CN1985776B - Biological spinal cord rack - Google Patents
Biological spinal cord rack Download PDFInfo
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- CN1985776B CN1985776B CN2005101207895A CN200510120789A CN1985776B CN 1985776 B CN1985776 B CN 1985776B CN 2005101207895 A CN2005101207895 A CN 2005101207895A CN 200510120789 A CN200510120789 A CN 200510120789A CN 1985776 B CN1985776 B CN 1985776B
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- spinal cord
- semipermeable membrane
- animal
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- adventitia
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Abstract
本发明公开了一种生物型脊髓支架，它由芯体(1)、包裹在芯体(1)外的半透膜(2)、固定在半透膜(2)上的螺旋骨架(3)以及包裹在螺旋骨架(3)上的外膜(4)组成，其中芯体(1)由通过非醛类固定剂交联固定和用活泼试剂及强氢键试剂去除抗原处理的动物脊髓制成，半透膜(2)及外膜(4)分别由通过非醛类固定剂交联固定和用活泼试剂及强氢键试剂去除抗原处理的动物膜组织制成。本发明的优点是：仿照人体脊髓的组成和结构设计，所有的构造都是天然生物材料制成，生物相容性好，无免疫原性，可被降解吸收，可诱导组织再生。
The invention discloses a biological spinal cord support, which consists of a core body (1), a semipermeable membrane (2) wrapped outside the core body (1), and a helical skeleton (3) fixed on the semipermeable membrane (2). And the outer membrane (4) wrapped on the helical skeleton (3), in which the core (1) is made of animal spinal cord that is cross-linked and fixed by non-aldehyde fixatives and treated with active reagents and strong hydrogen bond reagents to remove antigens , the semipermeable membrane (2) and the outer membrane (4) are respectively made of animal membrane tissue fixed by non-aldehyde fixative cross-linking and treated with active reagent and strong hydrogen bond reagent to remove antigen. The invention has the advantages of: imitating the composition and structure design of the human spinal cord, all structures are made of natural biological materials, have good biocompatibility, no immunogenicity, can be degraded and absorbed, and can induce tissue regeneration.
Description
Technical field
The present invention relates to a kind of medical treatment device that is used for the repair of spinal cord injury treatment, belong to and implant the class medical apparatus and instruments.
Background technology
Spinal cord injury often causes paralysis, does not find effective Therapeutic Method so far.Thought always in the past that spinal nerves was unrenewable, spinal cord injury is incurable disease.In recent years, the further investigation of nervus centralis and neural stem cell is found that the nervus centralis that comprises spinal nerves is can be regenerated, key is will have to be suitable for nervous tissue's regeneration and provisional substrate of rebuilding and good microenvironment.Here so-called provisional substrate be exactly for neural stem cell with and the hotbed of the neuronal cell that is differentiated to form and neurogliocyte division, propagation and migration.It can be degraded and absorbed, for neurocyte provides nutrient.So-called good microenvironment is meant that helping inducing nerve stem cell orienting is divided into neuronal cell and glial cell and the physical environment of these cell divisions of promotion, propagation and migration and the space of growth of new tissue.Organizational project custom simply is called " support " with these provisional substrate and microenvironments that can be used as tissue reconstruction, though not really definite, win simply.But prior art does not also have such support.
Summary of the invention
Biological spinal cord rack that the purpose of this invention is to provide a kind of good biocompatibility, can be degraded and absorbed and preparation method thereof.
Technical solution of the present invention is: biological spinal cord rack, by core body, be wrapped in the outer semipermeable membrane of core body, be fixed on the outer spiral skeleton of semipermeable membrane and be wrapped in the outer adventitia of spiral skeleton and form, wherein core body is made by removing antigenic animal spinal cord by crosslinked fixing and active reagent of no-aldehyde fixative and strong hydrogen bonding reagent, and semipermeable membrane and adventitia are made by removing antigenic animal membrane tissue by crosslinked fixing and active reagent of no-aldehyde fixative and strong hydrogen bonding reagent respectively.
