CN107080861A - A kind of repair materials of high induced activity, preparation method and application - Google Patents
A kind of repair materials of high induced activity, preparation method and application Download PDFInfo
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- CN107080861A CN107080861A CN201710124817.3A CN201710124817A CN107080861A CN 107080861 A CN107080861 A CN 107080861A CN 201710124817 A CN201710124817 A CN 201710124817A CN 107080861 A CN107080861 A CN 107080861A
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- growth factor
- immunogene
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- induced activity
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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
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
- A61L27/3629—Intestinal tissue, e.g. small intestinal submucosa
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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
- A61L27/14—Macromolecular materials
- A61L27/20—Polysaccharides
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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
- A61L27/24—Collagen
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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
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
- A61L27/3687—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
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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
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
- A61L27/3691—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation
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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
- A61L27/56—Porous materials, e.g. foams or sponges
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- 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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- 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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- 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
- A61L2300/40—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
- A61L2300/414—Growth factors
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
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- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/30—Materials or treatment for tissue regeneration for muscle reconstruction
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- A61L2430/32—Materials or treatment for tissue regeneration for nerve reconstruction
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- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/40—Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking
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Abstract
The present invention provides a kind of repair materials of high induced activity, preparation method and application, it is characterised in that：The material is made up of the natural macromolecular material with three-dimensional netted loose structure, including the three-decker being made up of intermediate layer and upper and lower superficial layer；Intermediate layer includes collagen, polysaccharide material, active factors and growth factor, and upper and lower superficial layer includes collagen, polysaccharide material and active factors, and the repair materials can degrade in vivo.One or more of growth factor can be included：Follistatin, nerve growth factor, platelet derived growth factor, epidermal growth factor, matrix gamma-carboxyl glutamate albumen etc., applied to the growth and regulation and control of the tissue such as cardiac muscle, nerve, smooth muscle, epithelium, or prevent the calcification of immunogene removal host material after implantation.
Description
Technical field
The present invention relates to medical biomaterial technical field, specially a kind of repair materials of high induced activity, preparation side
Method and application, the material are used to growth factor being compound in immunogene removal matrix, induction of the reinforcing material to particular organization
Repair.
Background technology
It is clinically to be widely used in stomach wall, the urinary tract, hard brain that immunogene, which removes submucous layer of small intestine (SIS) material,
The facial soft tissue defect repairs such as film, the reparation of blood heart pipe, the bio-medical material reinforced, are a kind of acellular, non-immunogenicities, can give birth to
Thing is degraded and with the good material of fibrous elasticity.
Patent of invention (103272278A) once disclosed a kind of preparation method of animal derived implantable biomaterial for medical purpose,
Describe by the preposition processing separation of animal tissue's material, previous cleaning, inactivation of virus, immunogene remove, sodium chloride processing, into
Type, packaging sterilizing are of different sizes, the curable product of thickness and mechanical strength.Immunogene removal technology is by animal groups
Knit or organ living cells' digestion, dissolving, remove the cell surface antigen for causing immune response, acquisition remains with the tune such as growth factor
Control the extracellular matrix (ECM) of the factor.It is by a variety of macromolecular substances such as I-type collagen, non-collagen that immunogene, which removes matrix,
The material compositions such as glycoprotein, aminoglycan, proteoglycans and growth factor, constitute a porous three-dimensional structure, are various cells
Suitable growth microenvironment is provided, attachment, form, migration, metabolism, propagation and the differentiation of various cells can be adjusted.Immunogene
Matrix is removed as tissue and the natural biological medical material of organ transplant, patients own cells' length is can induce after implanting
Enter, template is provided for cellular reconstitution damaged tissues, repair tissue or organ for vascularization, functionalization, and immunogene is removed
Matrix can progressively degrade, and with rebuilding tissue regeneration processes basic synchronization, final immunogene removes matrix sticking patch completely by host's group
Knit replacement.
Immunogene, which is removed, contains aminoglycan, proteoglycans and growth factor, aminoglycan, albumen in SIS matrix sticking patch
Glycan is conducive to fixation and the chemotactic of growth factor, and growth factor includes VEGF, TGF β 1, bFGF, therefore lacks for soft tissue
The reparation of damage, vascularization are obvious, can remold well and regenerating damaged tissue.
