CN1272079C - Multi-channel type biological absorptive nerve regeneration conduit and mfg method thereof - Google Patents
Multi-channel type biological absorptive nerve regeneration conduit and mfg method thereof Download PDFInfo
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- CN1272079C CN1272079C CN 02105864 CN02105864A CN1272079C CN 1272079 C CN1272079 C CN 1272079C CN 02105864 CN02105864 CN 02105864 CN 02105864 A CN02105864 A CN 02105864A CN 1272079 C CN1272079 C CN 1272079C
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Abstract
The present invention provides a multiple channel biologic absorption nerve regeneration guide tube and a preparation method thereof. The multiple channel biologic absorption nerve regeneration guide tube comprises a porosity biologic absorption high molecular hollow circular tube and multiple channel stuffing in the circular tube, which is a porosity biologic absorption high molecular thin film with a concave-convex surface to be filled by single layer or multiple layers in a folding mode or in a spiral shape.
Description
Technical field
The present invention relates to a kind of multi-channel type (multi-channel) biological absorptive nerve regeneration conduit (nerve regeneration conduit), particularly by the hollow circular tube of a porous biological absorptive macromolecule (bioresorbable polymers) and be filled in the nerve regeneration conduit that the porous biological absorptive macromolecule membrane with convex-concave surface in the pipe is constituted.
Background technology
After biomaterial for medical purpose (biomaterials) that the bioresorbable macromolecule is made and device implant into body are organized a period of time, can degraded (degradation) gradually via zymolytic effect in hydrolysis or the human body.The strand of original macromolecular material will progressively rupture, and make high-molecular weight macromolecular material form low-molecular-weight organic material gradually, form micromolecular compound at last, thereby be absorbed by bio-tissue.This by the characteristic of bio-absorbable, the puzzlement that will form medically so-called exotic reaction (foreign body reaction) in the macromolecular material implant into body tissue is greatly reduced.
In recent years, existing many research and utilization bioresorbable macromolecules are made nerve trachea, in the implantable impaired nerve of this nerve conduit, so as to repairing impaired nerve.Be used as the bioresorbable macromolecule kind of nerve trachea a lot of at present in the clinical medicine, the bioresorbable macromolecule of chemosynthesis is for example: polyglycolic acid (polyglycolic acid, PGA), polylactic acid (polylacticacid, PLA), poly-(hydroxyacetic acid-be total to-lactic acid) [poly (lactic-co-glycolic acid), PLGA], polycaprolactone (polycaprolactone, PCL) etc.The bioresorbable macromolecular material kind of natural generation is also quite a lot, for example: collagen, gelatin, silk, chitosan, chitin, algae albumen, hyaluronic acid, chondroitin sulfate or the like.
People such as Stensaas are in U.S. Pat 4662884 (1987), US4778467 (1988), having disclosed a kind of utilization has biocompatibility and does not have infiltrative material, as polyurethane (PU), silicone (silicon), politef (Teflon), celluloid (nitrocellulose) etc. are developed into auxiliary nervous regeneration and suppress the nerve trachea of neuroma (neuroma) growth.Completely in this patent described a kind of silicone rubber that utilizes and be material, make a conduit with file opening, the conduit of this file opening has the operation of being easy to, the characteristics that can close two ends and can form the environment that is isolated from the outside, by special device, also can suppress neuromatous generation simultaneously.
People such as Barrows have disclosed the prosthetic device and the restorative procedure of the neural lacerated wound of a kind of bioresorbable in U.S. Pat 4669474 (1987), US 4883618 (1989).This patent is to use the material of bioresorbable, degradability to make nerve trachea, for example: PLA, PGA Ju oxane ketone (polydioxanone), poly-(lactide-co-glycolide) materials such as [poly (lactide-co-glycolide)], use sinterable polymer technology or other combination technologies, above-mentioned biological absorptive material is made porous tubular structure device (tubular devices).These porous materials have 25%～95% porosity.
People such as Griffiths have disclosed a kind of neuranagenesis subsidiary conduit that utilizes collagen (collagen), fibrin (fibrin) cross-bedding to form the tube wall base material in U.S. Pat 4863668 (1989).When having implantation, reduces by this conduit antigenicity repulsive interaction and degradation speed characteristic slowly.Method of production is to utilize an axle center that has been coated with tetrafluoroethene, immerse in the collagen solution earlier, immerse in the fibrin solution after the drying again, step is carried out repeatedly according to this, with crosslinked 30 minutes of formaldehyde (formaldehyde) and GA glue acid (GA), promptly having finished can auxiliary nervous regenerated guide catheter at last.
People such as Valentini have disclosed a kind of semi-permeable neuranagenesis guide catheter (guidance channel in regenerating nerves) in U.S. Pat 4877029 (1989).Its employed semipermeable materials is acrylic copolymer (acrylic copolymer), polyurethane isocyanates (polyurethane isocyanate) and other semi-permeable biocompatible materialses.
People such as Yannas have disclosed the method that a kind of manufacturing has Biodegradable matter and the macromolecular material of directivity pore space structure is arranged in U.S. Pat 4955893 (1990), and this macromolecular material is used in the regenerated mode of damaged nerve tissue that helps.The material that is used is uncrosslinked collagen-glycosaminoglycans (collagen-glycosaminoglycan) macromolecule.The mode that preparation has the directivity pore space structure then is to utilize axial freezing procedure to reach, and this structure should promote the regeneration of injured nerve and the formation of blood vessel.
