Bioactive complex for organogenesis

FIELD: medicine, in particular bioactive complex for organogenesis.

SUBSTANCE: claimed complex represents multicomponent, bulk, three-dimensional structure, containing human allogene mesenchyme and epithelial cells and at least one layer of biocompatible polymer in form of collagen structure on network matrix. Biological complex of present invention is useful in regenerative and reparative reconstruction of any biological structures of mesemchyme-epothelial or mesodermal and ectodermal origin. Also disclosed are unified method for rebuilding of three-dimensional tissue defects and effective method for treatment of various gullet, urinary bladder parries, skin, gorge, eardrum, kidney, etc. defects. Complex also may be used in production of donor tissue equivalent bank.

EFFECT: active complexes for organogenesis useful in medicine.

3 ex, 1 dwg, 24 cl

 

The invention relates to medicine, namely to the active complexes biological purposes for use in obtaining a biological structure that possesses regenerative and reparative properties. This complex can be used to restore the body lost cells and partial reimbursement of living tissue organs and skin while restoring a deep three-dimensional defects mesenchyme-epithelial or mesoderm and ectodermal origin. In particular, this complex can be used for recovery of the esophagus, the walls of the bladder, skin burns, trophic ulcers and wounds of any etiology, recovery of the conjunctiva and orbit of the eye, the nasal septum, middle ear, kidney, internal sex organs, etc.

Known active complex biological products, including the component patterns representing a biodegradable polymer, component activation and formation, representing a chemotactic substance, and component growth (GB N 2215209 But, 1989). Known active complex is used for removing the biological defects and contains biodegradable polymer, component activation and formation, representing a chemotactic substance, and component height.

is the most closest analogue to the claimed invention is a biologically active complex used for organogenesis due to the "immigration" of cells from the surrounding complex of tissue in the component of its structure after transplantation of such a complex in the body. For this component of the structure of such a complex component includes growth and component adhesion (EN 2093191).

The disadvantage of all of these analogues is their narrow purpose and the inability to restore the defects of biological structures with mesenchyme-epithelial or mesoderm and ectodermal nature. As the common disadvantages of these methods are relatively low efficiency of recovery of defects depths less than 0.5 cm and the inability to reconstruct the three-dimensional defects of the skin depth of more than 0.5 cm, and the difficulty of fixation of the graft at the complex configurations of tissue defects.

The objective of the invention is the creation of a biologically active complex, suitable for regenerative and reparative any reconstruction of biological structures with mesenchyme-epithelial or mesoderm and ectodermal origin, creating a unified method of recovering three-dimensional tissue defects and to improve the efficiency of treatment of patients with various defects of the esophagus, the walls of the bladder, skin, larynx, trachea, kidney, internal genital the of lanov, the conjunctiva and orbit of the eye, the nasal septum, nasopharynx and the middle ear, etc.

To solve this problem developed biologically active complex based on macromolecular three-dimensional matrix comprising at least one component of the structure, at least one component activation and formation process of regeneration and/or repair tissue, at least one component of the growth and maturation of cells of the tissue.

This biological active complex can be produced commercially on an industrial scale to create a Bank of equivalents of donor tissue.

The invention consists in the creation of a biologically active complex for organogenesis, representing a multi-component, three-dimensional structure containing allogeneic cells of the mesenchyme and epithelium of the person and at least one layer of biocompatible polymer in the form of a mesh matrix with cell sizes from 1 to 5 mm, and preferably from 1 to 3 mm, within the collagen structure.

This biologically active complex is characterized by the fact that collagen structure made in the form of a collagen gel or sponge or mesh structure. At the same time as the collagen gel structure contains 0.1 to 0.15% solution of collagen in 0.1% acetic acid, and preferably 0,1-0,12%.

When this is active biological complex differs he further comprises cells of the mesoderm and/or ectodermal origin. Active biological complex characterized in that it further comprises autologous cells of the mesenchyme and/or epithelium of the person. The cells of the mesenchyme person pre-cultivated on collagen microsites.

