CN116785500A - Degradable polymer tissue engineering scaffold and preparation method and application thereof - Google Patents
Degradable polymer tissue engineering scaffold and preparation method and application thereof Download PDFInfo
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- CN116785500A CN116785500A CN202310879743.XA CN202310879743A CN116785500A CN 116785500 A CN116785500 A CN 116785500A CN 202310879743 A CN202310879743 A CN 202310879743A CN 116785500 A CN116785500 A CN 116785500A
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- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/28—Materials for coating prostheses
- A61L27/34—Macromolecular materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/225—Fibrin; Fibrinogen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/52—Hydrogels or hydrocolloids
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/60—Materials for use in artificial skin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
- A61L2300/254—Enzymes, proenzymes
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/606—Coatings
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Abstract
The invention discloses a preparation method of a degradable polymer tissue engineering scaffold, which comprises the following steps: taking a hydrogel dressing based on chitin derivatives with the thickness of 2-8 mm as an active polymer layer, wherein the porosity in the active polymer layer is 1-90%, and the pore size is 100-4000 mu m; preparing an absorbent layer on the active polymer layer, wherein the absorbent layer is selected from at least one of hydrophilic fiber layer, alginate layer, semipermeable polyurethane film and hydrocolloid layer to obtain active polymer layer-absorbent layer; and (3) sequentially and uniformly spraying a mixed solution of human serum albumin and silk fibroin, thrombin and a fibrin solution on the surface of the active polymer layer-absorbing layer to form a mesenchymal stem cell attaching layer, so as to obtain the degradable polymer tissue engineering scaffold. The special skin stent system produced by the invention has extremely high biocompatibility, has no rejection reaction after transplantation, and can fully ensure the use safety of the composite skin stent.
Description
Technical Field
The invention belongs to the field of tissue regeneration medicine, and particularly relates to a degradable polymer tissue engineering scaffold, and a preparation method and application thereof.
Background
Chitin derivatives (chitin polyesters) are obtained by chitin esterification in the presence of aliphatic and cyclic anhydrides and certain hydroxy acids. Chitin from which calcium carbonate has been previously removed is acylated in the presence of a selected catalyst (simultaneously as a reaction medium) and a selected anhydride or hydroxy acid. Chitin may be esterified at one or both positions. Chitin substituents may be derivatives of hydroxy acids (lactic acid, glycolic acid), straight-chain saturated aliphatic anhydrides (chain length of the acidic residue from C2 to C8, for example from acetic anhydride to octenic anhydride and from anhydrides such as acetic anhydride, butenoic anhydride), branched aliphatic unsaturated anhydrides (methacrylic anhydride, 2-butenoic anhydride) or cyclic anhydrides (maleic anhydride, glutaric anhydride, succinum anhydride, phthalic anhydride). Chitin may be substituted at one or two positions using one or two substituents of the same or different chain lengths.
In the case of leaching (leaching), the "chitin derivative" is a chitin polyester produced in the chitin esterification reaction in the presence of a catalyst and a linear saturated aliphatic anhydride having an acidic residual chain of C2 to C8 (e.g., from acetic anhydride to octen anhydride and from anhydrides such as acetic anhydride, butyric anhydride-propionic anhydride), branched unsaturated fatty anhydride (e.g., methacrylic anhydride, 2-butenoic anhydride) or cyclic anhydride (glutaric anhydride, sedge anhydride, phthalic anhydride).
Chitin and chitosan act as chemoattractants for macrophages or neutrophils, thereby initiating the healing process and stimulating the process of re-formation of granulation and epithelium while limiting scar formation. In addition, chitin and its derivatives have antibacterial and antifungal properties themselves. It is presumed that the cationic group bound to the anion of the bacterial cell wall inhibits biosynthesis, and that chitin damages molecular trafficking of the bacterial cell wall and accelerates death thereof.
