CN103100116A - Tissue adhesion prevention material, medicine-carrying material and preparation method thereof - Google Patents
Tissue adhesion prevention material, medicine-carrying material and preparation method thereof Download PDFInfo
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- CN103100116A CN103100116A CN2012105944250A CN201210594425A CN103100116A CN 103100116 A CN103100116 A CN 103100116A CN 2012105944250 A CN2012105944250 A CN 2012105944250A CN 201210594425 A CN201210594425 A CN 201210594425A CN 103100116 A CN103100116 A CN 103100116A
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Abstract
The invention provides application of a high polymer nanofiber membrane and/or medicine-carrying high polymer nanofiber membrane in preparation of a tissue adhesion prevention material and a medicine-carrying material. The fiber membrane comprises the basic materials selected from any one or several of hydroxy carboxylic acid homopolymers or multiple hydroxy carboxylic acid copolymers, hydroxy carboxylic acid and polyhydric alcohol copolymers, polyhydroxy carboxylic acid and polyhydric alcohol mixtures; the carried medicine comprises the components selected from any one or several of anti-inflammatory drugs, antibacterial agents and growth factors, preferably ibuprofen and anti-inflammatory drugs and silver-system antibacterial agents. The fiber membrane for preventing tissue adhesion prepared by the method has high porosity, highly bionic structure and biological functions, can effectively prevent exogenous healing, allow permeation of nutrient substances and promote endogenous healing and does not have cytotoxicity, and the medicine-carrying medicine is in sustained release.
Description
Technical field
The present invention relates to a kind of medical material, relate in particular to a kind of tissue adhesion's of control material and control tissue adhesion's medicine carrying material and the preparation method of above-mentioned material thereof.
Background technology
Adhesion of tendon is clinical common diseases, easily forms cicatricial adhesion after its fracture is repaired, and makes the original function of tendon reduce or lose.Owing to lacking effective adhesion prophylactico-therapeutic measures, even if after the operation of row adhesion release, still have the probability of adhesion again, usually make treatment be absorbed in the vicious cycle of " adhesion-loosening-adhesion again ", not only affect operative effect, and also exert a certain influence for patient's psychology, even cause the contradiction between doctors and patients.The agglutination of tendon comprises exogenous healing and endogenous healing dual mode.Wherein, endogenous healing refers to rely on the tendon self-healing that the proliferation for repairing ability of Tenocyte cell is completed; And exogenous healing refers to that the synovial membrane of tendon periphery and connective tissue produce granulation tissue at the tendon section, complete the tendinous tissue reparation by granulation tissue.This dual mode exists simultaneously in the tendon injury agglutination, but the nutriture inside and outside tendon and environmental condition are not simultaneously, and both effects are also different.Therefore, in the repair process of tendon, how the factor with exogenous reparation drops to minimum level, makes it as much as possible by the growth of endogenous mode of healing, is to avoid the key that sticks together.
The method of at present prevention adhesion of tendon is a lot, as application, postoperative early ambulant and the later stage functional exercise etc. of improvement, preventing local adhesion medicine and the isolated material of sewing method and suture; Wherein the application of all preventing local adhering materials of tendon and topical remedy is the focus of Recent study.
One, anti thin-film material
The early stage Antiadhesive film of using adopts non-biological material (as silicone rubber) more, but have that tissue reaction is large, rejection obviously, without permeability, affect tendon the endogenous healing with need the deficiency such as secondary operation taking-up, can make because of the nutrition that has intercepted tendon its generation degeneration when serious.Therefore, the Antiadhesive film of present this material formation substantially need not.
In recent years, the Antiadhesive film of being made by degradable high polymer material Chinese scholars is the most praised highly, in this class material, existing natural macromolecular material, as cellulose derivative, hyaluronic acid, chitin and derivant thereof etc., synthetic high molecular polymer is also arranged, as polylactic acid (polylactic acid, PLA), polyglycolic acid (polyglycolic acid, PGA) and their copolymer etc.PLA has good biocompatibility and biodegradability, and its catabolite is carbon dioxide and water, and to human body nonhazardous effect, by the approval of U.S. FDA and China SFDA, the product made from this material has been applied to clinical.