Collagen gel contains a ten-fold concentrate of culture medium "199" in the amount of from 7% to 40% by volume, and preferably from 10% to 20%, glutamine in an amount of from 0.1 to 1 mg/ml of gel, and preferably from 0.1 to 0.4 mg/ml, sodium bicarbonate in an amount of from 0.1 to 1 mg/ml of gel, and preferably from 0.25 to 0.4 mg/ml, phosphate buffer in an amount of from 0.01 to 0.1 mg/ml by volume, and preferably from 0.01 to 0.05 mg/ml While biologically active complex is characterized by the fact that collagen gel further comprises a matrix proteins. As matrix proteins can be used fibronectin and/or laminin, and/or protein in a concentration of from 0.1 to 100 µg/ml, and preferably from 1 to 5 μg/ml Collagen gel also contains growth factors. As growth factors can be used epidermal growth factor, and/or fibroblast growth factor, and/or transforming growth factor - α and βand/or a growth factor secreted by platelets, and/or a growth factor for hepatocytes in con is entrace from 1-300 ng/ml, and preferably from 1 to 100 ng/ml Also collagen gel further comprises antiseptics. As an antiseptic can be used ions of silver, copper and gold. Advanced collagen gel contains antibiotics. As the antibiotic can be used gentamicin at a concentration of from 0.08 to 0.4 mg/ml of gel, and preferably from 0.1 to 0.2 mg/ml and/or any other broad-spectrum antibiotics. This biologically active complex is characterized by the fact that collagen gel further comprises a postnatal or embryonic fibroblasts.

As epithelial cells of human rights in the composition are equivalent postnatal keratinocytes of human skin, deposited on the surface of the collagen gel in suspension and/or pre-cultured in vitro on collagen microsites.

Additionally, biologically active complex contains polymer layer. As the polymer layer in the composition is equivalent mesh implant and/or dressings. This biologically active complex is characterized by the fact that, as the mesh endoprosthesis use wikilove grid or its equivalent substitute. This biologically active complex is characterized by the fact that collagen gel further comprises a plasticizer.

The invention posna the tsya drawing.

Macromolecular three-dimensional structure can be made of collagen and depending on the method of drying may be created in the form of a gel, sponge, mesh patterns. Collagen performs also the function of the carrier of bioactive components, such as:

the medium for culturing human cells- 7-40%;
- glutamine- 0,1-1 mg/ml;
phosphate buffer- 0.01 to 0.11 mg/ml
- sodium bicarbonate- 0,1-1 mg/ml;

- 0,1-0,15% solution of collagen

in 0.1% acetic acid- the rest;

A structural component can serve as a polymeric base, for example, in the form of a perforated film or mesh of biocompatible polymer.

Component activation and formation process of regeneration and/or repair tissue are allogeneic donor cells of the mesenchyme, which is connective tissue and part of the circulatory system, or the cells of the mesoderm from which are formed striated muscles, such as the kidneys, internal reproductive organs and other Cells of the mesenchyme person represent fibroblasts isolated from a donor who expect or fetal (postnatal and/or embryonic fibroblasts) material and cultured in vitro, for example, on microsites (for example, collagen microspheres with a diameter of 150-300 microns).

The specified cell culture of fibroblasts to be paid in the amount of collagen and performs the equivalent function of connective tissue. On the surface of three-dimensional collagen matrix is applied or cultured epithelial cells.

Another component activation and formation of the regeneration process are epithelial cells. The cells of a person are the cells of the epidermis of human skin - keratinocytes isolated from skin of the donor or recipient or their mixture. These cells are put in suspension to the surface of collagen and/or pre-as well as fibroblasts cultivated in vitro on collagen microsites.

Three-dimensional collagen matrix may further comprise autologous cells of mesenchymal and/or mesoderm, and/or epithelial and/or ectodermal origin, as well as matrix proteins such as fibronectin and laminin at a concentration of from 0.1 to 100 µg/ml, and preferably from 1 to 5 µg/ml, which are a natural component of the extracellular matrix of fibroblasts in vitro. These extracellular matrix proteins contribute to the structuring of the collagen gel and accelerate this process.