The chitin and the derivatives thereof have the following advantages in regenerative medicine:
(1) The biocompatibility is high, and cell communication and tissue regeneration can be induced;
(2) Has more proper mechanical and physical properties;
(3) Biodegradability: gradually degrading at a proper rate not exceeding the regeneration and remodeling rate of the damaged wound surface, and not inducing immune response; the degradation products are nontoxic. The process is an enzymatic hydrolysis reaction based on acetyl residues (mainly in vivo lysozyme);
(4) Can be used for stem cells and other cells to adhere, proliferate, migrate and differentiate (the polymer can be combined with growth factors, mucin, serum protein, fibrin, thrombin and the like to promote cell attachment and hemostasis of wound surfaces), and promote stem cell migration in the culture process and the like;
(5) Chitin and its derivatives have certain physical antibacterial ability, and can be combined with antibiotics and chemical antibacterial agents to avoid wound infection, thus having important significance for wound healing difficult to cure;
(6) Chitin and its derivative polysaccharide can be used as carrier of medicine, and can ensure sustained release of medicine.
At present, severe burn treatment still mainly uses skin grafting, and is mainly carried out by adopting autologous skin, but when the wound area is large, the supply of autologous skin is limited, so that the medical requirement cannot be met, and because the autologous skin is transplanted and is realized by relying on surgery, the pain of a patient during treatment is increased, the healing of the wound of the patient is not facilitated, in addition, although the skin replacement product which is already appeared on the market and is used for clinic is used, the biological compatibility of the skin replacement product is poor, a strong immune response is induced, or animal or human perinatal waste tissues which are difficult to trace source exist in raw materials, and the like, so that certain potential safety hazards exist, large-scale industrial production cannot be carried out, and the market popularization progress of similar products is seriously imaged.
Disclosure of Invention
The primary object of the present invention is to provide a degradable polymer tissue engineering scaffold.
Still another object of the present invention is to provide a method for preparing the degradable polymer tissue engineering scaffold.
It is another object of the present invention to provide the use of the degradable polymeric tissue engineering scaffold described above.
The invention is realized in such a way that a preparation method of the degradable polymer tissue engineering scaffold comprises the following steps:
(1) Taking a hydrogel dressing based on chitin derivatives with the thickness of 2-8 mm as an active polymer layer, wherein the porosity in the active polymer layer is 1-90%, and the pore size is 100-4000 mu m;
(2) Preparing an absorbent layer on the active polymer layer, wherein the absorbent layer is selected from at least one of hydrophilic fiber layer, alginate layer, semipermeable polyurethane film and hydrocolloid layer to obtain active polymer layer-absorbent layer;
(3) And sequentially and uniformly spraying the human serum albumin, silk fibroin, thrombin and fibrin solution on the surface of the active polymer layer-absorbing layer to form a mesenchymal stem cell attaching layer, thereby obtaining the degradable polymer tissue engineering scaffold.
Preferably, the chitin derivative is selected from any one of hydroxy acid, linear saturated aliphatic anhydride, branched aliphatic unsaturated anhydride and cyclic anhydride;
the mixture of chitin derivatives is two or more chitin derivatives or the combination of chitin derivatives and other biocompatible and biodegradable polymers, wherein the polymers are at least one selected from polylactide, polyethylene glycol and 3-hydroxybutyrate polyester.
Preferably, the hydroxy acid is lactic acid or glycolic acid; the acid group chain length of the straight-chain saturated aliphatic acid anhydride is C2-C8, and is selected from any one of acetic anhydride, octenyl anhydride, acetic acid-propionic anhydride and butyric acid-propionic anhydride; the branched aliphatic unsaturated anhydride is methacrylic anhydride or 2-butenoic anhydride; the cyclic anhydride is selected from any one of maleic anhydride, glutaric anhydride, succinum anhydride and phthalic anhydride.
