CN104368044A - Collagen-based biodegradable spinal fusion cage and preparation method thereof - Google Patents
Collagen-based biodegradable spinal fusion cage and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a collagen-based biodegradable spinal fusion cage and a preparation method thereof. The collagen-based biodegradable spinal fusion cage comprises the following components in percentage by weight: 50%-90% of collagen, 1%-40% of a modified material and the balance of biodegradable high-molecular polymers, wherein the modified component is hydroxyapatite, chitosan, calcium phosphate or a mixture of three or two of the hydroxyapatite, the chitosan and the calcium phosphate at any ratio. The method comprises the following steps: firstly, preparing a mixed solution of the collagen and the modified component; paving a film to carry out ultraviolet crosslinking or chemical crosslinking after centrifuging, so as to obtain a massive material; processing the obtained massive material into the shape of the spinal fusion cage required for the clinical; and coating a layer of 0.01-5mm of biodegradable high-molecular polymer on the inner surface and the outer surface, so that the degradation rate is controllable. According to the spinal fusion cage prepared by adopting the method, the mechanical property of the material is ensured, the degradation time can be controlled; the clinical requirements of instruments can be met; the degradation product is free of a residue in the body; and the pain of a patient caused by a secondary surgery is avoided.
Description
Technical field
The invention belongs to biological and medicinal implant material field, relate to a kind of collagen-based degradable spinal fusion device and preparation method thereof, the material of this fusion device is made up of collagen protein-modified component/degradable high polymer material specifically.
Background technology
Spinal fusion is the effective means of the spine disorderses such as treatment spinal tuberculosis, infection, deformity, the change of lower limb type sexually transmitted disease (STD) and intervertebral disk injury.Spinal fusion device is a kind of medical apparatus and instruments for internal fixation of spine, be also spinal fusion surgery a kind of spinal column of commonly using be implanted into device.
Spinal fusion surgery was proposed by Hibbs the earliest in 1911, and after proposing the theory of intervertebral fusion to Mercer in 1936, spinal fusion surgery obtains and develops rapidly, had become the important means for the treatment of orthopaedic disease now.Within 1979, rustless steel hollow column with holes replaces iliac to be used for the cervical intervertebral fusion of horse by Bagby, claims Bagby cage (Bagbybasket).Nineteen eighty-three, the lumbar intervertebral being used for people merges by Bagby and Kuslish cooperation, and adds thread surface, material titanium alloy, is BAK (Bagby and Kuslish).Within 1988, they prepare BAK system with titanium alloy, i.e. titanium alloy open column shape body-Cage, because this Cage surface is threaded, and can from steady in upper and lower soleplate; Distracting force during implantation can make again fibrous ring, front and back ligament is in tension state, forms " strutting-compressive tension band " effect, through Clinical practice, respond well.
But the elastic modelling quantity of metal spinal fusion device, far away higher than cortical bone, can cause stress shielding in vivo, thus cause that implant site produces osteoporosis, osteanabrosis, implant site subside, fusion device loosens or the complication such as slippage.And the chip that metal fusion device produces makes body produce macrophage, il-1, interleukin-6, PGE2, tumor necrosis factor etc., affects the fusion of bone.By the macromolecule non-degradable material of synthetic (as polyether-ether-ketone, PEEK) spinal fusion device made, although elastic modelling quantity mates with vertebral bone, there is good corrosion resistance, can through X-ray, but because its biocompatibility is not fine, cause a series of complication: nerve root injury, fusion device loosen, fusion device subsides, intervertebral space and Neuroforamen height reduce, do not merge.
Collagen belongs to the structural protein of extracellular matrix, is extensively present in the tissues such as the skin of vertebrates and people, tendon, ligament, cartilage and bone or organ.Due to the source of collagen uniqueness, composition and construction features, make it have the features such as excellent biocompatibility, suitable degradability and poor antigen.Therefore from the viewpoint of to the requirement of material biological nature, collagen is applicable to making various biological support, but the shortcoming that in biomechanics, this mechanical property of materials is poor, degradation rate is fast again limit its range of application.Therefore design that a kind of biological safety is good, to improve plastic deformation ability and intensity, control its corrosion degradation speed be the problem that exploitation collagen-based orthopedic implanting material must solve.
The present invention proposes, with having the modified component promoting neuranagenesis, hemostatic function and excellent mechanical performances, collagen-modified component to be made the composite with good mechanical strength by cross-linking method.After this materials processing is become medically learned apparatus shape, within it outer surface one deck degradable high polymer material carrys out the degradation rate of control device again, obtains the spinal fusion device of the controlled collagen-modified component of degradation rate/degradable high polymer material composition.Coated macromolecule degraded coating must not have hole, otherwise first can come off with coating after bioresorbable and do not reach the object of control degradation.There is not been reported both at home and abroad for correlational study.