Animal tissue easily is degraded by microorganisms or decomposes, need to make it crosslinked fixing with fixative, use the glutaraldehyde agent that fixes traditionally, residual toxicity is arranged, we select the no-aldehyde fixative for use, as epoxide, two acid diamides, vulcabond, Polyethylene Glycol or carbodiimides, just there is not this shortcoming.With the epoxide is example, when the application epoxide replaces aldehydes to fix reagent, because epoxide is very unstable, the open loop cross-linking reaction easily takes place, the control reaction condition can accomplish to make its cross-linking products with collagen protein very stable, and degraded easily is only when regenerating tissues growth, propagation need lose its silkworm, secrete under kallikrein, fibrinolysin, the collaborative collagenase effect of glucocorticoid and it slowly could be decomposed into polypeptide and aminoacid, and be absorbed and used.A kind of like this passive type degraded is synchronous with the regeneration of tissue, is that the reproducibility that helps organizing is most repaired, and does not have the residual toxicity of aldehydes; According to modern immunology theory, the antigenicity of animal tissue mainly is to cause that by the active group of some specific position in the protein and special conformation these active groups mainly are-OH-NH
2-SH etc., special conformation then mainly is because some of protein molecule coiled strand held different hydrogen bond and caused, when handling animal tissue, easily combine with these groups with one or more with the active reagent (as anhydride, acyl chlorides, amide, epoxide etc.) that these groups react, it is closed, removes its antigen, simultaneously, also use strong hydrogen bonding reagent (as guanidine compound), displacement causes the hydrogen bond of special conformation, changes its conformation, effectively eliminates its antigenicity from many aspects.Core body among the present invention is to spend antigenic xenogenesis spinal cord substrate to make, no antigen, and good biocompatibility can be used as excellent substrates and carrier that neural stem cell and neuronal cell, glial cell are lived away from home, divide, bred and move.Semipermeable membrane and adventitia are that the membrane tissue with animals such as pig, cattle, sheep, monkeys obtains through serial biochemical treatment, have spinal cord is soft, spinal dura mater is similar composition and characteristic, good biocompatibility.The spiral skeleton can be cut into elongated slip by semipermeable membrane or adventitia, paste multilamellar and form in semipermeable membrane external spiral coiling, except that support is played a supporting role, formed spiral pit, also play the effect of provisional cerebrospinal fluid channel lumens, be similar to the effect of cavitas subarachnoidealis spinalis.
As the scheme of an optimization, be exactly the surface of described core body, semipermeable membrane and adventitia being arrived they respectively by coupling agent coupling polypeptide and glycosaminoglycan active component, make it to have the function that adheres to somatomedin, promotes tissue growth; For semipermeable membrane and adventitia; consider some membrane tissues; mechanical strength can't satisfy application requirements; and regular meeting causes the mechanical property loss of energy in biochemical treatment; so also be provided with the treatment step that collagen molecules is carried out graft modification; as segments such as suitable grafted polyurethane, polyamide, polyester, polylactic acid, polyglycolic acid in collagen molecules; improve the mechanical strength and the toughness of base material; grafted raw material is the performed polymer with them, and method can be selected high polymer grafting methods such as condensation, initiation, radiation for use.
One of described polypeptide is formed by 16 lysines (K16), glycine (G), arginine (R), aspartic acid (D), serine (S), proline (P) and cysteine (C) polycondensation, and described glycosaminoglycans is hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparin, Heparan sulfate or keratan sulfate.These polypeptide or glycosaminoglycans have wide spectrum to adhere to and enrichment to somatomedin, can excite the undifferentiated cell directed differentiation, have the function of the reproducibility reparation of inducing body tissue.
Described semipermeable membrane is goldbeater's skin or other the animal membrane tissue of handling through mechanical thinning of animal; Described adventitia is animal pericardium or diaphragm or fatty nethike embrane or pleura or peritoneum.