In the composition of the collagen matrix also can is to be introduced antiseptics, such as silver ions, copper or gold, and broad-spectrum antibiotics, such as gentamicin at concentrations not toxic to cells (from 0.08 to 0.4 mg/ml of gel, and preferably from 0.1 to 0.2 mg/ml), which can significantly reduce the likelihood of inflammation in the affected tissue.

To prepare the graft has a three-dimensional macromolecular structure having characteristics corresponding to the natural microenvironment of fibroblasts in vitro, and at the same time is a substrate for the cultivation of epithelial cells, in particular epidermal keratinocytes. Through the optimal parameters inherent in the structure of the formed graft, there is the possibility to transport the living cells in clinic and, not hurting, bring them to the wound as a graft.

If necessary, the active complex may include a plasticizer, typically in amounts of from 0.05 to 10 wt.%. The plasticizer is chosen, usually from a group of polyethylene glycol, sorbitol, glycerol, etc.

Active complex (structure of the graft) get outside of a living organism, and then it is brought into contact with the cells that formed the desired fabric, and it is in a suitable place, where the active complex, or in the body of a living organism, or outside the body, in the example in cell culture. Moreover, the active complex in the desired place of education of the fabric is brought into contact with viable, functionally active and specific cells. As you know, fabrics consist of specific differentiated cells produced by the cells of extracellular material, however, only the cells themselves are their own metabolic activity. Since the proposed active complex provides all the necessary conditions for the production of tissue, the invention makes possible the gathering and linking the necessary cells with the desired histology in the active complex, their reproduction and maturation depending on what functions they should perform as active complex contains suitable component for each separate stage of the formation of the fabric, ensuring that they receive in General.

The structure of the graft is adapted to the requirements of the recovered tissues of the body, because there is a certain specificity between cellular and extracellular components of tissues. Therefore, the source for receiving the transplant structures are mainly cellular materials of different tissues and organs.

For the convenience of fixing the biologically active complex on the wound surface and give the graft required form of the inventive component is ice further includes, at least one layer of polymeric bases, placed within the collagen gel or sponge or mesh structure. The polymer base may be in the form of a mesh implant or a perforated film, or as a dressing material. The specified mesh implant may be performed, for example, from wikilove grid with cell sizes from 1 to 5 mm, and preferably from 1 to 3 mm or its equivalent substitute properties: biocompatibility and elasticity.

Mesh implant placed, for example, in the thickness of the collagen gel, performs frame function, prevents the compression process of the gel and greatly simplifies the process of transferring tissue equivalent to the wound of the patient. In addition, the advantages of a mesh implant are that he is able to take various geometric shapes. Due to this layer of the graft, inside of which is a mesh implant, on the one hand, acquires the property be placed on the wound surface congruent form, and on the other hand, allows you to record the equivalent of the fabric at the edges of the wound.

If necessary, the complex may optionally have a mesh polymeric layer, located below or above the active biological complex.

Collagen gel is a solution of collagen in 0.1% acetic Ki the lot. In addition, collagen gel contains a ten-fold concentrate of culture medium "199", glutamine, sodium bicarbonate (Na2CO3) and phosphate buffer. Collagen gel performs the function of the carrier of bioactive components. Ready collagen gel has a three-dimensional structure having characteristics corresponding to the natural microenvironment of fibroblasts in vivo, and at the same time is a substrate for epithelial cells, in particular epidermal keratinocytes, and may have a different thickness (from 0.2 cm or more), a density of from 0.5 to 5 mg/ml, pH from 7.2 to 7.4. Due to the structure formed of the collagen gel becomes possible to deliver and transfer the cells to the wound of any configuration, size and depth.

Collagen gel are simply mixing all components at a temperature of 0-(+4)°C. If necessary, to the principal components of the collagen gel make matrix proteins, growth factors, antibiotics and/or antiseptics. Upon completion of the manufacturing process of gel in it make a suspension of allogeneic cell culture of fibroblasts on microsites. In tanks intended for the manufacture of the equivalent, placing a polymer network of a given size and fill is not yet frozen gel containing fibroblasts. The process polymerizati what happens when a temperature of 37° With and takes 30-40 minutes. Further frozen gel leave at 37°With in 2-3 days, while fibroblasts actively structure of collagen fibrils. Obtained at this stage, the equivalent of the tissue may be affected by cryopreservation in liquid nitrogen and left to save at low temperatures for up to 1 year. Further, if necessary, on the surface of the gel is to be applied epithelial cells on microsites and/or enzymatic desegregating cell suspension of epithelial cells. Within 48-72 hours of cultivation on collagen gel containing fibroblasts, keratinocytes form a colony of cells.