Preferably, in step (3), the spraying process includes the steps of: uniformly spraying a mixed solution containing 1 ug/mL-100 mg/mL of human serum albumin and 0.1-100mg/mL of silk fibroin on the surface of a polymer layer-absorbing layer for 5-60 s at a rate of 0.1-2 mL/s, uniformly spraying a solution containing 0.1-000U/mL of human thrombin at a rate of 0.1-2 mL/s after the material of the layer is basically dried, uniformly spraying a solution containing 0.2-5.0 mg/mL of fibrinogen at a rate of 0.1-2 mL/s after intervals of 5-5 h, standing at 37 ℃ for 5 min-5 h, and drying.
The invention further discloses the degradable polymer tissue engineering scaffold obtained by the preparation method.
The invention further discloses application of the degradable polymer tissue engineering scaffold in preparation of a damaged wound regeneration remodelling drug or a drug carrier.
The invention further discloses a composite tissue engineering scaffold system, which comprises the degradable polymer tissue engineering scaffold and stem cells loaded and combined on the degradable polymer tissue engineering scaffold.
The invention further discloses application of the composite tissue engineering scaffold system in preparing wound healing medicaments and/or skin and tissue regeneration medicaments.
The invention overcomes the defects of the prior art and provides a degradable polymer tissue engineering scaffold and a preparation method and application thereof. The hydrogel dressing based on chitin derivatives with the thickness of 2-8 mm is used as an active polymer layer, wherein the porosity in the active polymer layer is 1-90%, and the pore size is 100-4000 mu m; secondly, preparing an absorption layer on the active polymer layer, wherein the absorption layer is at least one selected from a hydrophilic fiber layer, an alginate layer, a semi-permeable polyurethane film and a hydrocolloid layer, so as to obtain an active polymer layer-absorption layer; and finally, sequentially and uniformly spraying the human serum albumin, silk fibroin, thrombin and fibrin solution on the surface of the active polymer layer-the absorbing layer to form a mesenchymal stem cell attaching layer, so as to obtain the degradable polymer tissue engineering scaffold.
The active polymer layer is a biocomposite based on one or more chitin derivatives (0.1-100 vol%) or a mixture of chitin derivatives (two or more chitin derivatives or chitin derivatives combined with other commonly available biocompatible, biodegradable polymers such as polylactide (polylactic), polyethylene glycol, 3-hydroxybutyrate polyester, etc.). Chitin derivatives refer to compounds derived from hydroxy acids (such as lactic acid, glycolic acid), linear saturated aliphatic anhydrides (acid group chain length C2-C8), (e.g., from acetic anhydride to octenic anhydride and from anhydrides such as acetic anhydride, butyric anhydride-propionic anhydride), branched aliphatic unsaturated anhydrides (e.g., methacrylic anhydride, 2-butene anhydride) or cyclic anhydrides (maleic anhydride, glutaric anhydride, succinum anhydride, phthalic anhydride). Chitin derivatives can undergo substitution reactions with one or two substituents of different lengths via one or two of their sites. The active polymer layer has a three-dimensional structure (including pores (straight or coiled) with a diameter of 0.1mm to 4.0mm, the ratio of pores in the dressing material being 1 to 90% by volume depending on the type of wound or the formation of pores of different sizes). The active polymer layer may further incorporate an absorbent layer that aids in wound repair.
In addition, the dressing properties of the active polymer layer can also be directly made into hydrogels with suspended chitin derivatives or their mixture molecules, which store large amounts of water (5-85 vol%) and can be directly applied to the wound surface, which due to their hydrophilic properties can ensure concentrated moisture retention and hydration of dry wounds and only absorb and bind wound exudates in a small range, which can be used for wounds without large areas of exudates. This type of active polymer layer dressing can be used to cover areas where skin is removed during skin grafting where secondary burns and abrasions have been covered.
The absorbent layer may be at least one of hydrophilic fiber layer, alginate layer, semipermeable polyurethane film, and hydrocolloid layer according to functional requirements.