People such as Japanese plum east have disclosed the method for the hollow conduit that a kind of manufacturing tube wall is made up of I class collagen (Type I collagen) in U.S. Pat 84963146 (1990), US 5026381 (1991), its characteristics are for having multilamellar and semi-permeable structure, and the nerve that is used to rupture is sentenced and facilitated neuranagenesis.These two patents have also disclosed the method for making nerve regeneration conduit simultaneously.According to the made conduit pore size of this patent is 0.006 μ m to 5 μ m, can allow nerve growth factor diffuse through, but cell can't pass through, so fibroblast etc. can not enter in the pipe.The method for preparing this hollow conduit is: add precipitant [should be mentioned that ammonium hydroxide (ammonium hydroxide) in the claim] in I class collagen solution, formation fiber precipitation, again it is contacted with a rotating shaft (spinningmandrel), thereby formation catheter configurations, pressurization afterwards reduces its diameter and removes supernatant, lyophilization again, crosslinked at last (cross-linking agent of mentioning in the claim is a formaldehyde).
People such as Joseph Nichols have disclosed a kind of I class collagen (Type I collagen) and made hollow conduit of material that contains laminin (laminin) of utilizing in U.S. Pat 5019087 (1991), in order to promote the neuranagenesis at the neural place of fracture.This patent has also disclosed the method for making nerve regeneration conduit simultaneously.The described conduit of this patent has the internal diameter of 1mm～1cm, and internal diameter depends on the size in gap between injured nerve.Conduit thickness is then between 0.05～0.2mm.
Frank Mares has disclosed a kind of nerve trachea that utilizes high-molecular weight lactic acid polymer to make and has assisted the injured nerve growth in U.S. Pat 5358475 (1994).Reveal in this patent,, can produce unexpected effect if the lactic acid polymer molecular weight between 234000 to 320000, restores nerve growth and function.
People such as Della have disclosed a kind of method of making the bioresorbable guiding channel device of neuranagenesis reparation usefulness in U.S. Pat 5735863 (1998).People such as Della use the bioabsorbable material solution of esterification hyaluronic acid (hyaluronic acid ester), coat the stainless steel shaft surface of rotation, then the hyaluronic acid with melting is wound in this rotating shaft surface with fiber form, thereby form a kind of tubulose bioresorbable device, this tube material can be used as the neural guiding device of repairing and uses.
People such as Dorigatti have disclosed the method for a kind of making pharmaceutical device (medical device) in U.S. Pat 5879359 (1999).This patent utilization Biodegradable material, (ester of HA fiber) is raw material as the HA cellulose ester, makes the conduit of a hollow tubular, this conduit can be used for neuranagenesis and repairing.The filament that this conduit is pumped into by interlaced HA cellulose ester is formed and is formed base material (matrix).
People such as Hadlock disclose the method for a kind of manufacturing multitube chamber (multi-lumen) guiding channel in U.S. Pat 85925053 (1999).It is made that guiding channel is to use the bioresorbable macromolecular material in this patent, and the tube chamber number in the guiding channel can be 5～5000.The internal diameter of each inner chamber is 2～500 microns, can utilize tissue culture technique, and (Schwanncells) plants in the channel lumen surface with schwann's cell.The method for making of passage is as follows: place some fine fibres in mould in advance, the macromolecular solution that will contain solvent again injects in the mould, solidified through freezing method afterwards, through the distillation mode solvent in this material is extracted out again, like this then can form a kind of base material of cellular structure, at last fine fibre is extracted out and the lane device in formation multitube chamber, this lane device is suitable for neural the reparation.
Aldini et al., 1996, " Effectiveness of a bioabsorbable conduitin the repair of peripheral nerves ", Biomaterials vol.17, pp.959-962. the author of this piece paper makes conduit with auxiliary nervous regeneration with L-lactide (L-lactide) and two kinds of Bioabsorbable high-molecular copolymers of 6-caprolactone (6-caprolactone).The internal diameter of this conduit is 1.3mm, and the thickness of tube wall then is 175 μ m.
Kiyotani et al., 1996, " Nerve regeneration across a 25-mm gapbridged by a polyglycolic acid-collagen tube:a histological andelectrophysiological evaluation of regenerated nerves ", BrainResearch vol.740, pp.66-74. the author of this piece paper utilizes bioabsorbable material PGA to make cancellated conduit for base material, on the conduit surfaces externally and internally, be coated with collagen, in pipe, add the neural factor (neurotrophic factor) of nourishing simultaneously, comprise nerve growth factor (nerve growth factor), alkaline fiber archeocyte somatomedin (basic fibroblastgrowth factor) and the gel (laminin-containing gel) that contains laminin.
Den Dunnen et al., 1996, " Light-microscopic andelectron-microscopic evaluation of short-term nerve regenerationusing a biodegradable poly (the nerve guide of DL-lactide-ε-caprolacton) ", Journal of Biomedical Materials Research vol.31, pp.105-115. the author of this piece paper utilize the Bioabsorbable macromolecular material to gather (DL-lactide-6-caprolactone) [poly (DL-lactide-ε-caprolactone)] to make an internal diameter be 1.5mm, pipe thickness is the nerve trachea of 0.30mm.
Widmer et al., 1998, " Manufacture of porous biodegradablepolymer conduits by an extrusion process for guided tissueregeneration ", Biomaterials vol.19, pp.1945-1955. the author of this piece paper is in conjunction with solvent cast (solvent casting) and the technology of extruding (extrusion), with two kinds of bioabsorbable material PLGA and poly-(L-lactic acid) [poly (L-lactic acid), PLLA] be made into tubular structure with pore space structure, so that apply in the work of tissue repair, for example in the future: periphery is neural.