Thus, the duration of the technological process of manufacturing of the living tissue equivalent is 4 to 6 days.

If the collagen gel with fibroblasts was withdrawn from cryogenesis, you need to check the cell viability, past cryopreservation, for example, by staining the sample cells Trifanova blue or other dyes that distinguish viable cells from dead. The number of viable cells should be at least 70% of their total number. Before further manipulation of the gel must be within 30-40 minutes to stand at 37°C.

In the case of treatment of wound surfaces means the school area or the presence of concurrent disease, impeding the recovery process defect in the composition of the collagen gel may be optionally included growth factors, influencing the activity of cells, including epidermal growth factor (EGF), fibroblast growth factor (FGF), transforming growth factor - α and β (TGF), a growth factor secreted by platelets (PDGF), growth factor hepatocyte (HGF) or combinations thereof in concentrations ranging from 1-300 ng/ml, and preferably from 1 to 100 ng/ml.

Collagen gel, sponge or mesh structure can be used in this case for transdermal input medicines. According to the present invention collagen gel can optionally contain other bioactive components, such as proteins, carbohydrates, nucleic acids, and inorganic and organic biologically active molecules: enzymes, antibiotics, antineoplastic agents, bacteriostatic agents, antibacterial agents, antiviral agents, gemostaticescoe agents, local anesthetics, hormones, antiangiogenic agents, antibodies, neurotransmitters, psychoactive drugs, drugs affecting reproductive organs, and the oligonucleotides, for example, protivocesterne.

From collagen gel by the method of freeze-drying receive the sponge, the water content of which retain from 2%to 6%.

Setca the second structure is obtained by pouring the collagen gel in a special form, followed by drying at room temperature.

The proposed biological complex in the form of sponge and mesh structure is used as bandages. It easily follows the relief of injury, tight to her, and easily fixed.

Biological complex in the form of a gel with the inclusion of allogeneic and/or autologous cells of the mesenchyme and epithelium is a living tissue equivalent.

The transplantation of living tissue equivalent under the action of the collagen gel containing fibroblasts are stimulated contraction of the connective tissue and collagen synthesis. Allogeneic fibroblasts and keratinocytes produce cytokines, including interleukins, growth factors, fibronectin, type IV collagen, laminin, thromboplastin and other substances, the total effect of which is expressed in stimulating the regeneration of damaged tissues. Allogenic keratinocytes also create conditions for epithelialization due to the formation of the basal membrane. Further allogeneic epithelium is replaced histotypes.

Example 1. The method is tested and implemented when restoring a volume of the defect cavity mastoid after surgery for chronic suppurative otitis media.

Patient M., 42 years old, medical history, No. 1052, was hospitalized in the City clinical hospital n.a. Spotline diagnosed with chronic GN is any otitis media. On the 11th day after admission the patient had an operation radical atticoantral formed cavity is covered with a skin graft. On the 3rd day after surgery occurred divergence imposed operating seams. This resulted in the defect area of about 3 cm2and a depth of 1 see the Bottom of the formed defect presents bone tissue. After 5 days the patient was transplantation of collagen gel containing allogeneic cells of the mesenchyme and epithelium, with the inclusion of wikilove grid placed in the thickness of the collagen gel. To 14 days after transplantation in newly formed granulation tissue was determined visually epithelium was noted active edge epithelialization. To 21 days after transplantation, there was a complete closure of the defect.

Example 2. The method is tested and implemented with the recovery of the skin after a deep burn.