Summary of the invention
The object of the invention is the preparation method of openly a kind of collagen-based degradable spinal fusion device, this fusion device both can have been avoided using the stress existing for metal fusion device block and produce the problems such as chip, non-degradable macromolecular material can be avoided again to deposit the problem such as biocompatibility.Spinal fusion device material of the present invention has degradability, and biocompatibility is good, can in vivo along with the formation of bone, and himself is constantly degraded, and is finally excreted by absorbing, and does not stay remnants.
Technical scheme of the present invention is summarized as follows: the vivo degradation spinal fusion device that a kind of collagen-based degradation rate is controlled, the matrix of this fusion device is collagen protein, used material modified be chitosan, hydroxyapatite, calcium phosphate or more three or both arbitrary proportion mixture, be combined with each other by crosslinked, improve the mechanical performance of collagen protein.Above-mentioned material is processed into the spinal fusion device of clinical required form, within it outer surface a layer thickness is at the degradable high polymer material of 0.01-5mm, control collagen group composite material degradation rate.Finally make the vivo degradation spinal fusion device that a kind of collagen-based degradation rate is controlled, solve the technical barrier existed clinically now.
Collagen-based degradable degraded spinal fusion device of the present invention, is controlled the speed of material premature degradation, is ensured the mechanical property in degradation process by collagen-material modified matrix by degradable macromolecule coating.
Major advantage of the present invention is:
1. degradation rate is easy to control.Polymeric coating layer of the present invention can be single high molecular component also can be two or more high molecular mixture.The degradation rate carrying out control device by high molecular point of strength selecting or coating layer thickness reaches clinical required effect.
2. the safe, practical property of raw materials is good.The matrix material adopted is collagen, chitosan, hydroxyapatite, calcium phosphate, and this different materials is drawn materials easy and is good biocompatibility, is all the bio-medical material be widely used at present.Do not have the chip untoward reaction of the degradable metal materials such as magnesium alloy, also can not as non-degradable macromolecular material Permanent implantation, have inflammatory reaction at a specified future date.
A preparation method for collagen-based degradable spinal fusion device, has following steps:
(1) according to ratio concentration preparation collagen and the mixed solution of modified component of claim 1;
(2) the centrifugal removing bubble of sufficient mixed solution will be dissolved, and by the viscous mixture plastic film mulch after centrifugal, thickness 5-30mm;
(3) diaphragm of (2) is cross-linked under draughty condition, after 24 hours, again adds mixed solution, until material thickness reaches necessary requirement, stop crosslinked, vacuum drying;
(4) the degradable high polymer organic solution of compound concentration 5%-10%;
(5) (3) resulting materials is processed into the spinal fusion device of clinical required size, within it outer surface sprays the macromolecule polymer solution that one deck configures, and makes coating layer thickness between 0.01-5mm, and coating must not have hole;
(6) vacuum drying, sterilizing, obtains required spinal fusion device.
Detailed description of the invention
Case study on implementation 1
Take the acetic acid wiring solution-forming 550ml that 10gI Collagen Type VI and 6g chitosan concentration are 0.05% respectively, centrifugal 5 minutes of 10000r/min, by the viscous mixture plastic film mulch after centrifugal, 10mm after film; By UV-crosslinked under the condition that ventilation condition is good for the diaphragm completed, continue after 24 hours to add collagen and chitosan centrifugal after mixture, stop crosslinked until build reaches 20mm, vacuum drying, and the spinal fusion device being processed into that length, width and height are respectively 4-18mm, 6-12mm, 12-32mm; Compound concentration is the PLGA organic solution of the molecular weight 200,000 of 10%, and the ultrasonic surfaces externally and internally being sprayed at apparatus, does not interspace, and coating layer thickness is 2mm.After vacuum drying, ethylene oxide sterilizing.
Body weight 50kg male and female do not limit Small-fat-tail sheep, at the other curved incision of the left side 12 rib spinal column of sheep, cut skin, subcutaneous tissue and muscular fascia successively, then incision obliquus externus abdominis m. and rectus abdominis m. are to outside peritoneum, cut off the 12nd rib, blunt separation, to psoas major leading edge, is separated the vertebral body that psoas major exposes rear, the Segmental model of ligation vertebral body.Bore an aperture with trepan in breast 12 waist 1 gap, after emptying intercalated disc and little broken bone, adopt setting device to settle fusion device, fusion device is placed in sheep breast 12 rib 1 gap, again the rib cut off is shredded the hole putting into fusion device central authorities, compress slightly, layer-by-layer suture otch.Postoperative fasting 6 hours, postoperative three days, gives intramuscular injection 2,400,000 units of Penicillin for twice by every day; Observe wound, and use povidone iodine clean wound.