Evans et al., 1999, " In vivo evaluation of poly (L-lactic acid) porous conduit for peripheral nerve regeneration ", Biomaterialsvol.20, pp.1109-1115. the author of this piece paper utilizes PLLA to make 12mm length, internal diameter 1.6mm, external diameter 3.2mm, has the nerve trachea of pore space structure, in order to repair the gap of rat sciatic nerve 10mm.
Rodriguez et al., 1999, " Highly permeablepolylactide-caprolactone nerve guides enhance peripheral nerveregeneration through long gaps ", Biomaterials vol.20, the author of this piece of pp.1489-1500. paper are blocked 6mm with sciatic nerve mouse comes the function of their nerve trachea developed of comparison as the animal model of neuranagenesis; They are respectively with bioabsorbable material poly-(L-lactide-ε-altogether-caprolactone) [poly (L-lactide-ε-co-caprolactone)] and examples of non-bioabsorbable material polysulfones (polysulfone, POS) make nerve trachea with various different permeabilities, length is 8mm, in order to connect sciatic gap.
Suzuki et al., 1999, " Cat peripheral nerve regeneration across50mm gap repaired with a novel nerve guide composed of freeze-driedalginate gel ", Neuroscience Letters vol.259, pp.75-78. the author of this piece paper makes the artificial nerve regeneration conduit of a biological absorbability with alginate jelly (alginate gel) through cryodesiccated program, does the sciatic animal experiment of cat with it again.
Steuer et al., 1999, " Biohybride nerve guide for regeneration:degradable polylactide fibers coated with rat Schwann cell ", Neuroscience Letters vol.277, pp.165-168. the author of this piece paper makes thread structure with polylactide (polylactides), handle with oxygen plasma (oxygen plasma) again, or after oxygen plasma treatment, be coated with one strata-D-lysine (poly-D-lysine) in material surface again, to understand the stickup adhesion property of schwann's cell at material surface.Experimental result shows: through oxygen plasma treatment material later, the adhesion situation of schwann's cell is better than what do not handle; If again through coating poly--material behind D-lysine, the adhesion situation of schwann's cell is better.
Matsumoto et al., 2000, " Peripheral nerve regeneration acrossan 80-mm gap bridged by a polyglycolic acid (PGA)-collagen tilledwith laminin-coated collagen fibers:a histological andelectrophysiological evaluation of regenerated nerves ", BrainResearch vol.868, pp.315-328. the author of this piece paper utilizes PGA and collagen to make an artificial nerve trachea, puts into the collagen rope that surface coated has laminin in conduit central authorities again.
Wan et al., 2001, " Fabriaction of poly (phosphoester) nerveguides by immersion precipitation and the control of porosity ", Biomaterials vol.22, pp.1147-1156. this piece paper has been introduced the method for making of P (BHET-EOP/TC) nerve trachea, and the generation how it controls pore space structure is described in detail in detail simultaneously.
Wang et al., 2001, " A new nerve conduit material composed ofa biodegradable poly (phosphoester) " Biomaterials vol.22, pp.1157-1169. the author of this piece paper is with poly phosphate [poly (phosphoester), PPE polymer] make molecular weight and polydispersity (polydispersity, PI) two kinds of all different conduits of numerical value.
Meek et al.，2001.，“Electromicroscopical evaluation ofshort-term nerve regeneration through a thin-walled biodegradablepoly(DLLA-ε-CL)nerve guide filled with modified denatured muscletissue”Biomaterials vol.22，pp.1177-1185。(DLLA-ε-CL) [poly (DLLA-ε-CL)] is that material is made the thin nerve trachea of tube wall to the author of this piece paper with poly-, (modified denatured muscle tissue MDMT) constructs to avoid conduit to subside with supporting tube to add the degeneration muscular tissue that improves simultaneously in pipe.
Summary of the invention
The object of the present invention is to provide a kind of multi-channel type biological absorptive nerve regeneration conduit.
Another object of the present invention is to provide a kind of method for preparing multi-channel type biological absorptive nerve regeneration conduit.
For realizing above-mentioned purpose of the present invention, multi-channel type biological absorptive nerve regeneration conduit of the present invention comprises: the high molecular hollow circular tube of a porous biological absorptive; And the multi-channel type implant in pipe, it is one to have the porous biological absorptive macromolecule membrane of convex-concave surface, with single or multiple lift filling, folding mode or be wound into helical form and fill.
The method that the present invention prepares multi-channel type biological absorptive nerve regeneration conduit comprises the following steps: to form a multi-channel type implant, it is by the porous biological absorptive macromolecule membrane with convex-concave surface, with single or multiple lift filling, folding mode or be wound into helical form fill constituted; Form the high molecular hollow circular tube of a porous biological absorptive; At last, the multi-channel type implant is inserted in the high molecular hollow circular tube of porous biological absorptive.
Structure of described multi-channel type biological absorptive nerve regeneration conduit and preparation method thereof specifically comprises:
Form the high molecular multi-channel type implant of porous biological absorptive:
At first, a biological absorbability macromolecule is dissolved in the organic solvent, forms a biological absorbability macromolecular solution.
Then, make this bioresorbable macromolecular solution have the film shape of a convex-concave surface.For example, this bio-absorbable macromolecular solution is coated one have the die surface of convex-concave surface or pour in the container, make this bioresorbable macromolecular solution have the film shape of a convex-concave surface.