The preparation method of biological spinal cord rack of the present invention may further comprise the steps:
(1), selects materials: collect the spinal cord and the membrane tissue of fresh animal, spinal cord is carefully cut off whole adventitias get medullary substance, reject blood vessel; Membrane tissue is pruned away except that unnecessary impurity and irregularity part the tension force typing;
(2), alkali treatment: use aqueous slkali soaking medullary substance and membrane tissue;
(3), defat: fat and oil-soluble impurities in extracting medullary substance with an organic solvent and the film material;
(4), crosslinked fixing: as to use the collagen molecules in crosslinked fixedly medullary substance of no-aldehyde fixative and the film material;
(5), remove antigen: use in active reagent sealing medullary substance and the film material albumen to cause antigenic specific activity group-OH ,-NH
2,-SH, and with the special hydrogen bond that causes special conformation in the strong hydrogen bonding reagent displacement base material protein molecule coiled strand.
(6), finished product preparation: on bar-shaped mould, the semipermeable membrane of corresponding size is bonded into tubular body with medical glue; Other gets the lengthy motion picture bar that above-mentioned arbitrary film material is cut into Rack, and coiled coil sticks on the semipermeable membrane at a certain distance, pastes multilamellar, forms the spiral skeleton; Again adventitia is bonded on the protruding beam of spiral skeleton and forms tubular body; Take out mould, carefully fill die with the antigen xenogenesis medullary substance of going that makes, add a little collagen colloidal sols or albumin glue in case of necessity and make binding agent, lyophilization again gets product.
As a kind of prioritization scheme, core body, semipermeable membrane and adventitia also comprise the treatment step by specific polypeptide of coupling agent coupling or glycosaminoglycans active component, promptly can adhere to the polypeptide or the glycosaminoglycans active component of somatomedin on the surface of core body, semipermeable membrane and adventitia by the coupling agent coupling.In addition, also pass through the treatment step of toughening modifying for semipermeable membrane and adventitia, promptly use condensation, initiation or radiation grafted method, suitable grafted polyurethane, polyamide, polyester, polylactic acid or polyglycolic acid segment in the collagen molecules of core body, semipermeable membrane and adventitia.
Employed aqueous slkali is NaOH, KOH or Ca (OH) in the preparation method of biological spinal cord rack
2Solution.
No-aldehyde fixative described in the preparation method of biological spinal cord rack is easily and the reagent of protein molecule generation cross-linking reaction such as in epoxide, two acid diamides, vulcabond, Polyethylene Glycol or the carbodiimides reagent one or both, and the epoxide here can be a monoepoxide
It also can be di-epoxide
Here R=C
nH
2n+1-, n=0-10 can also be low polyepoxide such as poly(propylene oxide).
Active reagent described in the preparation method of biological spinal cord rack is small molecular organic acid acid anhydride, acyl chlorides, amide or epoxide, and strong hydrogen bonding reagent is guanidine compound.
Coupling agent described in the preparation method of biological spinal cord rack be two acid diamides, dicarboxylic anhydride, carbodiimides, di-epoxide or other can with-NH
2,-OH ,-COOH play the bifunctional reagent of condensation reaction.
Advantage of the present invention is: copy the The Nomenclature Composition and Structure of Complexes design of human body spinal cord, core body is similar to the medullary substance (grey matter and white matter) of people's spinal cord, it is to spend antigen xenogenesis spinal cord substrate, introducing can adhere to the active component of neural stem cell and relevant somatomedin and make, can collect neural stem cell and induce its directed differentiation, promote the regeneration of myeloid tissue.Semipermeable membrane is similar to the spinal pia mater of spinal cord, can see through the nutrient substance in the spinal fluid.The spiral skeleton is except that playing a supportive role, and formed spiral pit plays the effect in the mobile chamber of cerebrospinal fluid.Adventitia is similar to spinal dura mater.All structures all are that natural biologic material is made, and good biocompatibility can be degraded and absorbed, but induced tissue regeneration.