(1) Hydrophilic fiber layer
Based on carboxymethyl cellulose (or other cellulose derivatives having similar physical and chemical properties), the cellulose derivatives are contained in an amount of from 5 to 100% by volume, the layer thicknesses are from 0.1 to 5.0mm, the shape and size depending on the inner layer, are compressed into a plate in the form of hydrophilic fibers. The hydrophilic fibrous layer contacts the wound exudate to form a gel coat, wherein the exudate is absorbed and trapped within the fibrous structure of the hydrophilic fibrous layer, thereby eliminating pathogenic bacteria. The hydrophilic fibrous layer is preferentially suitable for use on high risk infection wounds where large amounts of exudates are present. In addition, silver ions (0.1-2 vol%) may be added to provide bacteriostatic function to the hydrophilic fiber layer.
(2) Alginate layer
Based on alginate layer-calcium and sodium-calcium alginate obtained from alginic acid (D-mannuronic acid and L-glucuronic acid) sodium-calcium derivatives and polymers obtained from marine brown algae (GG, MM, MG blocks; L-glucuronic acid 25-85 vol%, mannuronic acid 20-70 vol%, glucuronic acid percentage content exceeding mannuronic acid percentage content; calcium ion content 0.1-10.0 vol%, sodium ion content 0.1-2.0%). The alginate layer is prepared from a compressed form of fibers. When wound exudate is absorbed, a gel incorporating the exudate forms around the fibers. The phenomenon of gelation is based on the exchange of calcium ions on the surface of the fibres and sodium ions in the exudates, and alginate layers can be used for moderate and severe exuding wounds.
(3) Semipermeable polyurethane membrane
Polyurethane content of 15-100% by volume and layer thickness of 0.1-5.0 mm, forms a barrier (waterproof) against microorganisms and water and allows the evaporation of gases from the wound surface while ensuring a moist, surface-dried wound environment and easy removal from direct contact with the wound. Thus, semipermeable polyurethane membranes are suitable for use in both light and medium exudation wounds.
(4) Hydrocolloid layer
The hydrocolloid layer is in the form of a plate and comprises an outer protective layer and an inner layer. The outer protective layer is semipermeable (for the purpose of protecting against contamination and invasion by pathogenic microorganisms) and the inner layer comprises a mixture of hydrophilic molecules (ensuring a suitable humidity) and gums (ensuring a slightly acidic pH) of carboxymethylcellulose (sodium carboxymethylcellulose and other types of carboxymethylcellulose) suspended in the hydrophobic pectin. During contact with wound exudate, the hydrocolloid layer swells and becomes a gel due to interactions of increasing molecules. The free space is filled with the absorbed exudates, which coagulates into a homogeneous viscous gel system. The hydrocolloid layer maintains a moist wound environment, constant temperature and slightly acidic pH conditions (lowering pain, acidic pH reduces prostaglandin production by PGE2 which sensitizes nerve endings). Hydrocolloid layers can be used for slightly and moderately exuding wounds.
The invention has the combined treatment effect by adopting the degradable polymer combined stem cell technology, and aims at the healing capability of the wound surface difficult to heal such as deep third-degree burn and the like. Because chitin is cationic and it mediates primarily electrostatic binding to anionic glycosaminoglycans (GAGs), proteoglycans, and other negatively charged molecules. And the mesenchymal stem cells can secrete a large amount of cytokines/growth factors, can be directly combined with GAG and are highly enriched and repaired on the surface of the material, so as to assist the stem cells to promote the orderly regeneration of surrounding tissues.
The invention has the inherent antibacterial effect, simultaneously allows the combination and the controlled release of exogenous antibacterial factors, has the interactive influence of the antibacterial effect of the chitin and the tissue anti-inflammatory effect of the MSC, has double effects on anti-infection and promoting tissue healing, and has obvious advantages compared with similar competitive products (polymer nets).