Result shows: fusion device has good histocompatibility, has no tissue necrosis phenomenon, and implant site has no rejection phenomenon.Microscopic observation: have a large amount of osseous tissue to be formed, without fibrous membrane formation around fusion device, also do not have macrophage and foreign-body giant cell and granulation tissue, have no various inflammatory cell.Postoperative 5 months fusion devices Partial digestion, osseous tissue is grown in fusion device, Bone density is passed in time and obviously increases, and the osseous tissue inside and outside fusion device is connected; Remaining fusion device is combined closely with osseous tissue.The intervertebral space of postoperative 5 months fusing stages plays effective supporting role.Case study on implementation 2
Other are with the size range of case study on implementation 1, and the ratio of collagen-chitosan changes 7: 3 into, and polymeric coating layer changes PLLA into.Then zoopery and observation experiment result is carried out with same animal experiment method.Observed result shows that surgical effect is identical with case study on implementation 1.
Case study on implementation 3
With the size range of case study on implementation 1, the ratio of collagen-chitosan changes 8: 2 into, and polymeric coating layer changes PDLLA into.Then zoopery and observation experiment result is carried out with same animal experiment method.Observed result shows that surgical effect is identical with case study on implementation 1.
Case study on implementation 4
With the raw material ratio of case study on implementation 1, the UV-crosslinked genipin that changes into is cross-linked, and the concentration of polymeric coating layer changes 5% into, and thickness changes 0.01mm into.Then zoopery and observation experiment result is carried out with same animal experiment method.Observed result shows that surgical effect is identical with case study on implementation 1.
Case study on implementation 5
With the raw material ratio of case study on implementation 2, UV-crosslinkedly change glutaraldehyde cross-linking into, the concentration of polymeric coating layer changes 7% into, and thickness changes 0.1mm into.Then zoopery and observation experiment result is carried out with same animal experiment method.Observed result shows that surgical effect is identical with case study on implementation 1.
Case study on implementation 6
With the raw material ratio of case study on implementation 3, UV-crosslinkedly change glutaraldehyde cross-linking into, the concentration of polymeric coating layer changes 9% into, and thickness changes 1mm into.Then zoopery and observation experiment result is carried out with same animal experiment method.Observed result shows that surgical effect is identical with case study on implementation 1.
Case study on implementation 7
With size range, the proportioning raw materials of case study on implementation 1, collagen changes II type into.Then zoopery and observation experiment result is carried out with same animal experiment method.Observed result shows that surgical effect is identical with case study on implementation 1.
Case study on implementation 8
With size range, the proportioning raw materials of case study on implementation 2, collagen changes type III into.Then zoopery and observation experiment result is carried out with same animal experiment method.Observed result shows that surgical effect is identical with case study on implementation 1.
Case study on implementation 9
With size range, the proportioning raw materials of case study on implementation 3, collagen changes V-type into.Then zoopery and observation experiment result is carried out with same animal experiment method.Observed result shows that surgical effect is identical with case study on implementation 1.
Case study on implementation 10
With size range, the proportioning raw materials of case study on implementation 1, chitosan changes hydroxyapatite into.Then zoopery and observation experiment result is carried out with same animal experiment method.Observed result shows that surgical effect is identical with case study on implementation 1.
Case study on implementation 11
With size range, the proportioning raw materials of case study on implementation 2, chitosan changes hydroxyapatite into.Then zoopery and observation experiment result is carried out with same animal experiment method.Observed result shows that surgical effect is identical with case study on implementation 1.
Case study on implementation 12
With size range, the proportioning raw materials of case study on implementation 3, chitosan changes hydroxyapatite into.Then zoopery and observation experiment result is carried out with same animal experiment method.Observed result shows that surgical effect is identical with case study on implementation 1.
Case study on implementation 13
With size range, the proportioning raw materials of case study on implementation 1, chitosan changes the mixture of chitosan and hydroxyapatite into.Then zoopery and observation experiment result is carried out with same animal experiment method.Observed result shows that surgical effect is identical with case study on implementation 1.