Description of drawings
Accompanying drawing 1 is the structural representation of the embodiment of the invention;
1, core body, 2, semipermeable membrane, 3, the spiral skeleton, 4, spinal dura mater.
The specific embodiment
Embodiment: as shown in Figure 1, biological spinal cord rack, by core body 1, be wrapped in the outer semipermeable membrane 2 of core body, be fixed on the spiral skeleton 3 on the semipermeable membrane 2 and be wrapped in spiral skeleton 3 outer adventitias 4 and forms, wherein core body 1, semipermeable membrane 2 and adventitia 4 are made by remove animal spinal cord, the animal membrane tissue that antigen reaches the treatment step by specific polypeptide of coupling agent coupling or glycosaminoglycans active component by crosslinked fixing, active reagent of no-aldehyde fixative and strong hydrogen bonding reagent respectively.
Concrete preparation process is as follows: one, the preparation of core material: get fresh Medulla Sus domestica, carefully wipe out spinal dura mater, arachnoidea and spinal pia mater, get medullary substance, carefully reject blood capillary, put into 0.2～2% NaOH solution and soaked 2 hours, take out, with water rinse three times.Taking-up drains away the water, and extracts wherein fat and oil-soluble impurities with organic solvent.Take out,, carry out crosslinked fixated response with it with the carbochain epoxide except that after desolvating.Take out, clean, lyophilization is reacted with it with acetic anhydride or butyryl oxide., the blocking antigen gene; The Tris buffer solution of reuse guanidine hydrochloride is handled, and changes to cause antigenic special conformation.Take out, clean, do on the tropocollagen molecule that polypeptide that coupling agent will form by 16 lysines (K16), glycine (G), arginine (R), aspartic acid (D), serine (S), proline (P) and cysteine (C) polycondensation or glycosaminoglycans be coupled to medullary substance with carbodiimides (R-N=C=N-R), clean, promptly get core material, place the normal saline cryopreservation standby.
Two, the preparation of semipermeable membrane 2 and adventitia 4: get bovine pericardium or Cor Sus domestica bag or pig pleura and Intestinum Sus domestica film respectively, clean, carefully remove unnecessary tissue and impurity, get solid smooth film body, clean, handled 2 hours with the KOH solution soaking of 0.1～2% concentration.Take out, more than three times, taking-up drains away the water, and extracts wherein fat and oil-soluble impurities with organic solvent with water rinse.Take out,, carry out crosslinked fixated response with it with the carbochain epoxide except that after desolvating.Take out, clean, lyophilization is reacted with it with acetic anhydride or butyryl oxide., the blocking antigen gene; The Tris buffer solution of reuse guanidine hydrochloride is handled, and changes to cause antigenic special conformation.Take out and clean, P is used in lyophilization
2O
5Making dehydrating condensation agent is grafted to the performed polymer of polyglycolic acid on the tropocollagen molecule of film material.Making coupling agent with carbodiimides (R-N=C=N-R) will be coupled on the tropocollagen molecule of above-mentioned film material by polypeptide or hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparin, Heparan sulfate or the keratan sulfate that 16 lysines (K16), glycine (G), arginine (R), aspartic acid (D), serine (S), proline (P) and cysteine (C) polycondensation form, clean, place the normal saline cryopreservation standby.Semipermeable membrane 2 is selected the best Intestinum Sus domestica film of the thinnest permeability for use, and adventitia 4 is selected thicker pig, bovine pericardium or pig barrier film for use.