Compared with the defects and shortcomings of the prior art, the invention has the following beneficial effects:
(1) The invention adopts three spraying processes, and evenly sprays the mixed solution of the human serum albumin and the silk fibroin with controllable dosage, thrombin and the fibrin solution on the surface of the absorption layer of the degradable polymer tissue engineering bracket respectively. On the one hand, the protective layer is favorable for stem cell attachment proliferation, and on the other hand, when the skin bracket is attached to a wound, wound surface protection (prevention of tissue fluid exudation) can be realized through human serum albumin on the skin bracket, so that the wound ulcer incidence rate is reduced, meanwhile, nutrients can be provided for damaged tissues, the healing of the wound is promoted, and when the skin bracket is attached to the wound, the hemostatic effect on the damaged part can be realized through the residual thrombin activity on the skin bracket and the effect of a fibrin source in blood of a patient. Silk fibroin can increase the flexibility of the scaffold to some extent.
(2) After the composite bracket material which is independently stored and the stem cell culture solution are soaked before the invention is used, stem cells from different sources can be carried and attached to the composite bracket material, so that better burn treatment effect is realized, the 'painful situation' that patients suffering from deep third-degree large-area burns rely on repeated skin grafting is solved, the operation difficulty and treatment cost of the patients are greatly reduced, and the healing effect of the tissue of the deep third-degree burns can be remarkably improved. Due to the existence of stem cells, specific connective tissues such as epidermis, dermis, blood vessels and the like can be locally induced to be orderly differentiated to form smaller scars, and meanwhile, the regeneration of special skin structures such as hair follicle sweat glands and the like can be promoted; finally, the regenerated skin with physiological functions is formed.
(3) The skin bracket attached to the wound has activity, so that the skin bracket can be attached to the wound part of the human body and can be integrated with the skin of the human body for a period of time, the permanent repair of the wound part is realized, the traditional repair process of multiple skin grafting is avoided, and the composite skin bracket can relieve the pain of patients born by repeated skin grafting.
(4) The material used in the invention has wide sources, is common inorganic and organic compounds, has low cost, is convenient for large-scale production, and effectively reduces the contradiction between skin supply and demand; in addition, the composite skin stent has the advantages of convenient material taking, simple manufacturing process, convenient operation of medical staff, convenient storage and transportation, commercial preparation and clinical application.
(5) The special skin stent system produced by the invention has extremely high biocompatibility (the attached MSC is also a low-immunogenicity cell), has no rejection reaction after transplantation, and can fully ensure the use safety of the composite skin stent.
(6) Experiments of deep third degree burn of large animals prove that the invention can promote the effective regeneration of advanced skin structures such as hair follicles by combining stem cells.
(7) The addition of silk proteins in the present invention can improve the flexibility of the polymeric material to some extent.
Drawings
FIG. 1 is a graph showing the effect of the degradable tissue engineering dressing (unbound MSC) of the invention on promoting wound healing; wherein A: dressing application wound surface, B: the dressing is highly fused with the wound surface;
FIG. 2 is a process of stem cell binding to scaffolds; wherein FIGS. 2A-B are activation of scaffolds, without seeding cells; FIGS. 2C-D are views showing the state after seeding cells;
FIG. 3 is a graph showing the synergistic improvement of deep third degree burn treatment effect of a degradable tissue engineering scaffold in combination with MSC; wherein. Left diagram: evaluation of efficacy of degradable tissue engineering scaffolds without MSC on deep third-degree burn model pigs (relatively few new hair); right figure: and evaluating the curative effect (hair regeneration induction) of the pig model of deep third-degree burn by combining the degradable tissue engineering scaffold of the MSC.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Example 1
The preparation of the active polymer layer of this example is the same as that described in example 1 of reference CN 104582745A, and comprises the following steps:
the active polymer layer is produced from a chitin derivative obtained by esterification with propionic anhydride (the concentration percentage of chitin derivative in the dressing is 100%). The derivative chitin, dissolved in acetone at a concentration of 10 to 30%, is poured through a nozzle of 2 to 8mm in diameter at a rate of 1 to 3 liters/min onto a flat non-absorbing surface (in the form of a belt) of 0.5 to 1.0 m/min at a constant transport rate and 100mm in width. Once the polymeric tapes are cured, the holes can be formed with a prepared stamp (needle size from 0.098 to 3.98 mm) in different routes, sizes and arrangement densities and shapes, thereby obtaining polymeric tapes with shapes that depend on the type and purpose of the dressing.