Patient S., 25 years old, medical history, No. 22063, was undergoing treatment at the burn center NII swap them. Nevskogo diagnosed with flame burn I-II-AB-IV degree buttocks, thighs, legs - 25% of the body surface (SHAB-IV degree - 12%). On the second day the patient underwent tangential necrectomy in the area - 12% of the surface. body. On the 4th day because of the deepening of the burn wounds and secondary education scabs produced by repeated necrectomy who I am. This simultaneously made the transplantation of living tissue equivalent in the field of deep burns on the anterior surface of the right tibia in the area of 160 cm2. To 14 days at the transplantation site was determined visually epithelium. To 23 days the skin at the transplantation site was fully restored. At the same time, in areas of deep burns surrounding the place of transplantation, wound to 23 days were presented by granulation tissue. Full recovery of the skin in these areas occurred only after the operation of autodermoplastiki 39 days.

Example 3. The method is tested and implemented with the restoration of the mucous membrane of the larynx.

Patient H., age 54, has been treated of Moscow in them PageRank diagnosed with cancer of the larynx stage T3N0M0. Had surgery - frontolateral resection of the larynx to the left with simultaneous grafting of biological active complex.

The manufacturer of the biological active complex was carried out in accordance with the description (page 7, second paragraph from the top). Additionally, at the stage of mixing of the components in the preparation of collagen gel formed in the structure of the biological active complex were made: epidermal growth factor at a concentration of 5 ng/ml, gentamicin - 0.16 mg/ml fibronectin - 2 µg/ml.

Biological active to the complex fixed to the periosteum of the sternum, used for plastics, so that the layer of epithelial cells facing the lumen of the larynx. The wound is sutured in layers, leaving the suction drainage in the donor zone. Imposed alcohol aseptic bandage. Postoperative complications were not. On the 30th day the patient was carried out FIBROLARYNGOSCOPY, when the inspection condition after resection of the larynx without signs of recurrence. There is a whitish plaque on the square 7×15 mm on the front wall podskladochny Department with the transition to middle Department. The gap in the middle and vestibular Department wide. At the transplantation site was taken biopsy, histological analysis showed stratified squamous epithelium with hyperkeratosis. On the 35th day after the transplantation, the patient was discharged home, restored free breathing and speech.

The creation of this structure is based on the following main principles:

1. The three-dimensional structure, which is achieved using the proposed active biological matrix.

2. The use of several types of cells, which is achieved by using cells of the mesenchyme and/or epithelium, and/or mesoderm, or ectoderm.

3. Allogenetic, which is achieved by the use of allogeneic human cells.

4. The use of skin cells, which is achieved by the use of epidermal cells - keratinocytes and the notches of the dermis - fibroblasts.

5. Convenience transplantation, fixing and attaching the implant to the required form, which is achieved by including in the composition of the polymer base, made in the form of a perforated film or mesh endoprosthesis.

The invention provides the possibility of closing the three-dimensional mesenchyme-epithelial defects single, unified, multi-component, three-dimensional living tissue equivalent that gives you the right to talk about new achievable technical result, non-obvious to a person skilled in this field.

Also, the use of this invention allows to increase the effectiveness of the treatment of various defects of the esophagus, the walls of the bladder, skin burns, trophic ulcers and wounds of any etiology, larynx, trachea, conjunctiva, orbit eye, nasal septum, nasopharynx and the middle ear, kidney and internal genital organs, which meets the conditions of industrial applicability.

1. Biologically active complex for organogenesis, representing multicomponent volumetric three-dimensional structure containing allogeneic cells of the mesenchyme and epithelium of the person and at least one layer of biocompatible polymer in the form of a mesh matrix with cell sizes from 1 to 5 mm, and preferably from 1 to 3 mm, within the collagen structure of the s.

2. Biologically active complex according to claim 1, characterized in that the collagen structure made in the form of a collagen gel or sponge or mesh structure.

3. Biologically active complex according to claim 2, characterized in that the collagen gel structure contains 0.1 to 0.15%solution of collagen, preferably 0,1-0,12%, in 0.1%acetic acid.

4. Biologically active complex according to claim 1, characterized in that it further comprises cells of the mesoderm and/or ectodermal origin.