The polylactic acid membrane that Zou Jian uses Dicon AS to be provided is observed the effect of prevention chicken tendon adhesion, the animal groups tendon of research discovery use Absorbable membrane and the adhesion of surrounding tissue are less, and the flex function that closely saves interphalangeal joint and metatarsophalangeal joints obviously is better than matched group.Confirm in research that polylactic acid is acid, easily form certain inflammatory reaction in the part, the acidity that therefore how to change polylactic acid is the focus of present research.Zou Jian etc. are wrapped in chicken with the polylactic acid Absorbable membrane and bend the dark tendon anastomosis of toe place, postoperative substantially reaches histological observation test group adhesion degree and is starkly lower than matched group, the functional rehabilitation test group obviously is better than matched group, and the anti-load forces not statistically significant of hamstring.The polylactic acid absorbability Antiadhesive film that the application such as Huang Qishun Chengdu Dicon AS produces holds the Flexion tendon injury part, makes comparisons with the blank group of parcel not, and result proof Absorbable membrane has the effect of good prevention adhesion of tendon.
But the degradation time of PLA is grown (〉 1 year), and the degradation time of PGA too short (＜January) therefore, is not the material of desirable prevention adhesion of tendon.
Although microsurgical technique, sewing method and tendon transplantation means have obtained certain progress at present, but to prevent to a great extent adhesion of tendon still very difficult, how to prevent the tendinous tissue in surrounding tissue intrusion agglutination, to avoid adhesion, is the important subject that present hands surgical field is badly in need of solution.Yet, in the tendon injury repair process, except paratenon's tendon of growing into causes adhesion, the local aseptic inflammation after damage and use Antiadhesive film after the material degradation product also to be recognized be the key factor that causes adhesion of tendon.
Two, the application of topical remedy
Antiinflammatory class, the class of defibrinating medicine are early to be used to prevent the medicine of adhesion of tendon, as corticosteroid, penicillin, indometacin, ibuprofen, suitable hydroxyproline etc., thereby have and suppress tendon pericyte and stick the effect that propagation prevents adhesion of tendon, at present, ibuprofen is as a kind of Epoxide hydrolase (COX) inhibitor, because its low side effect and high health giving quality are widely used in the acute and chronic analgesia.Except inhibition COX-2 played antiinflammatory action, ibuprofen also had the effect that suppresses COX-1, has been found to have than the better anti effect of selective COX-2-inhibitor 2.These medicines all have the effect that alleviates local adhesion of tendon, but that these medicines can be on tendon when preventing adhesion is interior in healing rate and the certain impact of mass formation, may cause serious whole body toxic and side effects, thereby limit clinical practice.
Somatomedin is small molecular weight protein, glycoprotein or the polypeptide protein of and secretion synthetic by various cells, is combined by the specific receptor on target cell, regulates the various biological behaviours of cell, as propagation, differentiation and the migration etc. of cell.Find that at present the main somatomedin relevant with the tendon injury repair process comprises: basic fibroblast growth factor (bFGF), VEGF (VEGF), transforming growth factor β, para-insulin like growth factor 1(IGF-1) etc.
Chan etc. have reported that normal Tenocyte cell and stndon sheath cell all can produce basic fibroblast growth factor (bFGF), studies show that further bFGF promotes healing process of tendons by cell proliferative response, and find that in Mus kneecap tendon model bFGF can promote the synthetic of Tenocyte cell propagation and III Collagen Type VI.Lan Xiufu is by detecting the expression of bFGF mRNA in rabbit rupture of achilles tendon agglutination, find bFGF mRNA obviously expression of i.e. appearance in the 1st day after wound, reached summit on the 7th day, keep and drop to a reduced levels after 2 months, and low expression level only appears in Normal group, thinks that therefore bFGF is playing an important role in early days that the rabbit rupture of achilles tendon heals.
Sha Defeng etc. are at the rat tendon damage place's of sewing up placement bFGF composite slow release degradative membrane, experimental result shows that bFGF composite slow release degradative membrane has the effect that increases the inner healing ability of tendon, and can make the inner healing of tendon faster than tendon week connective tissue proliferation, not only accelerate agglutination, and reached the effect that alleviates or prevent Adhesion formation.Somatomedin has very high biological activity, and action target spot is extensive; Simultaneously the half-life very short (several hours to a few minutes), the active loss soon, be subject to the impact of the many factors such as temperature and acid-base value in aqueous solution.