Then, this solution with film shape of convex-concave surface is contacted with a solidification liquid (coagulant), to form a preforming thing with porous biological absorptive thin film of convex-concave surface.The bioresorbable macromolecular solution preferably contacts with solidification liquid down for 5 ℃ to 60 ℃ in temperature, and better person contacts with solidification liquid down for 10 ℃ to 50 ℃ in temperature.The shape of this thin film preforming thing does not have certain restriction, as long as its at least one surface is concavo-convex.For example, the porous biological absorptive thin film of this convex-concave surface can comprise a base portion and a plurality of juts that protrude from base surface, and the thickness of base portion can be 0.05mm to 1.0mm, and the degree of depth of jut can be 0.05mm to 1.0mm.
This thin film with convex-concave surface can be single thin film or plural layers or folding or be wound into helical form, thereby forms a multi-channel type implant.
Form the high molecular hollow circular tube of porous biological absorptive:
At first, a biological absorbability macromolecule is dissolved in the organic solvent, forms a biological absorbability macromolecular solution.Make this bioresorbable macromolecular solution have a round tube shape.
Then, this solution with round tube shape is contacted with a solidification liquid, to form this porous biological absorptive hollow circular tube.
For example, this bioresorbable macromolecular solution can be coated a pole surface, so that this bio-absorbable macromolecular solution has a round tube shape.Now is inserted this pole that scribbles the bioresorbable macromolecular solution in one solidification liquid, to form the porous biological absorptive material of round tube shape on the pole surface.
At last, the porous biological absorptive material of round tube shape is detached from the pole surface, and obtain the porous biological absorptive hollow circular tube.
The pipe thickness of this hollow circular tube can be 0.05 to 1.5mm.
Form multi-channel type biological absorptive nerve regeneration conduit:
The porous biological absorptive macromolecule membrane that will have convex-concave surface, with single thin film, plural layers, folding mode or be wound into the helical form mode and insert in the high molecular hollow circular tube of porous biological absorptive, for example be wound into spiral helicine multi-channel type implant, insert in the hollow circular tube and can obtain multi-channel type biological absorptive nerve regeneration conduit of the present invention.Nerve regeneration conduit of the present invention has a plurality of passages, and the number of active lanes more than 10 is preferably arranged.
According to the present invention, be applicable to that the material with porous biological absorptive thin film of convex-concave surface of the present invention can be PCL, PLA, PGA, the PLGA copolymer, PCL-PLA copolymer, PCL-PGA copolymer, PCL-PEG co-polymer (polycaprolactone-polyethylene glycolcopolymer), or bioresorbable macromolecule such as its mixture.The high molecular molecular weight of this bioresorbable can be more than 20,000, preferably between 20,000 to 300,000.
The bioresorbable macromolecular material that is applicable to hollow circular tube can be PCL, PLA, PGA, PLGA copolymer, PCL-PLA copolymer, PCL-PGA copolymer, PCL-PEG co-polymer, or its mixture.The high molecular molecular weight of this bioresorbable can be more than 20,000, preferably between 20,000 to 300,000.
According to the present invention, also can have in the process of the multi-channel type implant of convex-concave surface and hollow circular tube in above-mentioned formation, in the bioresorbable macromolecular solution, add low-molecular-weight oligomer and form agent as hole.
Particularly, when forming the multi-channel type implant, a biological absorbability macromolecule and a low-molecular-weight oligomer are dissolved in the organic solvent together, form a biological absorbability macromolecular solution.Then, according to above-mentioned identical method, make this bioresorbable macromolecular solution formation have the film shape of convex-concave surface, contact with solidification liquid then, one have the porous biological absorptive thin film of convex-concave surface to form, again with the winding film curl, thereby form a multi-channel type implant.
When forming hollow circular tube, a biological absorbability macromolecule and a low-molecular-weight oligomer are dissolved in the organic solvent together, form a biological absorbability macromolecular solution.Then,, make this bioresorbable macromolecular solution form a round tube shape, contact with solidification liquid then, to form the porous biological absorptive hollow circular tube according to above-mentioned identical method.
Be applicable to low-molecular-weight oligomer of the present invention, its molecular weight is between 200 to 4000.Concrete example comprises polycaprolactonetriol (polycaprolactone triol, PCLTL), and polycaprolactone glycol (polycaprolactone diol, PCLDL), PCL, PLA, PEG, polypropylene glycol (polypropylene glycol, PPG), polytetramethylene glycol (polytetramethylene glycol, PTMG), and composition thereof.
Because low-molecular-weight oligomer has molecular weight to a certain degree, therefore these low-molecular-weight oligomers can diffuse in the solidification liquid with slower speed in bioresorbable macromolecular solution process of setting, and can form a kind of porous biological absorptive material with evenly mutual connectivity structure.Therefore, in the present invention, low-molecular-weight oligomer has been played the part of the role of hole formation agent.By kind, molecular weight and the content in bioresorbable macromolecule formation solution thereof of selecting low-molecular-weight oligomer, can adjust the porosity and the hole size of the hollow circular tube of final formation and multi-channel type implant within it.And, can make hollow circular tube and multi-channel type implant within it become mutual connection form.
According to the present invention, above-mentioned organic solvent in order to dissolving bioresorbable macromolecule and low-molecular-weight oligomer can be N, N-dimethyl amide (N, N-dimetbylformamide, DMF), N, N-dimethyl ethanamide (N, N-dimethylacetamide, DMAc), THF, alcohols, chloroform, 1,4-diox, or its mixture.The shared percentage by weight of bioresorbable macromolecule can be 5-50% in the bioresorbable solution, preferably 10-40%.The shared amount of low-molecular-weight oligomer can be the 10-80% of non-solvent portion weight in the solution in the bioresorbable solution.
