revealed.

Figure 2. Images of cross-sections of muscles after implantation of СаСО₃ cores covered with DexS. a – in 3 days after implantation; b – in 1 week after implantation; c – in 2 weeks after implantation, d – in 4 weeks after implantation. The samples were fixed in neutral 10% formalin for not less than 48 h.

Figure 3. Histologic sections of rat muscular tissues made in 3 days (a, b), 1 week (c), 2 weeks (d), and 4 weeks (e, f) after implantation of СаСО₃ cores covered with DexS. The samples were stained with hematoxylin and eosin. Magnification: 10× (а, c, d), 40× (b, e) and 100× (f).

СаСО₃ cores covered with DexS in muscular tissue in 2 weeks after implantation. In 2 weeks after implantation, macroscopic cavities were visible in the form of narrow fissures only in 1 animal; no cavities were observed in the remaining rats (Fig. 2 c). Capsules consisting of loosely arranged collagen fibers were revealed around fissure-like cavities. The capsules consisted of fibroblasts, macrophages, and lymphocytes. When a cavity was absent, a wide connective tissue interlayer was found in its place; this interlayer contained high amounts of cells, mainly fibroblasts, macrophages, lymphocytes, and multinucleated foreign body giant cells (MFBGC) arranged around isolated crystals of СаСО₃ (Fig. 3 d).

СаСО₃ cores covered with DexS in muscular tissue in 4 and 12 weeks after implantation. In 4 weeks after operation, the connective tissue interlayer (Fig. 2d) was revealed visually and with the aid of a microscope in the place where СаСО₃ cores have been implanted. Collagen fibers were completely formed; high amounts of cells were found. Fibroblasts, macrophages, MFBGC localized around isolated crystals of СаСО₃, and leukocytes were revealed (Fig. 3 e, f). The vessels in the connective tissue interlayer and in endomysium were slightly expanded. The morphology (structures of muscular tissue, endomysium and perimysium) observed in the implantation zone in 12 weeks after the operation was almost similar to normal.

Thus, it was demonstrated that in 3 days after implantation of СаСО₃ cores covered with DexS into muscular tissue, they were basically transformed into aragonite crystals, while cavities were formed in muscles in 1 of 5 cases; the cavities contained viscous liquid (obviously, solution of DexS). The cellular composition in the implantation zone indicated aseptic medium-grade inflammation. In 1 week after implantation, cavities filled with viscous liquid were observed in all cases. Note that this liquid is apparently solution of DexS (a natural bioresorbable polymer). СаСО₃ cores were not revealed visually. The light microscopy data showed that the amount of calcium carbonate crystals decreased considerably as compared to the case observed in 3 days after operation, which indicates active bioresorption of the cores. Cellular detritus was visible in the cavities, and macrophage shafts were formed around them. The connective tissue started to form; it contained increased numbers of macrophages and leukocytes, which is an indication of a chronic inflammation process. However, bioresorption of vaterites was ahead of formation of the connective tissue capsule, and already in 2 weeks after the beginning of the experiment, only traces of СаСО₃ were visible. In 4 weeks after operation, isolated СаСО₃ inclusions surrounded with MFBGC were visible. At the same time, the state of muscular tissue became normal again, which is a favorable outcome. In 12 weeks after beginning of the experiment, no СаСО₃ inclusions were found. It is important to note that no toxic (damaging) action of СаСО₃ cores on the surrounding tissues and the whole organism was revealed at any stages of the experiment. However, appearance of cavities at the early stages of the experiment should be taken into account; tumors should be treated carefully, since the above-mentioned cavities may facilitate formation of metastases.

Conclusion

The obtained data indicate that porous СаСО₃ vaterites covered with DexS are safe for medicinal use and capable of bioresorption; thus, they are promising materials for use as target drug delivery systems. The results of this study allow us to recommend the described systems as objects for further in vivo studies.

This work is a continuation of studies on the behavior of targeted drug delivery systems based on СаСО₃ vaterites in living systems, published earlier [25, 26].

Financial support

The study was performed within the framework of budget-supported research project №АААА-А20-120022090044-2, Institute of Macromolecular Compounds, RAS.

Compliance with ethical standards

The experiments involving animals were performed according to European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (Strasbourg, 1986) and WMA Declaration of Helsinki concerning welfare of laboratory animals (1996).

Conflict of interests

The authors declare no conflict of interests.

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12. Masood F. Polymeric nanoparticles for targeted drug delivery system for cancer therapy. Mater. Sci. Eng. C. 2016; 60: 569-578.
13. Mishra V, Kesharwani P, Amin MCM, Iyer A. Nanotechnology-based approaches for targeting and delivery of drugs and genes. 1st Ed. Academic Press 2017; 552.
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15. Huang S, Naka K, Chujo Y. Effect of molecular weights of poly(acrylic acid) on crystallization of calcium carbonate by the delayed addition method. Polymer J. 2008; 40: 154-162.
16. Wang C, He C, Tong Z , Liu X, Ren B, Zeng F. Combination of adsorption by porous CaCO3 microparticles and encapsulation by polyelectrolyte multilayer films for sustained drug delivery. Int J Pharm. 2006; 308: 160-167.
17. Richardson J, Maina J, Ejima H, Hu M, Guo J, Cho MY, et al. Versatile loading of diverse cargo into functional polymer capsules. Adv Sci. 2015; 2: 1400007. https://doi.org/10.1002/advs.201400007.
18. Wang J, Chen J, Zong J, Zhao D, Li F, Zhuo R, Cheng Si. Calcium carbonate/carboxymethyl chitosan hybrid microspheres and nanospheres for drug delivery. J Phys Chem C. 2010; 114: 18940-18945.
19. Zhao D, Zhuo R, Cheng S. Alginate modified nanostructured calcium carbonate with enhanced delivery efficiency for gene and drug delivery. Mol BioSystems. 2012; 8: 753-759.
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21. Sudareva N, Suvorova O, Saprykina N, Smirnova N, Bel'tiukov P, Petunov S, Radilov А, Vilesov A. Two-level delivery systems based on CaCO3 cores for oral administration of therapeutic peptides. J Microencapsulation 2018; 35: 619-634.
22. Binevski PV, Balabushevich NG, Uvarova VI, Vikulina AS, Volodkin D. Bio-friendly encapsulation of superoxide dismutase into vaterite CaCO3 crystals. Enzyme activity, release mechanism, and perspectives for ophthalmology. Colloids and Surfaces B: Biointerfaces 2019; 181: 437-449.
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" ["~DETAIL_TEXT"]=> string(27319) "

Introduction

One of the main lines of development in modern medicine and pharmacology is design of the methods for target delivery of pharmaceutical preparations into the damaged area of a body. This approach enables researchers to (i) increase the dose of a preparation present in the damaged organ; (ii) achieve prolonged action of a drug; (iii) exclude or considerably reduce possibility of toxic action of a drug on healthy organs and tissues. As a rule, conventional treatment involves introduction of a preparation into systemic blood circulation, whereupon the substance is distributed by blood in the organism of a patient. Therefore, in order to reach sufficiently high (i.e., therapeutically effective) concentration of a drug in the damaged area, it is necessary to introduce intentionally high amounts of this drug [1, 2]. The situation is also complicated by the fact that the majority of pharmaceutical preparations possess considerable toxicity; besides, in many cases, multiple administrations (courses of therapy) are necessary. In particular, a major problem of treatment of patients with oncological diseases is related to high or extremely high toxicity of modern chemotherapy drugs [3, 4]. Therefore, development of systems and methods for target drug delivery is an especially important and actual task.

In general, the process of target delivery of medicinal preparations proceeds as follows: (i) the drug-containing carrier is introduced into systemic blood circulation; (ii) the carrier circulates within an organism and is selectively accumulated in the damaged area; (iii) low doses of a drug preparation are gradually released from the carrier [1, 2, 5, 6]. However, the main disadvantage of this approach consists in the inability of carriers to be accumulated in a selected zone. Upon introducing into blood, carriers are distributed in the organism similarly to the conventional drugs [7]. An alternative procedure involves regional administration (for example, injecting drugs directly into the damaged area). This approach allows one to achieve predominant localization of carriers in the target provided that administration is performed with high accuracy.

Drug carriers are commonly designed on the basis of porous (hollow) micro- or nanospheres [8, 9]; however, particles without internal free volume can also be used (including liposomes, polymeric, oxide, metal particles, and the particles based on biocompatible non-toxic salts) [1, 2, 10-14]. Protective shells of various polymers are used to shield carriers and the enclosed drugs from the active internal media of an organism, and to provide prolongation of drug release. The polymers used to create these shells can be divided into two basic groups: synthetic (poly(acrylic acid) [15], polystyrene sulfonate [16], poly(ethylene oxide) [17]) and natural (carboxymethyl chitosan [18], alginate [19], hyaluronic acid [20], and dextran sulfate [21]).

The drug carriers used in the present work were based on porous microparticles of calcium carbonate (СаСО₃) covered with a layer of sodium salt of dextran sulfate; these objects meet the biological safety requirements and can be found in living organisms [22]. Spherical СаСО₃ porous vaterites (cores) were synthesized. Porous vaterite is one of three calcium carbonate polymorphs; other СаСО₃ modifications (cubic calcites and elongated aragonite crystals) do not possess porosity [23].

There are only few research papers concerning in vivo behavior of the СаСО₃-based drug carriers. In several works [21, 24], СаСО₃ vaterites containing various medicinal preparations were introduced to rats perorally and transdermally; their structures were studied after exposure to rat body for a certain time. The vaterites present in blood and plasma were destructed already in several hours after peroral administration [21, 25]. In the case of transdermal administration, vaterites underwent gradual bioresorption for one week without any morphological transformations [24]. In our earlier works, behavior of native СаСО₃-based carriers (without protective shells) in rat muscular tissue has been investigated [26]. It has been demonstrated that in 3 days after implantation of СаСО₃ cores into muscular tissue, structural transformation of calcium carbonate (from vaterite into aragonite) occurred; then, aragonite crystals were rapidly resorbed. In 2 weeks after operation, only traces of aragonite were found in tissues, and in 4 weeks, muscular tissue regained its normal state. No toxic action of the carriers on the surrounding tissues and the whole organism was revealed throughout the experiment.

We have found no papers describing in vivo behavior of СаСО₃-based carriers covered with dextran sulfate shells in muscular tissue.

The aim of the present work was to study in vivo behavior of porous spherical СаСО₃ vaterites (covered with protective shells of sodium salt of dextran sulfate) as components of target drug delivery systems in rat muscular tissue.

Materials and methods

Preparation of objects. Porous spherical vaterites (СаСО₃) were obtained by co-precipitation according to the technique described elsewhere [8] with several modifications [27]; namely, equal volumes of 1 M aqueous solutions of СаСl₂ × 2H₂O and Na₂CO₃ were poured together at stirring with an RW 20 anchor-type stirrer at 1 000 rpm. The mixture was stirred for 30 s. The suspension formed in 15 min was filtered with a Schott glass filter (#16); the precipitate was washed thrice with distilled water, then with aqueous solutions of acetone of increasing concentrations (30, 60, and 100%). The product was dried in thermostat at 40-50°С until a constant weight was reached. Diameters of the obtained cores varied from 1 to 4 μm. Then the cores were coated with polyanionic sodium salt of dextran sulfate (DexS) with ММ=9-20 kDa (Sigma Aldrich, USA). Calcium carbonate cores (50 mg) were added to 0.001 wt.% aqueous solution of DexS (10 mL). The suspension was stirred using a Multi Bio RS-24 rotor (Biosan, Latvia) for 1 h; the solid fraction was filtered off using a Schott glass filter (#16), washed thrice with distilled water and dried at 20°C.

Scanning electron microscopy. The samples were studied with the aid of a Supra 55VP scanning electron microscope (Carl Zeiss, Germany) using secondary electron imaging. Before measurements, the samples were covered with thin platinum layer.

Experiments with animals. The in vivo experiments involved 25 white 3-month-old male rats of Wistar strain (5 animals per each series of experiments). Weight of the animals varied from 200 to 250 g. For the study of in vivo bioresorption, СаСО₃ cores covered with DexS were sterilized in autoclave at 110°C for 1 h. Each weighed amount of СаСО₃ (10 mg) was hermetically packed in aluminum foil. The animals were operated under general anesthesia (intraperitoneal injections of Zoletil 100 dissolved in 20 mL of physiological solution and Rometar (20 mg/mL), 0.1 and 0.015 mL of solutions per 0.1 kg of animal body mass, respectively). The samples were placed into thigh great adductor muscle (musculus adductor magnus) of one hind extremity (one sample per animal). Then the wounds in extremities were sutured layer by layer using atraumatic needles and Prolene 4-0 suture. After outer suturing, the rats were caged individually, were fed standard diet, and had free access to water. All animals were active after surgery; no inflammation in the implantation area was observed, which is indicative of the absence of detrimental effects of implantation.

Morphological studies of СаСО₃ vaterites covered with DexS implanted in rat muscle tissue. In 3 days, 1, 2, 4 and 12 weeks after operation, samples of muscle tissue containing СаСО₃ covered with DexS were removed from animals, fixed with 10% neutral formalin in phosphate buffer (рН=7.4) for not less than 24 hrs, dehydrated using a series of ethanol solutions with increasing concentrations, and enclosed in paraffin blocks according to the standard histological technique. The paraffin cuts (5 μm in width) transverse to muscular fibers were obtained with the use of an Accu-Cut SRT 200 microtome (Sakura, Japan) and stained with Mayer hematoxylin and eosin (BioVitrum, Russia). The connective tissue was visualized according to the Mallory method (BioVitrum, Russia). Microscopic analysis was performed using a Leica DM750 light microscope (Germany) with a 10× ocular and 4, 10, 40, and 100× objectives. Images were recorded with an ICC50 camera (Leica, Germany).

Results and discussion

Fig. 1 presents SEM images of surfaces of СаСО₃ cores covered with DexS. It is seen that the cores are homogeneous in size; the average diameter of the majority of particles varies from 1 to 4 μm. The core surface is rough; nanometer-sized pores are observed. This structure is convenient for medicinal applications: the loaded substances can freely penetrate into the internal volume of a core, and prolonged release in the damaged area is facilitated. Besides, due to high porosity, transport of high amounts of a preparation is possible, which also contributes to therapeutic effect.

СаСО₃ cores covered with DexS in muscular tissue in 3 days after implantation. In 3 days after operation, in 1 of 5 operated animals, round plicated cavity was observed visually; this cavity contained transparent viscous liquid (apparently, DexS) and was surrounded by a thin СаСО₃ rim. High amount of leukocytes was found in the formed cavities (mainly neutrophiles and eosinophiles). In 4 of 5 cases, no cavities were revealed, and СаСО₃ was localized in muscular tissue in the form of round aggregates and whitish streaks (Fig. 2a). Histological studies showed that calcium carbonate was mainly present in the form of elongated crystals 40-120 μm long and 10-20 μm wide assembled in bundles and surrounded by rather wide cellular shaft. This “mound” or wall consisted of loose lying cells (mainly macrophages, little amounts of segment-nuclear leukocytes (neutrophiles, eosinophiles), single lymphocytes, and few fibroblasts (Fig. 3 a, b)). The vessels surrounding this cellular mound were varicose and plethoric; erythrocyte sludges (stacks of aggregated erythrocytes) were observed. Pronounced edema appeared between muscle fibers near implantation site. High amounts of macrophages were found in endomysium; the vessels were dramatically exaggerated and plethoric. No necrotic damage was revealed in the surrounding tissues.

The proposed mechanism of formation of cavities in muscular tissue involves the reaction between СаСО₃ cores and carbonic acid (the product of interaction between carbon dioxide and water, which is present in intercellular fluid). Carbon dioxide, in turn, is formed in the process of cellular respiration; however, it is mainly released by cells in the form of carbonic acid. The acid and the products of its dissociation exist in equilibrium. In addition, carbonic acid is included into the bicarbonate buffer system of blood plasma and intercellular fluid, which accounts for more than 50% of total buffer capacity [28]. The reaction between carbonic acid and СаСО₃ cores gives calcium hydrocarbonate Са(HСО₃)₂, an unstable compound, which dissolves well in water. Decrease in carbonic acid concentration in the reaction zone leads to beginning of decomposition of the salt to СаСО₃, carbon dioxide and water already at 15-20°C [29].

The average body temperature of rats is 38°C. Decrease in carbonic acid concentration in the implantation zone is caused by formation of a connective tissue capsule, which forms an impenetrable boundary between the reaction zone and intercellular fluid (containing buffer systems and products of muscle cell respiration). Consequently, СаСО₃ precipitates in the form of crystals (and not in the form of cores), and carbon dioxide that is released during decomposition forms a cavity. The most probable morphological modification of the appearing crystals is aragonite, which is formed at similar temperatures [30]. The main reaction equations can be written as follows:
СаСО₃ + CO₂ + H₂O → Са(HСО₃)₂,
or: СаСО₃ + H₂CO₃ → Са(HСО₃)₂;
Са(HСО₃)₂ → СаСО₃↓ + CO₂ ↑+ H₂O

The above reactions can proceed repeatedly and cease gradually as the interacting compounds are absorbed by the surrounding tissues and removed from the reaction zone.

СаСО₃ cores covered with DexS in muscular tissue in 1 week after implantation. In one week after operation, round cavities were detected in the implantation site in all cases; their sizes were larger than those formed in 3 days (Fig. 2 b). These cavities were also filled with a transparent viscous liquid; no СаСО₃ particles were visible. Microscopy studies revealed low amounts of calcium carbonate crystals accumulated at the periphery, on the inner surface of cavities. High amounts of cellular detritus and neutrophiles were present in the cavities (Fig. 3c). The cavities were surrounded with macrophage wall and a wide connective tissue capsule, in which fibroblasts were localized between young loose collagen fibers; macrophages, single segment-nuclear leukocytes and lymphocytes were also revealed. Many macrophages and lymphocytes penetrated into the cavity and were located inside it. The vessels in the forming capsule were exaggerated and plethoric; erythrocyte sludges were visible in some of them. Muscular tissue around the cavity was edematous; increased amounts of macrophages and lymphocytes were present in endomysium. The vessels in connective tissue interlayers were dramatically expanded and plethoric. No necrotic damage in the surrounding tissues was revealed.

Figure 2. Images of cross-sections of muscles after implantation of СаСО₃ cores covered with DexS. a – in 3 days after implantation; b – in 1 week after implantation; c – in 2 weeks after implantation, d – in 4 weeks after implantation. The samples were fixed in neutral 10% formalin for not less than 48 h.

Figure 3. Histologic sections of rat muscular tissues made in 3 days (a, b), 1 week (c), 2 weeks (d), and 4 weeks (e, f) after implantation of СаСО₃ cores covered with DexS. The samples were stained with hematoxylin and eosin. Magnification: 10× (а, c, d), 40× (b, e) and 100× (f).

СаСО₃ cores covered with DexS in muscular tissue in 2 weeks after implantation. In 2 weeks after implantation, macroscopic cavities were visible in the form of narrow fissures only in 1 animal; no cavities were observed in the remaining rats (Fig. 2 c). Capsules consisting of loosely arranged collagen fibers were revealed around fissure-like cavities. The capsules consisted of fibroblasts, macrophages, and lymphocytes. When a cavity was absent, a wide connective tissue interlayer was found in its place; this interlayer contained high amounts of cells, mainly fibroblasts, macrophages, lymphocytes, and multinucleated foreign body giant cells (MFBGC) arranged around isolated crystals of СаСО₃ (Fig. 3 d).

СаСО₃ cores covered with DexS in muscular tissue in 4 and 12 weeks after implantation. In 4 weeks after operation, the connective tissue interlayer (Fig. 2d) was revealed visually and with the aid of a microscope in the place where СаСО₃ cores have been implanted. Collagen fibers were completely formed; high amounts of cells were found. Fibroblasts, macrophages, MFBGC localized around isolated crystals of СаСО₃, and leukocytes were revealed (Fig. 3 e, f). The vessels in the connective tissue interlayer and in endomysium were slightly expanded. The morphology (structures of muscular tissue, endomysium and perimysium) observed in the implantation zone in 12 weeks after the operation was almost similar to normal.

Thus, it was demonstrated that in 3 days after implantation of СаСО₃ cores covered with DexS into muscular tissue, they were basically transformed into aragonite crystals, while cavities were formed in muscles in 1 of 5 cases; the cavities contained viscous liquid (obviously, solution of DexS). The cellular composition in the implantation zone indicated aseptic medium-grade inflammation. In 1 week after implantation, cavities filled with viscous liquid were observed in all cases. Note that this liquid is apparently solution of DexS (a natural bioresorbable polymer). СаСО₃ cores were not revealed visually. The light microscopy data showed that the amount of calcium carbonate crystals decreased considerably as compared to the case observed in 3 days after operation, which indicates active bioresorption of the cores. Cellular detritus was visible in the cavities, and macrophage shafts were formed around them. The connective tissue started to form; it contained increased numbers of macrophages and leukocytes, which is an indication of a chronic inflammation process. However, bioresorption of vaterites was ahead of formation of the connective tissue capsule, and already in 2 weeks after the beginning of the experiment, only traces of СаСО₃ were visible. In 4 weeks after operation, isolated СаСО₃ inclusions surrounded with MFBGC were visible. At the same time, the state of muscular tissue became normal again, which is a favorable outcome. In 12 weeks after beginning of the experiment, no СаСО₃ inclusions were found. It is important to note that no toxic (damaging) action of СаСО₃ cores on the surrounding tissues and the whole organism was revealed at any stages of the experiment. However, appearance of cavities at the early stages of the experiment should be taken into account; tumors should be treated carefully, since the above-mentioned cavities may facilitate formation of metastases.

Conclusion

The obtained data indicate that porous СаСО₃ vaterites covered with DexS are safe for medicinal use and capable of bioresorption; thus, they are promising materials for use as target drug delivery systems. The results of this study allow us to recommend the described systems as objects for further in vivo studies.

This work is a continuation of studies on the behavior of targeted drug delivery systems based on СаСО₃ vaterites in living systems, published earlier [25, 26].

Financial support

The study was performed within the framework of budget-supported research project №АААА-А20-120022090044-2, Institute of Macromolecular Compounds, RAS.

Compliance with ethical standards

The experiments involving animals were performed according to European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (Strasbourg, 1986) and WMA Declaration of Helsinki concerning welfare of laboratory animals (1996).

Conflict of interests

The authors declare no conflict of interests.

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string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27409" ["VALUE"]=> array(2) { ["TEXT"]=> string(545) "<p>Павел В. Попрядухин¹, Наталья Н. Сударева^1,2, Ольга М. Суворова¹, Галина Ю. Юкина², Елена Г. Сухорукова², Наталья Н. Сапрыкина¹, Илья А. Барсук³, Олег В. Галибин², Александр Д. Вилесов^1,2 </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(425) "

Павел В. Попрядухин¹, Наталья Н. Сударева^1,2, Ольга М. Суворова¹, Галина Ю. Юкина², Елена Г. Сухорукова², Наталья Н. Сапрыкина¹, Илья А. Барсук³, Олег В. Галибин², Александр Д. Вилесов^1,2

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¹ Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия
² Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
³ Военно-медицинская академия им. С. М. Кирова, Санкт-Петербург, Россия

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В настоящей работе изучено поведение пористых сферических ватеритов карбоната кальция (СаСО₃) покрытых защитной оболочкой из сульфата декстрана – систем адресной доставки лекарственных препаратов – в мышечной ткани крыс на сроках 3 сут., 1, 2, 4 и 12 нед., после имплантации. Было показано, что с течением времени происходит структурная трансформация и биорезорбция изучаемых носителей. Через 3 сут. наблюдается преобразование сферических структур в игольчатые с последующей их биорезорбцией в течение 2 нед. При этом патологического воздействия на окружающие ткани выявлено не было, что подтверждает безопасность применения покрытых защитной оболочкой СаСО₃ ватеритов и позволяет рекомендовать их для проведения дальнейших исследований в качестве систем адресной доставки лекарственных препаратов.