Therefore, desirable treatment pattern is to provide a carrier, makes it can be in the stable release of local slow, and at present not yet relevant for the similar report of carrier or product.
Summary of the invention
For the desirable carrier of present shortage so that medicine can local slow, the problem of stable release, the invention provides material of a kind of tissue adhesion of control and preparation method thereof.
First purpose of the present invention is to provide a kind of tissue adhesion's of control material, the base material of described material is fibrous membrane, and the fibrous membrane basic material is selected from: any one or a few in hydroxy carboxylic acid homopolymer or multiple hydroxy carboxylic acid copolymer, hydroxy carboxylic acid and polyol copolymer, polyhydroxycarboxyliacid acid and polyvalent alcohol mixture.
Described copolymer can be random copolymer, block copolymer or graft copolymer.
Wherein, hydroxy carboxylic acid is preferably alpha-hydroxy carboxylic acid compounds, and described alpha-hydroxy carboxylic acid compounds refers in described carboxylic acid, has at least a hydroxyl to be positioned on the carbon atom adjacent with carboxyl, and molecular structure is R
1-C (R
2) (OH)-COOH, wherein R
1Be selected from the alkyl of H or C-C10, the alkyl of H or C1-C5 more preferably, the alkyl of H or C1-C3 more preferably is as methyl, ethyl, propyl group, isopropyl etc., R
1Most preferably be methyl (being that alpha-hydroxy carboxylic acid compounds is lactic acid).
Wherein, described polyhydric alcohol is preferably dihydroxylic alcohols, more preferably α-dihydroxylic alcohols; Described α-dihydroxylic alcohols refers to have at least and is connected with respectively a hydroxyl on two adjacent carbon atoms, and molecular structure is R
3-C (R
4) (OH)-C (R
5) (OH)-R
6, wherein, R
3, R
4, R
5, R
6Be independently selected from respectively the alkyl of H or C1-C10, the alkyl of H or C1-C5 more preferably, the alkyl of H or C1-C3 more preferably is as methyl, ethyl, propyl group, isopropyl; R
3, R
4, R
5, R
6Most preferably being independently respectively H(is that polyhydric alcohol or α-dihydroxylic alcohols are ethylene glycol).
Fibrous membrane basic material of the present invention most preferably is lactic acid homopolymer or lactic acid and other alpha-hydroxy carboxylic acid compounds copolymer or lactic acid and α-divalent alcohol copolymers or its mixture; More preferably lactic acid and α-divalent alcohol copolymers, more preferably lactic acid and glycol copolymer, lactic acid and α-propylene glycol copolymers or its mixture, most preferably be lactic acid and glycol copolymer.
Should be noted in the discussion above that above-mentioned dihydroxylic alcohols also can substitute with epoxide, substitute ethylene glycol, the alternative α-propylene glycol of expoxy propane as oxirane, prepared polymer has identical structure.
In described fibrous membrane basic material, described homopolymer or copolymer weight average molecular weight are preferably respectively 10-1000 kDa, more preferably 20-800 kDa independently, 25-500 kDa more preferably, 30-100 kDa more preferably, 35-60 kDa more preferably is as 40-50 kDa.
In described fibrous membrane basic material, described homopolymer or molecular weight of copolymer distribution (Mw/Mn) are preferably respectively 1-3 independently, more preferably 1.2-2, more preferably 1.3-1.7, more preferably 1.5-1.6.
Wherein, in described copolymer, alpha-hydroxy carboxylic acid compounds (as lactic acid) is preferably 1 with α-dihydroxylic alcohols (as ethylene glycol or propylene glycol or its mixture, most preferably being ethylene glycol) monomer mole ratio
:(0.1-20), more preferably 1
:(0.5-19), more preferably 1
:(1-17), more preferably 1
:(2-16), more preferably 1
:(3-15), more preferably 1
:(5-13), more preferably 1
:(7-12), more preferably 1
:(8-11), more preferably 1
:(8-10), more preferably 1
:9.
When described fibrous membrane basic material is selected from the situation of described mixture, in mixture, the molecular weight and molecualr weight distribution of any one polymer can be implemented with reference to the molecular weight and molecualr weight distribution of described copolymer.In described compound, the monomer mole ratio of various polymer can be implemented according to monomer mole ratio in above-mentioned copolymer.