According to the present invention, above-mentioned solidification liquid preferably comprises a water and an organic solvent, and the percentage by weight of organic solvent is preferably 10-50% in the solidification liquid.Organic solvent can be the vinegar amine in the solidification liquid, ketone, alcohols, or its mixture.Organic solvent preferably includes ketone and alcohols in the solidification liquid.
The object lesson of organic solvent comprises DMF in the solidification liquid, DMAc, acetone, ketones solvents such as butanone, or methanol, ethanol, propanol, isopropyl alcohol, alcohols solvents such as butanols.
With the bioresorbable macromolecular solution with after solidification liquid contacts, preferably the porous biological absorptive material that is generated is inserted in the cleanout fluid and cleans.This cleanout fluid can comprise water and organic solvent, and this organic solvent can be ketone, alcohols, or its mixture.
The object lesson of organic solvent comprises acetone in the cleanout fluid, ketones solvents such as butanone, or methanol, ethanol, propanol, isopropyl alcohol, alcohols solvents such as butanols.
Description of drawings
Figure 1A to 1F shows the SEM photograph of the porous PCL thin film preforming thing of embodiment of the invention A1 gained, and its multiplying power is respectively 350X, 2000X, 100X, 350X, 500X, 350X;
Fig. 2 shows the SEM photograph of the porous PCL thin film preforming thing of embodiment of the invention A2 gained, and its multiplying power is 1000X;
Fig. 3 shows the SEM photograph of the porous PCL thin film preforming thing of embodiment of the invention A3 gained, and its multiplying power is 3500X;
Fig. 4 A and 4B show the SEM photograph of the porous PCL thin film preforming thing of embodiment of the invention A4 gained, and its multiplying power is respectively 500X, 350X;
Fig. 5 A and 5B show the SEM photograph of the porous PCL hollow circular tube of embodiment of the invention B1 gained, and its multiplying power is respectively 200X, 750X;
Fig. 6 shows the SEM photograph of the porous PCL hollow circular tube of embodiment of the invention B2 gained, and its multiplying power is 200X;
Fig. 7 shows the SEM photograph of the porous PCL hollow circular tube of embodiment of the invention B3 gained, and its multiplying power is 50X;
Fig. 8 A and 8B show the multi-channel type of embodiment of the invention C1 gained, the SEM photograph of bioresorbable nerve trachea, and its multiplying power is respectively 50X and 35X.
The specific embodiment
Below, the present invention will be for embodiment illustrating method of the present invention, feature and advantage, but not delimit the scope of the invention, scope of the present invention should be as the criterion with claims.
A: preparation bioresorbable porous macromolecule membrane preforming thing
Get PCL bioresorbable macromolecular material 15 gram of molecular weight about 80,000, and 15 gram-molecular weights are that 300 PEG is incorporated in the THF organic solvents of 70 grams, the back that stirs forms the PCL macromolecular solution.Then with solution coat or be poured into the die surface that a surface has concave convex texture.
Then, the concave convex texture shape mould of surface coverage PCL solution inserted in 25 ℃ the solidification liquid (solidification liquid form and solidification forming time as shown in table 1) and, form porous PCL material with solidification forming.Then the porous PCL material that forms is inserted and contained in the alcoholic acid cleanout fluid of 50wt% soaking and washing 2 hours, re-use clean water at last and clean, obtain having the porous PCL preforming material (numbering #1A-#1K) of convex-concave surface after the drying.The base portion thickness of the preforming material of control gained is about 0.1mm, and the jut degree of depth is about 0.2mm.
This porous PCL preforming material uses SEM to observe, shown in 1A-1F figure.The hole form of porous PCL preforming material presents mutual connectivity structure.
Table 1
| Specimen coding | The solidification liquid kind | Setting time (hour) | The hole form and the outward appearance of porous substrate | The SEM photograph |
| 1A | 30wt% ethanol | 4 | Hole is communicated with alternately, surperficial concave-convex surface | |
| 1B | 40wt% ethanol | 4 | Hole is communicated with alternately, surperficial concave-convex surface | Figure 1A (350X) |
| 1C | 45wt% ethanol | 4 | Hole is communicated with alternately, surperficial concave-convex surface | |
| 1D | 50wt% ethanol | 4 | Hole is communicated with alternately, surperficial concave-convex surface | |
| 1E | The 30wt% propanol | 4 | Hole is communicated with alternately, surperficial concave-convex surface | Figure 1B (2000X) |
| 1F | The 40wt% propanol | 4 | Hole is communicated with alternately, surperficial concave-convex surface | Fig. 1 C (100X) |
| 1G | The 45wt% propanol | 4 | Hole is communicated with alternately, surperficial concave-convex surface | |
| 1H | The 50wt% propanol | 4 | Hole is communicated with alternately, surperficial concave-convex surface | Fig. 1 D (350X) |
| 1I | 15wt% propanol+15wt% ethanol | 4 | Hole is communicated with alternately, surperficial concave-convex surface | Fig. 1 E (500X) |
| 1J | 20wt% propanol+20wt% ethanol | 4 | Hole is communicated with alternately, surperficial concave-convex surface | Fig. 1 F (350X) |
| 1K | 25wt% propanol+25wt% ethanol | 4 | Hole is communicated with alternately, surperficial concave-convex surface |
Embodiment A 2
Get PCL bioresorbable macromolecular material 15 gram of molecular weight about 80,000, and 15 gram-molecular weights are that 300 PCLTL is incorporated in the THF organic solvents of 70 grams, the back that stirs forms the PCL macromolecular solution.Then with solution coat or be poured into the die surface that a surface has concave convex texture.