Ключевые слова

Адресная доставка лекарственных препаратов, карбонат кальция, сульфат декстрана, биорезорбция, мышечная ткань, эксперимент in vivo.

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Pavel V. Popryadukhin¹, Natalia N. Sudareva^1,2, Оlga М. Suvorova¹, Galina Yu. Yukina², Еlena G. Sukhorukova², Natalia N. Saprykina¹, Ilya A. Barsuk³, Oleg V. Galibin², Aleksandr D. Vilesov^1,2

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¹ Institute of Macromolecular Compounds RAS, St. Petersburg, Russia
² Pavlov University, St. Petersburg, Russia
³ S.M.Kirov Military Medical Academy, St. Petersburg, Russia

Correspondence
Dr. Pavel V. Popryadukhin, Institute of Macromolecular Compounds, St. Petersburg, Russia
E-mail: pavelpnru@gmail.com

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The present work is focused on the study of target drug delivery systems comprised of porous spherical calcium carbonate vaterites (СаСО₃) covered with the dextran sulfate protective shell. Behavior of the objects was investigated in vivo. The samples were implanted into rat muscular tissue and removed after different periods of exposure (3 days, 1, 2, 4, and 12 weeks after operation). It was shown that certain transformations in structure of the implanted carriers occurred over time, after which they underwent bioresorption. In 3 days after implantation, spherical vaterites degraded, and needle-like calcium carbonate objects were formed; during the following two weeks, these objects were completely resorbed in living tissues. Since no pathogenic influence of the samples on the surrounding tissues was revealed, we believe that СаСО₃ vaterites covered with protective shells are safe for potential medicinal applications and can be recommended for further studies as target drug delivery systems.

Keywords

Target drug delivery, calcium carbonate, dextran sulfate, bioresorption, muscular tissue, in vivo experiment.

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Popryadukhin¹, Natalia N. Sudareva^1,2, Оlga М. Suvorova¹, Galina Yu. Yukina², Еlena G. Sukhorukova², Natalia N. Saprykina¹, Ilya A. Barsuk³, Oleg V. Galibin², Aleksandr D. Vilesov^1,2 </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(301) "

Pavel V. Popryadukhin¹, Natalia N. Sudareva^1,2, Оlga М. Suvorova¹, Galina Yu. Yukina², Еlena G. Sukhorukova², Natalia N. Saprykina¹, Ilya A. Barsuk³, Oleg V. Galibin², Aleksandr D. Vilesov^1,2

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Pavel V. Popryadukhin¹, Natalia N. Sudareva^1,2, Оlga М. Suvorova¹, Galina Yu. Yukina², Еlena G. Sukhorukova², Natalia N. Saprykina¹, Ilya A. Barsuk³, Oleg V. Galibin², Aleksandr D. Vilesov^1,2

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The present work is focused on the study of target drug delivery systems comprised of porous spherical calcium carbonate vaterites (СаСО₃) covered with the dextran sulfate protective shell. Behavior of the objects was investigated in vivo. The samples were implanted into rat muscular tissue and removed after different periods of exposure (3 days, 1, 2, 4, and 12 weeks after operation). It was shown that certain transformations in structure of the implanted carriers occurred over time, after which they underwent bioresorption. In 3 days after implantation, spherical vaterites degraded, and needle-like calcium carbonate objects were formed; during the following two weeks, these objects were completely resorbed in living tissues. Since no pathogenic influence of the samples on the surrounding tissues was revealed, we believe that СаСО₃ vaterites covered with protective shells are safe for potential medicinal applications and can be recommended for further studies as target drug delivery systems.

Keywords

Target drug delivery, calcium carbonate, dextran sulfate, bioresorption, muscular tissue, in vivo experiment.

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The present work is focused on the study of target drug delivery systems comprised of porous spherical calcium carbonate vaterites (СаСО₃) covered with the dextran sulfate protective shell. Behavior of the objects was investigated in vivo. The samples were implanted into rat muscular tissue and removed after different periods of exposure (3 days, 1, 2, 4, and 12 weeks after operation). It was shown that certain transformations in structure of the implanted carriers occurred over time, after which they underwent bioresorption. In 3 days after implantation, spherical vaterites degraded, and needle-like calcium carbonate objects were formed; during the following two weeks, these objects were completely resorbed in living tissues. Since no pathogenic influence of the samples on the surrounding tissues was revealed, we believe that СаСО₃ vaterites covered with protective shells are safe for potential medicinal applications and can be recommended for further studies as target drug delivery systems.

Keywords

Target drug delivery, calcium carbonate, dextran sulfate, bioresorption, muscular tissue, in vivo experiment.

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¹ Institute of Macromolecular Compounds RAS, St. Petersburg, Russia
² Pavlov University, St. Petersburg, Russia
³ S.M.Kirov Military Medical Academy, St. Petersburg, Russia

Correspondence
Dr. Pavel V. Popryadukhin, Institute of Macromolecular Compounds, St. Petersburg, Russia
E-mail: pavelpnru@gmail.com

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¹ Institute of Macromolecular Compounds RAS, St. Petersburg, Russia
² Pavlov University, St. Petersburg, Russia
³ S.M.Kirov Military Medical Academy, St. Petersburg, Russia

Correspondence
Dr. Pavel V. Popryadukhin, Institute of Macromolecular Compounds, St. Petersburg, Russia
E-mail: pavelpnru@gmail.com

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Павел В. Попрядухин¹, Наталья Н. Сударева^1,2, Ольга М. Суворова¹, Галина Ю. Юкина², Елена Г. Сухорукова², Наталья Н. Сапрыкина¹, Илья А. Барсук³, Олег В. Галибин², Александр Д. Вилесов^1,2

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Павел В. Попрядухин¹, Наталья Н. Сударева^1,2, Ольга М. Суворова¹, Галина Ю. Юкина², Елена Г. Сухорукова², Наталья Н. Сапрыкина¹, Илья А. Барсук³, Олег В. Галибин², Александр Д. Вилесов^1,2

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В настоящей работе изучено поведение пористых сферических ватеритов карбоната кальция (СаСО₃) покрытых защитной оболочкой из сульфата декстрана – систем адресной доставки лекарственных препаратов – в мышечной ткани крыс на сроках 3 сут., 1, 2, 4 и 12 нед., после имплантации. Было показано, что с течением времени происходит структурная трансформация и биорезорбция изучаемых носителей. Через 3 сут. наблюдается преобразование сферических структур в игольчатые с последующей их биорезорбцией в течение 2 нед. При этом патологического воздействия на окружающие ткани выявлено не было, что подтверждает безопасность применения покрытых защитной оболочкой СаСО₃ ватеритов и позволяет рекомендовать их для проведения дальнейших исследований в качестве систем адресной доставки лекарственных препаратов.

Ключевые слова

Адресная доставка лекарственных препаратов, карбонат кальция, сульфат декстрана, биорезорбция, мышечная ткань, эксперимент in vivo.

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В настоящей работе изучено поведение пористых сферических ватеритов карбоната кальция (СаСО₃) покрытых защитной оболочкой из сульфата декстрана – систем адресной доставки лекарственных препаратов – в мышечной ткани крыс на сроках 3 сут., 1, 2, 4 и 12 нед., после имплантации. Было показано, что с течением времени происходит структурная трансформация и биорезорбция изучаемых носителей. Через 3 сут. наблюдается преобразование сферических структур в игольчатые с последующей их биорезорбцией в течение 2 нед. При этом патологического воздействия на окружающие ткани выявлено не было, что подтверждает безопасность применения покрытых защитной оболочкой СаСО₃ ватеритов и позволяет рекомендовать их для проведения дальнейших исследований в качестве систем адресной доставки лекарственных препаратов.

Ключевые слова

Адресная доставка лекарственных препаратов, карбонат кальция, сульфат декстрана, биорезорбция, мышечная ткань, эксперимент in vivo.

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¹ Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия
² Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
³ Военно-медицинская академия им. С. М. Кирова, Санкт-Петербург, Россия

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¹ Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия
² Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
³ Военно-медицинская академия им. С. М. Кирова, Санкт-Петербург, Россия

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Introduction

Depopulation of the indigenous community is among the most urgent problems for Russia with its vast territories. Current total birth rate (TBR) in Russia is 1.3-1.5, which is lower than required for simple reproduction of the population (should be ≈2.12 [1]). It is obvious that the decline in TBR is observed in all industrial countries, where the majority of the population is concentrated in the cities. The depopulation process cannot be stopped completely, but it can be slowed down by socio-economic changes, as well as by reducing secondary infertility of women in their childbearing age.

Primary infertility is the inability to give birth to the first child. This index decreases by 0.1% per year, being about 1.9% [2]. Secondary infertility is the inability to give birth to children after a successful first pregnancy. The prevalence of secondary infertility increases sharply with age – from 2.6% in women aged 20-24 years to 27.1 % in women aged 40-44 years [2]. At the same time, in Russia and other Central and Eastern Europe countries, as well as in Central Asia, secondary infertility is detected in 18% of women aged 20-44 years, compared to only 7.2% in the high-resource countries [2, 3]. Different disorders of uterine endometrium resulting from disturbed pregnancies or various interventions are the main cause of secondary infertility.

Prevention of endometrial disorders

The endometrium is a complex, multicomponent system consisting of the integumentary and glandular epithelium, stroma, basic substance, and blood vessels. The epithelial component of the endometrium consists mainly of secretory and ciliated cells, as well as a few reticular cells, fibroblasts, macrophages, lymphocytes and labrocytes. The human endometrium is a dynamic tissue that undergoes periods of growth and death during the menstrual cycle. Endometrial growth is regulated by the balance between estrogen and progesterone [4]. If this balance is disturbed, hyperplasia (with a deficiency of progesterone) or hypoplasia (with a deficiency of estrogen) of the endometrium may occur.

Both hyperplasia and hypoplasia are causes of infertility. In hyperplasia, there is an overgrowth of the endometrium and uterine stroma, including the release of endometrial cells into the muscle layer and abdominal cavity. With hypoplasia, decreased thickness of the internal uterine mucosa is noted. Thickness of the endometrial layer should range between 7 and 13 mm for successful fertilization. Under the borderline conditions, the attachment of an egg to the endometrium is possible, but miscarriages are more common. Endometrial hyperplasia was found in 70-80% of cases when examining women with infertility. Changes in endometrial thickness may be often caused by metabolic and neuroendocrine disorders. To arrange appropriate management, the major reasons for endometrial disorders should be identified.

Adhesive plaques (synechiae) form in the uterus following surgical interventions (abortions, curettage, complicated pregnancies), the condition known as Asherman’s syndrome (AS) [5]. Synechiae are outgrowths (adhesions) of the sclerotized endometrium that disturb normal anatomy and physiology of the uterine mucosa [6]. The main cause of AS is damage and trauma to the basal layer during gynecological procedures. Less often, intrauterine synechiae are formed after endometritis, the uterine mucosa inflammation caused by schistosomiasis or genital tuberculosis [7]. Synechiae are also formed in intrauterine adhesion (IUA), a disease of the uterus with aberrant occurrence of adhesions within uterus and/or cervix. Patients with IUA often have menstrual irregularities and suffer from pelvic pain. IUA can prevent blastocyst implantation, impair blood supply to the uterus and early fetus, and finally lead to miscarriage or complete infertility in patients.

The leading factor in the formation of synechiae is considered to be mechanical trauma of basal endometrial layer after childbirth or abortion (wound phase). Pathomorphology of intrauterine synechiae is still unclear. A major role in pathogenesis of intrauterine adhesions is assigned to macrophages, the cellular mediators of inflammation. After mechanical damage, macrophages show increased phagocytic and secretory activity and, within 5 days, become the main component of local leukocyte population. Macrophages promote the migration of new mesothelial cells to the damaged surface, which initially form small "islands" on the damaged surface, and then thin layers of mesothelial cells [8]. Certain cytokines, such as fibroblast growth factor (bFGF), platelet growth factor (PDGF), and transforming growth factor β1 (TGF-β1) seem to be involved in the pathogenesis [9]. The role of chemokines and chemokine receptors CXL12/CXCR4/CXCR7 axis in the development of AS was also shown: interaction of the CXCL12 chemokine with the CXCR4 receptor in mouse models caused a decrease in fibrosis and improved fertility [10]. Wang et al. studied the role of nuclear factor-kappaB (NF-KB) in the AS pathogenesis. As a result, NF-KB expression was significantly increased in endometrial samples from the AS patients compared to the control group. The role of NF-KB in the pathogenesis of AS was further confirmed in a rat model [11]. Xue et al. found that expression of TGF-β and connective tissue growth factor (CTGF) in endometrial tissue with adhesions was significantly increased. Moreover, the activity of the NF-KB signaling pathway in endometrial tissue with synechiae was also higher and positively correlated with expression of TGF-β and CTGF. Blocking the NF-KB signaling pathway with a specific inhibitor led to a decrease in TGF-β expression in RL95-2 cells, which confirmed an association between NF-KB and TGF-β signaling pathway in endometrial cells. In addition, the expression of TGF-β and CTGF has been associated with the recurrent IUA, so it can be used as a potential marker of IUA pathology [12].

Chronic activation of cellular and humoral proinflammatory responses is accompanied by increased production of cytokines and other biologically active substances that cause microcirculation disorders, exudation and deposition of fibrin in the endometrial layer, which forms connective tissue fibrinous adhesions in the stroma and/or intrauterine synechia of varying severity. In numerous studies, biopsies obtained from patients with intrauterine adhesions compared to patients with normal endometrium contained 50-80 % of fibrous tissue versus 13-20%, respectively. Due to the fact, that placental tissue fragments can cause fibroblast activation and collagen formation before endometrial regeneration. Occurrence of intrauterine synechiae is more likely in patients with missed abortion than in patients with incomplete abortion. In terms of possible injury to the uterine mucosa, the first 4 weeks after delivery or termination of pregnancy are considered most dangerous. From the histological point of view, endometrial stroma in AS is replaced by fibrous tissue, and the uterine glands are replaced by inactive cubic epithelium that is insensitive to hormonal stimulation. As a result, the normal anatomy and physiology of the uterine mucosa change.

When synechiae are formed, endometrial cells can grow in the muscle layer, which leads to endometriosis. Due to a difficult vaginal discharge of menstrual blood, the endometrium enters abdominal cavity via fallopian tubes. Menstrual blood contains stem cells that may grow in such inappropriate microenvironment.

Hormone therapy is ineffective in AS. The main method of treatment is surgical removal of synechiae, which is problematic in severe cases, due to the inability to locate the adhesions (fusions of the uterine walls). Despite the removal of adhesions, they are re-formed in 25% of women with moderate AS and 75% with severe pathology. Pregnancy occured in 25-75% of operated women, full-term children were born in 26-79% of cases. Different results are reported, due to absence of generally recognized AS classification and lack of common approach to secondary prevention of the disease

Endometrium regeneration using surface-functionalized hydrogels

Recovery of the uterine endometrium is facilitated by introduction of various biological substances that are able to stimulate regeneration of the tissue leading to restoration of reproductive capacity [14]. Type of biomaterial is an important factor in tissue engineering since it may provide structural support mimicking native uterine endometrial tissues [15]. The biomimetic should include a supporting layer and biologically active molecules. Both components should facilitate cellular and extracellular signaling, nutrient transport, stem cell recruitment, proliferation, and differentiation. The biomaterials can release drugs, growth factors, small molecules, and other biologically active compounds in a controlled manner. Recent studies have shown that, in addition to traditional regeneration of uterus promoted by the biomaterials, their combination with modified cells, e.g., cell layers, intercellular boundaries, surface-functionalized frameworks and decellularized biological tissue, may also exhibit functional or structural advantages. These approaches may provide recovery of altered uterine structures to some degree by inducing biomimetic changes and restoring the regenerative microenvironment [16, 17].

Regeneration of endometrium with modified hydrogels

Many endometrial regeneration strategies are focused on modifying the surface or structure of gels for better biocompatibility and stronger adhesion to endometrial surface; delivery of bioactive growth factors, hormones, and extracellular vesicles [18, 19]. Li et al. [19] developed a collagen hydrogel loaded with fibroblast growth factor bFGF conjugated to the collagen-binding domain (CBD). This combination significantly reduced the random bFGF diffusion in vivo and increased the delivery of the factor to the endometrium. Recombinant proteins with CBD were released in the damaged area and maintained an effective concentration for a long time. The complex framework induced high neovascularization, alignment of muscle fibers and thick layers of the endometrium which contributed to effective tissue recovery. However, the incidence of pregnancy in this study was low, indicating that functional recovery of the endometrium was not achieved. Similarly, Lin et al. [20] loaded vascular endothelial growth factor VEGF conjugated with CBD onto a collagen scaffold to improve angiogenesis and endometrial re-epithelization. The authors compared the efficacy of free growth factor, and VEGF included in the gel, aiming for regeneration of a full-layer injury in rat uterus. The resulting growth of vascular tissue provided the damaged areas with nutrients and oxygen. In addition, targeted VEGF release activated matrix metalloproteinases and initiated endometrial remodeling by increasing the number of inflammatory cells at early regeneration stages. The results showed a 31.2% improvement in pregnancy rate when using CBD/VEGF collagen gel (50.0%) compared to only local VEGF injection (18.8%).

Xu et al. [21] used a temperature-sensitive hydrogel loaded with keratinocyte growth factor KGF, which stimulates tissue repair. The hydrogel made it possible to control release and long-term retention of the drug in damaged uterus. The authors found that the modified KGF-hydrogel framework promoted cell autophagy by inhibiting the mammalian rapamycin signaling pathway; improved the expression level of the CD31 stem cell marker; endothelial migration and proliferation of endometrial glandular epithelial cells and luminal epithelial cells. Functional repair of the epithelium was due to the restoration of corresponding microenvironment by reducing inflammation and immune responses [22, 23].

In addition to biologically active proteins some studies aimed at restoring the endometrium have analyzed a role of secreted extracellular vesicles derived from stem cells [17, 22, 24]. A modified stem cell secretome-containing hydrogel was based on hyaluronic acid (HA), which increased the release of a number of regeneration-related growth factors, such as epidermal growth factor EGF, bFGF, insulin-like growth factor IGF-1, and IGF-binding protein IGFBP. The cross-linked gel served as a carrier and increased in vivo retention time for the stem cell secretions, thus been associated with an increase in endometrial thickness and higher number of endometrial glands if compared to the usage of non-modified gel. Nanoscale functionalization of endometrial scaffolds simulates the natural environment, provides stable release of bioactive molecules and transmission of signals from extracellular vesicles during uterine regeneration [25].

Endometrium regeneration on the basis of of gel-cell scaffolds

Endometrial mesenchymal cells

Biomaterials provide structural and mechanical support to help restoration of the architecture and functionality of damaged tissues. However, the scaffold biomaterial is not sufficient enough to repair large uterine defects. Vascularization, recruitment of native cells, and inhibition of scar formation should be considered [26]. Cell culture on the scaffold structures increases biological functions, prolonging cell survival and stimulating cell proliferation, differentiation, and vascularization [27]. E.g., the resident mesenchymal stromal cells (MSCs) could be incorporated into the polymer gels. Kim et al. [28] used endometrial mesenchymal stromal cells (dEMSCs) encapsulated in a HA hydrogel in a mouse model of uterine infertility. Two weeks after the injury, the fibrous tissue decreased and the endometrial thickness increased. The authors showed increased expression of embryonic markers, including desmin, CD44, and platelet endothelial cell adhesion molecules in regenerating endometrium. Successful implantation of the transferred embryos was accompanied by normal development and live birth of offspring after treatment of the damaged uterus with the dEMSC-HA hydrogel. Isotopic analysis of endometrial cell proliferation showed a significant reduction in recovery time with dEMSC-HA compared to isolated mesenchymal stem cells from bone marrow or endometrium. The gels were gradually eliminated from the uterus, due to HA-degrading hyaluronidase activity in uterus, thus allowing the incorporated cells to attach to endometrium in the damaged area and temporarily provide rigidity of the framework necessary for endometrial regeneration.

dEMSCs exert protective effect not only in patients with hypometriosis, but also at the AS. For example, a group of 7 patients suffering from severe AS underwent triple irrigation of uterine cavity with a suspension of autologous menstrual blood-derived endometrial stem cells. In all women, this treatment, along with additional estrogen therapy, was followed by increased endometrium thickness. In 5 out of 7 patients, the thickness reached 7 mm or more, thus being sufficient for implantation. Moreover, one of these women soon became pregnant in natural way, and two more, due to extracorporeal fertilization [29].

Endometrial perivascular cells

These cells could be also applied to promote local vascularization. Their ability to restore angiogenesis and inhibit scar formation when choosing cell types for uterine repair is of fundamental importance. Endometrial perivascular cells (En-PSCs) carrying CD146 markers and platelet growth factor receptor PDGFR-β loaded into a collagen gel had a similar effect upon stem cells in the endometrial layer [30]. En-PSCs, if additionally transfected with the CYR61 angiogenic inducer, were shown to promote vascular formation. Development of CYR61-transfected En-PSC-loaded collagen scaffold significantly increased the density of blood vessels, since it stimulated release of angiogenic factors from extracellular matrix and, generally, accelerated the in vivo neovascularization.

Bone marrow-derived mesenchymal stromal stem cells

A significant number of studies show the effectiveness of stem cells derived from bone marrow (BMSCs) for endometrial and uterine regeneration due to their ease of isolation and reparative potential [31-33]. Administration of BMSCs, supplemented by cauterization (electroacopuncture), improved fertility by activating the CXCR4 chemokine receptor, enhanced expression of cytokeratins and vimentin, VEGF and bFGF [31]. Effect of BMSCs incorporated into polyglycerol sebacinate (PGS) gel was compared with effect of BMSC-loaded collagen, or polylactic and glycolic acid (PLGA) copolymer gels. The authors showed an increase in TGF-β1, bFGF synthesis, and better recovery of endometrial morphology when using PGS gel. However, the fertility rates were comparable to those achieved with collagen-based gel (72%), but higher than with PLGA carrier (42%) [34]. Similar data were reported by Qi et al. [32]. The authors studied ability of BMSCs-PGS scaffolds for restoration of uterine soft tissue deformities under various dynamic conditions without external stimuli. The authors compared efficacy of the materials loaded with different cell types. PGS with BMSCs showed better stimulation of endometrial proliferation and differentiation. Moreover, the in vivo studies have shown longer retention time for BMSCs in situ and more effective vascularization of the PGS scaffold.

Yang et al. [33] used BMSCs encapsulated in a gel based on pluronic F-127 (PF-127) and vitamin C, which resulted in an increased membrane stability. In addition, vitamin C reduced the secretion of TNF-α and interleukin 6 (IL-6) due to its antioxidant activity, maintained redox homeostasis, and promoted a pro-regenerative trend by increasing the IL-10 levels. BMSC/PF-127+vitamin C hydrogel restored endometrial thickness and reduced fibrous areas of endometrial stromal tissues.

Meanwhile, the BMSCs therapy in patients with AS still lacked efficiency in terms of fertility. Indeed, introduction of autologous BMSCs into subendometrial myometrium in 6 women suffering from AS stimulated an increase in endometrial thickness and normalized menstrual cycles, but this biological effect in all patients did not result into successful extracorporeal fertilization attempts [35].