Second purpose of the present invention is to provide a kind of tissue adhesion's of control medicine carrying material, and described medicine carrying material comprises the described control of first purpose of the present invention tissue adhesion's material, in described control tissue adhesion's medicine carrying material, can also drug component be arranged load.
Described drug component can be to comprise any one or a few the medicine that is selected from anti-inflammatory drug, antibacterials, somatomedin, is preferably to comprise at least a anti-inflammatory drug or at least a antibacterials or its mixture.
Wherein, described somatomedin refers to small molecular weight protein, glycoprotein or the polypeptide protein of and secretion synthetic by various cells, its can by with target cell on receptors bind, regulate the various biological behaviours of cell, as propagation, differentiation and the migration etc. of cell; Preferably, described somatomedin is selected from: basic fibroblast growth factor (bFGF), VEGF (VEGF), transforming growth factor β, para-insulin like growth factor 1(IGF-1) in any one or arbitrarily several combination.
Wherein, described anti-inflammatory drug refers to and is used for the treatment of the sustain damage medicine of the rear inflammatory reaction that occurs of tissue; It can be steroidal drug, or non-steroidal drug, and be preferably non-steroidal anti-inflammatory drug, described non-steroidal anti-inflammatory drug can be salicylic acid, acetic acid class, phenoxy propionic acid, fenamic acids, indoles etc., most preferably be phenoxy propionic acid, as naproxen, venlofen, ketone ibuprofen etc., most preferably be ibuprofen.
Drug component of the present invention is preferably and contains at least anti-inflammatory drug, be preferably ibuprofen, can be independent anti-inflammatory drug (as ibuprofen), can be also the combination of anti-inflammatory drug (as ibuprofen) and other anti-inflammatory drug and/or antibacterials (being antibacterials as silver).Wherein, described anti-inflammatory drug can be directly to load in described fibrous membrane, perhaps anti-inflammatory drug is loaded in other carrier, and then is carried in described fibrous membrane.
Wherein, described antibacterials refer to the medicine with sterilization or bacteriostatic activity, comprise that antibiotic, sulfonamides, imidazoles nitro glyoxaline, quinolones and silver are antibacterials.
Drug component of the present invention is preferably and contains at least antibacterials, and being preferably silver is antibacterials, can be that independent silver is antibacterials, can be also the combination of silver and other anti-inflammatory drug and/or antibacterials.Wherein, described silver is that antibacterials can be directly to load in described fibrous membrane, is perhaps that antibacterials load in other carrier with silver, and then is carried in described fibrous membrane.
Described silver is that antibacterials are preferably silver oxide, as Ag
4O
4
Described silver is that the form that antibacterials are preferably with nano-particle is loaded in described fibrous membrane, and described nano particle diameter is preferably 10-200 nm, is preferably 30-150 nm, is preferably 60-100 nm.
Control tissue adhesion's of the present invention material and/or medicine carrying material, wherein, if there is anti-inflammatory drug (as ibuprofen), anti-inflammatory drug (as ibuprofen) mass content is preferably 0.1-30 %, be preferably 1-20 %, be preferably 2-10 %, as 4 %, 6 %, 8 % etc.
Control tissue adhesion's of the present invention medicine carrying material, wherein, if there are antibacterials, the antibacterials mass content is preferably: in every 100 g basic materials, contain antibacterials 0.1-30 g, be preferably 1-20 g, be preferably 2-15 g, as 4 g, 8 g, 12 g etc.
But should be understood that, in control tissue adhesion's of the present invention material and/or its medicine carrying material, can also comprise the additive that other is available, can also add other available medicine in described drug component.
In fibrous membrane basic material of the present invention, average fibre diameter is preferably 0.1-10 μ m, is preferably 0.3-8 μ m, is preferably 0.5-5 μ m, is preferably 0.8-2 μ m, is preferably 0.8-1.5 μ m, is preferably 1-1.5 μ m.
In fibrous membrane basic material of the present invention, fiber is random arranges, and porosity is preferably 50-98 %, is preferably 55-80 %, is preferably 60-75%.
According to the first preferred embodiment of control tissue adhesion medicine carrying material of the present invention, wherein, the fibrous membrane basic material in described control tissue adhesion material is polylactic acid, and negative Ag-bearing is antibacterials.