Then, the mould with concave convex texture of surface coverage PCL solution inserted in 25 ℃ the solidification liquid (solidification liquid form and solidification forming time as shown in table 2) and, form porous PCL material with solidification forming.Afterwards the porous PCL material that forms is inserted and contained in the alcoholic acid cleanout fluid of 50wt% soaking and washing 2 hours, re-use clean water at last and clean, obtain the porous PCL preforming material (numbering #2A, #2B) of tool convex-concave surface after the drying.
This porous PCL preforming material uses SEM to observe, and as shown in Figure 2, confirms that porous PCL preforming material hole form presents mutual connectivity structure.
Table 2
| Specimen coding | The solidification liquid kind | Setting time (hour) | The hole form and the outward appearance of porous substrate | The SEM photograph |
| 2A | 40wt% ethanol | 4 | Hole is communicated with alternately, surperficial concave-convex surface | Fig. 2 (1000X) |
| 2B | The 40wt% propanol | 4 | Hole is communicated with alternately, surperficial concave-convex surface |
Embodiment A 3
Get PCL bioresorbable macromolecular material 15 gram of molecular weight about 80,000, and 15 gram-molecular weights are that 300 PTMG goes in the THF organic solvents of 70 grams, whisk even back and form the PCL macromolecular solution.With solution coat or be poured into the die surface that a surface has concave convex texture.
Then, the mould that the surface of surface coverage PCL solution is had a concave convex texture is inserted in 25 ℃ the solidification liquid (solidification liquid form and solidification forming time as shown in table 3) and with solidification forming, is formed porous PCL material.Afterwards the porous PCL material that forms is inserted and contained in the alcoholic acid cleanout fluid of 50wt% soaking and washing 2 hours, re-use clean water at last and clean, obtain the porous PCL preforming material (numbering #3A, #3B) of tool convex-concave surface after the drying.
This porous PCL preforming material uses SEM to observe, and as shown in Figure 3, confirms that porous PCL preforming material hole form presents mutual connectivity structure.
Table 3
| Specimen coding | The solidification liquid kind | Setting time (hour) | The hole form and the outward appearance of porous substrate | The SEM photograph |
| 3A | 40wt% ethanol | 4 | Hole is communicated with alternately, surperficial concave-convex surface | |
| 3B | The 40wt% propanol | 4 | Hole is communicated with alternately, surperficial concave-convex surface | Fig. 3 (1000X) |
Embodiment A 4
Get PCL bioresorbable macromolecular material 15 gram of molecular weight about 80,000, and 15 gram-molecular weights are that 300 PEG is incorporated in the THF organic solvents of 70 grams, the back that stirs forms the PCL macromolecular solution.Then with solution coat or be poured into the die surface that a surface has concave convex texture.Mould depth of groove condition is as shown in table 4.The jut degree of depth (d) by mould depth of groove may command thin film preforming thing.
Then, the mould that the surface of surface coverage PCL solution is had a concave convex texture inserts that (solidification liquid consists of the 40/60wt% ethanol/water) forms porous PCL material with solidification forming in 25 ℃ the solidification liquid.Then the porous PCL material that forms is inserted and contained in the alcoholic acid cleanout fluid of 50wt% soaking and washing 2 hours, re-use clean water at last and clean, obtain the porous PCL preforming material (numbering #4A, #4B, #4C) of tool convex-concave surface after the drying.
This porous PCL preforming material uses SEM to observe, and shown in Fig. 4 A, 4B, confirms that porous PCL preforming material hole form presents mutual connection, and has the convex-concave surface structure.
Table 4
| Specimen coding | The mould flute degree of depth | Setting time (hour) | The hole form and the outward appearance of porous substrate | The SEM photograph |
| 4A | 0.1mm | 4 | Hole is communicated with alternately, surperficial concave-convex surface | Fig. 4 A (500X) |
| 4B | 0.2mm | 4 | Hole is communicated with alternately, surperficial concave-convex surface | Fig. 4 B (350X) |
| 4C | 0.3mm | 4 | Hole is communicated with alternately, surperficial concave-convex surface |
B: preparation porous biological absorptive polymeric hollow pipe
Get PCL bioresorbable macromolecular material 15 gram of molecular weight about 80,000, and 15 gram-molecular weights are that 300 PEG is incorporated in the THF organic solvents of 70 grams, the back that stirs forms the PCL macromolecular solution.Then PCL solution is poured in the cylindric spreader, this cylindric spreader has always the footpath and is the center hole of 3.0mm.Then, be that the pole of 2mm passes cylindric spreader with an external diameter, make the PCL homogeneous solution of the about 0.5mm of pole surface coated one layer thickness.
The pole of surface coated PCL homogeneous solution is placed in (solidification liquid composition and solidification forming time are as shown in table 5) in the solidification liquid.In this solidification liquid, PCL solution solidifies gradually and forms a kind of porous PCL material, then porous PCL pipe is detached pole.Afterwards the porous PCL material that forms is inserted and contained in the alcoholic acid cleanout fluid of 50wt% soaking and washing 2 hours, re-use clean water at last and clean, obtain porous PCL hollow circular tube (numbering #5A, #5B) after the drying.
This porous PCL hollow circular tube uses SEM to observe, and shown in Fig. 5 A, 5B, hollow circular tube tube wall hole form presents mutual connectivity structure.