But when for the tissue repair such as cardiac muscle, nerve, smooth muscle, epithelium, immunogene removes SIS matrix sticking patch to this
The inducing action for the reconstruction organized a bit is limited, primarily serves physical barriers effect, forms tissue repair microenvironment, prevent week
Enclose tissue and grow into damaged part formation adhesion, scar.Other immunogene removes SIS matrix sticking patch and is applied to should also during blood vessel valve
Consider its anti-calcification function, it is considered to which its increase prevents the growth factor of calcification.
The organs such as heart, blood vessel, nerve, bladder, esophagus, uterus are applied to make immunogene remove SIS matrix sticking patch, it is real
Existing its, which strengthens function of organization, to be repaired, and can be combined it with single, a variety of growth factors, to promote it to particular organization, organ
The induction regulating controlling effect of cell.But growth factor half-life short in vivo, therefore internal release behavior also needs to further
Solve.
The content of the invention
Growth factor is compound in immunogene there is provided one kind for the above-mentioned deficiency of prior art and removes matrix by the present invention
In, can reinforcing material to particular organization induce repair high induced activity repair materials.
In order to solve the above-mentioned technical problem, the technical solution adopted by the present invention is：A kind of repair materials of high induced activity,
It is characterized in that：The material is made up of the natural macromolecular material with three-dimensional netted loose structure, including by intermediate layer and it is upper,
The three-decker that undersurface layer is constituted；Intermediate layer includes collagen, polysaccharide material, active factors and growth factor, upper and lower table
Surface layer includes collagen, polysaccharide material and active factors, and the repair materials can degrade in vivo.
The repair materials are made with animal intestinal submucosa tissue material.
The animal is mammal, preferably pig or ox.
Described collagen is the composition for including I types, type III, IV types and VI collagen types.
Described polysaccharide material is the composition comprising chondroitin sulfate and hyaluronic acid.
Described active factors is the composition for including fibronectin splicing variants, laminin, integrin and its part.
Described growth factor include but is not limited to follistatin, nerve growth factor, platelet derived growth factor,
The composition of the one or more growth factor such as epidermal growth factor, matrix gamma-carboxyl glutamate albumen.
The time of described internal degraded is 3-6 months.
Described upper surface layer and the porosity of the three-dimensional netted loose structure of undersurface layer are 45~70%.
The porosity of the three-dimensional netted loose structure in described intermediate layer is 75~90%.
The above-mentioned specific porosity of the present invention can control growth factor release, can select a variety of growth factors.
The repair materials of high induced activity of the present invention, long 1-20cm, wide 1-10cm, thickness 1-4mm.
The present invention also provides a kind of preparation method of the repair materials of above-mentioned high induced activity, using under animal mucous membrane of small intestine
Layer tissue is as raw material, and by organizing preposition processing, inactivation of virus, immunogene is removed, prepared by dry, slurry, be molded and freezing
Drying steps, obtain and remove Zoonotic virus risk, cell component, DNA compositions and α-Gal antigens, retain extracellular matrix into
The repair materials of the high induced activity divided.
The preparation method of the repair materials of above-mentioned high induced activity, specific step includes：
(1) the preposition processing of tissue：Animal intestinal submucosa tissue material is taken, cleans and is filtered dry water；
(2) inactivation of virus：Virus is carried out using Peracetic acid-alcohol solution dipping animal intestinal submucosa tissue material
Inactivation；Then handled in Vltrasonic device；
(3) immunogene is removed：Immunogene removes liquid and uses the PBS solution containing trypsase and EDTA, and immunogene is removed
Process is carried out in supersonic wave cleaning machine；Then cleaned in Vltrasonic device, obtain submucous layer of small intestine host material；
(4) dry：The host material removed through immunogene obtained by step (3) is fixed on mould, then together
It is put in oven drying；
(5) prepared by slurry：It will be shredded, ground using liquid nitrogen frozen reducing mechanism by the host material after step (3) cleaning
It is broken, obtain particle；Particle adds acetic acid solution, is crushed after vacuum drying；Then growth factor solution, shape are added into particle
Into slurry；
(6) it is molded：Take the dried submucous layer of small intestine host material film that is obtained by step (4) as upper surface layer and
Undersurface layer, the slurry obtained by step (5) is added between two superficial layers, is laid on mould and is molded；
(7) it is freeze-dried：Material after shaping is positioned in vacuum freeze drier and carries out vacuum freeze drying.