5. Biologically active complex according to claim 1, characterized in that it further comprises autologous cells of the mesenchyme and/or epithelium of the person.

6. Biologically active complex according to claim 1, characterized in that the cells of the mesenchyme person pre-cultivated on collagen microsites.

7. Biologically active complex according to claim 2, characterized in that the collagen gel contains a ten-fold concentrate of culture medium "199" in the amount of 7 to 40% by volume, and preferably 10% to 20%.

8. Biologically active complex according to claim 2, characterized in that the collagen gel contains glutamine in an amount of 0.1 - 1 mg/ml of gel, and preferably 0.1 - 0.4 mg/ml

9. Biologically active complex according to claim 2, characterized in that the collagen gel contains sodium bicarbonate in an amount of 0.1 to 1 mg/ml of gel and preferably 0.25 to 0.4 mg/ml

10. Biologically active complex according to claim 2, characterized in that the collagen gel contains a phosphate buffer in an amount of 0.01 - 0.1 mg/ml by volume, and preferably from 0.01 to 0.05 mg/ml

11. Biologically active complex according to claim 1, characterized in that the collagen gel further comprises a matrix proteins.

12. Biologically active complex according to claim 11, characterized in that the matrix proteins can be used fibronectin and/or laminin, and/or protein in a concentration of 0.1 - 100 μg/ml, and preferably 1 to 5 mcg/ml

13. Biologically active complex according to claim 2, characterized in that the collagen gel further comprises growth factors.

14. Biologically active complex according to item 13, characterized in that as growth factors can be used epidermal growth factor, and/or fibroblast growth factor, and/or transforming growth factor - α and β and/or a growth factor secreted by platelets, and/or a growth factor for hepatocytes at concentrations of 1 to 300 ng/ml, and preferably 1 to 100 ng/ml.

15. Biologically active complex according to claim 2, characterized in that the collagen gel further comprises antiseptics.

16. Biologically active complex according to item 15, characterized in that as an antiseptic can be used ions of silver, copper and gold.

p> 17. Biologically active complex according to claim 2, characterized in that the collagen gel further comprises antibiotics.

18. Biologically active complex 17, characterized in that the quality of the antibiotic can be used gentamicin at a concentration of 0.08 to 0.4 mg/ml of gel, and preferably 0.1 to 0.2 mg/ml and/or any other broad-spectrum antibiotics.

19. Biologically active complex according to claim 2, characterized in that the collagen gel further comprises a postnatal or embryonic fibroblasts.

20. Biologically active complex according to claim 1, characterized in that as the epithelial cells of the human composition are equivalent postnatal keratinocytes of human skin, deposited on the surface of the collagen gel in suspension and/or pre-cultured in vitro on collagen microsites.

21. Biologically active complex according to claim 1, characterized in that the complex contains an additional polymer layer.

22. Biologically active complex according to claim 1, characterized in that the polymer layer in the composition is equivalent mesh implant and/or dressings.

23. Biologically active complex according to claim 1, characterized in that as the mesh endoprosthesis use wikilove grid or its equivalent substitute.

24. And the active biological complex according to claim 1, characterized in that the collagen gel further comprises a plasticizer.



 

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FIELD: medicine, in particular bioactive complex for organogenesis.

SUBSTANCE: claimed complex represents multicomponent, bulk, three-dimensional structure, containing human allogene mesenchyme and epithelial cells and at least one layer of biocompatible polymer in form of collagen structure on network matrix. Biological complex of present invention is useful in regenerative and reparative reconstruction of any biological structures of mesemchyme-epothelial or mesodermal and ectodermal origin. Also disclosed are unified method for rebuilding of three-dimensional tissue defects and effective method for treatment of various gullet, urinary bladder parries, skin, gorge, eardrum, kidney, etc. defects. Complex also may be used in production of donor tissue equivalent bank.

EFFECT: active complexes for organogenesis useful in medicine.

3 ex, 1 dwg, 24 cl

FIELD: medicine.

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FIELD: medicine.

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EFFECT: enhanced effectiveness in recovering combined injuries of cartilage and bone tissue in articulations having defects.

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FIELD: medicine.

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