Table 5
| Specimen coding | The solidification liquid kind | Setting time (hour) | The hole form of porous substrate | The SEM photograph |
| 5A | 40wt% ethanol | 4 | The mutual connection | Fig. 5 A (200X) |
| 5B | The 40wt% propanol | 4 | The mutual connection | Fig. 5 B (750X) |
Embodiment B 2
Get PCL bioresorbable macromolecular material 15 gram of molecular weight about 80,000, and 15 gram-molecular weights are that 300 PCLTL is incorporated in the THF organic solvents of 70 grams, the back that stirs forms the PCL macromolecular solution.Then PCL solution is poured in the cylindric spreader, this cylindric spreader has always the footpath and is the center hole of 3.0mm.The pole that with an external diameter is 2mm then passes cylindric spreader, makes the PCL homogeneous solution of the about 0.5mm of pole surface coated one layer thickness.
The pole of surface coated PCL homogeneous solution is placed in (solidification liquid composition and solidification forming time are as shown in table 6) in the solidification liquid.In this solidification liquid, PCL solution solidifies gradually and forms a kind of porous PCL material, then porous PCL pipe is detached pole.Afterwards the porous PCL material that forms is inserted and contained in the alcoholic acid cleanout fluid of 50wt% soaking and washing 2 hours, re-use clean water at last and clean, obtain porous PCL hollow circular tube (numbering #6A, #6B) after the drying.
This porous PCL hollow circular tube uses SEM to observe, and as shown in Figure 6, hollow circular tube tube wall hole form presents mutual connectivity structure.
Table 6
| Specimen coding | The solidification liquid kind | Setting time (hour) | The hole form of porous substrate | The SEM photograph |
| 6A | 40wt% ethanol | 4 | The mutual connection | |
| 6B | The 40wt% propanol | 4 | The mutual connection | Fig. 6 (200X) |
Embodiment B 3
Get PCL bioresorbable macromolecular material 15 gram of molecular weight about 80,000, and 15 gram-molecular weights are that 300 PEG is incorporated in the THF organic solvents of 70 grams, the back that stirs forms the PCL macromolecular solution.Then PCL solution is poured in the cylindric spreader, it is the center hole (cylindric spreader size is as shown in table 7) of 3.0～6.0mm directly that this cylindric spreader has always.Then, be that the pole of 2.0～4.0mm passes cylindric spreader with an external diameter, make the PCL homogeneous solution of the about 0.5～1.0mm of pole surface coated one layer thickness.
The circle handful of surface coated PCL homogeneous solution is placed in (solidification liquid consists of the 40/60wt% ethanol/water) in the solidification liquid, and in this solidification liquid, PCL solution solidifies gradually and forms a kind of porous PCL material, then porous PCL pipe is detached circle and holds in both hands.Afterwards the porous PCL material that forms is inserted and contained in the alcoholic acid cleanout fluid of 50wt% soaking and washing 2 hours, re-use clean water at last and clean, obtain porous PCL hollow circular tube (numbering #7A, #7B, #7C) after the drying.
This different size porous PCL hollow circular tube uses SEM to observe, and as shown in Figure 7, hollow circular tube tube wall hole form presents mutual connectivity structure.
Table 7
| Specimen coding | Cylindric spreader size (outlet size/pole size) (unit: mm) | Setting time (hour) | The hole form of porous substrate | The SEM photograph |
| 7A | 3.2/2.0 | 4 | The mutual connection | Fig. 7 (50X) |
| 7B | 4.5/3.2 | 4 | The mutual connection | |
| 7C | 6.0/4.0 | 4 | The mutual connection |
C: multi-channel type biological absorptive nerve trachea
The porous biological absorptive PCL thin film preforming thing with convex-concave surface that embodiment A 1～A4 is made is wound into spiral helicine pipe, again the round bundle of this coiling is inserted (porous biological absorptive polymeric hollow pipe size is as shown in table 8) in the porous biological absorptive polymeric hollow pipe that makes by Embodiment B 1～B3, thereby form multi-channel type biological absorptive nerve regeneration conduit (numbering #8A, #8B, #8C).
This multi-channel type nerve regeneration conduit uses SEM to observe, and shown in Fig. 8 A, Fig. 8 B, learns that number of active lanes is about more than 150, and is communicated with form alternately for multichannel.
Table 8
| Specimen coding | Porous biological absorptive polymeric hollow pipe size (outside dimension/internal diameter size) (unit: mm) | The hole form of porous substrate | The SEM photograph |
| 8A | 3.2/2.0 | The mutual connection | Fig. 8 (50X) |
| 8B | 4.5/3.2 | The mutual connection | Fig. 8 (35X) |
| 8C | 6.0/4.0 | The mutual connection |
Though the present invention has disclosed preferred embodiment as above; yet not delimit the scope of the invention, anyly be familiar with this operator, without departing from the spirit and scope of the present invention; all can do corresponding change or retouching, so protection scope of the present invention should be as the criterion with defining of claims.
Claims (20)
1. multi-channel type biological absorptive nerve regeneration conduit is characterized in that it comprises:
The high molecular hollow circular tube of one porous biological absorptive; And
Multi-channel type implant in pipe, it is one to have the porous biological absorptive macromolecule membrane of convex-concave surface.
2. nerve regeneration conduit as claimed in claim 1, the pipe thickness that it is characterized in that described hollow circular tube is between 0.05 to 1.5mm.
3. nerve regeneration conduit as claimed in claim 1 is characterized in that the pore space structure of described hollow circular tube tube wall is the mutual form that is communicated with.
4. nerve regeneration conduit as claimed in claim 1 is characterized in that the material of described hollow circular tube is selected from PCL, PLA, PGA, PLGA copolymer, PCL-PLA copolymer, the PCL-PGA copolymer, the PCL-PEG copolymer, and composition thereof the arbitrary bioresorbable macromolecule in the group that formed.