Case study on implementation 14
With size range, the proportioning raw materials of case study on implementation 2, chitosan changes the mixture of chitosan and hydroxyapatite into.Then zoopery and observation experiment result is carried out with same animal experiment method.Observed result shows that surgical effect is identical with case study on implementation 1.
Case study on implementation 15
With size range, the proportioning raw materials of case study on implementation 3, chitosan changes the mixture of chitosan and hydroxyapatite into.Then zoopery and observation experiment result is carried out with same animal experiment method.Observed result shows that surgical effect is identical with case study on implementation 1.
Case study on implementation 16
With size range, the proportioning raw materials of case study on implementation 1, chitosan changes calcium phosphate into.Then zoopery and observation experiment result is carried out with same animal experiment method.Observed result shows that surgical effect is identical with case study on implementation 1.
Case study on implementation 17
With size range, the proportioning raw materials of case study on implementation 2, chitosan changes calcium phosphate into.Then zoopery and observation experiment result is carried out with same animal experiment method.Observed result shows that surgical effect is identical with case study on implementation 1.
Case study on implementation 18
With size range, the proportioning raw materials of case study on implementation 3, chitosan changes calcium phosphate into.Then zoopery and observation experiment result is carried out with same animal experiment method.Observed result shows that surgical effect is identical with case study on implementation 1.
Claims (6)
1. collagen-based degradable spinal fusion device and preparation method thereof, it is characterized in that material component is by weight percentage: collagen protein 50%-90%, material modified 1%-40%, all the other are degradable high polymer.
2. a kind of collagen-based degradable spinal fusion device according to claim 1 and preparation method thereof, is characterized in that collagen protein is I, II, III or V-type.
3. a kind of collagen-based degradable spinal fusion device according to claim 1 and preparation method thereof, is characterized in that its material modified arbitrary proportion mixture for hydroxyapatite, chitosan, calcium phosphate or more the two or three.
4. a kind of collagen-based degradable spinal fusion device according to claim 1 and preparation method thereof, it is characterized in that involved degradable polymer is polycaprolactone, lactide polymer, the lactide-copolymer of lactide or mixture of above-mentioned arbitrary proportion, polymer molecular weight is 100,000-100 ten thousand.
5. a kind of collagen-based degradable spinal fusion device according to claim 1 and preparation method thereof, is characterized in that preparation method is as follows:
(1) according to ratio concentration preparation collagen and the mixed solution of modified component of claim 1;
(2) the centrifugal removing bubble of sufficient mixed solution will be dissolved, and by the viscous mixture plastic film mulch after centrifugal, thickness 5-30mm;
(3) diaphragm of (2) is cross-linked under draughty condition, after 24 hours, again adds mixed solution, until material thickness reaches necessary requirement, stop crosslinked, vacuum drying;
(4) the degradable high polymer organic solution of compound concentration 5%-10%;
(5) (3) resulting materials is processed into the spinal fusion device of clinical required size, within it outer surface sprays the macromolecule polymer solution that one deck configures, and makes coating layer thickness between 0.01-10mm, and coating must not have hole;
(6) vacuum drying, sterilizing, obtains required spinal fusion device.
6. preparation method according to claim 1, it is characterized in that described cross-linking method is UV-crosslinked or chemical crosslinking, the cross-linking agent of chemical crosslinking is genipin or glutaraldehyde.
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| CN106730012A (en) * | 2017-02-08 | 2017-05-31 | 于晓兵 | A kind of degradable spinal fusion device of collagen-based and preparation method thereof |
| CN110831638A (en) * | 2017-06-02 | 2020-02-21 | 盖斯特里希医药公司 | Resorbable crosslinked form stable membranes |
| RU2838780C1 (en) * | 2024-10-03 | 2025-04-22 | Федеральное государственное бюджетное научное учреждение "Российский научный центр хирургии имени академика Б.В. Петровского" (ФГБНУ "РНЦХ им. акад. Б.В. Петровского") | Method for implantation of biocompatible biodegradable cervical cage in place of destroyed intervertebral disk for fusion of adjacent vertebrae and biocompatible biodegradable cervical cage for its implementation |
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| RU2838780C1 (en) * | 2024-10-03 | 2025-04-22 | Федеральное государственное бюджетное научное учреждение "Российский научный центр хирургии имени академика Б.В. Петровского" (ФГБНУ "РНЦХ им. акад. Б.В. Петровского") | Method for implantation of biocompatible biodegradable cervical cage in place of destroyed intervertebral disk for fusion of adjacent vertebrae and biocompatible biodegradable cervical cage for its implementation |
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Application publication date: 20150225 |