As a result of this process, an active polymer layer is produced which has a three-dimensional porous or non-porous structure (in the case of porous structures, the diameter of the pores is 0.1mm to 4.0mm, straight or coiled, or mixed-size pores, the percentage of pores in a single dressing being from 1 to 90%).
The prepared active polymer is immersed in a solution of the excipient and then absorbed from the solution by evaporating the solvent to be additionally impregnated with the excipient or other sterilizing substance. The active polymer layer is impregnated with an excipient, for example Ag in an amount of 0.01% + Ion, 0.01% Ca 2+ Ions. The active polymer is also impregnated with neomycin, bactericide and antibiotic having antibacterial properties.
The technical parameters characterizing a single layer dressing depend on the active polymer layer thickness and porosity:
oxygen permeability (cm) 3 /m 2 )：1000～9000；
Elongation percentage: 0.5-400%;
tensile Strength (kg/cm) 2 )：1～200；
PBS absorptivity (0.2-50 g PBS/24h/100 cm) 2 Dressing).
Example 2
The preparation of the active polymer layer of this example is the same as that described in example 2 of reference CN 104582745A, and comprises the following steps:
the active polymer layer was produced by mixing three chitin derivatives (acetic acid derivative 10%, valeric acid derivative 10% and butyric acid derivative 80%). On a flat non-absorbing surface (in the form of a belt) of width 100mm at a constant transport rate of 0.5-1.0 m/min by means of a nozzle of diameter 2-8 mmThe dissolved polymer mixture to which the excipient (described below) having a concentration of 5 to 30% in ethanol was added was poured at a rate of 0.5 to 3 liters/min. Next, after the poured layer cures, a living polymer is formed. The active polymer obtained is formed into a shape depending on the type and purpose of the dressing. The active polymer layer is impregnated with an excipient, such as K + Ion, citric acid in an amount of 1.5%, bismuth salt in an amount of 0.001%. The living polymer is also impregnated with bacteriocidal agents: vancomycin (0.1%).
The technical parameters characterizing a single layer dressing depend on the active polymer layer thickness and porosity:
oxygen permeability (cm) 3 /m 2 )：500～3000；
Elongation percentage: 0.5-500%;
tensile Strength (kg/cm) 2 )：1～200；
PBS absorptivity (0.2-50 g PBS/24h/100 cm) 2 Dressing).
Example 3
The preparation process of the active polymer layer-absorbent layer of this example comprises the following specific steps:
the active polymer layer is made of a mixture of three chitin derivatives (obtained by sequentially chitin esterification with the following anhydrides: 20% of propane acetate, 40% of butane propane and 20% of methacrylic acid), combined with a widely available biocompatible biodegradable polymer polyethylene glycol (polyethylene glycol percentage 20%). The active polymer layer was prepared and impregnated with excipients as described in example 1. The active polymer layer 1 was impregnated with 2.5% by mass of Ag + Ion, 0.1% K + Ion, bismuth salt in an amount of 0.1%. The living polymer 1 is also saturated with metronidazole (0.3%).
The absorbent layer is bonded to the active polymer layer 1 by a peripheral adhesive system (polyethylene adhesive) to give an active polymer layer-absorbent layer. Wherein the absorbent layer is made of hydrophilic fibers that are commercially available.
Example 4
The preparation process of the active polymer layer-absorbent layer of this example comprises the following specific steps:
the active polymer layer is made of a mixture of three chitin derivatives (obtained by successive chitin esterification reactions with the following anhydrides: 20% of propane acetate, 40% of succinate and 20% of phthalate), combined with a widely obtained biocompatible biodegradable polymer polyethylene glycol (polyethylene glycol percentage 20%). The active polymer layer was prepared and impregnated with excipients as described in example 1. The active polymer layer was impregnated with Ag in an amount of 2.5% + Ion, ca in an amount of 1.0% 2+ Ion, 0.1% Zn 2+ Ions. The living polymer 1 is also saturated with metronidazole (0.3%).