Three, the preparation of biological spinal cord rack: on the pole mould of setting diameter, tubular body is justified in the bonding formation in the limit, semipermeable membrane 2 limit of corresponding size with medical glue.Other gets the lengthy motion picture bar that above-mentioned arbitrary film is cut into Rack, with medical glue with the lengthy motion picture bar at a certain distance coiled coil paste on the tube wall of spinal pia mater, around the viscosity number layer, be formed with the spiral skeleton 3 of certain support force, the medical glue of reuse is adhered to adventitia 4 on the protruding beam of spiral skeleton 3, and self is bonded into the pipe body in the limit, limit again.Deviate from the pole mould, carefully the core material that makes is filled in the cylindrical cavity of die and forms core body 1, add a small amount of medical protein glue in case of necessity and make excipient.Packing density should not be too tight, also should not be too loose, fill in postlyophilization with typing with moderate for well, and so far, biological spinal cord rack just integral body is made.Pack with the normal saline liquid storage of going bail for,, promptly obtain product with cobalt-60 radiation sterilization.
Claims (10)
1. biological spinal cord rack, it is characterized in that: it by core body (1), be wrapped in the outer semipermeable membrane (2) of core body (1), be fixed on the spiral skeleton (3) on the semipermeable membrane (2) and the adventitia (4) that is wrapped on the spiral skeleton (3) is formed, wherein core body (1) is by fixing and make with the animal spinal cord that active reagent and strong hydrogen bonding reagent removal antigen are handled by the no-aldehyde fixative being crosslinked, and semipermeable membrane (2) and adventitia (4) are respectively by fixing and make with the animal membrane tissue of active reagent and the processing of strong hydrogen bonding reagent removal antigen by the no-aldehyde fixative being crosslinked.
2. biological spinal cord rack according to claim 1, it is characterized in that: described core body (1) is made by the animal spinal cord of handling by coupling agent coupling polypeptide and glycosaminoglycan active component, described semipermeable membrane (2) and adventitia (4) are made by the animal membrane tissue of handling by coupling agent coupling polypeptide and glycosaminoglycan active component respectively, and the animal membrane of making semipermeable membrane (2) and adventitia (4) is organized also and handled by toughening modifying.
3. biological spinal cord rack according to claim 2, it is characterized in that: one of described polypeptide is formed by 16 lysines (K16), glycine (G), arginine (R), aspartic acid (D), serine (S), proline (P) and cysteine (C) polycondensation, and described glycosaminoglycans is hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparin, Heparan sulfate or keratan sulfate.
4. according to claim 1 or 2 or 3 described biological spinal cord racks, it is characterized in that: described semipermeable membrane (2) is the goldbeater's skin of animal or other animal membrane tissue of handling through mechanical thinning; Described adventitia (4) is animal pericardium, diaphragm, fatty nethike embrane, pleura, peritoneum; The little lengthy motion picture bar spiral that described spiral skeleton (3) is cut into by described semipermeable membrane (2) or adventitia (4) is pasted and is made.
5. the preparation method of the described biological spinal cord rack of claim 1, it is characterized in that: it may further comprise the steps:
A, select materials: spinal cord and the membrane tissue of collecting fresh animal also prune away and remove unnecessary impurity and irregularity part, pure medullary substance and solid film material;
B, alkali treatment: use aqueous slkali soaking medullary substance and film material;
C, defat: fat and oil-soluble impurities in extracting medullary substance with an organic solvent and the film material;
D, crosslinked fixing: use the collagen molecules in crosslinked fixedly medullary substance of no-aldehyde fixative and the film material;
E, removal antigen: use in active reagent sealing medullary substance and the film material protein to cause antigenic specific activity group-OH ,-NH
2,-SH, and with the special hydrogen bond that causes special conformation in the strong hydrogen bonding reagent displacement base material protein molecule coiled strand;
F, finished product preparation: on bar-shaped mould, the semipermeable membrane (2) of corresponding size is bonded into tubular body with medical glue; Other gets the lengthy motion picture bar that above-mentioned arbitrary film is cut into Rack, and coiled coil sticks on the semipermeable membrane (2) at a certain distance, forms spiral skeleton (3); Again adventitia (4) is bonded on the protruding beam of spiral skeleton (3) and forms tubular body; Take out mould, the careful filling center cavity of the medullary substance that makes is formed core body (1).