Umbilical cord mesenchymal stromal cells

Wharton’s jelly of the umbilical cord is an alternative source of MSCs, from which stem cells are isolated (UCMSCs). Introduction of UCMSCs as a component of a collagen carrier improved endometrial proliferation, differentiation, and neovascularization after implantation of UCMSCs scaffolds into the endometrium [36]. All 26 patients with AS showed positive dynamics, increased endometrial thickness, and decreased the number of intrauterine adhesions. Ten patients soon became pregnant after completing the treatment. The newborn children were born without any obvious birth defects or placental pathology. UCMSCs mixed with gelatin and collagen fibers stimulated pronounced angiogenesis and reduced scar formation in the damaged area. The composite cell framework destroyed collagen in the scarred areas, probably, by increasing the amount of matrix metalloproteinase 9, FGF-2, and VEGF, and led to angiogenesis and cyclic endometrial regeneration [37]. Xin et al. [38] found that the UCMSC-loaded collagen scaffold reduced cell apoptosis and improved the state of endometrial stromal cells due to eventual paracrine action. The scaffold did not induce inflammation and contributed to collagen remodeling in regenerating endometrium. In addition, the UCMSCs-loaded collagen scaffold induced early rapid re-epithelization by increasing level of cell proliferation and expression of cytokeratin, which is vital for the subsequent endometrial repair after damage.

Growth effects of platelet-rich plasma

Inclusion of platelet-rich plasma (PRP) in the structure of hydrogels is a point for research of uterine endometrial regeneration. In a number of studies, PRP was used to stimulate MSCs obtained from the menstrual blood. Transplantation of these MSCs stimulated thickening of the endometrium [39].

In women who underwent endometrial electroacupuncture for the first time, the effect of autologous PRP administration on endometrial thickness was evaluated. PRP infusion resulted in endometrial thickening up to 7 mm observed 48-72 hours later. Successful pregnancy occurred then after progesterone administration [40]. Similar data were obtained in a randomized clinical trial (n=83) among women with hypometriosis suffering from poor endometrial response to standard hormone replacement therapy. After PRP administration, there was a significant increase in endometrial thickness; in this group, the frequency of implantation and clinical pregnancy per cycle also increased significantly [41].

Application of autologous PRP in rat model with ethanol-induced endometrial injury led to endometrial regeneration. The authors concluded that intrauterine administration of autologous PRP stimulates and accelerates endometrial regeneration, along with reduced formation of fibrosis [42].

There are also studies in which the authors did not show that intrauterine PRP injection improves the results of hysteroscopy after surgical removal of intrauterine adhesions [43].

Hypothetical mechanisms of stem cell actions

Most research groups did not show real engraftment of transplanted mesenchymal cells, which confirms the current opinion about paracrine nature of therapeutic effects caused by allogeneic MSCs [44-48].

Cellular elements can be administered to patients as intravascular infusions [49, 50], intramuscularly [51] or directly into the uterine cavity. Both enriched MSCs or stromal cell suspensions can be used [35, 52, 53]. No serious side effects or signs of cell engraftment were observed in these studies. There is no doubt that further research and clinical trials are needed to optimize the use of cell therapy.

In healthy female body, cytokine environment and immune cellular repertoire depend on the phase of menstrual cycle [44], which are important for reducing fibrosis and restoration of endometrium. It is believed that successful endometrial repair technology is directly related to the activity of local inflammation. To achieve maximal therapeutic effect, it is necessary to ensure optimal mechanism and timely delivery of cellular elements, depending on the cycle phase. It is also necessary to minimize potential risks associated with the delivery method. For example, AS is often associated with disturbed blood flow in uterine spiral arterioles. Therefore, intravascular administration of these cellular elements cannot be used in this case.

Currently, most researchers believe that stem cells can only have a systemic and paracrine therapeutic effect, since they, probably, act as immunomodulators [46, 54, 55]. Immunomodulatory effects result from destruction of these cells or their absorption. This may explain the reparative tissue response during local injection of MSCs [56].

It is also suggested that the release of paracrine factors may represent the main effect of cellular therapy. In this case, the usage of exosomes/microvesicles opens some prospectives for regenerative medicine [57]. E.g., excretory microvesicles (eMVs) isolated from intrauterine fluid also have a protective effect [57-60]. In addition, MSCs have been shown to produce eMVs that have immunomodulatory effect on T cells [61].

During experiments on co-cultivation of mouse embryos and endometrial sMVs, an increase in the number of blastomeres, as well as vascular epithelium and platelets in embryos was observed [62]. These results led to the attempts of intrauterine infusion of PRP which includes eMVs components. In clinical trials, PRP infusion increased epithelial thickness [40, 63, 64], and, as a result, the number of successful implantations and natural pregnancies occurred. The fact that exosomes and other eMVs are an alternative to "direct" cell therapy and allow avoiding its negative consequences is confirmed by the high efficiency of PDGF-α, which is contained in platelets, in tissue repair and regeneration [65].

Clinical usage of antiadhesive polymers to prevent Ascherman’s syndrome

As noted above, the AS adhesions within uterus make it difficult to outflow menstrual blood and reduce women's fertility. Hormone therapy is not effective for AS. The main method of therapy is the removal of adhesions in one way or another. After removing the adhesions, new endometrial damage occurs, which often leads to the formation of the adhesions de novo. To prevent the formation of new adhesions, a number of studies have suggested using copolymers of hyaluronic acid and carboxymethylcellulose etc. for temporary separation of the uterine walls, which can provide the time required for re-epithelization of the wound surface.

For the prevention of AS and IUA in Russia and worldwide, various anti-adhesive materials are used, for example, Antiadhesin (Russia), Seprafilm film (France) based on sodium hyaluronate and sodium salt of carboxymethylcellulose (HA-CMC), Oxiplex/AP gel (USA) based on carboxymethylcellulose (CMC) and polyethylene oxide [8, 66-68], and others.

The use of barrier anti-adhesive agents based on HA-CMC reduces the risk of adhesion formation in the uterine cavity. According to a randomized study [68], intrauterine administration of an anti-adhesive barrier agent containing HA and CMC can not only prevent the formation or reduce the severity of intrauterine adhesions, but also contributes to the preservation of reproductive function. A total of 150 patients with incomplete or missed abortions participated in the clinical study. In the treatment group (Seprafilm) (n=50), membranes were inserted into the endometrial and cervical canal cavity after suction evacuation and/or curettage. The control group (n=100) did not get any treatment. Both groups were divided into two subgroups: patients who had no previous suction or curettage, and those who had at least one previous abortion or curettage. Further fertility was assessed by pregnancy success in all groups. The formation of endometrial synechiae was evaluated using hysterosalpingography in patients of all groups without pregnancy success 8 months after the intervention. The safety of using Seprafilm was evaluated by recording any adverse reactions and performing ultrasound monitoring. Of the subgroups without previous abortions, all 32 patients (100%) who received Seprafilm became pregnant in the next 8 months; in the control group, pregnancy occurred only in 54% of cases. They also showed that patients in the Seprafilm group with one or more previous interventions and no pregnancy after 8 months did not have adhesions in 90% of cases, and only in 50% of cases in the untreated group.

HA performs important physiological functions in the body, including joint lubrication, regulation of blood vessel wall permeability, regulation of protein and electrolyte transport, and wound healing. HA can bind to a large number of water molecules improving tissue hydration, increasing cell resistance to mechanical damage, and reducing post-traumatic formation of granulation and fibrous tissue. Due to its unique biocompatibility and enzymatic biodegradation, HA is often used to prevent postoperative adhesions [69, 70]. HA gel significantly reduces the frequency of IUA after intrauterine surgery, regardless of the type of intervention or the presence of primary diseases. It has been shown that treatment with HA gel increases the frequency of pregnancy after intrauterine surgery [71].

Heat-sensitive matrices based on poly-N-isopropylacrylamide

Poly-N-isopropylacrylamide (PNIPAM) is a polymer that performs a phase transition from a liquid to a gel state when heated above 37°C. As the temperature rises, PNIPAM forms a three-dimensional hydrogel that compresses and pushes the liquid out, releasing the contents into the surrounding tissue. Accordingly, PNIPAM, when administered, provides separation of the uterine walls. At the same time, it creates an enriched environment around itself that stimulates endometrial regeneration. Unlike PNIPAM, HA and CMC swell in the uterus, collecting intrauterine fluid and filling the internal volume. Theoretically, PNIPAM may be more promising for preventing adhesions. Currently, PNIPAM gels are being studied in vitro and in model systems, for example, for the cultivation of chondrocytes. Incubation of chondrocytes with PNIPAM showed that the cells were viable for 24 days, increased in number, and produced type II collagen and glycosaminoglycans [72].

For the functionalization of hydrogels, modification of PNIPAM is possible by including hydrophilic bioactive substances, such as cell culture supernates, eMVs or exosomes of MSCs, PRP, and other molecules. This modification may separate thermosetting and hydrophilic functions and allows each component to act independently. This concept was demonstrated by the Yoshioka group, who developed a tissue culture framework based on PNIPAM-graft-PEG [73-75]. The authors modified PNIPAM by including butyl ether of methacrylic acid in order to shift the phase transition point to a lower temperature. In subsequent studies in cell culture, the authors reported a system with a gelation temperature of 7°C in the cell culture medium [76]. It is known that thermosetting polymers with a hydrophobic component form dispersed gels in aqueous media above the critical point when the concentration exceeds the critical minimum. This phenomenon is associated with particle aggregation due to thermosetting flocculation of Poly(styrene-graft-NIPAM) particles [77, 78]. Poly(styrene-co-NIPAM) particles were used to form core-shell solid particles. Recently, thermosetting dispersed gels with Poly-ε-caprolactone cores and shells consisting of a polyethylene glycol brush were also obtained. Microdispersion procedure allowed to produce gels which were used as a thermally reversible cell culture system for mouse 3T3 fibroblasts [79] or C2C12 myoblasts [80].

Conclusions

The use of biopolymers and biomimetics based on combinations of polymers with various growth factors or live cells opens up new opportunities for the treatment of endometrial disorders. To this purpose, practical clinicians use gels based on hyaluronic acid, carboxymethyl cellulose, collagen, polyethylene oxide and others with certain efficiency. The main task of biopolymers is to separate the walls of the uterus, thus preventing synechiae, e.g., in Asherman’s syndrome. To improve treatment of hypo- and hypermetriosis, the gels should contain appropriate biological factors able to stimulate or inhibit the endometrial growth. Most of such biomimetic substances are currently at the pre-clinical testing stage. Some data from clinical studies have shown promising results of this approach for the treatment of female infertility.

Conflict of interest

Authors declare no conflict of interest.

Acknowledgements

The work was supported by the Ministry of Health of the Russian Federation for 2020-2022 (no. AAAA-A20-120022790039-1).

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Introduction

Depopulation of the indigenous community is among the most urgent problems for Russia with its vast territories. Current total birth rate (TBR) in Russia is 1.3-1.5, which is lower than required for simple reproduction of the population (should be ≈2.12 [1]). It is obvious that the decline in TBR is observed in all industrial countries, where the majority of the population is concentrated in the cities. The depopulation process cannot be stopped completely, but it can be slowed down by socio-economic changes, as well as by reducing secondary infertility of women in their childbearing age.

Primary infertility is the inability to give birth to the first child. This index decreases by 0.1% per year, being about 1.9% [2]. Secondary infertility is the inability to give birth to children after a successful first pregnancy. The prevalence of secondary infertility increases sharply with age – from 2.6% in women aged 20-24 years to 27.1 % in women aged 40-44 years [2]. At the same time, in Russia and other Central and Eastern Europe countries, as well as in Central Asia, secondary infertility is detected in 18% of women aged 20-44 years, compared to only 7.2% in the high-resource countries [2, 3]. Different disorders of uterine endometrium resulting from disturbed pregnancies or various interventions are the main cause of secondary infertility.

Prevention of endometrial disorders

The endometrium is a complex, multicomponent system consisting of the integumentary and glandular epithelium, stroma, basic substance, and blood vessels. The epithelial component of the endometrium consists mainly of secretory and ciliated cells, as well as a few reticular cells, fibroblasts, macrophages, lymphocytes and labrocytes. The human endometrium is a dynamic tissue that undergoes periods of growth and death during the menstrual cycle. Endometrial growth is regulated by the balance between estrogen and progesterone [4]. If this balance is disturbed, hyperplasia (with a deficiency of progesterone) or hypoplasia (with a deficiency of estrogen) of the endometrium may occur.

Both hyperplasia and hypoplasia are causes of infertility. In hyperplasia, there is an overgrowth of the endometrium and uterine stroma, including the release of endometrial cells into the muscle layer and abdominal cavity. With hypoplasia, decreased thickness of the internal uterine mucosa is noted. Thickness of the endometrial layer should range between 7 and 13 mm for successful fertilization. Under the borderline conditions, the attachment of an egg to the endometrium is possible, but miscarriages are more common. Endometrial hyperplasia was found in 70-80% of cases when examining women with infertility. Changes in endometrial thickness may be often caused by metabolic and neuroendocrine disorders. To arrange appropriate management, the major reasons for endometrial disorders should be identified.

Adhesive plaques (synechiae) form in the uterus following surgical interventions (abortions, curettage, complicated pregnancies), the condition known as Asherman’s syndrome (AS) [5]. Synechiae are outgrowths (adhesions) of the sclerotized endometrium that disturb normal anatomy and physiology of the uterine mucosa [6]. The main cause of AS is damage and trauma to the basal layer during gynecological procedures. Less often, intrauterine synechiae are formed after endometritis, the uterine mucosa inflammation caused by schistosomiasis or genital tuberculosis [7]. Synechiae are also formed in intrauterine adhesion (IUA), a disease of the uterus with aberrant occurrence of adhesions within uterus and/or cervix. Patients with IUA often have menstrual irregularities and suffer from pelvic pain. IUA can prevent blastocyst implantation, impair blood supply to the uterus and early fetus, and finally lead to miscarriage or complete infertility in patients.

The leading factor in the formation of synechiae is considered to be mechanical trauma of basal endometrial layer after childbirth or abortion (wound phase). Pathomorphology of intrauterine synechiae is still unclear. A major role in pathogenesis of intrauterine adhesions is assigned to macrophages, the cellular mediators of inflammation. After mechanical damage, macrophages show increased phagocytic and secretory activity and, within 5 days, become the main component of local leukocyte population. Macrophages promote the migration of new mesothelial cells to the damaged surface, which initially form small "islands" on the damaged surface, and then thin layers of mesothelial cells [8]. Certain cytokines, such as fibroblast growth factor (bFGF), platelet growth factor (PDGF), and transforming growth factor β1 (TGF-β1) seem to be involved in the pathogenesis [9]. The role of chemokines and chemokine receptors CXL12/CXCR4/CXCR7 axis in the development of AS was also shown: interaction of the CXCL12 chemokine with the CXCR4 receptor in mouse models caused a decrease in fibrosis and improved fertility [10]. Wang et al. studied the role of nuclear factor-kappaB (NF-KB) in the AS pathogenesis. As a result, NF-KB expression was significantly increased in endometrial samples from the AS patients compared to the control group. The role of NF-KB in the pathogenesis of AS was further confirmed in a rat model [11]. Xue et al. found that expression of TGF-β and connective tissue growth factor (CTGF) in endometrial tissue with adhesions was significantly increased. Moreover, the activity of the NF-KB signaling pathway in endometrial tissue with synechiae was also higher and positively correlated with expression of TGF-β and CTGF. Blocking the NF-KB signaling pathway with a specific inhibitor led to a decrease in TGF-β expression in RL95-2 cells, which confirmed an association between NF-KB and TGF-β signaling pathway in endometrial cells. In addition, the expression of TGF-β and CTGF has been associated with the recurrent IUA, so it can be used as a potential marker of IUA pathology [12].

Chronic activation of cellular and humoral proinflammatory responses is accompanied by increased production of cytokines and other biologically active substances that cause microcirculation disorders, exudation and deposition of fibrin in the endometrial layer, which forms connective tissue fibrinous adhesions in the stroma and/or intrauterine synechia of varying severity. In numerous studies, biopsies obtained from patients with intrauterine adhesions compared to patients with normal endometrium contained 50-80 % of fibrous tissue versus 13-20%, respectively. Due to the fact, that placental tissue fragments can cause fibroblast activation and collagen formation before endometrial regeneration. Occurrence of intrauterine synechiae is more likely in patients with missed abortion than in patients with incomplete abortion. In terms of possible injury to the uterine mucosa, the first 4 weeks after delivery or termination of pregnancy are considered most dangerous. From the histological point of view, endometrial stroma in AS is replaced by fibrous tissue, and the uterine glands are replaced by inactive cubic epithelium that is insensitive to hormonal stimulation. As a result, the normal anatomy and physiology of the uterine mucosa change.

When synechiae are formed, endometrial cells can grow in the muscle layer, which leads to endometriosis. Due to a difficult vaginal discharge of menstrual blood, the endometrium enters abdominal cavity via fallopian tubes. Menstrual blood contains stem cells that may grow in such inappropriate microenvironment.

Hormone therapy is ineffective in AS. The main method of treatment is surgical removal of synechiae, which is problematic in severe cases, due to the inability to locate the adhesions (fusions of the uterine walls). Despite the removal of adhesions, they are re-formed in 25% of women with moderate AS and 75% with severe pathology. Pregnancy occured in 25-75% of operated women, full-term children were born in 26-79% of cases. Different results are reported, due to absence of generally recognized AS classification and lack of common approach to secondary prevention of the disease

Endometrium regeneration using surface-functionalized hydrogels

Recovery of the uterine endometrium is facilitated by introduction of various biological substances that are able to stimulate regeneration of the tissue leading to restoration of reproductive capacity [14]. Type of biomaterial is an important factor in tissue engineering since it may provide structural support mimicking native uterine endometrial tissues [15]. The biomimetic should include a supporting layer and biologically active molecules. Both components should facilitate cellular and extracellular signaling, nutrient transport, stem cell recruitment, proliferation, and differentiation. The biomaterials can release drugs, growth factors, small molecules, and other biologically active compounds in a controlled manner. Recent studies have shown that, in addition to traditional regeneration of uterus promoted by the biomaterials, their combination with modified cells, e.g., cell layers, intercellular boundaries, surface-functionalized frameworks and decellularized biological tissue, may also exhibit functional or structural advantages. These approaches may provide recovery of altered uterine structures to some degree by inducing biomimetic changes and restoring the regenerative microenvironment [16, 17].

Regeneration of endometrium with modified hydrogels

Many endometrial regeneration strategies are focused on modifying the surface or structure of gels for better biocompatibility and stronger adhesion to endometrial surface; delivery of bioactive growth factors, hormones, and extracellular vesicles [18, 19]. Li et al. [19] developed a collagen hydrogel loaded with fibroblast growth factor bFGF conjugated to the collagen-binding domain (CBD). This combination significantly reduced the random bFGF diffusion in vivo and increased the delivery of the factor to the endometrium. Recombinant proteins with CBD were released in the damaged area and maintained an effective concentration for a long time. The complex framework induced high neovascularization, alignment of muscle fibers and thick layers of the endometrium which contributed to effective tissue recovery. However, the incidence of pregnancy in this study was low, indicating that functional recovery of the endometrium was not achieved. Similarly, Lin et al. [20] loaded vascular endothelial growth factor VEGF conjugated with CBD onto a collagen scaffold to improve angiogenesis and endometrial re-epithelization. The authors compared the efficacy of free growth factor, and VEGF included in the gel, aiming for regeneration of a full-layer injury in rat uterus. The resulting growth of vascular tissue provided the damaged areas with nutrients and oxygen. In addition, targeted VEGF release activated matrix metalloproteinases and initiated endometrial remodeling by increasing the number of inflammatory cells at early regeneration stages. The results showed a 31.2% improvement in pregnancy rate when using CBD/VEGF collagen gel (50.0%) compared to only local VEGF injection (18.8%).

Xu et al. [21] used a temperature-sensitive hydrogel loaded with keratinocyte growth factor KGF, which stimulates tissue repair. The hydrogel made it possible to control release and long-term retention of the drug in damaged uterus. The authors found that the modified KGF-hydrogel framework promoted cell autophagy by inhibiting the mammalian rapamycin signaling pathway; improved the expression level of the CD31 stem cell marker; endothelial migration and proliferation of endometrial glandular epithelial cells and luminal epithelial cells. Functional repair of the epithelium was due to the restoration of corresponding microenvironment by reducing inflammation and immune responses [22, 23].

In addition to biologically active proteins some studies aimed at restoring the endometrium have analyzed a role of secreted extracellular vesicles derived from stem cells [17, 22, 24]. A modified stem cell secretome-containing hydrogel was based on hyaluronic acid (HA), which increased the release of a number of regeneration-related growth factors, such as epidermal growth factor EGF, bFGF, insulin-like growth factor IGF-1, and IGF-binding protein IGFBP. The cross-linked gel served as a carrier and increased in vivo retention time for the stem cell secretions, thus been associated with an increase in endometrial thickness and higher number of endometrial glands if compared to the usage of non-modified gel. Nanoscale functionalization of endometrial scaffolds simulates the natural environment, provides stable release of bioactive molecules and transmission of signals from extracellular vesicles during uterine regeneration [25].

Endometrium regeneration on the basis of of gel-cell scaffolds

Endometrial mesenchymal cells

Biomaterials provide structural and mechanical support to help restoration of the architecture and functionality of damaged tissues. However, the scaffold biomaterial is not sufficient enough to repair large uterine defects. Vascularization, recruitment of native cells, and inhibition of scar formation should be considered [26]. Cell culture on the scaffold structures increases biological functions, prolonging cell survival and stimulating cell proliferation, differentiation, and vascularization [27]. E.g., the resident mesenchymal stromal cells (MSCs) could be incorporated into the polymer gels. Kim et al. [28] used endometrial mesenchymal stromal cells (dEMSCs) encapsulated in a HA hydrogel in a mouse model of uterine infertility. Two weeks after the injury, the fibrous tissue decreased and the endometrial thickness increased. The authors showed increased expression of embryonic markers, including desmin, CD44, and platelet endothelial cell adhesion molecules in regenerating endometrium. Successful implantation of the transferred embryos was accompanied by normal development and live birth of offspring after treatment of the damaged uterus with the dEMSC-HA hydrogel. Isotopic analysis of endometrial cell proliferation showed a significant reduction in recovery time with dEMSC-HA compared to isolated mesenchymal stem cells from bone marrow or endometrium. The gels were gradually eliminated from the uterus, due to HA-degrading hyaluronidase activity in uterus, thus allowing the incorporated cells to attach to endometrium in the damaged area and temporarily provide rigidity of the framework necessary for endometrial regeneration.

dEMSCs exert protective effect not only in patients with hypometriosis, but also at the AS. For example, a group of 7 patients suffering from severe AS underwent triple irrigation of uterine cavity with a suspension of autologous menstrual blood-derived endometrial stem cells. In all women, this treatment, along with additional estrogen therapy, was followed by increased endometrium thickness. In 5 out of 7 patients, the thickness reached 7 mm or more, thus being sufficient for implantation. Moreover, one of these women soon became pregnant in natural way, and two more, due to extracorporeal fertilization [29].

Endometrial perivascular cells

These cells could be also applied to promote local vascularization. Their ability to restore angiogenesis and inhibit scar formation when choosing cell types for uterine repair is of fundamental importance. Endometrial perivascular cells (En-PSCs) carrying CD146 markers and platelet growth factor receptor PDGFR-β loaded into a collagen gel had a similar effect upon stem cells in the endometrial layer [30]. En-PSCs, if additionally transfected with the CYR61 angiogenic inducer, were shown to promote vascular formation. Development of CYR61-transfected En-PSC-loaded collagen scaffold significantly increased the density of blood vessels, since it stimulated release of angiogenic factors from extracellular matrix and, generally, accelerated the in vivo neovascularization.