In step (2) of the present invention the concentration of volume percent of Peracetic acid be 0.1%-5%, ethanol percent by volume it is dense
Spend for 5%-40% (being configured to solution with water), the volume ratio of Peracetic acid-ethanol solution and intestinal submucosa tissue material
For (3-20) ︰ 1, inactivation time 2-4 hours, temperature range is 10-40 DEG C.It is processed as in step (2) Vltrasonic device：Using pH value
For the 7.0 ultrasonically treated intestinal submucosa tissue material of PBS solution, solution temperature is 20 DEG C, under PBS solution and mucous membrane of small intestine
The ratio (volume ratio) of layer tissue material is 30 ︰ 1, preferred process 3 times, every time 20 minutes；Then it is clear using 20 DEG C of purified water
Wash, purified water is 30 ︰ 1 with intestinal submucosa tissue material proportion, is terminated to detection electrical conductivity for below 10 μ S/cm；Cleaning
Process is carried out in supersonic wave cleaning machine, the preferred 40kHz of frequency, preferred more than the 3000W of power.
It is the PBS solution containing trypsase and EDTA that immunogene, which removes liquid, in step (3) of the present invention, and immunogene removes liquid
The mass percent concentration of middle trypsase is 0.01-0.2%, preferably 0.02-0.05%；EDTA concentration is 0.1-1mmol/
L, preferably 0.4-0.8mmol/L；The pH value that immunogene removes liquid is 7.0-8.0, preferably 7.2-7.5；The immunogene is removed
Liquid is with intestinal submucosa tissue material volume ratio for (20-40) ︰ 1, immunogene removal process is at least including two supersonic frequencies
Carried out in the supersonic wave cleaning machine of rate, wherein Frequency scope is 20-40KHz, and higher frequency is 60-90KHz, wherein low frequency
5-40min, high-frequency therapeutic treatment 5-40min are handled, temperature range is 20-35 DEG C.Using trypsase and EDTA, make cell and cell
Connection between epimatrix is destroyed；Cell is crushed using low frequency ultrasound, while being acted on using high frequency ultrasound broken
Cell and extracellular matrix, further make cell detachment extracellular matrix, reach immunogene remove purpose.Using above-mentioned side
Formula, strengthens to each step during whole cell detachment matrix, cell is completely disengaged from from matrix, reaches most
Good immunogene removal effect.Then handled respectively with PBS solution and cooling water for injection in supersonic wave cleaning machine, obtain small
Intestinal submucosa matrix material；PH value 7.2-7.4 PBS solution and intestinal submucosa tissue material proportion for (20-40) ︰ 1,
Water for injection is with intestinal submucosa tissue material proportion for (20-40) ︰ 1, water for injection is handled to detection cleaning and injected
Terminated with water conductivity difference for below 1 μ S/cm；The preferred 40kHz of supersonic frequency, preferred more than the 3000W of power.
Step (4) drying of the present invention is：It is 8- that immunogene removal organization material is placed in into 25-40 DEG C of temperature, time
In the environment of 16 hours, upper surface layer or undersurface layer are formed.
Step (5) the of the present invention slurry is prepared as：Host material after step (3) is cleaned is shredded, cold using liquid nitrogen
The grinding of agar crushing device is broken, and the host material shredded is crushed, then gone out by sieved through sieve below 250 μm of particle diameter,
It is preferred that less than 150 μm of particle (being used for the uniformity for controlling open structure, the open structure of the smaller formation of particle is more uniform)；
The acetic acid solution that mass percent is 0.3% is added in grain, is crushed after vacuum drying；Then by growth factor and granular mass ratio
For (1-50):10000 ratio adds the growth factor aqueous solution into particle, forms slurry, for preparing intermediate layer (activity
Layer).
Freeze-drying described in of the invention (7) is：Superficial layer is freeze-dried with active layer, pre-freeze is protected to -45 DEG C
It is warm 1-2 hours, then adjust the temperature to -15 DEG C, be incubated 5-7 hour, then adjust the temperature to 0 DEG C, insulation 2 hours is finally adjusted
Temperature is incubated 4 hours to 25 DEG C, forms composite construction.