The absorbent layer is bonded to the active polymer layer by a peripheral adhesive system 2 (polyethylene adhesive). The absorbent layer is made of alginate.
Example 5
The preparation of the degradable polymer tissue engineering scaffold comprises the following steps:
uniformly spraying a mixed solution containing 1 ug/mL-100 mg/mL of human serum albumin and 0.1-100mg/mL of silk fibroin on the surface of the active polymer layer-absorbing layer prepared in the embodiment 3, uniformly spraying the solution containing 0.1-1000U/mL of human thrombin at a uniform speed at a flow speed of 0.1-2 mL/s after the layer of material is basically dried, spraying the solution containing 0.2-5.0 mg/mL of fibrinogen at a constant speed of 0.1-2 mL/s after intervals of 5 min-5 h, standing at 37 ℃ for 5 min-5 h, and drying to obtain the degradable polymer tissue engineering scaffold 1.
Example 6
24 hours before transplanting to a patient, preparing a composite tissue engineering scaffold system, wherein the preparation process specifically comprises the following steps:
(1) Pretreatment of degradable polymer tissue engineering scaffold
The degradable polymer tissue engineering scaffold prepared in the above example 5 is cut according to the required size and placed in a cell culture dish with different specifications (the absorption layer after the stem cell attaching solution is sprayed upwards), and a proper amount of commercial (gentamycin-containing) professional culture medium (goods number: LF-BIO, MSCM CatNo: LF0101A with 2-5% serum substitute) is added for soaking for 5 min-5 h.
(2) Mesenchymal Stem Cell (MSC) culture
Umbilical cord mesenchymal stem cells (also can use autologous bone marrow of a patient, MSC from fat sources or iPS cells from somatic cell transdifferentiation sources) obtained through primordial separation or commercial purchase are cultured to a logarithmic growth phase, and are prepared into single-cell suspension through pancreatin digestion treatment, after centrifugation at 1000rpm/min, 1mL of commercial professional culture medium (goods No. LF-BIO, MSCM CatNo: LF0101A is added with 2-5% serum substitutes) is resuspended, and the mixture is kept stand at 37 ℃ for standby.
(3) Preparation of composite tissue engineering scaffold system (Stem cell attached tissue engineering scaffold)
Uniformly planting the resuspended MSC on the surface of the pretreated tissue engineering scaffold stem cell attaching layer (avoiding the cells from falling into other areas of the culture dish as much as possible), and then placing at 37 ℃ and 5 vol% CO 2 Is cultured for 24 hours in a static culture box.
Application example 1
The degradable polymer tissue engineering scaffold obtained in the embodiment 3 of the invention is attached to the surface of a large-area burn of a patient, the inflammatory reaction of the wound surface is controlled after 3 days, the surface and the tissue are highly fused, and the tissue regeneration locally occurs, as shown in figure 1.
The visible light and laser confocal microscope of the degradable polymer tissue engineering scaffold obtained in the embodiment 3 of the invention proves that Mesenchymal Stem Cells (MSC) can grow attached to the surface of the scaffold, as shown in figure 2.
Application example 2
The composite tissue engineering scaffold system prepared in the example 6 is applied to a large animal deep third degree burn model (pig), and the result is shown in fig. 3, so that the system can effectively promote tissue wound healing and induce regeneration of skin accessory structures such as hair follicles, and the treatment effect is better than that of a pure scaffold product without stem cells.
Application example 3
The composite tissue engineering scaffold system in the sterile culture in the embodiment 6 is carefully taken out by forceps in the sterile environment of an operating room, an absorption layer carrying stem cells is taken as a bottom surface and is uniformly attached to a wound part after debridement treatment, and the composite tissue engineering scaffold system can replace skin transplantation and meet the treatment requirement of patients suffering from deep three-degree large-area burns.