Bone marrow-derived mesenchymal stromal stem cells

A significant number of studies show the effectiveness of stem cells derived from bone marrow (BMSCs) for endometrial and uterine regeneration due to their ease of isolation and reparative potential [31-33]. Administration of BMSCs, supplemented by cauterization (electroacopuncture), improved fertility by activating the CXCR4 chemokine receptor, enhanced expression of cytokeratins and vimentin, VEGF and bFGF [31]. Effect of BMSCs incorporated into polyglycerol sebacinate (PGS) gel was compared with effect of BMSC-loaded collagen, or polylactic and glycolic acid (PLGA) copolymer gels. The authors showed an increase in TGF-β1, bFGF synthesis, and better recovery of endometrial morphology when using PGS gel. However, the fertility rates were comparable to those achieved with collagen-based gel (72%), but higher than with PLGA carrier (42%) [34]. Similar data were reported by Qi et al. [32]. The authors studied ability of BMSCs-PGS scaffolds for restoration of uterine soft tissue deformities under various dynamic conditions without external stimuli. The authors compared efficacy of the materials loaded with different cell types. PGS with BMSCs showed better stimulation of endometrial proliferation and differentiation. Moreover, the in vivo studies have shown longer retention time for BMSCs in situ and more effective vascularization of the PGS scaffold.

Yang et al. [33] used BMSCs encapsulated in a gel based on pluronic F-127 (PF-127) and vitamin C, which resulted in an increased membrane stability. In addition, vitamin C reduced the secretion of TNF-α and interleukin 6 (IL-6) due to its antioxidant activity, maintained redox homeostasis, and promoted a pro-regenerative trend by increasing the IL-10 levels. BMSC/PF-127+vitamin C hydrogel restored endometrial thickness and reduced fibrous areas of endometrial stromal tissues.

Meanwhile, the BMSCs therapy in patients with AS still lacked efficiency in terms of fertility. Indeed, introduction of autologous BMSCs into subendometrial myometrium in 6 women suffering from AS stimulated an increase in endometrial thickness and normalized menstrual cycles, but this biological effect in all patients did not result into successful extracorporeal fertilization attempts [35].

Umbilical cord mesenchymal stromal cells

Wharton’s jelly of the umbilical cord is an alternative source of MSCs, from which stem cells are isolated (UCMSCs). Introduction of UCMSCs as a component of a collagen carrier improved endometrial proliferation, differentiation, and neovascularization after implantation of UCMSCs scaffolds into the endometrium [36]. All 26 patients with AS showed positive dynamics, increased endometrial thickness, and decreased the number of intrauterine adhesions. Ten patients soon became pregnant after completing the treatment. The newborn children were born without any obvious birth defects or placental pathology. UCMSCs mixed with gelatin and collagen fibers stimulated pronounced angiogenesis and reduced scar formation in the damaged area. The composite cell framework destroyed collagen in the scarred areas, probably, by increasing the amount of matrix metalloproteinase 9, FGF-2, and VEGF, and led to angiogenesis and cyclic endometrial regeneration [37]. Xin et al. [38] found that the UCMSC-loaded collagen scaffold reduced cell apoptosis and improved the state of endometrial stromal cells due to eventual paracrine action. The scaffold did not induce inflammation and contributed to collagen remodeling in regenerating endometrium. In addition, the UCMSCs-loaded collagen scaffold induced early rapid re-epithelization by increasing level of cell proliferation and expression of cytokeratin, which is vital for the subsequent endometrial repair after damage.

Growth effects of platelet-rich plasma

Inclusion of platelet-rich plasma (PRP) in the structure of hydrogels is a point for research of uterine endometrial regeneration. In a number of studies, PRP was used to stimulate MSCs obtained from the menstrual blood. Transplantation of these MSCs stimulated thickening of the endometrium [39].

In women who underwent endometrial electroacupuncture for the first time, the effect of autologous PRP administration on endometrial thickness was evaluated. PRP infusion resulted in endometrial thickening up to 7 mm observed 48-72 hours later. Successful pregnancy occurred then after progesterone administration [40]. Similar data were obtained in a randomized clinical trial (n=83) among women with hypometriosis suffering from poor endometrial response to standard hormone replacement therapy. After PRP administration, there was a significant increase in endometrial thickness; in this group, the frequency of implantation and clinical pregnancy per cycle also increased significantly [41].

Application of autologous PRP in rat model with ethanol-induced endometrial injury led to endometrial regeneration. The authors concluded that intrauterine administration of autologous PRP stimulates and accelerates endometrial regeneration, along with reduced formation of fibrosis [42].

There are also studies in which the authors did not show that intrauterine PRP injection improves the results of hysteroscopy after surgical removal of intrauterine adhesions [43].

Hypothetical mechanisms of stem cell actions

Most research groups did not show real engraftment of transplanted mesenchymal cells, which confirms the current opinion about paracrine nature of therapeutic effects caused by allogeneic MSCs [44-48].

Cellular elements can be administered to patients as intravascular infusions [49, 50], intramuscularly [51] or directly into the uterine cavity. Both enriched MSCs or stromal cell suspensions can be used [35, 52, 53]. No serious side effects or signs of cell engraftment were observed in these studies. There is no doubt that further research and clinical trials are needed to optimize the use of cell therapy.

In healthy female body, cytokine environment and immune cellular repertoire depend on the phase of menstrual cycle [44], which are important for reducing fibrosis and restoration of endometrium. It is believed that successful endometrial repair technology is directly related to the activity of local inflammation. To achieve maximal therapeutic effect, it is necessary to ensure optimal mechanism and timely delivery of cellular elements, depending on the cycle phase. It is also necessary to minimize potential risks associated with the delivery method. For example, AS is often associated with disturbed blood flow in uterine spiral arterioles. Therefore, intravascular administration of these cellular elements cannot be used in this case.

Currently, most researchers believe that stem cells can only have a systemic and paracrine therapeutic effect, since they, probably, act as immunomodulators [46, 54, 55]. Immunomodulatory effects result from destruction of these cells or their absorption. This may explain the reparative tissue response during local injection of MSCs [56].

It is also suggested that the release of paracrine factors may represent the main effect of cellular therapy. In this case, the usage of exosomes/microvesicles opens some prospectives for regenerative medicine [57]. E.g., excretory microvesicles (eMVs) isolated from intrauterine fluid also have a protective effect [57-60]. In addition, MSCs have been shown to produce eMVs that have immunomodulatory effect on T cells [61].

During experiments on co-cultivation of mouse embryos and endometrial sMVs, an increase in the number of blastomeres, as well as vascular epithelium and platelets in embryos was observed [62]. These results led to the attempts of intrauterine infusion of PRP which includes eMVs components. In clinical trials, PRP infusion increased epithelial thickness [40, 63, 64], and, as a result, the number of successful implantations and natural pregnancies occurred. The fact that exosomes and other eMVs are an alternative to "direct" cell therapy and allow avoiding its negative consequences is confirmed by the high efficiency of PDGF-α, which is contained in platelets, in tissue repair and regeneration [65].

Clinical usage of antiadhesive polymers to prevent Ascherman’s syndrome

As noted above, the AS adhesions within uterus make it difficult to outflow menstrual blood and reduce women's fertility. Hormone therapy is not effective for AS. The main method of therapy is the removal of adhesions in one way or another. After removing the adhesions, new endometrial damage occurs, which often leads to the formation of the adhesions de novo. To prevent the formation of new adhesions, a number of studies have suggested using copolymers of hyaluronic acid and carboxymethylcellulose etc. for temporary separation of the uterine walls, which can provide the time required for re-epithelization of the wound surface.

For the prevention of AS and IUA in Russia and worldwide, various anti-adhesive materials are used, for example, Antiadhesin (Russia), Seprafilm film (France) based on sodium hyaluronate and sodium salt of carboxymethylcellulose (HA-CMC), Oxiplex/AP gel (USA) based on carboxymethylcellulose (CMC) and polyethylene oxide [8, 66-68], and others.

The use of barrier anti-adhesive agents based on HA-CMC reduces the risk of adhesion formation in the uterine cavity. According to a randomized study [68], intrauterine administration of an anti-adhesive barrier agent containing HA and CMC can not only prevent the formation or reduce the severity of intrauterine adhesions, but also contributes to the preservation of reproductive function. A total of 150 patients with incomplete or missed abortions participated in the clinical study. In the treatment group (Seprafilm) (n=50), membranes were inserted into the endometrial and cervical canal cavity after suction evacuation and/or curettage. The control group (n=100) did not get any treatment. Both groups were divided into two subgroups: patients who had no previous suction or curettage, and those who had at least one previous abortion or curettage. Further fertility was assessed by pregnancy success in all groups. The formation of endometrial synechiae was evaluated using hysterosalpingography in patients of all groups without pregnancy success 8 months after the intervention. The safety of using Seprafilm was evaluated by recording any adverse reactions and performing ultrasound monitoring. Of the subgroups without previous abortions, all 32 patients (100%) who received Seprafilm became pregnant in the next 8 months; in the control group, pregnancy occurred only in 54% of cases. They also showed that patients in the Seprafilm group with one or more previous interventions and no pregnancy after 8 months did not have adhesions in 90% of cases, and only in 50% of cases in the untreated group.

HA performs important physiological functions in the body, including joint lubrication, regulation of blood vessel wall permeability, regulation of protein and electrolyte transport, and wound healing. HA can bind to a large number of water molecules improving tissue hydration, increasing cell resistance to mechanical damage, and reducing post-traumatic formation of granulation and fibrous tissue. Due to its unique biocompatibility and enzymatic biodegradation, HA is often used to prevent postoperative adhesions [69, 70]. HA gel significantly reduces the frequency of IUA after intrauterine surgery, regardless of the type of intervention or the presence of primary diseases. It has been shown that treatment with HA gel increases the frequency of pregnancy after intrauterine surgery [71].

Heat-sensitive matrices based on poly-N-isopropylacrylamide

Poly-N-isopropylacrylamide (PNIPAM) is a polymer that performs a phase transition from a liquid to a gel state when heated above 37°C. As the temperature rises, PNIPAM forms a three-dimensional hydrogel that compresses and pushes the liquid out, releasing the contents into the surrounding tissue. Accordingly, PNIPAM, when administered, provides separation of the uterine walls. At the same time, it creates an enriched environment around itself that stimulates endometrial regeneration. Unlike PNIPAM, HA and CMC swell in the uterus, collecting intrauterine fluid and filling the internal volume. Theoretically, PNIPAM may be more promising for preventing adhesions. Currently, PNIPAM gels are being studied in vitro and in model systems, for example, for the cultivation of chondrocytes. Incubation of chondrocytes with PNIPAM showed that the cells were viable for 24 days, increased in number, and produced type II collagen and glycosaminoglycans [72].

For the functionalization of hydrogels, modification of PNIPAM is possible by including hydrophilic bioactive substances, such as cell culture supernates, eMVs or exosomes of MSCs, PRP, and other molecules. This modification may separate thermosetting and hydrophilic functions and allows each component to act independently. This concept was demonstrated by the Yoshioka group, who developed a tissue culture framework based on PNIPAM-graft-PEG [73-75]. The authors modified PNIPAM by including butyl ether of methacrylic acid in order to shift the phase transition point to a lower temperature. In subsequent studies in cell culture, the authors reported a system with a gelation temperature of 7°C in the cell culture medium [76]. It is known that thermosetting polymers with a hydrophobic component form dispersed gels in aqueous media above the critical point when the concentration exceeds the critical minimum. This phenomenon is associated with particle aggregation due to thermosetting flocculation of Poly(styrene-graft-NIPAM) particles [77, 78]. Poly(styrene-co-NIPAM) particles were used to form core-shell solid particles. Recently, thermosetting dispersed gels with Poly-ε-caprolactone cores and shells consisting of a polyethylene glycol brush were also obtained. Microdispersion procedure allowed to produce gels which were used as a thermally reversible cell culture system for mouse 3T3 fibroblasts [79] or C2C12 myoblasts [80].

Conclusions

The use of biopolymers and biomimetics based on combinations of polymers with various growth factors or live cells opens up new opportunities for the treatment of endometrial disorders. To this purpose, practical clinicians use gels based on hyaluronic acid, carboxymethyl cellulose, collagen, polyethylene oxide and others with certain efficiency. The main task of biopolymers is to separate the walls of the uterus, thus preventing synechiae, e.g., in Asherman’s syndrome. To improve treatment of hypo- and hypermetriosis, the gels should contain appropriate biological factors able to stimulate or inhibit the endometrial growth. Most of such biomimetic substances are currently at the pre-clinical testing stage. Some data from clinical studies have shown promising results of this approach for the treatment of female infertility.

Conflict of interest

Authors declare no conflict of interest.

Acknowledgements

The work was supported by the Ministry of Health of the Russian Federation for 2020-2022 (no. AAAA-A20-120022790039-1).

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["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27397" ["VALUE"]=> array(2) { ["TEXT"]=> string(278) "<p> Мария В. Коновалова¹, Дарья С. Царегородцева^1,2, Римма А. Полтавцева³, Елена В. Свирщевская^1,3 </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(218) "

Мария В. Коновалова¹, Дарья С. Царегородцева^1,2, Римма А. Полтавцева³, Елена В. Свирщевская^1,3

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27398" ["VALUE"]=> array(2) { ["TEXT"]=> string(683) "<p>¹ Институт биоорганической химии им. академиков М. М. Шемякина и Ю. А. Овчинникова РАН, Москва, Россия<br> ² Первый Московский государственный медицинский университет им. И. М. Сеченова Минздрава РФ, Москва, Россия<br> ³ Научный центр акушерства, гинекологии и перинатологии им. акад. В. И. Кулакова Минздрава РФ, Москва, Россия</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(623) "

¹ Институт биоорганической химии им. академиков М. М. Шемякина и Ю. А. Овчинникова РАН, Москва, Россия
² Первый Московский государственный медицинский университет им. И. М. Сеченова Минздрава РФ, Москва, Россия
³ Научный центр акушерства, гинекологии и перинатологии им. акад. В. И. Кулакова Минздрава РФ, Москва, Россия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27399" ["VALUE"]=> array(2) { ["TEXT"]=> string(3381) "<p style="text-align: justify;">Одной из острых проблем России является вторичное бесплодие женщин детородного возраста. Оно часто вызвано повреждением базального слоя эндометрия при выполнении гинекологических процедур: дилатации полости матки, лечебно-диагностическом выскабливании полости матки, кесаревом сечении, операциях на матке, а также после беременностей, протекающих с осложнениями. Как результат могут развиваться гипо- или гиперметриоз, а также формироваться внутриматочные спайки – синехии, приводящие к развитию синдрома Ашермана. Несмотря на большое количество накопленных клинических данных, отсутствует эффективный способ лечения вторичного бесплодия. В настоящее время с определенным успехом для терапии гипометриоза и синдрома Ашермана используют различные биополимеры и композиты на основе биополимеров с включением активных молекул, генов, их кодирующих, обогащенной тромбоцитами плазмы крови, стволовых клеток или микровезикул/экзосом стволовых клеток. Для использования в клинике сертифицированы гели на основе гиалуроната натрия, карбоксиметилцеллюлозы, полиэтиленоксида, коллагена и другие. Гели биополимеров являются, с одной стороны, разобщающими стенки матки препаратами (барьерная функция), а, с другой стороны, могут работать, как носители биологически активных молекул и клеток. Биомиметики с разной эффективностью способны стимулировать регенерацию и нормализацию эндометрия, что способствует восстановлению репродуктивной способности. Методики лечения на основе биомиметиков находятся в стадии исследований. В обзоре приведены данные по эффективности лечения патологий эндометрия матки с помощью биотерапевтических подходов. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Бесплодие, гипометриоз, гиперметриоз, синдром Ашермана, барьерные материалы, биогели, биомиметики.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3325) "

Одной из острых проблем России является вторичное бесплодие женщин детородного возраста. Оно часто вызвано повреждением базального слоя эндометрия при выполнении гинекологических процедур: дилатации полости матки, лечебно-диагностическом выскабливании полости матки, кесаревом сечении, операциях на матке, а также после беременностей, протекающих с осложнениями. Как результат могут развиваться гипо- или гиперметриоз, а также формироваться внутриматочные спайки – синехии, приводящие к развитию синдрома Ашермана. Несмотря на большое количество накопленных клинических данных, отсутствует эффективный способ лечения вторичного бесплодия. В настоящее время с определенным успехом для терапии гипометриоза и синдрома Ашермана используют различные биополимеры и композиты на основе биополимеров с включением активных молекул, генов, их кодирующих, обогащенной тромбоцитами плазмы крови, стволовых клеток или микровезикул/экзосом стволовых клеток. Для использования в клинике сертифицированы гели на основе гиалуроната натрия, карбоксиметилцеллюлозы, полиэтиленоксида, коллагена и другие. Гели биополимеров являются, с одной стороны, разобщающими стенки матки препаратами (барьерная функция), а, с другой стороны, могут работать, как носители биологически активных молекул и клеток. Биомиметики с разной эффективностью способны стимулировать регенерацию и нормализацию эндометрия, что способствует восстановлению репродуктивной способности. Методики лечения на основе биомиметиков находятся в стадии исследований. В обзоре приведены данные по эффективности лечения патологий эндометрия матки с помощью биотерапевтических подходов.

Ключевые слова

Бесплодие, гипометриоз, гиперметриоз, синдром Ашермана, барьерные материалы, биогели, биомиметики.

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Maria V. Konovalova¹, Daria S. Tsaregorodtseva^1,2, Rimma A. Poltavtseva³, Elena V. Svirshchevskaya^1,3

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27404" ["VALUE"]=> array(2) { ["TEXT"]=> string(684) "<p>¹ Shemyakin-Ovchinnikov Institute of Bioorganic Сhemistry RAS, Moscow, Russia<br> ² Sechenov’s First Moscow State Medical University, Moscow, Russia<br> ³ V. I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia</p><br> <p><b>Correspondence</b><br> Elena Svirshchevskaya, PhD, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 16/10 Miklukho-Maklaya St, Moscow, 117997, Russia<br> Phone: +7 (910) 464 8760<br> Fax: +7 (495) 330 4011<br> E-mail: esvir@mail.ibch.ru</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(570) "

¹ Shemyakin-Ovchinnikov Institute of Bioorganic Сhemistry RAS, Moscow, Russia
² Sechenov’s First Moscow State Medical University, Moscow, Russia
³ V. I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia

Correspondence
Elena Svirshchevskaya, PhD, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 16/10 Miklukho-Maklaya St, Moscow, 117997, Russia
Phone: +7 (910) 464 8760
Fax: +7 (495) 330 4011
E-mail: esvir@mail.ibch.ru

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Secondary infertility among women in their childbearing age is one of sufficient problems in Russia. It is often caused by damage to the basal layer of endometrium when performing gynecological procedures, e.g., dilatation of uterine cavity, diagnostic curettage, cesarean section, uterine surgey, as well as consequences of complicated pregnancies. As a result, hypo- or hypermetriosis may develop, along with intrauterine adhesions (synechiae), leading to the development of Asherman’s syndrome. Despite large amounts of medical data, there are no quite effective ways to treat secondary infertility. Currently, various biological polymers and composite materials based on biopolymers with incorporated active molecules, genetic substances, platelet-rich plasma, stem cells or microvesicles/exosomes of stem cells are used with some success for treatment of hypometriosis and Asherman’s syndrome. Gel substances based on sodium hyaluronate, carboxymethylcellulose, polyethylene oxide, collagen and others are certified for clinical use. Biopolymer gels serve, on the one hand, as the materials separating the uterine walls (barrier function), and, on the other hand, they work as carriers of biologically active molecules and cells. Biomimetics can stimulate the regeneration and normalization of endometrium at different efficiency rates, thus promoting restoration of reproductive capacity. Biomimetic-based therapies are under investigation. The present review provides data on treatment efficiency of endometrial disorders by means of biotherapeutic approaches.

Keywords

Infertility, hypometriosis, Asherman's syndrome, barrier materials, biogels, biomimetics.

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Konovalova¹, Daria S. Tsaregorodtseva^1,2, Rimma A. Poltavtseva³, Elena V. Svirshchevskaya^1,3</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(152) "

Maria V. Konovalova¹, Daria S. Tsaregorodtseva^1,2, Rimma A. Poltavtseva³, Elena V. Svirshchevskaya^1,3

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Maria V. Konovalova¹, Daria S. Tsaregorodtseva^1,2, Rimma A. Poltavtseva³, Elena V. Svirshchevskaya^1,3

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Secondary infertility among women in their childbearing age is one of sufficient problems in Russia. It is often caused by damage to the basal layer of endometrium when performing gynecological procedures, e.g., dilatation of uterine cavity, diagnostic curettage, cesarean section, uterine surgey, as well as consequences of complicated pregnancies. As a result, hypo- or hypermetriosis may develop, along with intrauterine adhesions (synechiae), leading to the development of Asherman’s syndrome. Despite large amounts of medical data, there are no quite effective ways to treat secondary infertility. Currently, various biological polymers and composite materials based on biopolymers with incorporated active molecules, genetic substances, platelet-rich plasma, stem cells or microvesicles/exosomes of stem cells are used with some success for treatment of hypometriosis and Asherman’s syndrome. Gel substances based on sodium hyaluronate, carboxymethylcellulose, polyethylene oxide, collagen and others are certified for clinical use. Biopolymer gels serve, on the one hand, as the materials separating the uterine walls (barrier function), and, on the other hand, they work as carriers of biologically active molecules and cells. Biomimetics can stimulate the regeneration and normalization of endometrium at different efficiency rates, thus promoting restoration of reproductive capacity. Biomimetic-based therapies are under investigation. The present review provides data on treatment efficiency of endometrial disorders by means of biotherapeutic approaches.

Keywords

Infertility, hypometriosis, Asherman's syndrome, barrier materials, biogels, biomimetics.

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Secondary infertility among women in their childbearing age is one of sufficient problems in Russia. It is often caused by damage to the basal layer of endometrium when performing gynecological procedures, e.g., dilatation of uterine cavity, diagnostic curettage, cesarean section, uterine surgey, as well as consequences of complicated pregnancies. As a result, hypo- or hypermetriosis may develop, along with intrauterine adhesions (synechiae), leading to the development of Asherman’s syndrome. Despite large amounts of medical data, there are no quite effective ways to treat secondary infertility. Currently, various biological polymers and composite materials based on biopolymers with incorporated active molecules, genetic substances, platelet-rich plasma, stem cells or microvesicles/exosomes of stem cells are used with some success for treatment of hypometriosis and Asherman’s syndrome. Gel substances based on sodium hyaluronate, carboxymethylcellulose, polyethylene oxide, collagen and others are certified for clinical use. Biopolymer gels serve, on the one hand, as the materials separating the uterine walls (barrier function), and, on the other hand, they work as carriers of biologically active molecules and cells. Biomimetics can stimulate the regeneration and normalization of endometrium at different efficiency rates, thus promoting restoration of reproductive capacity. Biomimetic-based therapies are under investigation. The present review provides data on treatment efficiency of endometrial disorders by means of biotherapeutic approaches.

Keywords

Infertility, hypometriosis, Asherman's syndrome, barrier materials, biogels, biomimetics.