The present invention further provides a kind of application of the repair materials of above-mentioned high induced activity, it is specially：Height induction is lived
The repair materials of property can include one or more of growth factor：Follistatin, nerve growth factor, blood platelet source
Growth factor, epidermal growth factor, matrix gamma-carboxyl glutamate albumen etc..
A kind of application of the repair materials of high induced activity, can be applied to the tissue damage such as cardiac muscle, nerve, smooth muscle, epithelium
The reparation of wound.
A kind of application of the repair materials of high induced activity, be securable to the position of injury tissue there is provided mechanics support with
Insulation blocking, and growth factor, the regeneration of high activity organization of regulation control and repair process are slowly discharged, being chronically implanted prevents the calcium of material
Change.
Compared with prior art, the present invention has following remarkable advantage and beneficial effect：
(1) trypsase and EDTA are used, the connection between cell and extracellular matrix is destroyed；Using low frequency ultrasound
Cell is crushed, while acting on broken cell and extracellular matrix using high frequency ultrasound, further makes cell detachment
Extracellular matrix, reaches de- cell purpose.Using aforesaid way, each step during whole cell detachment matrix is carried out
Reinforcing, makes cell be completely disengaged from from matrix.Reach optimal immunogene removal effect.
(2) efficiency crushing technology：Low temperature ultra high shear crushing technology, protect collagen, biotic factor composition not by
Destruction；
(3) it is degradable to absorb：Degradable in vivo, degradation process is controllable, and the action period is long；
(4) multilayer close membrane：Three-decker, upper and lower surface layer removes hypothallus for complete immunogene, intermediate layer be containing
Growth factor layer, forms sandwich structure, while controlling material degradation and growth factor release process；
(5) a variety of growth factors can apply the reconstruction of different cell various organizations：A kind of reparation of high induced activity
Material, can include one or more of growth factor：Follistatin, nerve growth factor, platelet derived growth because
Son, epidermal growth factor, matrix gamma-carboxyl glutamate albumen etc., the life applied to the tissue such as cardiac muscle, nerve, smooth muscle, epithelium
Long and regulation and control, or prevent the calcification of immunogene removal host material after implantation.
Brief description of the drawings
Shown in Fig. 1 is the structure chart for the heteroimmune original removal host material that high induced activity of the invention carries albumen；
Shown in Fig. 2 is the microcosmic of the heteroimmune original removal host material different layers that high induced activity of the invention carries albumen
Structure SEM photograph, wherein left figure are that immunogene removes hypothallus, and right figure is growth factor layer；
Shown in Fig. 3 is the heteroimmune original removal host material active factors release that high induced activity of the invention carries albumen
Curve；
Shown in Fig. 4 is that high induced activity of the invention carries the heteroimmune original of albumen and removes host material nerve cell is deposited
The influence of motility rate.
Embodiment
The present invention is further described in detail with reference to embodiments, but is not limited to this.
Intestinal submucosa tissue material of the present invention is derived from mammal, trees-Osima jacoti, Osima excavata organization material
(SIS) or calf intestinal submucosa tissue material be applied to embodiments of the invention.
Embodiment 1：
The preparation method of the present embodiment animal sources implantable Biological Repair piece, including following operating procedure：
(1) the preposition processing of tissue：
Intestinal submucosa tissue material is taken to be divided into wide 10cm, long 15cm given size rejects lymphoid tissue, with certainly
Water is rinsed 3 times, then is rinsed with purified water to surface without spot, and the intestinal submucosa tissue material after flushing is positioned over into filter
On the water treatment plants such as net, more than 5 minutes are stood, water is filtered dry.
(2) inactivation of virus：
Inactivation of virus is carried out using Peracetic acid-alcohol solution dipping intestinal submucosa tissue material, the process can be
Carried out in stainless steel cask.The concentration of volume percent of Peracetic acid is the 2%, volume hundred of ethanol in Peracetic acid-ethanol solution
It is 20% to divide specific concentration, and the ratio (volume ratio) of Peracetic acid-ethanol solution and intestinal submucosa tissue material is 5 ︰ 1, is gone out
Live time 2 hours, temperature range is 20 DEG C；Then respectively with PBS and purifying water process in Vltrasonic device；Wherein use pH value
For the 7.2-7.4 ultrasonically treated intestinal submucosa tissue material of PBS solution, solution temperature is 20 DEG C, and PBS solution is glued with small intestine
The volume ratio of film lower-hierarchy material is 30 ︰ 1, preferred process 3 times, every time 20 minutes；Then cleaned using 20 DEG C of purified water,
Purified water is 30 ︰ 1 with intestinal submucosa tissue material proportion, is terminated to detection electrical conductivity for below 10 μ S/cm；Cleaning process
Carried out in supersonic wave cleaning machine, frequency 40kHz, more than power 3000W.