It should be noted that, deep three-degree and above burn wounds, charring of connective tissue occurs mostly, and for such patients, charred tissues and surrounding tissues need to be thoroughly removed, fresh tissues are fully exposed, after appropriate hemostatic treatment, a stem cell tissue engineering scaffold is attached to the treated wounds, and the wounds are timely wrapped by combining hemostatic sponge and vaseline gauze, but excessive adhesion of the dressings and the wounds needs to be avoided. In the process of wound healing, dressing such as gauze is replaced regularly, wound healing conditions are checked in time, if the wound healing conditions are absorbed too fast by a bracket, the dressing can be considered to be applied again, but in general, the dressing of the same wound part is carried out for less than 3 times, and the wound healing can be realized.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (8)
1. The preparation method of the degradable polymer tissue engineering scaffold is characterized by comprising the following steps of:
(1) Taking a hydrogel dressing based on chitin derivatives with the thickness of 2-8 mm as an active polymer layer, wherein the porosity in the active polymer layer is 1-90%, and the pore size is 100-4000 mu m;
(2) Preparing an absorbent layer on the active polymer layer, wherein the absorbent layer is selected from at least one of hydrophilic fiber layer, alginate layer, semipermeable polyurethane film and hydrocolloid layer to obtain active polymer layer-absorbent layer;
(3) And sequentially and uniformly spraying the human serum albumin, silk fibroin, thrombin and fibrin solution on the surface of the active polymer layer-absorbing layer to form a mesenchymal stem cell attaching layer, thereby obtaining the degradable polymer tissue engineering scaffold.
2. The method according to claim 1, wherein the chitin derivative is selected from any one of hydroxy acid, linear saturated aliphatic acid anhydride, branched aliphatic unsaturated anhydride, and cyclic anhydride;
the mixture of chitin derivatives is two or more chitin derivatives or the combination of chitin derivatives and other biocompatible and biodegradable polymers, wherein the polymers are at least one selected from polylactide, polyethylene glycol and 3-hydroxybutyrate polyester.
3. The method of claim 2, wherein the hydroxy acid is lactic acid or glycolic acid; the acid group chain length of the straight-chain saturated aliphatic acid anhydride is C2-C8, and is selected from any one of acetic anhydride, octenyl anhydride, acetic acid-propionic anhydride and butyric acid-propionic anhydride; the branched aliphatic unsaturated anhydride is methacrylic anhydride or 2-butenoic anhydride; the cyclic anhydride is selected from any one of maleic anhydride, glutaric anhydride, succinum anhydride and phthalic anhydride.
4. The method of claim 1, wherein in step (3), the spraying process comprises the steps of: uniformly spraying a mixed solution containing 1 ug/mL-100 mg/mL of human serum albumin and 0.1-100mg/mL of silk fibroin on the surface of a polymer layer-absorbing layer for 5-60 s at a rate of 0.1-2 mL/s, uniformly spraying a solution containing 0.1-000U/mL of human thrombin at a rate of 0.1-2 mL/s after the material of the layer is basically dried, uniformly spraying a solution containing 0.2-5.0 mg/mL of fibrinogen at a rate of 0.1-2 mL/s after intervals of 5-5 h, standing at 37 ℃ for 5 min-5 h, and drying.
5. A degradable polymer tissue engineering scaffold obtained by the method of any one of claims 1 to 4.
6. The use of the degradable polymer tissue engineering scaffold of claim 5 in the preparation of a drug or drug carrier for damaged wound regeneration and remodeling.
7. A composite tissue engineering scaffold system comprising the degradable polymer tissue engineering scaffold of claim 5 and stem cells loaded on the degradable polymer tissue engineering scaffold.
8. The use of the composite tissue engineering scaffold system of claim 7 in the preparation of wound healing medicaments and/or skin and tissue regeneration medicaments.
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