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¹ Shemyakin-Ovchinnikov Institute of Bioorganic Сhemistry RAS, Moscow, Russia
² Sechenov’s First Moscow State Medical University, Moscow, Russia
³ V. I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia

Correspondence
Elena Svirshchevskaya, PhD, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 16/10 Miklukho-Maklaya St, Moscow, 117997, Russia
Phone: +7 (910) 464 8760
Fax: +7 (495) 330 4011
E-mail: esvir@mail.ibch.ru

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¹ Shemyakin-Ovchinnikov Institute of Bioorganic Сhemistry RAS, Moscow, Russia
² Sechenov’s First Moscow State Medical University, Moscow, Russia
³ V. I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia

Correspondence
Elena Svirshchevskaya, PhD, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 16/10 Miklukho-Maklaya St, Moscow, 117997, Russia
Phone: +7 (910) 464 8760
Fax: +7 (495) 330 4011
E-mail: esvir@mail.ibch.ru

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Мария В. Коновалова¹, Дарья С. Царегородцева^1,2, Римма А. Полтавцева³, Елена В. Свирщевская^1,3

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Мария В. Коновалова¹, Дарья С. Царегородцева^1,2, Римма А. Полтавцева³, Елена В. Свирщевская^1,3

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Оно часто вызвано повреждением базального слоя эндометрия при выполнении гинекологических процедур: дилатации полости матки, лечебно-диагностическом выскабливании полости матки, кесаревом сечении, операциях на матке, а также после беременностей, протекающих с осложнениями. Как результат могут развиваться гипо- или гиперметриоз, а также формироваться внутриматочные спайки – синехии, приводящие к развитию синдрома Ашермана. Несмотря на большое количество накопленных клинических данных, отсутствует эффективный способ лечения вторичного бесплодия. В настоящее время с определенным успехом для терапии гипометриоза и синдрома Ашермана используют различные биополимеры и композиты на основе биополимеров с включением активных молекул, генов, их кодирующих, обогащенной тромбоцитами плазмы крови, стволовых клеток или микровезикул/экзосом стволовых клеток. Для использования в клинике сертифицированы гели на основе гиалуроната натрия, карбоксиметилцеллюлозы, полиэтиленоксида, коллагена и другие. Гели биополимеров являются, с одной стороны, разобщающими стенки матки препаратами (барьерная функция), а, с другой стороны, могут работать, как носители биологически активных молекул и клеток. Биомиметики с разной эффективностью способны стимулировать регенерацию и нормализацию эндометрия, что способствует восстановлению репродуктивной способности. Методики лечения на основе биомиметиков находятся в стадии исследований. В обзоре приведены данные по эффективности лечения патологий эндометрия матки с помощью биотерапевтических подходов. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Бесплодие, гипометриоз, гиперметриоз, синдром Ашермана, барьерные материалы, биогели, биомиметики.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3325) "

Одной из острых проблем России является вторичное бесплодие женщин детородного возраста. Оно часто вызвано повреждением базального слоя эндометрия при выполнении гинекологических процедур: дилатации полости матки, лечебно-диагностическом выскабливании полости матки, кесаревом сечении, операциях на матке, а также после беременностей, протекающих с осложнениями. Как результат могут развиваться гипо- или гиперметриоз, а также формироваться внутриматочные спайки – синехии, приводящие к развитию синдрома Ашермана. Несмотря на большое количество накопленных клинических данных, отсутствует эффективный способ лечения вторичного бесплодия. В настоящее время с определенным успехом для терапии гипометриоза и синдрома Ашермана используют различные биополимеры и композиты на основе биополимеров с включением активных молекул, генов, их кодирующих, обогащенной тромбоцитами плазмы крови, стволовых клеток или микровезикул/экзосом стволовых клеток. Для использования в клинике сертифицированы гели на основе гиалуроната натрия, карбоксиметилцеллюлозы, полиэтиленоксида, коллагена и другие. Гели биополимеров являются, с одной стороны, разобщающими стенки матки препаратами (барьерная функция), а, с другой стороны, могут работать, как носители биологически активных молекул и клеток. Биомиметики с разной эффективностью способны стимулировать регенерацию и нормализацию эндометрия, что способствует восстановлению репродуктивной способности. Методики лечения на основе биомиметиков находятся в стадии исследований. В обзоре приведены данные по эффективности лечения патологий эндометрия матки с помощью биотерапевтических подходов.

Ключевые слова

Бесплодие, гипометриоз, гиперметриоз, синдром Ашермана, барьерные материалы, биогели, биомиметики.

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Одной из острых проблем России является вторичное бесплодие женщин детородного возраста. Оно часто вызвано повреждением базального слоя эндометрия при выполнении гинекологических процедур: дилатации полости матки, лечебно-диагностическом выскабливании полости матки, кесаревом сечении, операциях на матке, а также после беременностей, протекающих с осложнениями. Как результат могут развиваться гипо- или гиперметриоз, а также формироваться внутриматочные спайки – синехии, приводящие к развитию синдрома Ашермана. Несмотря на большое количество накопленных клинических данных, отсутствует эффективный способ лечения вторичного бесплодия. В настоящее время с определенным успехом для терапии гипометриоза и синдрома Ашермана используют различные биополимеры и композиты на основе биополимеров с включением активных молекул, генов, их кодирующих, обогащенной тромбоцитами плазмы крови, стволовых клеток или микровезикул/экзосом стволовых клеток. Для использования в клинике сертифицированы гели на основе гиалуроната натрия, карбоксиметилцеллюлозы, полиэтиленоксида, коллагена и другие. Гели биополимеров являются, с одной стороны, разобщающими стенки матки препаратами (барьерная функция), а, с другой стороны, могут работать, как носители биологически активных молекул и клеток. Биомиметики с разной эффективностью способны стимулировать регенерацию и нормализацию эндометрия, что способствует восстановлению репродуктивной способности. Методики лечения на основе биомиметиков находятся в стадии исследований. В обзоре приведены данные по эффективности лечения патологий эндометрия матки с помощью биотерапевтических подходов.

Ключевые слова

Бесплодие, гипометриоз, гиперметриоз, синдром Ашермана, барьерные материалы, биогели, биомиметики.

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¹ Институт биоорганической химии им. академиков М. М. Шемякина и Ю. А. Овчинникова РАН, Москва, Россия
² Первый Московский государственный медицинский университет им. И. М. Сеченова Минздрава РФ, Москва, Россия
³ Научный центр акушерства, гинекологии и перинатологии им. акад. В. И. Кулакова Минздрава РФ, Москва, Россия

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¹ Институт биоорганической химии им. академиков М. М. Шемякина и Ю. А. Овчинникова РАН, Москва, Россия
² Первый Московский государственный медицинский университет им. И. М. Сеченова Минздрава РФ, Москва, Россия
³ Научный центр акушерства, гинекологии и перинатологии им. акад. В. И. Кулакова Минздрава РФ, Москва, Россия

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Introduction

Cardiovascular diseases are the leading cause of human morbidity worldwide. Systemic atherosclerosis is considered to be one of the most common, severe, and life-threatening conditions [1]. Despite a variety of pharmaceutical and surgical treatment approaches to this pathology, they frequently lack the desired effectiveness. Since the beginning of the 21^st century, development of endovascular techniques has changed clinical indications and operative techniques in all the areas of vascular surgery. The classical bypass surgery, which required arterial substitutes, is now less used [2]. Hence, the goal of vascular research should be centered not on the search for an ideal arterial substitute, but on improving minimally invasive techniques such as cell therapy and regenerative medicine, aiming to develop new treatments of atherosclerosis in the near future.

Stem cell therapy is a novel and promising strategy which potentially is more effective than single-agent drug therapies for many diseases [3, 4]. Stem cells function in the repair of injured tissues in two ways: by secretion of related cytokines [5], or by differentiating into the cell types at the site of injury, in order to exert its original function [6].

Multipotent mesenchymal stem cells (MSCs) which possess self-renewal potential and can differentiate into various cell types, such as osteoblasts, chondrocytes or adipocytes [7], may be isolated from adult tissues, including bone marrow, adipose tissue, and birth-associated tissues, such as placenta, umbilical cord, cord blood or amnion. MSCs are identified by three characteristics: (1) adherence to the culture dishes; (2) differentiation into osteoblasts, chondroblasts and adipocytes, and (3) expression of specific surface markers (CD90, CD105, CD73 and CD44), as well as lacking expression of several other markers including CD34 and HLA-DR [8-10].

Wharton`s jelly-derived MSCs (WJ-MSCs) have a high proliferation rate; they do not show any teratogenic, or carcinogenic behavior in case of transplantation [11]. The bone marrow and adipose tissue, among others, are, generally, used as sources of MSCs [7, 12]. Recent findings have shown that MSCs from human umbilical cord have advantages such as large numbers on harvest, strong proliferation and differentiation capacity and low immunogenicity compared to MSCs from the bone marrow [13].

Porous scaffolds prepared from natural polysaccharides are promising matrices for mimicking the in vivo ECM (extracellular matrix), since they resemble glycosaminoglycans (GAGs), which are essential ECM components [14]. Hyaluronic acid (HA) is a natural anionic polymer found in synovial fluid, skin, and cartilage, being among the major GAG components of brain ECM [15]. HA is used for diverse biomedical applications, due to its biocompatibility and water binding capacity [16, 17]. Due to its remarkable hydrodynamic characteristics, particularly in terms of viscosity and ability to retain water, HA plays a significant role in assembly of extracellular and pericellular matrices by regulating their porosity and malleability [18].

The negative charge of HA hinders cell adhesion. Therefore, it is blended with other biomaterials to promote cell attachment [19]. Chitosan (CHI) is a widely used natural cationic polymer derived from crustacean shells that resembles GAGs, and has broad tissue engineering applications in view of its biocompatibility, biodegradability, hydrophilicity, low cost and availability [17]. The cationic nature of chitosan allows it to interact with negatively charged polymers and to form a polyelectrolyte complex (PEC) through ionic bonding [20].

Endothelial cells are one of the major components of the vessel wall, and these cells are important contributors to vascular tissue repair and regeneration [21]. The aim of present study was to explore the potential of WJ-MSCs seeded on HA/CHI multilayers to differentiate into endothelial-like cells, by identifying and evaluating endothelial cell morphology, and studying endothelial cell-specific gene expression at mRNA and protein levels.

Materials and methods

Polyelectrolytes multilayer films and collagen film

Hyaluronic acid solution (0.2 mg/mL in NaCl 0.15 M) and chitosan solution (0.2 mg/mL in NaCl 0.15 M/HCl 2mM) were used to produce the polyelectrolyte multilayers. Reagents were obtained from commercial sources and used without any further purification. Chitosan low-molecular weight and hyaluronan (200 kDa) were obtained from Sigma Aldrich (Germany). Each experiment was preceded by a cleaning step of the cover glasses as follows: 15 min with 1% sodium dodecyl sulfate (Sigma Aldrich, Germany) at 100°C, extensive ultrapure water rinse, 15 min at 100°C with 0.1 M HCl and, finally, cover glasses were thoroughly rinsed with ultrapure water. Coverslips were incubated in CHI solution for 5 min, thoroughly washed in NaCl (0.5 M) and then incubated in HA solution for 5 min. (CHIHA)₁₀ films were built up after 20 alternate depositions of polycation and polynion layers. The type I collagen (100 μg/mL, purchased from BD Biosciences, France) was used as positive control for cellular adhesion. The collagen solution was added to the coverslips and incubated for 1 hour at room temperature. Then, the solution was carefully aspirated and the surface of glasses was rinsed 3 times with serum-free α-MEM.

Stem cell and mature endothelial cell isolation and culture

Fresh human umbilical cords were obtained after full-term births with informed consent using the guidelines approved by the Hanan Hospital. Umbilical cord vessels were removed manually from cord segments, and the exposed Wharton’s jelly was cut into very small pieces or explants. These explants were cultured in α-MEM (Lonza, Belgium) supplemented with 10% decomplemented fetal bovine serum (FBS), 2 mM L-glutamine, 100 IU/mL Penicillin/streptomycin and 2.5 mg/mL Fungizon® (Fisher, France) at 37°C and in 5% CO₂. At the fourth passage, WJ-MSCs were characterized by flow cytometry (FACSCalibur; BD Bioscience), as previously described [22], by assessing the expression of CD73, CD90, CD44, CD105, CD34, CD45 and HLA-DR, and then used in our experimental procedure.

Human umbilical vein endothelial cells (HUVECs) were isolated according to the method of Jaffe et al. [23]. Briefly, the umbilical cords were washed in HBSS solution and HUVECs were extracted from umbilical cords veins using Trypsin. Then HUVECs were cultured at 37°C in 5% CO₂ in 25 cm² tissue-culture-treated flask (suitable for cell attachment and growth) in complete medium. The medium consisted of an equal mixture of M199/RPMI 1640 media supplemented with 20% human serum albumin, 2 mM L-glutamine, 20 mM HEPES, 100 IU/mL Penicillin, 2.5 mg/mL Fungizon®, being replaced every two days. The cells were used at the second passage culture and were seeded at 3×10³ cells/cm².

Endothelial cell differentiation

WJ-MSCs were seeded in 6-well plates at 3000 cells/cm² on CHI/HA or on COL-I coated glass substrates in α-MEM for 2 days. The unstimulated cells were then incubated in the complete Endothelial Basal Medium (EBM-2, Lonza®), without growth factor supplements, whereas the stimulated were are incubated in complete Endothelial Growth Medium (EGM2, Lonza® supplemented with EPCs-differentiating medium) for 2 weeks.

endothelial basal medium (EBM-2, Lonza®) supplemented with 0.5% FBS. The culture medium was changed every 2 days. The cells cultured on both surfaces (glass and PEMs architectures) were observed daily by phase contrast microscopy (Leica) to check their morphology.

Evaluation of endothelium-specific mRNA markers

Transcript levels of CD31 (PECAM-1 platelet endothelial cell adhesion molecule), CDH5 (Vascular endothelial Cadherin) and KDR (VEGFR-2 vascular endothelial growth factor 2) genes were quantified by real-time qPCR. Total RNA were isolated with RNeasy mini kit (Qiagen, GmbH, Hilden, Germany) according to the manufacturer’s instructions. Complementary DNA synthesis was performed with 350 ng total RNA using iScript cDNA synthesis kit (Bio-Rad, USA). Real-time qPCR was conducted as described previously [24]. As a positive control, RNA isolated from human umbilical vein endothelial cells (HUVECs) was used. These cells were isolated from the umbilical cord veins and cultured in M199/RPMI medium.

Measurement of gene expression was performed in duplicate; a non-template blank served as a negative control. qPCR was carried out using iQ SYBR® Green Supermix (Bio-Rad®) and in-home designed primers (using Primer3) for human CD-31, VE-cadherin, VEGF-R2 and ribosomal protein. Forward and reverse primers (Eurogenetec) were as follows:
CD31: 5’-ATGATGCCCAGTTTGAGGTC-3’; 5’-ACGTCTTCAGTGGGGTTGTC-3’,
KDR: 5’-GTGACCAACATGGAGTCGTG-3’; 5’-TGCTTCACAGAAGACCATGC-3’;
CDH5: 5’-CCTACCAGCCCAAAGTGTGT-3’; 5’-GACTTGGCATCCCATTGTCT-3’;
RPS29: 5’-TCATCTTCCAGCCCAAATTC-3’; 5’-CTTGAACGGTTACCACCTCA-3’

PCR was performed with MyCycler™ Personal Thermal Cycler (Bio-Rad®). Cycling parameters were 3 min at 95°C; 40 cycles of 3 min at 60°C for CD31, VEGF-R2 and RP29 and 62°C for VE-cadherin and 1 min at 72°C. The results were normalized to the housekeeping gene for S29 ribosomal protein. Analyses and fold differences were determined using the comparative CT method. The fold changes were calculated from the ΔΔCT values using the formula 2^-ΔΔCT, and the data were normalized relative to the reference gene values and then expressed as percentage of values obtained in HUVEC for each assayed mRNA.

Detection of endothelium-specific protein markers

Total proteins from cultured cells were prepared as previously described [26]. 25 μg proteins from each sample were heated at 95°C for 5 min in Laemmli sample buffer (BioRad, USA), and the total proteins were separated in acrylamide gel (10% for VEGF-R2, Vascular endothelial growth factor receptor 2, and 7% for CD31 and VE-cadherin. After electrophoresis, the gels were blotted to nitrocellulose membranes. GAPDH was used as loading control. Western blots were performed by using primary antibodies for endothelial VEGFR2 markers with 1/1000 milk/TBST (Tris-Buffered Saline Tween 20 0.5% from Cell Signaling Technology, UK); VE-cadherin with 1/1000 BSA (Bovine Serum Albumin/TBST from Abcam, USA); CD31 with 1/1000 BSA/TBST (Dako, France). The membranes were blocked with the blocking buffer TBS (Tris Buffer Saline) for 1h at room temperature and incubated with primary antibodies under gentle shaking at 4°C overnight. After extensive washing by TBS, the membranes were incubated for 1 h at room temperature with secondary antibodies conjugated to horseradish peroxidase (HRP). HRP activity was detected by enhanced chemiluminescence (ECL, Santa Cruz Biotechnology, USA). Santa Cruz Luminol Reagent A & B associated, will be oxidized by HRP in presence of hydrogen peroxide emitting the light. Densitometry of the obtained bands was estimated by ImageJ software.

Evaluation of endothelial-like cells functionality in terms of LDL-uptaking assay

Low-density lipoprotein (LDL)-uptake assay was performed as described previously. At day 15, WJ-MSCs seeded on collagen and PEMs architectures were incubated for 4 h at 37°C in RPMI 1640 without phenol red supplemented with 0.8 μg/mL Dil-Ac-LDL (Tebu-bio, France) labeled with rhodamine. Cells were washed with RPMI 1640 without phenol red to remove Dil-Ac-LDL. They were then fixed with 4% paraformaldehyde and nuclei were counterstained using 4',6-diamidino-2-phenylindole DAPI. The cells were observed using fluorescence microscopy (Leica microscope, *40) after using the appropriate excitation and emission filters for Rhodamin B (554nmEx/571nmEm).

Von Willebrand Factor (vWF) immunostaining

After 15 days of endothelial differentiation, the WJ-MSCs seeded on collagen and PEMs architectures were analyzed to assess vWF expression. The cells were fixed by 4% paraformaldehyde, permeabilized with PBS/Triton X-100 (0.1%) for 15 min, blocked with 1% BSA and stained by murine anti-vWF (1/100 Dako, France). After two washes with PBS, the appropriate secondary antibody labeled with Alexa-Fluor-488 (diluted at 1/100) was incubated for 30 min at 37°C. The cells were then observed by fluorescence microscopy (Zeiss microscopy, × 630 magnification) using the (485Ex/538Em) spectral line.

Statistical analysis

Data were presented as a mean ± SEM for each condition. Each experiment was repeated independently three times (n=3). Pairwise comparisons were performed using one-factor ANOVA with Fisher correction (Stat view IVs, Abacus Concepts Inc., Berkley, CA). Differences were considered significant for p (rejection level of the null-hypothesis of equal means) values < 0.05.

Results and discussion

Characterization of WJ-MSCs

Morphological characterization of MSCs (4^th passage) was performed according to the criteria defined by the International Society for Cellular Therapy [25]. MCSs derived from WJ of three umbilical cords displayed a homogeneous fibroblast-like morphology. Cells were analyzed regarding the expression of specific molecular markers by Fluorescein-Activated Cell Sorting analysis and showed that WJMSCs and BM-MSCs were positive for CD105, CD73, and CD90, and negative for CD45, CD34, CD86, and HLA-DR. These data revealed that WJ-MSCs used in this study showed the typical MSC characteristics (Data not shown).

Evaluation of endothelial markers expression at the mRNA and protein levels

n order to evaluate the effect of different adhesion matrices on differentiation of WJ-MSCs in endothelial-like cells, we measured the expression of endothelial markers by q-PCR and Western Blot. The three endothelial-specific molecules CD31, VE-cadherin and VEGF-R2 (KDR) are known to play an important role in the endothelium maturation during angiogenesis process [26]. CD31, also known as platelet endothelial cell adhesion molecule-1 (PECAM-1), is a type I integral membrane glycoprotein that is expressed at high levels on early and mature endothelial cells, platelets, and most leukocyte subpopulations. PECAM-1 is known to have various roles in vascular biology including angiogenesis, platelet function, and thrombosis [27]. VEGF-R2 is expressed on vascular endothelial cells and lymphatic endothelial cells; it regulates vascular endothelial function. VEGF is an important growth factor for the endothelial differentiation [28]. The endothelial-specific cadherin, vascular endothelial cadherin (VE-cadherin) is required for vascular genesis and the repair of damaged vessels [29].

The mRNA and protein levels of the three endothelial specific markers CD31, VEGF-R2 (KDR) and VE-cadherin were analyzed by real-time qPCR and Western blot (Figures 1 and 2). Relative expression of the three molecules was analyzed at mRNA and protein levels, and expressed relative to appropriate HUVEC values. WJ-MSCs seeded on CHI/HA or collagen and incubated in EBM-2 did not express the three markers at the protein level whereas their expression at the mRNA level was barely detectable (<1% of the levels found in HUVECs for CD31 and CDH5). In WJ-MSCs incubated in EGM-2 for 15 days, mRNA level was higher on CHI/HA than on collagen for CD31 and KDR (increase by 67%, and 79%, respectively). However, only the KDR increase was statistically significant. At the protein level, KDR expression was higher on CHI/HA relative to collagen (45% increase), but this difference was not statistically significant. CD31 protein levels were unchanged between collagen and CHI/HA, whereas CDH5 level was higher on CHI/HA relative to collagen (4% increase), and the difference was statistically significant. The fold change between collagen and CHI/HA at mRNA level was more important than fold change at protein level. After 15 days of differentiation, the transcription of endothelial genes give rise to high levels of mRNA from these genes. The translation process might take more culture time, to produce similar levels of proteins.

Higher mRNA and protein expression of these three markers in differentiated WJ-MSCs seeded on CHI/HA could contribute to more pronounced endothelial differentiation as compared with differentiated WJ-MSCs seeded on collagen. However, collagen is a recommended surface, allowing MSCs chondrogenic and osteogenic differentiation after 21 days [30]. In our report, we have not detected expression of VEGF-R2 protein on the collagen surface; maybe we needed more than 15 days to notice the translation of VEGF-R2 gene.

The capacity to differentiate towards endothelial phenotype is a characteristic of mesenchymal stem cells [30-32], and our results showed that WJ-MSCs express endothelial markers at mRNA and protein levels after 15-day cultures in presence of endothelial growth factors. However, the main purpose of this study was to evaluate endotheliogenic potential of WJ-MSCs seeded onto CHI/HA scaffolds. First, we verified the endothelial potential of WJ-MSCs in monolayer culture conditions both in proliferation (data not shown) and differentiation media. In proliferation medium, no endothelial differentiation was observed during the entire experimental time (15 days), further confirming the stem-cell origin of isolated cells. In differentiation medium, RT-PCR and Western Blot confirmed a better endothelial potential of these cells on CHI/HA.

Our choice of the CHI/HA scaffold was based on some studies that demonstrated the efficacy of this natural scaffold in enhancing hMSCs differentiation into stromal cells. hMSCs were induced to differentiate to chondrogenic, osteogenic, and adipogenic phenotypes [33]. Recent studies have shown the potential of WJ-MSCs to differentiate towards cardiomyocytes using CHI/HA scaffolds [34]. In our study, we have demonstrated that WJ-MSCs are able to differentiate into endothelial cells on CHI/HA films. Therefore, we can deduce that a combination of these cells with this natural scaffold is advantageous for cardio-vascular tissue engineering. Same conclusive results were observed in healing of diabetic skin wound by the proliferation and differentiation of human umbilical cords mesenchymal stem cells (hUCMSCs) on the collagen/chitosan laser drilling acellular dermal matrix (CCLDADM) scaffold, a natural scaffold used in vivo [35].