5. nerve regeneration conduit as claimed in claim 1 is characterized in that described number of active lanes is more than 10.
6. nerve regeneration conduit as claimed in claim 1, it is characterized in that described porous biological absorptive thin film with convex-concave surface comprises a base portion and a plurality of juts that protrude from this base surface, the thickness of this base portion is between between the 0.05mm to 1.0mm.
7. nerve regeneration conduit as claimed in claim 6 is characterized in that the degree of depth of described jut is between between the 0.05mm to 1.0mm in the described porous biological absorptive thin film with convex-concave surface.
8. nerve regeneration conduit as claimed in claim 1, it is characterized in that described material with porous biological absorptive thin film of convex-concave surface is selected from PCL, PLA, PGA, the PLGA copolymer, PCL-PLA copolymer, PCL-PGA copolymer, the PCL-PEG copolymer, and composition thereof the arbitrary bioresorbable macromolecule in the group that formed.
9. nerve regeneration conduit as claimed in claim 1 is characterized in that described porous biological absorptive macromolecule membrane with convex-concave surface is monolayer, multilamellar, rugosity or is wound into helical form.
10. nerve regeneration conduit as claimed in claim 9 is characterized in that described porous biological absorptive macromolecule membrane with convex-concave surface is wound into helical form.
11. a method for preparing multi-channel type biological absorptive nerve regeneration conduit is characterized in that it comprises:
Form a multi-channel type implant, it is one to have the porous biological absorptive macromolecule membrane of convex-concave surface;
Form the high molecular hollow circular tube of a porous biological absorptive; And
This multi-channel type implant is inserted in the high molecular hollow circular tube of this porous biological absorptive.
12. method as claimed in claim 11 is characterized in that described formation method with porous biological absorptive thin film of convex-concave surface is:
One biological absorbability macromolecule is dissolved in the organic solvent, forms a biological absorbability macromolecular solution;
Make this bio-absorbable macromolecular solution form one and have the film shape of convex-concave surface;
This solution with film shape of convex-concave surface is contacted with a solidification liquid, to form a porous biological absorptive thin film with convex-concave surface.
13. method as claimed in claim 12 is characterized in that comprising also a low-molecular-weight oligomer is dissolved in the organic solvent that the molecular weight of this oligomer is between 200 to 4000 in the step of described formation bioresorbable macromolecular solution.
14. method as claimed in claim 13 is characterized in that described low-molecular-weight oligomer is selected from by PCLTL, PCLDL, PCL, PLA, PEG, PPG, PTMG, and composition thereof in the group that formed any one.
15. method as claimed in claim 11 is characterized in that the formation method of the high molecular hollow circular tube of described porous biological absorptive is:
One biological absorbability macromolecule is dissolved in the organic solvent, forms a biological absorbability macromolecular solution;
Make this bioresorbable macromolecular solution have a round tube shape; And
This solution with round tube shape is contacted with a solidification liquid, to form this porous biological absorptive hollow circular tube.
16. method as claimed in claim 11 is characterized in that described porous biological absorbs
The formation method of property hollow circular tube is:
One biological absorbability macromolecule is dissolved in the organic solvent, forms a biological absorbability macromolecular solution;
This bioresorbable macromolecular solution is coated a pole surface, so that this bioresorbable macromolecular solution has a round tube shape;
This pole that scribbles the bioresorbable macromolecular solution is inserted in the solidification liquid, on the pole surface, to form the porous biological absorptive material of round tube shape; And
The porous biological absorptive material of round tube shape is detached from the pole surface, thereby obtain the porous biological absorptive hollow circular tube.
17. method as claimed in claim 16 is characterized in that comprising also a low-molecular-weight oligomer is dissolved in the organic solvent that the molecular weight of this oligomer is between 200 to 4000 in the step of described formation bioresorbable macromolecular solution.
18. method as claimed in claim 17 is characterized in that described low-molecular-weight oligomer is selected from by PCLTL, PCLDL, PCL, PLA, PEG, PPG, PTMG, and composition thereof in the group that formed any one.
19. method as claimed in claim 11 is characterized in that described porous biological absorptive macromolecule membrane with convex-concave surface is monolayer, multilamellar, rugosity or is wound into helical form.
20. method as claimed in claim 19 is characterized in that described porous biological absorptive macromolecule membrane with convex-concave surface is wound into helical form.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100560037C (en) * | 2007-12-06 | 2009-11-18 | 崔树森 | Artificial nerve catheter from the functional amplification of body |
| CN102008360B (en) * | 2010-10-13 | 2015-12-16 | 中山大学 | A kind of structure of the artificial neural network sample catheter for repairing spinal cord injury |
| CN102688076B (en) * | 2011-03-25 | 2014-09-10 | 广州迈普再生医学科技有限公司 | Nerve conduit and preparation method thereof |
| CN105310794B (en) * | 2015-02-14 | 2019-10-25 | 南通大学 | A kind of preparation method of porous artificial nerve catheter of the inner wall with orientation structure |
| WO2019046808A1 (en) | 2017-09-01 | 2019-03-07 | Poly-Med, Inc. | Polymers for additive manufacturing |
| CN109430118B (en) * | 2018-08-27 | 2021-05-11 | 吴常文 | Method for improving reproductive capacity of cuttlefish |
| CN109701075A (en) * | 2018-11-08 | 2019-05-03 | 中国人民解放军总医院 | A kind of flexible peripheral neurologic defect repairs conduit and preparation method thereof |
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