(3) immunogene is removed：
Immunogene removes liquid and uses trypsase and concentration containing mass percent 0.02% for 0.5mmol/L EDTA
PH value be 7 PBS solution, it is 30 ︰ 1 that immunogene, which removes liquid and intestinal submucosa tissue material mixing ratio (volume ratio),
Immunogene removal process is carried out in multiple frequency ultrasonic device, and ultrasonic power is in more than 5000W；Multiple frequency ultrasonic at least includes two
Supersonic frequency, Frequency scope is 35KHz, and higher frequency is 70KHz, wherein low frequency processing 5min, high-frequency therapeutic treatment 10min,
Temperature is 22 DEG C.Then submucous layer of small intestine matrix is obtained respectively with PBS solution and purifying water process in supersonic wave cleaning machine
Material；PH value 7.2-7.4 PBS solution and intestinal submucosa tissue material proportion are 30 ︰ 1, purified water with mucous membrane of small intestine
Layer tissue material proportion is 30 ︰ 1, and it is 1 μ S/cm that water for injection electrical conductivity difference is handled to detection cleaning with 24 DEG C of waters for injection
Terminate below；The preferred 40kHz of supersonic frequency, preferred more than the 3000W of power.
(4) dry：
Carry out, baking oven is preheated to after 40 DEG C, what will be obtained by step (3) goes through immunogene in hundred grades of baking ovens of thermal cycle
The host material removed is fixed on mould, and is together put in oven drying, and the time is 16 hours.
(5) prepared by slurry：
It will be shredded by the host material after step (3) cleaning, grind broken using liquid nitrogen frozen reducing mechanism, by what is shredded
Host material and liquid nitrogen feeder are crushed, the particle then gone out by sieved through sieve below 150 μm of particle diameter；Particle is added
The acetic acid solution of 0.3% (mass percent), granular mass is (0.5-2) with acetic acid solution mass ratio:1, broken after vacuum drying
It is broken into particle；Then it is (1-50) by growth factor and granular mass ratio:10000 ratio adds growth factor into particle
(such as epidermal growth factor) aqueous solution, such as with 20:10000 ratio is added, and forms slurry.Wherein, according to granular mass
And proportionate relationship determines growth factor quality, then growth factor and water are configured to the matter of solution, wherein growth factor and water
Amount is than being (1-50):1000, then solution is instilled in particle and is well mixed；Purified water further can also be added to adjust
Slurry viscosity；The water of 5-50 times of the water, preferably 30 times of granular mass can be added.
(6) molding control：
The dried submucous layer of small intestine host material film obtained by step (4) is taken as superficial layer, on two surfaces
The slurry obtained by step (5) is added between layer, mould is laid in.
(7) it is freeze-dried：
Material after shaping is laid in vacuum freeze drier, the door of cryodesiccation chamber is closed, circulating pump about 1min is opened, opens
Compressor is opened to freeze drying box refrigeration, by step (6) mould together with material pre-freeze to -45 DEG C, 2 hours is incubated, is then turned on vacuum
Pump, adjusts the temperature to -15 DEG C, is incubated 6 hours, then adjusts the temperature to 0 DEG C, is incubated 2 hours, finally adjusts the temperature to 25 DEG C, guarantor
Temperature 4 hours, vacuum freeze drying is completed.
Preparation method in the present embodiment can also be comprised the steps of：
(8) sterilizing parsing：
Sterilized using oxirane, sterilising conditions are：First 40 DEG C of temperature is incubated 4 hours, and humidity 70% is then passed to
Concentration 500mg/L oxirane, sterilizes 6 hours；Resolving is carried out in the Resolution Room of ventilation, temperature control 20 DEG C it
Between, time 14d.
Structure of title compound of the present invention is as shown in Figure 1：Including upper and lower superficial layer (upper surface layer and undersurface layer) and centre
Layer, microstructure is as shown in Figure 2.