Evaluation of endothelial-like cells functionality by LDL uptake assay

LDL-uptake assay is applied for detection of functional endothelial cells. WJMSCs, when seeded on CHI/HA and collagen, captured DiIAcLDL to the cytoplasm after 4 hour-incubation in RPMI medium supplemented with DiI-Ac-LDL. However, MSCs were unable to uptake DiI-Ac-LDL after culturing in the growth medium as negative controls (Fig. 3). These results confirm that, after two weeks, WJ-MSCs seeded on CHI/HA and collagen exhibit endothelial cell phenotype. In this respect, Gaffney et al. investigated lipoprotein uptake by means of flow cytometry and showed that the cells in a G2/M (mitosis) phase incorporated about 45% more Dil-Ac-LDL than those in a G1/S (latency) phase [36]. Higher Dil-Ac-LDL uptake of endothelium-like cells on PEMs suggests that more cells are in the G2/M phase on PEMs, a feature of higher proliferation.

Figure 3. LDL-Uptake assay

WJ-MSCs cellular uptake of labeled acetylated LDLs. Double immunofluorescence of nuclei (blue) and for DI-Ac-LDLs (red) for unstimulated (a, b) and stimulated (c, d) WJMSCs after 15 days of culture on collagen and CHI/HA. Internalized labels were detected by Leica fluorescence microscopy (objective *40 oil).

Detection of endothelial-specific marker expression: vWF (von Willebrand Factor) by immunocytochemistry

Von Willebrand adherence factor (vWF) protein contributes to platelet function by mediating the initiation and progression of thrombus formation at the sites of vascular injury. Moreover, novel findings have been obtained on the link between regulation of VWF multimer size and microvascular thrombosis. This progress in basic research has provided critical information to define with greater precision the role of vWF in vascular biology and pathology, including its possible involvement in the onset of atherosclerosis and its acute thrombotic complications. Therefore we have used the expression of vWF as a functionality test of our endothelial-like cells [37]. The cells were examined for expression of endothelial-specific marker (vWF) by immunocytochemistry.

WJ-MSCs seeded on CHI/HA showed a high fluorescence specific to this marker after endothelial differentiation for 15 days. MSCs did not show any positive signal after they were cultured in the growth medium (EBM2) on the same scaffold, as negative controls. On collagen layer, the cells were not marked, that was predicted because they needed more culture time to express vWF protein (Fig. 4).

Figure 4. vWF immunostaining

Double immunofluorescence staining for nuclei (blue), and for prothrombogenic von Willebrand Factor for stimulated (a, b) and unstimulated (d, e) WJ-MSCs after 15 days of culture on collagen and CHI/HA (Zeiss Microscope, objective*63 oil). N=3.

These promising results showed the possibility to combine the use of WJ-MSCs and CHI/HA films aiming for vascular tissue engineering, by evaluating the capacity of WJ-MSCs to differentiate into smooth muscle cells on CHI/HA, coating the surface of alginate hydrogels with CHI/HA films, and enrolling them in order to form a tubular vascular graft.

These promising data showed that the combination of WJ-MSCs and CHI/HA may lead to brilliant results, regarding endothelial differentiation and angiogenesis. One may recommend using of these cells and materials for vascular tissue engineering and regeneration therapy. More studies can be done to evaluate the capacity of WJ-MSCs to differentiate into smooth muscle cells on CHI/HA, to coat the surface of alginate hydrogels with CHI/HA films and to enroll them, in order to form a tubular vascular graft.

Conclusion

These first quite encouraging results showed that it is possible to obtain CEs-like in a non-traumatic way (from Wharton's jelly of human umbilical cords) and in a short time (15 days). Our technique, based on the use of polyelectrolyte films, could therefore be used in the field of vascular engineering for the development of functional vascular substitutes comprising an endothelium resulting from differentiation of mesenchymal stem cells, which would limit the risks of graft rejection and could be applied to patients who require vessel replacement.

Acknowledgements

The authors would like to thank Al Hanan Hospital for providing the umbilical cords used in our researches and Azm & Saadeh society for funding this work.

The authors have no conflicts of interest to declare.

Ethical Statement: The research work was approved by the ethical committee of the Lebanese University, Centre Azm for research in Applied Biotechnology and the ethical Committee of Al Hanan Hospital-Tripoli, Lebanon.

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Introduction

Cardiovascular diseases are the leading cause of human morbidity worldwide. Systemic atherosclerosis is considered to be one of the most common, severe, and life-threatening conditions [1]. Despite a variety of pharmaceutical and surgical treatment approaches to this pathology, they frequently lack the desired effectiveness. Since the beginning of the 21^st century, development of endovascular techniques has changed clinical indications and operative techniques in all the areas of vascular surgery. The classical bypass surgery, which required arterial substitutes, is now less used [2]. Hence, the goal of vascular research should be centered not on the search for an ideal arterial substitute, but on improving minimally invasive techniques such as cell therapy and regenerative medicine, aiming to develop new treatments of atherosclerosis in the near future.

Stem cell therapy is a novel and promising strategy which potentially is more effective than single-agent drug therapies for many diseases [3, 4]. Stem cells function in the repair of injured tissues in two ways: by secretion of related cytokines [5], or by differentiating into the cell types at the site of injury, in order to exert its original function [6].

Multipotent mesenchymal stem cells (MSCs) which possess self-renewal potential and can differentiate into various cell types, such as osteoblasts, chondrocytes or adipocytes [7], may be isolated from adult tissues, including bone marrow, adipose tissue, and birth-associated tissues, such as placenta, umbilical cord, cord blood or amnion. MSCs are identified by three characteristics: (1) adherence to the culture dishes; (2) differentiation into osteoblasts, chondroblasts and adipocytes, and (3) expression of specific surface markers (CD90, CD105, CD73 and CD44), as well as lacking expression of several other markers including CD34 and HLA-DR [8-10].

Wharton`s jelly-derived MSCs (WJ-MSCs) have a high proliferation rate; they do not show any teratogenic, or carcinogenic behavior in case of transplantation [11]. The bone marrow and adipose tissue, among others, are, generally, used as sources of MSCs [7, 12]. Recent findings have shown that MSCs from human umbilical cord have advantages such as large numbers on harvest, strong proliferation and differentiation capacity and low immunogenicity compared to MSCs from the bone marrow [13].

Porous scaffolds prepared from natural polysaccharides are promising matrices for mimicking the in vivo ECM (extracellular matrix), since they resemble glycosaminoglycans (GAGs), which are essential ECM components [14]. Hyaluronic acid (HA) is a natural anionic polymer found in synovial fluid, skin, and cartilage, being among the major GAG components of brain ECM [15]. HA is used for diverse biomedical applications, due to its biocompatibility and water binding capacity [16, 17]. Due to its remarkable hydrodynamic characteristics, particularly in terms of viscosity and ability to retain water, HA plays a significant role in assembly of extracellular and pericellular matrices by regulating their porosity and malleability [18].

The negative charge of HA hinders cell adhesion. Therefore, it is blended with other biomaterials to promote cell attachment [19]. Chitosan (CHI) is a widely used natural cationic polymer derived from crustacean shells that resembles GAGs, and has broad tissue engineering applications in view of its biocompatibility, biodegradability, hydrophilicity, low cost and availability [17]. The cationic nature of chitosan allows it to interact with negatively charged polymers and to form a polyelectrolyte complex (PEC) through ionic bonding [20].

Endothelial cells are one of the major components of the vessel wall, and these cells are important contributors to vascular tissue repair and regeneration [21]. The aim of present study was to explore the potential of WJ-MSCs seeded on HA/CHI multilayers to differentiate into endothelial-like cells, by identifying and evaluating endothelial cell morphology, and studying endothelial cell-specific gene expression at mRNA and protein levels.

Materials and methods

Polyelectrolytes multilayer films and collagen film

Hyaluronic acid solution (0.2 mg/mL in NaCl 0.15 M) and chitosan solution (0.2 mg/mL in NaCl 0.15 M/HCl 2mM) were used to produce the polyelectrolyte multilayers. Reagents were obtained from commercial sources and used without any further purification. Chitosan low-molecular weight and hyaluronan (200 kDa) were obtained from Sigma Aldrich (Germany). Each experiment was preceded by a cleaning step of the cover glasses as follows: 15 min with 1% sodium dodecyl sulfate (Sigma Aldrich, Germany) at 100°C, extensive ultrapure water rinse, 15 min at 100°C with 0.1 M HCl and, finally, cover glasses were thoroughly rinsed with ultrapure water. Coverslips were incubated in CHI solution for 5 min, thoroughly washed in NaCl (0.5 M) and then incubated in HA solution for 5 min. (CHIHA)₁₀ films were built up after 20 alternate depositions of polycation and polynion layers. The type I collagen (100 μg/mL, purchased from BD Biosciences, France) was used as positive control for cellular adhesion. The collagen solution was added to the coverslips and incubated for 1 hour at room temperature. Then, the solution was carefully aspirated and the surface of glasses was rinsed 3 times with serum-free α-MEM.

Stem cell and mature endothelial cell isolation and culture

Fresh human umbilical cords were obtained after full-term births with informed consent using the guidelines approved by the Hanan Hospital. Umbilical cord vessels were removed manually from cord segments, and the exposed Wharton’s jelly was cut into very small pieces or explants. These explants were cultured in α-MEM (Lonza, Belgium) supplemented with 10% decomplemented fetal bovine serum (FBS), 2 mM L-glutamine, 100 IU/mL Penicillin/streptomycin and 2.5 mg/mL Fungizon® (Fisher, France) at 37°C and in 5% CO₂. At the fourth passage, WJ-MSCs were characterized by flow cytometry (FACSCalibur; BD Bioscience), as previously described [22], by assessing the expression of CD73, CD90, CD44, CD105, CD34, CD45 and HLA-DR, and then used in our experimental procedure.

Human umbilical vein endothelial cells (HUVECs) were isolated according to the method of Jaffe et al. [23]. Briefly, the umbilical cords were washed in HBSS solution and HUVECs were extracted from umbilical cords veins using Trypsin. Then HUVECs were cultured at 37°C in 5% CO₂ in 25 cm² tissue-culture-treated flask (suitable for cell attachment and growth) in complete medium. The medium consisted of an equal mixture of M199/RPMI 1640 media supplemented with 20% human serum albumin, 2 mM L-glutamine, 20 mM HEPES, 100 IU/mL Penicillin, 2.5 mg/mL Fungizon®, being replaced every two days. The cells were used at the second passage culture and were seeded at 3×10³ cells/cm².

Endothelial cell differentiation

WJ-MSCs were seeded in 6-well plates at 3000 cells/cm² on CHI/HA or on COL-I coated glass substrates in α-MEM for 2 days. The unstimulated cells were then incubated in the complete Endothelial Basal Medium (EBM-2, Lonza®), without growth factor supplements, whereas the stimulated were are incubated in complete Endothelial Growth Medium (EGM2, Lonza® supplemented with EPCs-differentiating medium) for 2 weeks.

endothelial basal medium (EBM-2, Lonza®) supplemented with 0.5% FBS. The culture medium was changed every 2 days. The cells cultured on both surfaces (glass and PEMs architectures) were observed daily by phase contrast microscopy (Leica) to check their morphology.

Evaluation of endothelium-specific mRNA markers

Transcript levels of CD31 (PECAM-1 platelet endothelial cell adhesion molecule), CDH5 (Vascular endothelial Cadherin) and KDR (VEGFR-2 vascular endothelial growth factor 2) genes were quantified by real-time qPCR. Total RNA were isolated with RNeasy mini kit (Qiagen, GmbH, Hilden, Germany) according to the manufacturer’s instructions. Complementary DNA synthesis was performed with 350 ng total RNA using iScript cDNA synthesis kit (Bio-Rad, USA). Real-time qPCR was conducted as described previously [24]. As a positive control, RNA isolated from human umbilical vein endothelial cells (HUVECs) was used. These cells were isolated from the umbilical cord veins and cultured in M199/RPMI medium.

Measurement of gene expression was performed in duplicate; a non-template blank served as a negative control. qPCR was carried out using iQ SYBR® Green Supermix (Bio-Rad®) and in-home designed primers (using Primer3) for human CD-31, VE-cadherin, VEGF-R2 and ribosomal protein. Forward and reverse primers (Eurogenetec) were as follows:
CD31: 5’-ATGATGCCCAGTTTGAGGTC-3’; 5’-ACGTCTTCAGTGGGGTTGTC-3’,
KDR: 5’-GTGACCAACATGGAGTCGTG-3’; 5’-TGCTTCACAGAAGACCATGC-3’;
CDH5: 5’-CCTACCAGCCCAAAGTGTGT-3’; 5’-GACTTGGCATCCCATTGTCT-3’;
RPS29: 5’-TCATCTTCCAGCCCAAATTC-3’; 5’-CTTGAACGGTTACCACCTCA-3’

PCR was performed with MyCycler™ Personal Thermal Cycler (Bio-Rad®). Cycling parameters were 3 min at 95°C; 40 cycles of 3 min at 60°C for CD31, VEGF-R2 and RP29 and 62°C for VE-cadherin and 1 min at 72°C. The results were normalized to the housekeeping gene for S29 ribosomal protein. Analyses and fold differences were determined using the comparative CT method. The fold changes were calculated from the ΔΔCT values using the formula 2^-ΔΔCT, and the data were normalized relative to the reference gene values and then expressed as percentage of values obtained in HUVEC for each assayed mRNA.

Detection of endothelium-specific protein markers

Total proteins from cultured cells were prepared as previously described [26]. 25 μg proteins from each sample were heated at 95°C for 5 min in Laemmli sample buffer (BioRad, USA), and the total proteins were separated in acrylamide gel (10% for VEGF-R2, Vascular endothelial growth factor receptor 2, and 7% for CD31 and VE-cadherin. After electrophoresis, the gels were blotted to nitrocellulose membranes. GAPDH was used as loading control. Western blots were performed by using primary antibodies for endothelial VEGFR2 markers with 1/1000 milk/TBST (Tris-Buffered Saline Tween 20 0.5% from Cell Signaling Technology, UK); VE-cadherin with 1/1000 BSA (Bovine Serum Albumin/TBST from Abcam, USA); CD31 with 1/1000 BSA/TBST (Dako, France). The membranes were blocked with the blocking buffer TBS (Tris Buffer Saline) for 1h at room temperature and incubated with primary antibodies under gentle shaking at 4°C overnight. After extensive washing by TBS, the membranes were incubated for 1 h at room temperature with secondary antibodies conjugated to horseradish peroxidase (HRP). HRP activity was detected by enhanced chemiluminescence (ECL, Santa Cruz Biotechnology, USA). Santa Cruz Luminol Reagent A & B associated, will be oxidized by HRP in presence of hydrogen peroxide emitting the light. Densitometry of the obtained bands was estimated by ImageJ software.

Evaluation of endothelial-like cells functionality in terms of LDL-uptaking assay

Low-density lipoprotein (LDL)-uptake assay was performed as described previously. At day 15, WJ-MSCs seeded on collagen and PEMs architectures were incubated for 4 h at 37°C in RPMI 1640 without phenol red supplemented with 0.8 μg/mL Dil-Ac-LDL (Tebu-bio, France) labeled with rhodamine. Cells were washed with RPMI 1640 without phenol red to remove Dil-Ac-LDL. They were then fixed with 4% paraformaldehyde and nuclei were counterstained using 4',6-diamidino-2-phenylindole DAPI. The cells were observed using fluorescence microscopy (Leica microscope, *40) after using the appropriate excitation and emission filters for Rhodamin B (554nmEx/571nmEm).

Von Willebrand Factor (vWF) immunostaining

After 15 days of endothelial differentiation, the WJ-MSCs seeded on collagen and PEMs architectures were analyzed to assess vWF expression. The cells were fixed by 4% paraformaldehyde, permeabilized with PBS/Triton X-100 (0.1%) for 15 min, blocked with 1% BSA and stained by murine anti-vWF (1/100 Dako, France). After two washes with PBS, the appropriate secondary antibody labeled with Alexa-Fluor-488 (diluted at 1/100) was incubated for 30 min at 37°C. The cells were then observed by fluorescence microscopy (Zeiss microscopy, × 630 magnification) using the (485Ex/538Em) spectral line.

Statistical analysis

Data were presented as a mean ± SEM for each condition. Each experiment was repeated independently three times (n=3). Pairwise comparisons were performed using one-factor ANOVA with Fisher correction (Stat view IVs, Abacus Concepts Inc., Berkley, CA). Differences were considered significant for p (rejection level of the null-hypothesis of equal means) values < 0.05.

Results and discussion

Characterization of WJ-MSCs

Morphological characterization of MSCs (4^th passage) was performed according to the criteria defined by the International Society for Cellular Therapy [25]. MCSs derived from WJ of three umbilical cords displayed a homogeneous fibroblast-like morphology. Cells were analyzed regarding the expression of specific molecular markers by Fluorescein-Activated Cell Sorting analysis and showed that WJMSCs and BM-MSCs were positive for CD105, CD73, and CD90, and negative for CD45, CD34, CD86, and HLA-DR. These data revealed that WJ-MSCs used in this study showed the typical MSC characteristics (Data not shown).

Evaluation of endothelial markers expression at the mRNA and protein levels

n order to evaluate the effect of different adhesion matrices on differentiation of WJ-MSCs in endothelial-like cells, we measured the expression of endothelial markers by q-PCR and Western Blot. The three endothelial-specific molecules CD31, VE-cadherin and VEGF-R2 (KDR) are known to play an important role in the endothelium maturation during angiogenesis process [26]. CD31, also known as platelet endothelial cell adhesion molecule-1 (PECAM-1), is a type I integral membrane glycoprotein that is expressed at high levels on early and mature endothelial cells, platelets, and most leukocyte subpopulations. PECAM-1 is known to have various roles in vascular biology including angiogenesis, platelet function, and thrombosis [27]. VEGF-R2 is expressed on vascular endothelial cells and lymphatic endothelial cells; it regulates vascular endothelial function. VEGF is an important growth factor for the endothelial differentiation [28]. The endothelial-specific cadherin, vascular endothelial cadherin (VE-cadherin) is required for vascular genesis and the repair of damaged vessels [29].

The mRNA and protein levels of the three endothelial specific markers CD31, VEGF-R2 (KDR) and VE-cadherin were analyzed by real-time qPCR and Western blot (Figures 1 and 2). Relative expression of the three molecules was analyzed at mRNA and protein levels, and expressed relative to appropriate HUVEC values. WJ-MSCs seeded on CHI/HA or collagen and incubated in EBM-2 did not express the three markers at the protein level whereas their expression at the mRNA level was barely detectable (<1% of the levels found in HUVECs for CD31 and CDH5). In WJ-MSCs incubated in EGM-2 for 15 days, mRNA level was higher on CHI/HA than on collagen for CD31 and KDR (increase by 67%, and 79%, respectively). However, only the KDR increase was statistically significant. At the protein level, KDR expression was higher on CHI/HA relative to collagen (45% increase), but this difference was not statistically significant. CD31 protein levels were unchanged between collagen and CHI/HA, whereas CDH5 level was higher on CHI/HA relative to collagen (4% increase), and the difference was statistically significant. The fold change between collagen and CHI/HA at mRNA level was more important than fold change at protein level. After 15 days of differentiation, the transcription of endothelial genes give rise to high levels of mRNA from these genes. The translation process might take more culture time, to produce similar levels of proteins.

Higher mRNA and protein expression of these three markers in differentiated WJ-MSCs seeded on CHI/HA could contribute to more pronounced endothelial differentiation as compared with differentiated WJ-MSCs seeded on collagen. However, collagen is a recommended surface, allowing MSCs chondrogenic and osteogenic differentiation after 21 days [30]. In our report, we have not detected expression of VEGF-R2 protein on the collagen surface; maybe we needed more than 15 days to notice the translation of VEGF-R2 gene.

The capacity to differentiate towards endothelial phenotype is a characteristic of mesenchymal stem cells [30-32], and our results showed that WJ-MSCs express endothelial markers at mRNA and protein levels after 15-day cultures in presence of endothelial growth factors. However, the main purpose of this study was to evaluate endotheliogenic potential of WJ-MSCs seeded onto CHI/HA scaffolds. First, we verified the endothelial potential of WJ-MSCs in monolayer culture conditions both in proliferation (data not shown) and differentiation media. In proliferation medium, no endothelial differentiation was observed during the entire experimental time (15 days), further confirming the stem-cell origin of isolated cells. In differentiation medium, RT-PCR and Western Blot confirmed a better endothelial potential of these cells on CHI/HA.

Our choice of the CHI/HA scaffold was based on some studies that demonstrated the efficacy of this natural scaffold in enhancing hMSCs differentiation into stromal cells. hMSCs were induced to differentiate to chondrogenic, osteogenic, and adipogenic phenotypes [33]. Recent studies have shown the potential of WJ-MSCs to differentiate towards cardiomyocytes using CHI/HA scaffolds [34]. In our study, we have demonstrated that WJ-MSCs are able to differentiate into endothelial cells on CHI/HA films. Therefore, we can deduce that a combination of these cells with this natural scaffold is advantageous for cardio-vascular tissue engineering. Same conclusive results were observed in healing of diabetic skin wound by the proliferation and differentiation of human umbilical cords mesenchymal stem cells (hUCMSCs) on the collagen/chitosan laser drilling acellular dermal matrix (CCLDADM) scaffold, a natural scaffold used in vivo [35].

Evaluation of endothelial-like cells functionality by LDL uptake assay

LDL-uptake assay is applied for detection of functional endothelial cells. WJMSCs, when seeded on CHI/HA and collagen, captured DiIAcLDL to the cytoplasm after 4 hour-incubation in RPMI medium supplemented with DiI-Ac-LDL. However, MSCs were unable to uptake DiI-Ac-LDL after culturing in the growth medium as negative controls (Fig. 3). These results confirm that, after two weeks, WJ-MSCs seeded on CHI/HA and collagen exhibit endothelial cell phenotype. In this respect, Gaffney et al. investigated lipoprotein uptake by means of flow cytometry and showed that the cells in a G2/M (mitosis) phase incorporated about 45% more Dil-Ac-LDL than those in a G1/S (latency) phase [36]. Higher Dil-Ac-LDL uptake of endothelium-like cells on PEMs suggests that more cells are in the G2/M phase on PEMs, a feature of higher proliferation.

Figure 3. LDL-Uptake assay

WJ-MSCs cellular uptake of labeled acetylated LDLs. Double immunofluorescence of nuclei (blue) and for DI-Ac-LDLs (red) for unstimulated (a, b) and stimulated (c, d) WJMSCs after 15 days of culture on collagen and CHI/HA. Internalized labels were detected by Leica fluorescence microscopy (objective *40 oil).

Detection of endothelial-specific marker expression: vWF (von Willebrand Factor) by immunocytochemistry

Von Willebrand adherence factor (vWF) protein contributes to platelet function by mediating the initiation and progression of thrombus formation at the sites of vascular injury. Moreover, novel findings have been obtained on the link between regulation of VWF multimer size and microvascular thrombosis. This progress in basic research has provided critical information to define with greater precision the role of vWF in vascular biology and pathology, including its possible involvement in the onset of atherosclerosis and its acute thrombotic complications. Therefore we have used the expression of vWF as a functionality test of our endothelial-like cells [37]. The cells were examined for expression of endothelial-specific marker (vWF) by immunocytochemistry.