6. preparation method according to claim 5, it is characterized in that: it also is provided with the treatment step by specific polypeptide of coupling agent coupling or glycosaminoglycans active component between e and f step, promptly can adhere to the polypeptide or the glycosaminoglycans active component of somatomedin on the surface of described medullary substance and film material by the coupling agent coupling.
7. preparation method according to claim 5, it is characterized in that: it also is provided with the treatment step of toughening modifying between e and f step for the film material, promptly use condensation, initiation or radiation grafted method, in the collagen molecules of described film material, suitably connect polyurethane, polyamide, polyester, polylactic acid or polyglycolic acid segment.
8. preparation method according to claim 5, it is characterized in that: described no-aldehyde fixative is easily and in epoxide, two acid diamides, vulcabond or the carbodiimides reagent of protein molecule generation cross-linking reaction one or both, and the epoxide here is a monoepoxide
Or di-epoxide
Here R=C
nH
2n+1-, n=0-10, or poly(propylene oxide).
9. preparation method according to claim 5 is characterized in that: described active reagent is small molecular organic acid acid anhydride or acyl chlorides or amide or epoxide, and strong hydrogen bonding reagent is guanidine compound.
10. preparation method according to claim 7 is characterized in that: described coupling agent is two acid diamides, dicarboxylic anhydride, di-epoxide or carbodiimides.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2005101207895A CN1985776B (en) | 2005-12-20 | 2005-12-20 | Biological spinal cord rack |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2005101207895A CN1985776B (en) | 2005-12-20 | 2005-12-20 | Biological spinal cord rack |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1985776A CN1985776A (en) | 2007-06-27 |
| CN1985776B true CN1985776B (en) | 2011-08-03 |
Family
ID=38182810
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2005101207895A Expired - Lifetime CN1985776B (en) | 2005-12-20 | 2005-12-20 | Biological spinal cord rack |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1985776B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101278865B (en) * | 2008-05-09 | 2010-04-07 | 南通大学 | Compartmental tissue engineered spinal cord |
| CN106175981A (en) * | 2016-03-04 | 2016-12-07 | 上海沐春投资管理有限公司 | A kind of part band film intravenous type support |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5976192A (en) * | 1995-06-07 | 1999-11-02 | Baxter International Inc. | Method of forming an externally supported tape reinforced vascular graft |
| CN1237914A (en) * | 1996-11-20 | 1999-12-08 | 清水庆彦 | artificial nerve tube |
| US6544762B1 (en) * | 1994-10-06 | 2003-04-08 | Regents Of The University Of Minnesota | Magnetically oriented tissue-equivalent and biopolymer tubes and rods |
| US6572650B1 (en) * | 1998-06-05 | 2003-06-03 | Organogenesis Inc. | Bioengineered vascular graft support prostheses |
| JP2003190192A (en) * | 2001-12-28 | 2003-07-08 | Japan Science & Technology Corp | Peripheral nerve regeneration method |
-
2005
- 2005-12-20 CN CN2005101207895A patent/CN1985776B/en not_active Expired - Lifetime
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6544762B1 (en) * | 1994-10-06 | 2003-04-08 | Regents Of The University Of Minnesota | Magnetically oriented tissue-equivalent and biopolymer tubes and rods |
| US5976192A (en) * | 1995-06-07 | 1999-11-02 | Baxter International Inc. | Method of forming an externally supported tape reinforced vascular graft |
| CN1237914A (en) * | 1996-11-20 | 1999-12-08 | 清水庆彦 | artificial nerve tube |
| US6572650B1 (en) * | 1998-06-05 | 2003-06-03 | Organogenesis Inc. | Bioengineered vascular graft support prostheses |
| JP2003190192A (en) * | 2001-12-28 | 2003-07-08 | Japan Science & Technology Corp | Peripheral nerve regeneration method |
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| Publication number | Publication date |
|---|---|
| CN1985776A (en) | 2007-06-27 |
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Granted publication date: 20110803 |