Chemical composition to resulting materials of the present invention is detected, as shown in table 1 below：
Table 1
| Albumen (%) | Carbohydrate (%) | Lipid (%) | Moisture | Ash content | Growth factor |
| 75%-85% | 15%-25% | <1% | <5% | <1% | 0.01-2% |
Embodiment 2：Performance detection
1) the heteroimmune original removal host material that high induced activity carries albumen is three-decker, and upper and lower surface layer is complete
Superficial layer, intermediate layer is, containing growth factor layer, to form sandwich structure, superficial layer is comparatively dense, can control material degradation row
For with growth factor release speed, and growth factor layer be porous structure layer, beneficial to preserve growth factor.Surface layer porosity is
67.4 ± 5.2%, and growth factor layer percent opening 90.5 ± 7.0%.
2) mechanics properties testing shows that sample stretches fracture strength up to 105N/cm, and suture confining force is more than 21N.
3) according to biological agent residual DNA detection method《Chinese Pharmacopoeia》Version the 4th in 2015, using fluorescence colour
The sample DNA residual quantity that detection embodiment 1 is provided, the 2.56 ± 0.14ng/ of DNA residual quantities for the sample that embodiment 1 is provided
mg。
4) using the DNA copy number of real-time quantitative PCR method detection virus, 3 batches of samples are detected.As a result：Viral DNA copies number
For 0.
5) according to GB/T 14233.2-2005《Medical infusion, blood transfusion, instrument used for injection method of inspection part 2：Biology
Test method》The sample that detection embodiment 1 is provided is carried out, as a result：Bacterium endogenous toxic material covers for 20EU/.
6) galactosidase (α-Gal) clearance rate immunogene remove before processing material Gal values be 23.41 ± 2.34 ×
1014The Gal values of sample are 0.13 ± 0.02 × 10 in/mg, embodiment 114/ mg, galactosidase (α-Gal) clearance rate exists
More than 99.40%.
7) I, III, IV type and VI collagen types are detected using Immunohistochemical Staining, are positive.Polysaccharide material content
Detection shows that content of chondroitin sulfate average value is 5687 ± 201 μ g/g in sample, and hyaluronic acid (HA) reserved average value is
354±35μg/g。
8) using Immunohistochemical Staining detection active factors fibronectin splicing variants, laminin, integrin, in sun
Property.
Embodiment 3：The detection of active factors release profiles
The heteroimmune original removal host material of high induced activity load albumen prepares sample by embodiment 1 and is placed in 12 orifice plates
In, the PBS (pH 7.4) of 2 milliliters of addition in every hole.The 5%CO at 37 DEG C of saturated humidity2The CO of atmosphere2It is incubated in incubator
1st, 3,5,7,14,21,28d (my god), then PBS is transferred in centrifuge tube, and detect that platelet derived growth factor contains in PBS solution
M1 is measured, to add initial incremental amount as denominator M0, growth factor release rate=M1/M0 is calculated.As shown in Figure 3, growth factor is released
Put stably and controllable, it is that the 19.92 ± 1.96%, the 3rd day release rate is 46.32 ± 3.36% that solid sub- release rate is grown at the 1st day, the
Total release rate reaches 86.56 ± 3.42% when release rate is 64.16 ± 2.50%, 28 days within 7 days.Therefore growth factor sustainable week
More than 28 days phase, do not occur phenomenon of burst release, embody high induced activity.Embodiment 4：Add thin to nerve after nerve growth factor
The influence of born of the same parents' survival rate
The heteroimmune original removal host material that high induced activity carries albumen prepares sample by embodiment 1, wherein add
Growth factor replaces with nerve growth factor, prepares sample and is cut to sample, is placed in 96 holes and carries out neuronal cell cultures, uses
MTT tests the survival rate of nerve cell, and blank control group only adds culture medium.Structure as shown in Figure 4, culture 3 days when, test group
Cell survival rate is higher than blank control group by 29.62 ± 2.66%, and when cultivating 5 days, test group cell survival rate compares blank control group
High by 50.04 ± 12.69%, when cultivating 7 days, test group cell survival rate is higher than blank control group by 54.87 ± 9.47%, therefore high
Nerve cell is significantly improved after the heteroimmune original removal host material addition nerve growth factor of induced activity load albumen to deposit
Motility rate.