WJ-MSCs seeded on CHI/HA showed a high fluorescence specific to this marker after endothelial differentiation for 15 days. MSCs did not show any positive signal after they were cultured in the growth medium (EBM2) on the same scaffold, as negative controls. On collagen layer, the cells were not marked, that was predicted because they needed more culture time to express vWF protein (Fig. 4).

Figure 4. vWF immunostaining

Double immunofluorescence staining for nuclei (blue), and for prothrombogenic von Willebrand Factor for stimulated (a, b) and unstimulated (d, e) WJ-MSCs after 15 days of culture on collagen and CHI/HA (Zeiss Microscope, objective*63 oil). N=3.

These promising results showed the possibility to combine the use of WJ-MSCs and CHI/HA films aiming for vascular tissue engineering, by evaluating the capacity of WJ-MSCs to differentiate into smooth muscle cells on CHI/HA, coating the surface of alginate hydrogels with CHI/HA films, and enrolling them in order to form a tubular vascular graft.

These promising data showed that the combination of WJ-MSCs and CHI/HA may lead to brilliant results, regarding endothelial differentiation and angiogenesis. One may recommend using of these cells and materials for vascular tissue engineering and regeneration therapy. More studies can be done to evaluate the capacity of WJ-MSCs to differentiate into smooth muscle cells on CHI/HA, to coat the surface of alginate hydrogels with CHI/HA films and to enroll them, in order to form a tubular vascular graft.

Conclusion

These first quite encouraging results showed that it is possible to obtain CEs-like in a non-traumatic way (from Wharton's jelly of human umbilical cords) and in a short time (15 days). Our technique, based on the use of polyelectrolyte films, could therefore be used in the field of vascular engineering for the development of functional vascular substitutes comprising an endothelium resulting from differentiation of mesenchymal stem cells, which would limit the risks of graft rejection and could be applied to patients who require vessel replacement.

Acknowledgements

The authors would like to thank Al Hanan Hospital for providing the umbilical cords used in our researches and Azm & Saadeh society for funding this work.

The authors have no conflicts of interest to declare.

Ethical Statement: The research work was approved by the ethical committee of the Lebanese University, Centre Azm for research in Applied Biotechnology and the ethical Committee of Al Hanan Hospital-Tripoli, Lebanon.

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Уровни мРНК, кодирующих CD31 и KDR были выше после культивирования на ГХ-субстрате, нежели на коллагеновом покрытии, при достоверном повышении экспрессии KDR. На уровне белков, показана тенденция к повышению уровней KDR и CDH5 после инкубации на ГХ-субстрате, по сравнению с коллагеном. Кроме того, МСК-ЖВ, культивированные на ГХ, имели высокие уровни экспрессии эндотелиальных маркеров после 15 суток культивирования в среде EGM-2®.</p> <h3>Выводы</h3> <p style="text-align: justify;">В данной работе мы сообщаем о новом биосовместимом субстрате, который способствует дифференцировке МСК-ЖВ в эндотелиоподобные клетки. Разработка этого субстрата является новым подходом в тканевой инженерии для создания аллогенных сосудистых трансплантатов. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Мезенхимные стволовые клетки, желе Вортона, дифференцировка, эндотелий, хитозан, гиалуроновая кислота, многослойный субстрат, тканевая инженерия.</p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(297) "Эндотелиальная дифференцировка мезенхимных стволовых клеток из соединительной ткани пуповины (желе Вортона) на многослойных пленках из хитозана/гиалуронинана " ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(297) "Эндотелиальная дифференцировка мезенхимных стволовых клеток из соединительной ткани пуповины (желе Вортона) на многослойных пленках из хитозана/гиалуронинана " ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(297) "Эндотелиальная дифференцировка мезенхимных стволовых клеток из соединительной ткани пуповины (желе Вортона) на многослойных пленках из хитозана/гиалуронинана " ["SECTION_META_TITLE"]=> string(297) "Эндотелиальная дифференцировка мезенхимных стволовых клеток из соединительной ткани пуповины (желе Вортона) на многослойных пленках из хитозана/гиалуронинана " ["SECTION_META_KEYWORDS"]=> string(297) "Эндотелиальная дифференцировка мезенхимных стволовых клеток из соединительной ткани пуповины (желе Вортона) на многослойных пленках из хитозана/гиалуронинана " ["SECTION_META_DESCRIPTION"]=> string(297) "Эндотелиальная дифференцировка мезенхимных стволовых клеток из соединительной ткани пуповины (желе Вортона) на многослойных пленках из хитозана/гиалуронинана " ["SECTION_PICTURE_FILE_ALT"]=> string(297) "Эндотелиальная дифференцировка мезенхимных стволовых клеток из соединительной ткани пуповины (желе Вортона) на многослойных пленках из хитозана/гиалуронинана " ["SECTION_PICTURE_FILE_TITLE"]=> string(297) "Эндотелиальная дифференцировка мезенхимных стволовых клеток из соединительной ткани пуповины (желе Вортона) на многослойных пленках из хитозана/гиалуронинана " ["SECTION_PICTURE_FILE_NAME"]=> string(100) "endotelialnaya-differentsirovka-mezenkhimnykh-stvolovykh-kletok-iz-soedinitelnoy-tkani-pupoviny-zhel" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(297) "Эндотелиальная дифференцировка мезенхимных стволовых клеток из соединительной ткани пуповины (желе Вортона) на многослойных пленках из хитозана/гиалуронинана " ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(297) "Эндотелиальная дифференцировка мезенхимных стволовых клеток из соединительной ткани пуповины (желе Вортона) на многослойных пленках из хитозана/гиалуронинана " ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(100) "endotelialnaya-differentsirovka-mezenkhimnykh-stvolovykh-kletok-iz-soedinitelnoy-tkani-pupoviny-zhel" ["ELEMENT_PREVIEW_PICTURE_FILE_NAME"]=> string(100) "endotelialnaya-differentsirovka-mezenkhimnykh-stvolovykh-kletok-iz-soedinitelnoy-tkani-pupoviny-zhel" ["ELEMENT_DETAIL_PICTURE_FILE_NAME"]=> string(100) "endotelialnaya-differentsirovka-mezenkhimnykh-stvolovykh-kletok-iz-soedinitelnoy-tkani-pupoviny-zhel" } ["FIELDS"]=> array(1) { ["IBLOCK_SECTION_ID"]=> string(3) "171" } ["PROPERTIES"]=> array(18) { ["KEYWORDS"]=> array(36) { ["ID"]=> string(2) "19" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:46:01" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(27) "Ключевые слова" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "KEYWORDS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "19" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "4" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "Y" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(27) "Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" } ["SUBMITTED"]=> array(36) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27383" ["VALUE"]=> string(22) "08/25/2020 12:00:00 am" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(22) "08/25/2020 12:00:00 am" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL } ["ACCEPTED"]=> array(36) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27384" ["VALUE"]=> string(22) "11/14/2020 12:00:00 am" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(22) "11/14/2020 12:00:00 am" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL } ["PUBLISHED"]=> array(36) { ["ID"]=> string(2) "22" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Дата публикации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "PUBLISHED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "22" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" 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["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHORS"]=> array(36) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27385" ["VALUE"]=> array(2) { ["TEXT"]=> string(163) "<p>Хана Деннауи¹, Элиана Шуэри², Шаза Хармуш¹ </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(115) "

Хана Деннауи¹, Элиана Шуэри², Шаза Хармуш¹

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27386" ["VALUE"]=> array(2) { ["TEXT"]=> string(631) "<p>¹ Лаборатория прикладной биотехнологии: биомолекулы, биотерапия и биопроцессы, научно-прикладной центр биотехнологии AZM, докторская школа науки и технологий, Ливанский университет, Триполи, Ливан <br> ² Отделение медицинской генетики, факультет медицины, университет Св. Иосифа (USJ), Мар-Микаэл, Бейрут, Ливан</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(589) "

¹ Лаборатория прикладной биотехнологии: биомолекулы, биотерапия и биопроцессы, научно-прикладной центр биотехнологии AZM, докторская школа науки и технологий, Ливанский университет, Триполи, Ливан
² Отделение медицинской генетики, факультет медицины, университет Св. Иосифа (USJ), Мар-Микаэл, Бейрут, Ливан

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Простота заготовки мезенхимных стволовых клеток из желе Вортона (МСК-ЖВ), выраженная пластичность дифференцировки и низкая иммуногенность делают их удобным средством аллогенной клеточной терапии. Целью данного исследования было изучение способности к дифференцировке в эндотелиоподобные клетки МСК-ЖВ, культивированных на гиалуронан-хитозановых (ГХ) многослойных носителях.

Материалы и методы

В этой работе мы проводили дифференцировку МСК-ЖВ в ангиогенном направлении с применением полиэлектролитной многослойной пленки в качестве субстрата. МСК-ЖВ культивировали на ГХ-многослойной пленке и стимулировали факторами культуральной среды EGM-2®. Коллаген типа I использовали в качестве контрольного субстрата. Определяли экспрессию специфических мРНК, а именно: CD31, рецептора фактора роста сосудистого эндотелия типа 2 (VEGF2) и эндотелиального сосудистого кадхерина (VE), наряду с уровнями абсорбции Dil-ацетилированного липопротеина низкой плотности и экспрессией белкового фактора Виллебранда.

Результаты

Выделенные МСК-ЖВ имели типичную морфологию фибробластоподобных клеток. Уровни мРНК, кодирующих CD31 и KDR были выше после культивирования на ГХ-субстрате, нежели на коллагеновом покрытии, при достоверном повышении экспрессии KDR. На уровне белков, показана тенденция к повышению уровней KDR и CDH5 после инкубации на ГХ-субстрате, по сравнению с коллагеном. Кроме того, МСК-ЖВ, культивированные на ГХ, имели высокие уровни экспрессии эндотелиальных маркеров после 15 суток культивирования в среде EGM-2®.

Выводы

В данной работе мы сообщаем о новом биосовместимом субстрате, который способствует дифференцировке МСК-ЖВ в эндотелиоподобные клетки. Разработка этого субстрата является новым подходом в тканевой инженерии для создания аллогенных сосудистых трансплантатов.

Ключевые слова

Мезенхимные стволовые клетки, желе Вортона, дифференцировка, эндотелий, хитозан, гиалуроновая кислота, многослойный субстрат, тканевая инженерия.

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Hana Dennaoui¹, Eliane Chouery², Chaza Harmoush¹

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¹ Laboratory of Applied Biotechnology: Biomolecules, Biotherapies and Bioprocesses, AZM Centre for Biotechnology Research and its Applications, Doctoral School of Science and Technology, Lebanese University, Tripoli, Lebanon
² Medical Genetics Unit, Faculty of Medicine, Saint Joseph University (USJ), Mar Mikhaël, Beirut, Lebanon

Correspondence
Dr. Hana Dennaoui, Laboratory of Applied Biotechnology: Biomolecules, Biotherapies and Bioprocesses, AZM Centre for Biotechnology Research and its Applications, Doctoral School of Science and Technology, Lebanese University, El Mitein St, Tripoli, Lebanon
E-mail: hana.dennaoui@hotmail.com

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The ease of harvesting of mesenchymal stem cells from Wharton’s jelly (WJ-MSCs), their great differentiation plasticity and low immunogenicity make them a suitable tool for allogeneic cell therapy. The aim of present study was to explore the potential of WJ-MSCs seeded on chitosan/hyaluronic acid (HA/CHI) multilayers to differentiate into endothelial-like cells.

Methods

In this study, we differentiate WJ-MSCs into an angiogenic lineage using polyelectrolyte multilayer film as a substrate. WJ-MSCs were cultivated on HA/CHI multilayer film and stimulated (or not) with EGM-2® culture medium. Type I collagen was used as control. mRNA and protein expression of CD31, vascular endothelial growth factor-receptor 2 (VEGF2) and vascular endothelial (VE)-cadherin, along with Dil-acetylated low-density lipoprotein-uptake and von Willebrand Factor protein expression were performed.

Results

The isolated MSCs showed typical fibroblast-like morphology. We have shown that WJ-MSCs express endothelial markers after 15 days of culture in EGM-2® medium. The mRNA levels were higher on CHI/HA than on collagen for CD31 and KDR, with only KDR increase being statistically significant. At the protein level, a trend for increase in KDR and CDH5 levels was also shown on CHI/HA relative to collagen. Moreover, the WJ-MSCs seeded on CHI/HA showed a high fluorescence specific to von Willebrand factor after endothelial differentiation for 15 days.

Conclusion

We report here a new biocompatible coating allowing differentiation of WJ-MSCs into endothelial-like cells. This substrate opens new routes in tissue engineering to design allogeneic vascular grafts.

Keywords

Mesenchymal stem cells, Wharton’s jelly, differentiation, endothelial lineage, chitosan, hyaluronic acid, multilayer substrate, tissue engineering.

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Hana Dennaoui¹, Eliane Chouery², Chaza Harmoush¹

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Hana Dennaoui¹, Eliane Chouery², Chaza Harmoush¹

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The ease of harvesting of mesenchymal stem cells from Wharton’s jelly (WJ-MSCs), their great differentiation plasticity and low immunogenicity make them a suitable tool for allogeneic cell therapy. The aim of present study was to explore the potential of WJ-MSCs seeded on chitosan/hyaluronic acid (HA/CHI) multilayers to differentiate into endothelial-like cells.

Methods

In this study, we differentiate WJ-MSCs into an angiogenic lineage using polyelectrolyte multilayer film as a substrate. WJ-MSCs were cultivated on HA/CHI multilayer film and stimulated (or not) with EGM-2® culture medium. Type I collagen was used as control. mRNA and protein expression of CD31, vascular endothelial growth factor-receptor 2 (VEGF2) and vascular endothelial (VE)-cadherin, along with Dil-acetylated low-density lipoprotein-uptake and von Willebrand Factor protein expression were performed.

Results

The isolated MSCs showed typical fibroblast-like morphology. We have shown that WJ-MSCs express endothelial markers after 15 days of culture in EGM-2® medium. The mRNA levels were higher on CHI/HA than on collagen for CD31 and KDR, with only KDR increase being statistically significant. At the protein level, a trend for increase in KDR and CDH5 levels was also shown on CHI/HA relative to collagen. Moreover, the WJ-MSCs seeded on CHI/HA showed a high fluorescence specific to von Willebrand factor after endothelial differentiation for 15 days.

Conclusion

We report here a new biocompatible coating allowing differentiation of WJ-MSCs into endothelial-like cells. This substrate opens new routes in tissue engineering to design allogeneic vascular grafts.

Keywords

Mesenchymal stem cells, Wharton’s jelly, differentiation, endothelial lineage, chitosan, hyaluronic acid, multilayer substrate, tissue engineering.

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The ease of harvesting of mesenchymal stem cells from Wharton’s jelly (WJ-MSCs), their great differentiation plasticity and low immunogenicity make them a suitable tool for allogeneic cell therapy. The aim of present study was to explore the potential of WJ-MSCs seeded on chitosan/hyaluronic acid (HA/CHI) multilayers to differentiate into endothelial-like cells.

Methods

In this study, we differentiate WJ-MSCs into an angiogenic lineage using polyelectrolyte multilayer film as a substrate. WJ-MSCs were cultivated on HA/CHI multilayer film and stimulated (or not) with EGM-2® culture medium. Type I collagen was used as control. mRNA and protein expression of CD31, vascular endothelial growth factor-receptor 2 (VEGF2) and vascular endothelial (VE)-cadherin, along with Dil-acetylated low-density lipoprotein-uptake and von Willebrand Factor protein expression were performed.

Results

The isolated MSCs showed typical fibroblast-like morphology. We have shown that WJ-MSCs express endothelial markers after 15 days of culture in EGM-2® medium. The mRNA levels were higher on CHI/HA than on collagen for CD31 and KDR, with only KDR increase being statistically significant. At the protein level, a trend for increase in KDR and CDH5 levels was also shown on CHI/HA relative to collagen. Moreover, the WJ-MSCs seeded on CHI/HA showed a high fluorescence specific to von Willebrand factor after endothelial differentiation for 15 days.

Conclusion

We report here a new biocompatible coating allowing differentiation of WJ-MSCs into endothelial-like cells. This substrate opens new routes in tissue engineering to design allogeneic vascular grafts.

Keywords

Mesenchymal stem cells, Wharton’s jelly, differentiation, endothelial lineage, chitosan, hyaluronic acid, multilayer substrate, tissue engineering.

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¹ Laboratory of Applied Biotechnology: Biomolecules, Biotherapies and Bioprocesses, AZM Centre for Biotechnology Research and its Applications, Doctoral School of Science and Technology, Lebanese University, Tripoli, Lebanon
² Medical Genetics Unit, Faculty of Medicine, Saint Joseph University (USJ), Mar Mikhaël, Beirut, Lebanon

Correspondence
Dr. Hana Dennaoui, Laboratory of Applied Biotechnology: Biomolecules, Biotherapies and Bioprocesses, AZM Centre for Biotechnology Research and its Applications, Doctoral School of Science and Technology, Lebanese University, El Mitein St, Tripoli, Lebanon
E-mail: hana.dennaoui@hotmail.com

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¹ Laboratory of Applied Biotechnology: Biomolecules, Biotherapies and Bioprocesses, AZM Centre for Biotechnology Research and its Applications, Doctoral School of Science and Technology, Lebanese University, Tripoli, Lebanon
² Medical Genetics Unit, Faculty of Medicine, Saint Joseph University (USJ), Mar Mikhaël, Beirut, Lebanon

Correspondence
Dr. Hana Dennaoui, Laboratory of Applied Biotechnology: Biomolecules, Biotherapies and Bioprocesses, AZM Centre for Biotechnology Research and its Applications, Doctoral School of Science and Technology, Lebanese University, El Mitein St, Tripoli, Lebanon
E-mail: hana.dennaoui@hotmail.com

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Хана Деннауи¹, Элиана Шуэри², Шаза Хармуш¹

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Хана Деннауи¹, Элиана Шуэри², Шаза Хармуш¹

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Целью данного исследования было изучение способности к дифференцировке в эндотелиоподобные клетки МСК-ЖВ, культивированных на гиалуронан-хитозановых (ГХ) многослойных носителях.</p> <h3>Материалы и методы</h3> <p style="text-align: justify;">В этой работе мы проводили дифференцировку МСК-ЖВ в ангиогенном направлении с применением полиэлектролитной многослойной пленки в качестве субстрата. МСК-ЖВ культивировали на ГХ-многослойной пленке и стимулировали факторами культуральной среды EGM-2®. Коллаген типа I использовали в качестве контрольного субстрата. Определяли экспрессию специфических мРНК, а именно: CD31, рецептора фактора роста сосудистого эндотелия типа 2 (VEGF2) и эндотелиального сосудистого кадхерина (VE), наряду с уровнями абсорбции Dil-ацетилированного липопротеина низкой плотности и экспрессией белкового фактора Виллебранда.</p> <h3>Результаты</h3> <p style="text-align: justify;">Выделенные МСК-ЖВ имели типичную морфологию фибробластоподобных клеток. Уровни мРНК, кодирующих CD31 и KDR были выше после культивирования на ГХ-субстрате, нежели на коллагеновом покрытии, при достоверном повышении экспрессии KDR. На уровне белков, показана тенденция к повышению уровней KDR и CDH5 после инкубации на ГХ-субстрате, по сравнению с коллагеном. Кроме того, МСК-ЖВ, культивированные на ГХ, имели высокие уровни экспрессии эндотелиальных маркеров после 15 суток культивирования в среде EGM-2®.</p> <h3>Выводы</h3> <p style="text-align: justify;">В данной работе мы сообщаем о новом биосовместимом субстрате, который способствует дифференцировке МСК-ЖВ в эндотелиоподобные клетки. Разработка этого субстрата является новым подходом в тканевой инженерии для создания аллогенных сосудистых трансплантатов. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Мезенхимные стволовые клетки, желе Вортона, дифференцировка, эндотелий, хитозан, гиалуроновая кислота, многослойный субстрат, тканевая инженерия.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3777) "

Простота заготовки мезенхимных стволовых клеток из желе Вортона (МСК-ЖВ), выраженная пластичность дифференцировки и низкая иммуногенность делают их удобным средством аллогенной клеточной терапии. Целью данного исследования было изучение способности к дифференцировке в эндотелиоподобные клетки МСК-ЖВ, культивированных на гиалуронан-хитозановых (ГХ) многослойных носителях.

Материалы и методы

В этой работе мы проводили дифференцировку МСК-ЖВ в ангиогенном направлении с применением полиэлектролитной многослойной пленки в качестве субстрата. МСК-ЖВ культивировали на ГХ-многослойной пленке и стимулировали факторами культуральной среды EGM-2®. Коллаген типа I использовали в качестве контрольного субстрата. Определяли экспрессию специфических мРНК, а именно: CD31, рецептора фактора роста сосудистого эндотелия типа 2 (VEGF2) и эндотелиального сосудистого кадхерина (VE), наряду с уровнями абсорбции Dil-ацетилированного липопротеина низкой плотности и экспрессией белкового фактора Виллебранда.

Результаты

Выделенные МСК-ЖВ имели типичную морфологию фибробластоподобных клеток. Уровни мРНК, кодирующих CD31 и KDR были выше после культивирования на ГХ-субстрате, нежели на коллагеновом покрытии, при достоверном повышении экспрессии KDR. На уровне белков, показана тенденция к повышению уровней KDR и CDH5 после инкубации на ГХ-субстрате, по сравнению с коллагеном. Кроме того, МСК-ЖВ, культивированные на ГХ, имели высокие уровни экспрессии эндотелиальных маркеров после 15 суток культивирования в среде EGM-2®.

Выводы

В данной работе мы сообщаем о новом биосовместимом субстрате, который способствует дифференцировке МСК-ЖВ в эндотелиоподобные клетки. Разработка этого субстрата является новым подходом в тканевой инженерии для создания аллогенных сосудистых трансплантатов.

Ключевые слова

Мезенхимные стволовые клетки, желе Вортона, дифференцировка, эндотелий, хитозан, гиалуроновая кислота, многослойный субстрат, тканевая инженерия.

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Простота заготовки мезенхимных стволовых клеток из желе Вортона (МСК-ЖВ), выраженная пластичность дифференцировки и низкая иммуногенность делают их удобным средством аллогенной клеточной терапии. Целью данного исследования было изучение способности к дифференцировке в эндотелиоподобные клетки МСК-ЖВ, культивированных на гиалуронан-хитозановых (ГХ) многослойных носителях.

Материалы и методы

В этой работе мы проводили дифференцировку МСК-ЖВ в ангиогенном направлении с применением полиэлектролитной многослойной пленки в качестве субстрата. МСК-ЖВ культивировали на ГХ-многослойной пленке и стимулировали факторами культуральной среды EGM-2®. Коллаген типа I использовали в качестве контрольного субстрата. Определяли экспрессию специфических мРНК, а именно: CD31, рецептора фактора роста сосудистого эндотелия типа 2 (VEGF2) и эндотелиального сосудистого кадхерина (VE), наряду с уровнями абсорбции Dil-ацетилированного липопротеина низкой плотности и экспрессией белкового фактора Виллебранда.

Результаты

Выделенные МСК-ЖВ имели типичную морфологию фибробластоподобных клеток. Уровни мРНК, кодирующих CD31 и KDR были выше после культивирования на ГХ-субстрате, нежели на коллагеновом покрытии, при достоверном повышении экспрессии KDR. На уровне белков, показана тенденция к повышению уровней KDR и CDH5 после инкубации на ГХ-субстрате, по сравнению с коллагеном. Кроме того, МСК-ЖВ, культивированные на ГХ, имели высокие уровни экспрессии эндотелиальных маркеров после 15 суток культивирования в среде EGM-2®.

