Two, background technology
Fracture is the result of mechanicalness over loading, is the destruction of the seriality generation of bone.All fracture all can cause the complex injury of skeleton and surrounding soft tissue thereof.The healing of fracture is complicated process, and it is subjected to influence of various factors such as overall health of patients, local factor and degree of injury.In many influence factors, confession of the blood of fracture site and periosteum state are directly connected to the process of union of fracture.And factors such as the contact of fracture end, soft tissue embedding, also the healing important influence to fracturing.Orthopedist's common recognition is: in bone surgery, the fracture end periosteum stripping is partly more extensive, and the degree of the sclerotin at fracture site position and periosteum ischemia is just more serious; Embedding if any soft tissues such as muscle, tendon, fascias between the fracture site, will be to cause the most important reason of postoperative fracture disunion.In recent years, more and more many studies show that: the effect of the induced osteogenesis of bone formation generation albumen (BMP), promotion union of fracture can be clinical practice and brings positive impact.
At the complexity of orthopaedic disease itself, surgical doctor takes to alleviate fracture site tissue, muscle injury usually as far as possible, reduces scheme treatments such as periosteum stripping scope.But this can increase the difficulty of operation, the time of prolongation operation undoubtedly, and increases the risk of operation, and the probability of Post-operative complications and sequela is increased.Therefore how avoiding operation back " the embedded growth of fracture site soft tissue, prevent nonunion " is a great problem of present medical circle.
Three, summary of the invention
At the blank in the above-mentioned field, one of purpose of the present invention provides a kind of biological absorbent artificial periosteum.
Another purpose of the present invention provides a kind of preparation method of biological absorbent artificial periosteum.
These and other objects of the present invention will further embody and set forth by following detailed description and explanation.
Biological absorbent artificial periosteum of the present invention, be the perforated membrane with loose structure, the dense film of non-porous structure or the composite membrane of part meshed portion non-porous structure, be 100000 by biodegradable macromolecule member material that absorbs and the medicine with promotion union of fracture function with weight ratio: 0.1-2: 1 forms; Further, the weight ratio of the two is 10000: 1-2: 1; Further, the weight ratio of macromolecule member material and medicine is 1000: 1-1.5: 1, and what can select is that the weight ratio of molecular film material and medicine is 10: 1-1: 1.
In biological absorbent artificial periosteum of the present invention, the macromolecule member material that the biodegradable that is adopted absorbs can be synthetic high polymer, also can be natural polymer.Synthetic class Biodegradable high molecular be poly (l-lactic acid) (PLLA), poly-DL-lactic acid (PDLLA), copolymerization (L-lactic acid/DL-lactic acid) (PL-DL-LA), copolymerization (Acetic acid, hydroxy-, bimol. cyclic ester/lactide) (PLGA), polycaprolactone (PCL), poly-(Acetic acid, hydroxy-, bimol. cyclic ester/lactide/caprolactone) terpolymer (PGLC), polycaprolactone/polyethyleneglycol block copolymer (PCE), polycaprolactone/polyethyleneglycol/polylactide terpolymer (PCEL), and Biopol GO 4 (PHB), poly-hydroxy pentane ester (PHV) and the two aliphatic polyester family macromolecule or its blends such as copolymer.The natural biological degraded macromolecular is collagen, gelatin, chitosan and/or hyaluronic acid.
In biological absorbent artificial periosteum of the present invention, described medicine with promotion union of fracture function is one or more in exogenous skeletal growth factor bone formation generation albumen (BMP), basic fibroblast growth factor (bFGF), insulin like growth factor, nerve growth factor (NGF) and the platelet source multiplicaiton factor (PDGF).
The method for preparing biological absorbent artificial periosteum of the present invention comprises that solution-cast film build method, the hot-extrudable film build method of hot pressing, solution are injected into film method, porogen pore film build method, freeze-dried film build method, EFI and are spun into film method or are woven into one or more of film method.
In the method for preparing biological absorbent artificial periosteum of the present invention, described method specifically can adopt following steps: the macromolecule member material dissolution with solvents that elder generation absorbs biodegradable, add then and have the medicine that promotes the union of fracture function, back injection politef mould stirs, after treating the oxolane bone dry, desolventizing is 1～3 day under room temperature and vacuum condition, obtain the dense film that thickness is 0.1～0.4 millimeter non-porous structure, perhaps with macromolecular solution-30～--50 ℃ freezing down after desolventizing 1～3 day under vacuum condition again, obtain the perforated film that thickness is 0.1～0.4 millimeter loose structure.
Described method also can adopt following steps: the macromolecule member material dissolution with solvents that elder generation absorbs biodegradable, add then and have the medicine that promotes the union of fracture function, the back electric jet spinning spray webbing of employing that stirs becomes the nonwoven film, desolventizing 1～3 day under room temperature and vacuum condition obtains the perforated film that thickness is 0.1～0.4 millimeter loose structure again.
Above-mentioned solvent can be oxolane, dioxane, acetone, chloroform or dichloromethane, can be used alone, and also can use the mixture of arbitrary proportion.
The present invention adopts macromolecule membrane to combine with the somatomedin with promote osteogenesis, play the mechanical isolation effect that in fracture healing process, can prevent the soft tissue impaction fracture broken ends of fractured bone effectively, can promote fracture site position blood circulation, stimulating osteoblast to enliven again, thereby reach the purpose that promotes union of fracture, shortens healing time.