To sum up, a kind of repair materials of high induced activity of the present invention：
(1) DNA residuals can reach below 10ng/mg, 30-50ng/mg low compared with like product, galactosidase clearance
It is higher, more than 99% can be reached；
(2) reduction causes allergy, infection, inflammation, granuloma, the risk of localized abscesses；
(3) active growth factor in extracellular matrix is retained；
(4) the multiple beneficial growth factor added using aminoglycan, proteoglycans grappling；
(5) degradable in vivo, growth factor release is controllable, and the action period is long, with height induction energy living；
(6) controllable mechanical performance, growth factor release and mechanical property are controlled by different number of plies close membranes；
(7) production process can realize standardization, industrialization.
The above embodiment of the present invention is the description of the invention and cannot be used for the limitation present invention, the right with the present invention
Any change in claim suitable implication and scope, is all considered as being included within the scope of the claims.
Claims (11)
1. a kind of repair materials of high induced activity, it is characterised in that：The material is by with the natural of three-dimensional netted loose structure
High polymer material is constituted, including the three-decker being made up of intermediate layer and upper and lower superficial layer；Intermediate layer includes collagen, many
Sugar substance, active factors and growth factor, upper and lower superficial layer include collagen, polysaccharide material and active factors, the reparation
Material can degrade in vivo.
2. repair materials according to claim 1, it is characterised in that：The repair materials are with animal submucous layer of small intestine group
Material is knitted to be made.
3. repair materials according to claim 2, it is characterised in that：The animal is mammal, preferably pig or ox.
4. the repair materials of high induced activity according to claim 1, it is characterised in that：Described collagen be comprising
I types, type III, the composition of IV types and VI collagen types；Described polysaccharide material is to include chondroitin sulfate and hyaluronic acid
Composition；Described active factors is the composition for including fibronectin splicing variants, laminin, integrin and its part；
Described growth factor includes follistatin, nerve growth factor, platelet derived growth factor, epidermal growth factor, base
One or more of their compositions in matter gamma-carboxyl glutamate albumen.
5. the repair materials of high induced activity according to claim 1, it is characterised in that：The time of described internal degraded
For 3-6 months.
6. the repair materials of high induced activity according to claim 1, it is characterised in that：Described upper surface layer and following table
The porosity of the three-dimensional netted loose structure of surface layer is 45~70%, the hole of the three-dimensional netted loose structure in described intermediate layer
Rate is 75~90%；The repair materials long 1-20cm, wide 1-10cm, thickness 1-4mm.
7. a kind of preparation method of the repair materials of high induced activity, it is characterised in that：Using animal intestinal submucosa tissue
As raw material, by organizing preposition processing, inactivation of virus, immunogene is removed, prepared by dry, slurry, shaping and freeze-drying are walked
Suddenly, obtain and remove Zoonotic virus risk, cell component, DNA compositions and α-Gal antigens, retain repairing for extracellular matrix components
Multiple material.
8. the preparation method of the repair materials of high induced activity according to claim 7, it is characterised in that：Step includes：
(1) the preposition processing of tissue：Animal intestinal submucosa tissue material is taken, cleans and is filtered dry water；
(2) inactivation of virus：Virus is carried out using Peracetic acid-alcohol solution dipping animal intestinal submucosa tissue material to go out
It is living；Then cleaned in Vltrasonic device；
(3) immunogene is removed：Immunogene removes liquid and uses the PBS solution containing trypsase and EDTA, immunogene removal process
Carried out in multiple frequency ultrasonic device；Then cleaned in supersonic wave cleaning machine, obtain submucous layer of small intestine host material；
(4) dry：The host material removed through immunogene obtained by step (3) is fixed on mould, and is together put in baking oven
Dry；
(5) prepared by slurry：It will be shredded by the host material after step (3) cleaning, grind broken using liquid nitrogen frozen reducing mechanism,
Obtain particle；Particle adds acetic acid solution, and particle is broken for after vacuum drying；Then growth factor solution is added into particle,
Form slurry；
(6) it is molded：The dried submucous layer of small intestine host material film that is obtained by step (4) is taken as first surface layer and the
Two superficial layers, the slurry obtained by step (5) is added between two superficial layers, is laid on mould；
(7) it is freeze-dried：Material after shaping is positioned in vacuum freeze drier and carries out vacuum freeze drying.