Выводы

В данной работе мы сообщаем о новом биосовместимом субстрате, который способствует дифференцировке МСК-ЖВ в эндотелиоподобные клетки. Разработка этого субстрата является новым подходом в тканевой инженерии для создания аллогенных сосудистых трансплантатов.

Ключевые слова

Мезенхимные стволовые клетки, желе Вортона, дифференцировка, эндотелий, хитозан, гиалуроновая кислота, многослойный субстрат, тканевая инженерия.

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¹ Лаборатория прикладной биотехнологии: биомолекулы, биотерапия и биопроцессы, научно-прикладной центр биотехнологии AZM, докторская школа науки и технологий, Ливанский университет, Триполи, Ливан
² Отделение медицинской генетики, факультет медицины, университет Св. Иосифа (USJ), Мар-Микаэл, Бейрут, Ливан

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¹ Лаборатория прикладной биотехнологии: биомолекулы, биотерапия и биопроцессы, научно-прикладной центр биотехнологии AZM, докторская школа науки и технологий, Ливанский университет, Триполи, Ливан
² Отделение медицинской генетики, факультет медицины, университет Св. Иосифа (USJ), Мар-Микаэл, Бейрут, Ливан

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<sup>1</sup> Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия<br>
<sup>2</sup> Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия<br>
<sup>3</sup> Военно-медицинская академия им. С. М. Кирова, Санкт-Петербург, Россия</p>
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1 Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия

2 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

3 Военно-медицинская академия им. С. М. Кирова, Санкт-Петербург, Россия
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                    [TEXT] => <p style="text-align: justify;">В настоящей работе изучено поведение пористых сферических ватеритов карбоната кальция (СаСО<sub>3</sub>) покрытых защитной оболочкой из сульфата декстрана – систем адресной доставки лекарственных препаратов – в мышечной ткани крыс на сроках 3 сут., 1, 2, 4 и 12 нед., после имплантации. Было показано, что с течением времени происходит структурная трансформация и биорезорбция изучаемых носителей. Через 3 сут. наблюдается преобразование сферических структур в игольчатые с последующей их биорезорбцией в течение 2 нед. При этом патологического воздействия на окружающие ткани выявлено не было, что подтверждает безопасность применения покрытых защитной оболочкой СаСО<sub>3</sub> ватеритов и позволяет рекомендовать их для проведения дальнейших исследований в качестве систем адресной доставки лекарственных препаратов.</p>
<h2>Ключевые слова</h2>
<p style="text-align: justify;">Адресная доставка лекарственных препаратов, карбонат кальция, сульфат декстрана, биорезорбция, мышечная ткань, эксперимент <i>in vivo</i>.</p>
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В настоящей работе изучено поведение пористых сферических ватеритов карбоната кальция (СаСО3) покрытых защитной оболочкой из сульфата декстрана – систем адресной доставки лекарственных препаратов – в мышечной ткани крыс на сроках 3 сут., 1, 2, 4 и 12 нед., после имплантации. Было показано, что с течением времени происходит структурная трансформация и биорезорбция изучаемых носителей. Через 3 сут. наблюдается преобразование сферических структур в игольчатые с последующей их биорезорбцией в течение 2 нед. При этом патологического воздействия на окружающие ткани выявлено не было, что подтверждает безопасность применения покрытых защитной оболочкой СаСО3 ватеритов и позволяет рекомендовать их для проведения дальнейших исследований в качестве систем адресной доставки лекарственных препаратов.
Ключевые слова
Адресная доставка лекарственных препаратов, карбонат кальция, сульфат декстрана, биорезорбция, мышечная ткань, эксперимент in vivo.
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                    [TEXT] => <p>Pavel V. Popryadukhin<sup>1</sup>, Natalia N. Sudareva<sup>1,2</sup>, Оlga М. Suvorova<sup>1</sup>, Galina Yu. Yukina<sup>2</sup>, Еlena G. Sukhorukova<sup>2</sup>, Natalia N. Saprykina<sup>1</sup>, Ilya A. Barsuk<sup>3</sup>, Oleg V. Galibin<sup>2</sup>, Aleksandr D. Vilesov<sup>1,2</sup> </p>
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                    [TEXT] => <p><sup>1</sup> Institute of Macromolecular Compounds RAS, St. Petersburg, Russia<br>
<sup>2</sup> Pavlov University, St. Petersburg, Russia<br>
<sup>3</sup> S.M.Kirov Military Medical Academy, St. Petersburg, Russia</p><br>
<p><b>Correspondence</b><br>
Dr. Pavel V. Popryadukhin, Institute of Macromolecular Compounds, St. Petersburg, Russia<br>
E-mail: pavelpnru@gmail.com</p>
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1 Institute of Macromolecular Compounds RAS, St. Petersburg, Russia

2 Pavlov University, St. Petersburg, Russia

3 S.M.Kirov Military Medical Academy, St. Petersburg, Russia


Correspondence

Dr. Pavel V. Popryadukhin, Institute of Macromolecular Compounds, St. Petersburg, Russia

E-mail: pavelpnru@gmail.com
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                    [TEXT] => <p style="text-align: justify;">The present work is focused on the study of target drug delivery systems comprised of porous spherical calcium carbonate vaterites (СаСО<sub>3</sub>) covered with the dextran sulfate protective shell. Behavior of the objects was investigated <i>in vivo</i>. The samples were implanted into rat muscular tissue and removed after different periods of exposure (3 days, 1, 2, 4, and 12 weeks after operation). It was shown that certain transformations in structure of the implanted carriers occurred over time, after which they underwent bioresorption. In 3 days after implantation, spherical vaterites degraded, and needle-like calcium carbonate objects were formed; during the following two weeks, these objects were completely resorbed in living tissues. Since no pathogenic influence of the samples on the surrounding tissues was revealed, we believe that СаСО<sub>3</sub> vaterites covered with protective shells are safe for potential medicinal applications and can be recommended for further studies as target drug delivery systems.</p>
<h2>Keywords</h2>
<p style="text-align: justify;">Target drug delivery, calcium carbonate, dextran sulfate, bioresorption, muscular tissue, <i>in vivo</i> experiment.</p>

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Keywords
Target drug delivery, calcium carbonate, dextran sulfate, bioresorption, muscular tissue, in vivo experiment.

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<sup>2</sup> Первый Московский государственный медицинский университет им. И. М. Сеченова Минздрава РФ, Москва, Россия<br>
<sup>3</sup> Научный центр акушерства, гинекологии и перинатологии им. акад. В. И. Кулакова Минздрава РФ, Москва, Россия</p>
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1 Институт биоорганической химии им. академиков М. М. Шемякина и Ю. А. Овчинникова РАН, Москва, Россия

2 Первый Московский государственный медицинский университет им. И. М. Сеченова Минздрава РФ, Москва, Россия

3 Научный центр акушерства, гинекологии и перинатологии им. акад. В. И. Кулакова Минздрава РФ, Москва, Россия
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                    [TEXT] => <p style="text-align: justify;">Одной из острых проблем России является вторичное бесплодие женщин детородного возраста. Оно часто вызвано повреждением базального слоя эндометрия при выполнении гинекологических процедур: дилатации полости матки, лечебно-диагностическом выскабливании полости матки, кесаревом сечении, операциях на матке, а также после беременностей, протекающих с осложнениями. Как результат могут развиваться гипо- или гиперметриоз, а также формироваться внутриматочные спайки – синехии, приводящие к развитию синдрома Ашермана. Несмотря на большое количество накопленных клинических данных, отсутствует эффективный способ лечения вторичного бесплодия. В настоящее время с определенным успехом для терапии гипометриоза и синдрома Ашермана используют различные биополимеры и композиты на основе биополимеров с включением активных молекул, генов, их кодирующих, обогащенной тромбоцитами плазмы крови, стволовых клеток или микровезикул/экзосом стволовых клеток. Для использования в клинике сертифицированы гели на основе гиалуроната натрия, карбоксиметилцеллюлозы, полиэтиленоксида, коллагена и другие. Гели биополимеров являются, с одной стороны, разобщающими стенки матки препаратами (барьерная функция), а, с другой стороны, могут работать, как носители биологически активных молекул и клеток.
Биомиметики с разной эффективностью способны стимулировать регенерацию и нормализацию эндометрия, что способствует восстановлению репродуктивной способности. Методики лечения на основе биомиметиков находятся в стадии исследований. В обзоре приведены данные по эффективности лечения патологий эндометрия матки с помощью биотерапевтических подходов. </p>
<h2>Ключевые слова</h2>
<p style="text-align: justify;">Бесплодие, гипометриоз, гиперметриоз, синдром Ашермана, барьерные материалы, биогели, биомиметики.</p>
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Биомиметики с разной эффективностью способны стимулировать регенерацию и нормализацию эндометрия, что способствует восстановлению репродуктивной способности. Методики лечения на основе биомиметиков находятся в стадии исследований. В обзоре приведены данные по эффективности лечения патологий эндометрия матки с помощью биотерапевтических подходов. 
Ключевые слова
Бесплодие, гипометриоз, гиперметриоз, синдром Ашермана, барьерные материалы, биогели, биомиметики.
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                    [TEXT] => <p><sup>1</sup> Shemyakin-Ovchinnikov Institute of Bioorganic Сhemistry RAS, Moscow, Russia<br>
<sup>2</sup> Sechenov’s First Moscow State Medical University, Moscow, Russia<br>
<sup>3</sup> V. I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia</p><br>
<p><b>Correspondence</b><br>
Elena Svirshchevskaya, PhD, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 16/10 Miklukho-Maklaya St, Moscow, 117997, Russia<br>
Phone: +7 (910) 464 8760<br>
Fax: +7 (495) 330 4011<br>
E-mail: esvir@mail.ibch.ru</p>
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1 Shemyakin-Ovchinnikov Institute of Bioorganic Сhemistry RAS, Moscow, Russia

2 Sechenov’s First Moscow State Medical University, Moscow, Russia

3 V. I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia


Correspondence

Elena Svirshchevskaya, PhD, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 16/10 Miklukho-Maklaya St, Moscow, 117997, Russia

Phone: +7 (910) 464 8760

Fax: +7 (495) 330 4011

E-mail: esvir@mail.ibch.ru
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                    [TEXT] => <p style="text-align: justify;">Secondary infertility among women in their childbearing age is one of sufficient problems in Russia. It is often caused by damage to the basal layer of endometrium when performing gynecological procedures, e.g., dilatation of uterine cavity, diagnostic curettage, cesarean section, uterine surgey, as well as consequences of complicated pregnancies. As a result, hypo- or hypermetriosis may develop, along with intrauterine adhesions (synechiae), leading to the development of Asherman’s syndrome. Despite large amounts of medical data, there are no quite effective ways to treat secondary infertility. Currently, various biological polymers and composite materials based on biopolymers with incorporated active molecules, genetic substances, platelet-rich plasma, stem cells or microvesicles/exosomes of stem cells are used with some success for treatment of hypometriosis and Asherman’s syndrome. Gel substances based on
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<p style="text-align: justify;">Infertility, hypometriosis, Asherman's syndrome, barrier materials, biogels, biomimetics.</p>
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Secondary infertility among women in their childbearing age is one of sufficient problems in Russia. It is often caused by damage to the basal layer of endometrium when performing gynecological procedures, e.g., dilatation of uterine cavity, diagnostic curettage, cesarean section, uterine surgey, as well as consequences of complicated pregnancies. As a result, hypo- or hypermetriosis may develop, along with intrauterine adhesions (synechiae), leading to the development of Asherman’s syndrome. Despite large amounts of medical data, there are no quite effective ways to treat secondary infertility. Currently, various biological polymers and composite materials based on biopolymers with incorporated active molecules, genetic substances, platelet-rich plasma, stem cells or microvesicles/exosomes of stem cells are used with some success for treatment of hypometriosis and Asherman’s syndrome. Gel substances based on
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Keywords
Infertility, hypometriosis, Asherman's syndrome, barrier materials, biogels, biomimetics.
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                    [TEXT] => <p><sup>1</sup> Лаборатория прикладной биотехнологии: биомолекулы, биотерапия и биопроцессы, научно-прикладной центр биотехнологии AZM, докторская школа науки и технологий, Ливанский университет, Триполи, Ливан <br>
<sup>2</sup> Отделение медицинской генетики, факультет медицины, университет Св. Иосифа (USJ), Мар-Микаэл, Бейрут, Ливан</p>
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1 Лаборатория прикладной биотехнологии: биомолекулы, биотерапия и биопроцессы, научно-прикладной центр биотехнологии AZM, докторская школа науки и технологий, Ливанский университет, Триполи, Ливан 

2 Отделение медицинской генетики, факультет медицины, университет Св. Иосифа (USJ), Мар-Микаэл, Бейрут, Ливан
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                    [TEXT] => <p style="text-align: justify;">Простота заготовки мезенхимных стволовых клеток из желе Вортона (МСК-ЖВ), выраженная пластичность дифференцировки и низкая иммуногенность делают их удобным средством аллогенной клеточной терапии. Целью данного исследования было изучение способности к дифференцировке в эндотелиоподобные клетки МСК-ЖВ, культивированных на гиалуронан-хитозановых (ГХ) многослойных носителях.</p>
<h3>Материалы и методы</h3>
<p style="text-align: justify;">В этой работе мы проводили дифференцировку МСК-ЖВ в ангиогенном направлении с применением полиэлектролитной многослойной пленки в качестве субстрата. МСК-ЖВ культивировали на ГХ-многослойной пленке и стимулировали факторами культуральной среды EGM-2®. Коллаген типа I использовали в качестве контрольного субстрата. Определяли экспрессию специфических мРНК, а именно: CD31, рецептора фактора роста сосудистого эндотелия типа 2 (VEGF2) и эндотелиального сосудистого кадхерина (VE), наряду с уровнями абсорбции Dil-ацетилированного липопротеина низкой плотности и экспрессией белкового фактора Виллебранда.</p>
<h3>Результаты</h3>
<p style="text-align: justify;">Выделенные МСК-ЖВ имели типичную морфологию фибробластоподобных клеток. Уровни мРНК, кодирующих CD31 и KDR были выше после культивирования на ГХ-субстрате, нежели на коллагеновом покрытии, при достоверном повышении экспрессии KDR. На уровне белков, показана тенденция к повышению уровней KDR и CDH5 после инкубации на ГХ-субстрате, по сравнению с коллагеном. Кроме того, МСК-ЖВ, культивированные на ГХ, имели высокие уровни экспрессии эндотелиальных маркеров после 15 суток культивирования в среде EGM-2®.</p>
<h3>Выводы</h3>
<p style="text-align: justify;">В данной работе мы сообщаем о новом биосовместимом субстрате, который способствует дифференцировке МСК-ЖВ в эндотелиоподобные клетки. Разработка этого субстрата является новым подходом в тканевой инженерии для создания аллогенных сосудистых трансплантатов. </p>
<h2>Ключевые слова</h2>
<p style="text-align: justify;">Мезенхимные стволовые клетки, желе Вортона, дифференцировка, эндотелий, хитозан, гиалуроновая кислота, многослойный субстрат, тканевая инженерия.</p>
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Простота заготовки мезенхимных стволовых клеток из желе Вортона (МСК-ЖВ), выраженная пластичность дифференцировки и низкая иммуногенность делают их удобным средством аллогенной клеточной терапии. Целью данного исследования было изучение способности к дифференцировке в эндотелиоподобные клетки МСК-ЖВ, культивированных на гиалуронан-хитозановых (ГХ) многослойных носителях.
Материалы и методы
В этой работе мы проводили дифференцировку МСК-ЖВ в ангиогенном направлении с применением полиэлектролитной многослойной пленки в качестве субстрата. МСК-ЖВ культивировали на ГХ-многослойной пленке и стимулировали факторами культуральной среды EGM-2®. Коллаген типа I использовали в качестве контрольного субстрата. Определяли экспрессию специфических мРНК, а именно: CD31, рецептора фактора роста сосудистого эндотелия типа 2 (VEGF2) и эндотелиального сосудистого кадхерина (VE), наряду с уровнями абсорбции Dil-ацетилированного липопротеина низкой плотности и экспрессией белкового фактора Виллебранда.
Результаты
Выделенные МСК-ЖВ имели типичную морфологию фибробластоподобных клеток. Уровни мРНК, кодирующих CD31 и KDR были выше после культивирования на ГХ-субстрате, нежели на коллагеновом покрытии, при достоверном повышении экспрессии KDR. На уровне белков, показана тенденция к повышению уровней KDR и CDH5 после инкубации на ГХ-субстрате, по сравнению с коллагеном. Кроме того, МСК-ЖВ, культивированные на ГХ, имели высокие уровни экспрессии эндотелиальных маркеров после 15 суток культивирования в среде EGM-2®.
Выводы
В данной работе мы сообщаем о новом биосовместимом субстрате, который способствует дифференцировке МСК-ЖВ в эндотелиоподобные клетки. Разработка этого субстрата является новым подходом в тканевой инженерии для создания аллогенных сосудистых трансплантатов. 
Ключевые слова
Мезенхимные стволовые клетки, желе Вортона, дифференцировка, эндотелий, хитозан, гиалуроновая кислота, многослойный субстрат, тканевая инженерия.
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Hana Dennaoui1, Eliane Chouery2, Chaza Harmoush1 
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                    [TEXT] => <p><sup>1</sup> Laboratory of Applied Biotechnology: Biomolecules, Biotherapies and Bioprocesses, AZM Centre for Biotechnology Research and its Applications, Doctoral School of Science and Technology, Lebanese University, Tripoli, Lebanon <br>
<sup>2</sup> Medical Genetics Unit, Faculty of Medicine, Saint Joseph University (USJ), Mar Mikhaël, Beirut, Lebanon</p><br> 
<p><b>Correspondence</b><br>
Dr. Hana Dennaoui, Laboratory of Applied Biotechnology: Biomolecules, Biotherapies and Bioprocesses, AZM Centre for Biotechnology Research and its Applications, Doctoral School of Science and Technology, Lebanese University, El Mitein St, Tripoli, Lebanon<br>
E-mail: hana.dennaoui@hotmail.com</p>
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1 Laboratory of Applied Biotechnology: Biomolecules, Biotherapies and Bioprocesses, AZM Centre for Biotechnology Research and its Applications, Doctoral School of Science and Technology, Lebanese University, Tripoli, Lebanon 

2 Medical Genetics Unit, Faculty of Medicine, Saint Joseph University (USJ), Mar Mikhaël, Beirut, Lebanon

 
Correspondence

Dr. Hana Dennaoui, Laboratory of Applied Biotechnology: Biomolecules, Biotherapies and Bioprocesses, AZM Centre for Biotechnology Research and its Applications, Doctoral School of Science and Technology, Lebanese University, El Mitein St, Tripoli, Lebanon

E-mail: hana.dennaoui@hotmail.com
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                    [TEXT] => <p style="text-align: justify;">The ease of harvesting of mesenchymal stem cells from Wharton’s jelly (WJ-MSCs), their great differentiation plasticity and low immunogenicity make them a suitable tool for allogeneic cell therapy. The aim of present study was to explore the potential of WJ-MSCs seeded on chitosan/hyaluronic acid (HA/CHI) multilayers to differentiate into endothelial-like cells.</p>
<h3>Methods</h3>
<p style="text-align: justify;">In this study, we differentiate WJ-MSCs into an angiogenic lineage using polyelectrolyte multilayer film as a substrate. WJ-MSCs were cultivated on HA/CHI multilayer film and stimulated (or not) with EGM-2® culture medium. Type I collagen was used as control. mRNA and protein expression of CD31, vascular endothelial growth factor-receptor 2 (VEGF2) and vascular endothelial (VE)-cadherin, along with Dil-acetylated low-density lipoprotein-uptake and von Willebrand Factor protein expression were performed.</p>
<h3>Results</h3>
<p style="text-align: justify;">The isolated MSCs showed typical fibroblast-like morphology. We have shown that WJ-MSCs express endothelial markers after 15 days of culture in EGM-2® medium. The mRNA levels were higher on CHI/HA than on collagen for CD31 and KDR, with only KDR increase being statistically significant. At the protein level, a trend for increase in KDR and CDH5 levels was also shown on CHI/HA relative to collagen. Moreover, the WJ-MSCs seeded on CHI/HA showed a high fluorescence specific to von Willebrand factor after endothelial differentiation for 15 days.</p>
<h3>Conclusion</h3>
<p style="text-align: justify;">We report here a new biocompatible coating allowing differentiation of WJ-MSCs into endothelial-like cells. This substrate opens new routes in tissue engineering to design allogeneic vascular grafts.</p>
<h2>Keywords</h2>
<p style="text-align: justify;">Mesenchymal stem cells, Wharton’s jelly, differentiation, endothelial lineage, chitosan, hyaluronic acid, multilayer substrate, tissue engineering. </p>
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The ease of harvesting of mesenchymal stem cells from Wharton’s jelly (WJ-MSCs), their great differentiation plasticity and low immunogenicity make them a suitable tool for allogeneic cell therapy. The aim of present study was to explore the potential of WJ-MSCs seeded on chitosan/hyaluronic acid (HA/CHI) multilayers to differentiate into endothelial-like cells.
Methods
In this study, we differentiate WJ-MSCs into an angiogenic lineage using polyelectrolyte multilayer film as a substrate. WJ-MSCs were cultivated on HA/CHI multilayer film and stimulated (or not) with EGM-2® culture medium. Type I collagen was used as control. mRNA and protein expression of CD31, vascular endothelial growth factor-receptor 2 (VEGF2) and vascular endothelial (VE)-cadherin, along with Dil-acetylated low-density lipoprotein-uptake and von Willebrand Factor protein expression were performed.
Results
The isolated MSCs showed typical fibroblast-like morphology. We have shown that WJ-MSCs express endothelial markers after 15 days of culture in EGM-2® medium. The mRNA levels were higher on CHI/HA than on collagen for CD31 and KDR, with only KDR increase being statistically significant. At the protein level, a trend for increase in KDR and CDH5 levels was also shown on CHI/HA relative to collagen. Moreover, the WJ-MSCs seeded on CHI/HA showed a high fluorescence specific to von Willebrand factor after endothelial differentiation for 15 days.
Conclusion
We report here a new biocompatible coating allowing differentiation of WJ-MSCs into endothelial-like cells. This substrate opens new routes in tissue engineering to design allogeneic vascular grafts.
Keywords
Mesenchymal stem cells, Wharton’s jelly, differentiation, endothelial lineage, chitosan, hyaluronic acid, multilayer substrate, tissue engineering. 
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            [IBLOCK_ID] => 2
            [NAME] => PDF ENG
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => PDF_EN
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => F
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 44
            [FILE_TYPE] => doc, txt, rtf, pdf
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => 
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 27394
            [VALUE] => 2345
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 2345
            [~DESCRIPTION] => 
            [~NAME] => PDF ENG
            [~DEFAULT_VALUE] => 
        )

    [NAME_LONG] => Array
        (
            [ID] => 45
            [TIMESTAMP_X] => 2023-04-13 00:55:00
            [IBLOCK_ID] => 2
            [NAME] => Название (для очень длинных заголовков)
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => NAME_LONG
            [DEFAULT_VALUE] => Array
                (
                    [TYPE] => HTML
                    [TEXT] => 
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 45
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 80
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 
            [VALUE] => 
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 
            [~DESCRIPTION] => 
            [~NAME] => Название (для очень длинных заголовков)
            [~DEFAULT_VALUE] => Array
                (
                    [TYPE] => HTML
                    [TEXT] => 
                )

        )

)