Biological absorbent artificial periosteum is a kind of good biocompatibility, the biodegradable and macromolecule membrane that absorbs.Utilize the barrier action of polymeric membrane, fracture face and surrounding tissue effectively can be isolated, prevent that the fibroblast in the surrounding tissue from invading fracture face, between fracture face and surrounding tissue, to form a physical barriers.The degradation rate of biological absorbent artificial periosteum of the present invention is determined according to the time parameter that postoperative body fibrin oozes out, owing to finally become water and carbon dioxide after the macromolecule degraded, therefore can be absorbed by the body or be excreted, finally can be fully disappear in the body and can be not residual in vivo.Because polymeric membrane has excellent biological compatibility, direct contact bone fracture, therefore can make somatomedin such as bone formation generation albumen or medicine directly surgical wound and on every side the position discharge, have the curative effect faster, higher, and dosage can significantly reduce than the systemic administration of routine.
Macromolecular material in the biological absorbent artificial periosteum had both played the buffer action of anti-surrounding tissue impaction fracture section of machinery, played pharmaceutical carrier again and to the controlled delivery of pharmaceutical agents release action; And the medicine in the film can play the effect that promotes osteoplastic effect, can play the stimulation bone resorption, therefore bone is rebuild to have dual regulation.
The formation of endochondral ossification and blood capillary is the important step of induced osteogenesis, but and the mesenchymal cell of exogenous skeletal growth factor BMP inducing peripheral tissue to be converted into the bone of irreversibility be cell, make that the position forms cartilage and osseous tissue beyond skeleton or skeleton; And basic fibroblast growth factor (bFGF) has the effect that stimulates chondrocyte proliferation, and is a kind of very strong capillary proliferation stimulant.
Biodegradable high molecular in the biological absorbent artificial periosteum of the present invention degradation time in vivo is 3-500 days, biological absorbent artificial periosteum promptly of the present invention will be in 3-500 days complete obiteration in the body.
The all raw material of Shi Yonging all is conventional uses in the present invention, can buy from market.
In the present invention, refer in particular to as non-, all amount, percentage ratios are unit of weight.
Below further specify the present invention by specific embodiment, but embodiment only be used for the explanation, can not limit the scope of the invention.
Four, the specific embodiment
Embodiment 1,
Copolymerization (Acetic acid, hydroxy-, bimol. cyclic ester/lactide) is (molecular weight 80,000) 10 parts (PLGA), with adding bone formation generation albumen (BMP) 0.001 part after 180 parts of dissolvings of oxolane, back injection politef mould stirs, after treating the oxolane bone dry, desolventizing is 48 hours under the room temperature vacuum condition, obtains thickness and be 0.1 millimeter atresia compact texture solid film.
Embodiment 2,
Press method and the step of embodiment 1, but adopt 0.01 part of 10 parts of collagens, 100 parts in water and insulin like growth factor (PDGF), the politef mould is injected in the back that stirs, and is freezing down at-40 ℃, vacuum and dehydration below-40 ℃ 48 hours, obtain thickness and be 0.3 millimeter perforated membrane then.
Embodiment 3,
Press method and the step of embodiment 1, but adopt 1 part of 10 parts of poly-(Acetic acid, hydroxy-, bimol. cyclic ester/lactide/caprolactone) terpolymers (PGLC) (molecular weight 50,000), 200 parts of dioxane and basic fibroblast growth factor (b-FGF), freezing down at-40 ℃, then vacuum and desolventizing below-40 ℃ 48 hours, obtain thickness and be 0.2 millimeter loose structure film.
Embodiment 4,
Press method and the step of embodiment 1, but adopt 0.001 part of 10 parts of hyaluronic acids, 190 parts in water and fibroblast growth factor (bFGF),-40 ℃ down freezing, then vacuum and desolventizing below-40 ℃ 48 hours, obtain thickness and be 0.2 millimeter loose structure film.
Embodiment 5,
Press method and the step of embodiment 1, but adopt (PL-DL-LA) (molecular weight 50,000) 10 parts of copolymerization (L-lactic acid/DL-lactic acid), with adding platelet source multiplicaiton factor (PDGF) 0.0001 part after 200 parts of dissolvings of acetone, back injection politef mould stirs, after treating the acetone bone dry, desolventizing is 48 hours under the room temperature vacuum condition, obtains thickness and be 0.1 millimeter atresia compact texture solid film.
Embodiment 6,
Press method and the step of embodiment 1, but adopt polycaprolactone/polyethyleneglycol/polylactide terpolymer (molecular weight 60,000) 10 parts, with adding bone formation generation albumen (BMP) 0.0005 part after 180 parts of dissolvings of dioxane, back injection politef mould stirs, in the room temperature vacuum drying oven, keep 48 hours after freeze-dried again to eliminate solvent fully, obtain thickness and be 0.15 millimeter perforated membrane.
Embodiment 7,
Press method and the step of embodiment 1, but adopt 10 parts of chitosans, add 0.001 part of nerve growth factor (NGF) after 125 parts of dissolvings of acetic acid weak solution, it is 0.10 millimeter porous nonwoven film that the electric jet spinning in back that stirs obtains thickness.
Embodiment 8,
Press method and the step of embodiment 7, the chitosan acetic acid weak solution electricity consumption jet spinning that will contain nerve growth factor (NGF) is sprayed onto part and is equipped with on the prepared atresia dense film of embodiment 1, obtains being the composite construction film of part meshed portion atresia.
Embodiment 9,
Press method and the step of embodiment 7, the hyaluronic acid solution electricity consumption jet spinning that will contain 0.01 part of 10 parts of hyaluronic acids, 35 parts of water/alcohol mixed solutions and nerve growth factor (NGF) is sprayed onto on the substrate, obtains the nonwoven film of loose structure.