9. the preparation method of the repair materials of high induced activity according to claim 8, it is characterised in that：
The concentration of volume percent of Peracetic acid is that 0.1%-5%, the concentration of volume percent of ethanol are 5%- in step (2)
40%, the volume ratio of Peracetic acid-ethanol solution and intestinal submucosa tissue material is (3-20) ︰ 1, inactivation time 2-4 is small
When, temperature range is 10-40 DEG C, more than ultrasonic power 5000W；It is processed as in step (2) Vltrasonic device：Use pH value for
7..2-7.4 the ultrasonically treated intestinal submucosa tissue material of PBS solution, solution temperature is 20 DEG C, and PBS solution is glued with small intestine
The volume ratio of film lower-hierarchy material is 30 ︰ 1, preferred process 3 times, every time 20 minutes；Then cleaned using 20 DEG C of purified water,
Purified water is 30 ︰ 1 with intestinal submucosa tissue material proportion, is terminated to detection electrical conductivity for below 10 μ S/cm；Cleaning process
Carried out in supersonic wave cleaning machine, frequency 40kHz, more than power 3000W；
It is the PBS solution containing trypsase and EDTA that immunogene, which removes liquid, in step (3), and immunogene removes trypsase in liquid
Mass percent concentration be 0.01-0.2%, EDTA concentration is 0.1-1mmol/L, and the pH value that immunogene removes liquid is 7.0-
8.0；The immunogene removes liquid with intestinal submucosa tissue material volume ratio for (20-40) ︰ 1, immunogene removal process exists
Carried out in the supersonic wave cleaning machine at least including two supersonic frequencies, wherein Frequency scope is 20-40KHz, higher frequency
For 60-90KHz, wherein low frequency processing 5-40min, high-frequency therapeutic treatment 5-40min, temperature range is 20-35 DEG C；Then in ultrasonic wave
Handled respectively with PBS solution and cooling water for injection in cleaning machine, obtain submucous layer of small intestine host material；PH value 7.2-7.4
PBS solution and intestinal submucosa tissue material proportion be (20-40) ︰ 1, water for injection and intestinal submucosa tissue material
Ratio is (20-40) ︰ 1, water for injection handles to detection cleaning water for injection electrical conductivity difference and terminated for below 1 μ S/cm；It is super
The preferred 40kHz of acoustic frequency, preferred more than the 3000W of power；
Step (4) drying is：Immunogene is removed in the environment that organization material is placed in 25-40 DEG C of temperature, the time is 8-16 hours,
Form upper surface layer or undersurface layer；
Step (5) described slurry is prepared as：Host material after step (3) is cleaned is shredded, and uses liquid nitrogen frozen reducing mechanism
Grinding is broken, and the host material shredded is crushed, then gone out by sieved through sieve below 250 μm of particle diameter；Added in particle
Mass percent is 0.3% acetic acid solution, is crushed after vacuum drying；Then it is (1- by growth factor and granular mass ratio
50):10000 ratio adds the growth factor aqueous solution into particle, slurry is formed, for preparing intermediate layer；
Freeze-drying described in step (7) is：Superficial layer is freeze-dried with active layer, pre-freeze is incubated 1-2 to -45 DEG C
Hour, then adjust the temperature to -15 DEG C, be incubated 5-7 hour, then adjust the temperature to 0 DEG C, insulation 2 hours is finally adjusted the temperature to
25 DEG C, 4 hours are incubated, composite construction is formed.
10. the preparation method of the repair materials of high induced activity according to claim 9, it is characterised in that：Step (3) is exempted from
The mass percent concentration that epidemic focus removes trypsase in liquid is 0.02-0.05%, and EDTA concentration is 0.4-0.8mmol/L,
The pH value that immunogene removes liquid is 7.2-7.5.
11. a kind of application of repair materials of high induced activity in implantation instrument is repaired, it is characterised in that：It is described to repair implantation
The reparation that Application of device is damaged in cardiac muscle, nerve, smooth muscle, epithelial tissue, or be fixed on the position of injury tissue there is provided power
Learn and support and insulation blocking, and slowly discharge growth factor.
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| CN108066043A (en) * | 2017-12-22 | 2018-05-25 | 山东赛克赛斯生物科技有限公司 | A kind of medical embedded sticking patch and preparation method and application |
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