According to the second preferred embodiment of preventing and treating tissue adhesion's medicine carrying material of the present invention, wherein, described control tissue adhesion's fibrous membrane basic material is lactic acid and glycol copolymer, and load has ibuprofen as anti-inflammatory drug.
In first and second preferred embodiment of the present invention, polylactic acid, lactic acid and glycol copolymer, silver are that antibacterials, anti-inflammatory drug (as ibuprofen) have the implication that limits as mentioned.
The 3rd purpose of the present invention is to provide a kind of method for preparing the material of preventing and treating the tissue adhesion, and step comprises:
Wherein, can also comprise the medicine of required load in described spinning material, therefore, the present invention the 4th aspect is to provide a kind of method for preparing the medicine carrying material of preventing and treating the tissue adhesion, and described method comprises the steps:
In preparation of the present invention control tissue adhesion's material and/or the method for medicine carrying material, the implication of described basic material, medicine, consumption are all identical with content defined in first purpose of the present invention.
And those skilled in the art can be understood that, the fibrous membrane that said method of the present invention obtains or the fibrous membrane of medicine carrying, can be directly as material and/or the medicine carrying material of preventing and treating the tissue adhesion, perhaps, take described fibrous membrane and/or drug-loading fibre film as base material, add other this area usual component or adopt this area conventional means to make required control tissue adhesion's material and/or medicine carrying material.
Described solvent can be organic solvent, inorganic solvent or its any mixture, and is preferably aliphatic hydrocarbon, aromatic hydrocarbon, chlorohydrocarbon, alcohol, ketone, aldehyde, ester, nitrile, carboxylic acid, sulfoxide, amide solvent.
The example of described aliphatic hydrocarbon comprises: pentane, hexane, octane, cyclohexane extraction etc.
The example of described aromatic hydrocarbon comprises: styrene, benzene,toluene,xylene.
The example of described chlorohydrocarbon comprises: dichloromethane, chloroform, carbon tetrachloride, bromofom, chlorobenzene, dichloro-benzenes (paracide, o-dichlorohenzene), sym-tetrachloroethane etc.
The example of described alcohol comprises: methanol, ethanol, ethylene glycol, propanol, isopropyl alcohol, propylene glycol, the tert-butyl alcohol, glycerol, butanediol, pentanediol, glycol monoethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether etc.
The example of described ketone comprises: acetone, butanone, methyl butyl ketone, Ketohexamethylene etc.
The example of described aldehyde comprises: acetaldehyde, propionic aldehyde, glutaraldehyde, Biformyl etc.
The example of described ester comprises: methyl acetate, ethyl acetate, propyl acetate, butyl acetate, pentyl acetate, methyl formate, Ethyl formate, butyl formate, amyl formate etc.
The example of described nitrile is as acetonitrile.
The example of described carboxylic acid comprises: formic acid, acetic acid etc.
The example of described sulfoxide comprises: dimethyl sulfoxide, thionyl chloride, diphenyl sulfoxide etc.
The example of described amide comprises: DMF, N, N-diethylformamide.
Described inorganic solvent is generally water.
In preparation method of the present invention, described electrostatic spinning parameter is preferably:
1) voltage: be preferably 5-30 kV, be preferably 6-25 kV, be preferably 8-20 kV, be preferably 10-20 kV, as 15kV;
2) receiving range: be preferably 5-50 cm, be preferably 6-30 cm, be preferably 8-25cm, be preferably 10-20 cm, as 15cm;
3) spinning solution feeding speed: be preferably 0.5-10 ml/h, be preferably 0.6-8 ml/h, be preferably 0.8-7 ml/h, be preferably 1-5 ml/h, be preferably 2-4 ml/h, as 3 ml/h.
In first preferred embodiment of preparation method of the present invention, step comprises:
In second preferred embodiment of preparation method of the present invention, step comprises:
The control tissue adhesion's of method preparation provided by the present invention material and/or medicine carrying material, have higher porosity, high biomimetic features and biological function, not only can effectively stop exogenous healing, also allow the infiltration of nutrient substance, promote the endogenous healing.
And control tissue adhesion's provided by the present invention material and/or medicine carrying material prove there is no cytotoxicity by zoopery, show preventing adhesiving effect obviously and have the inflammation-inhibiting effect, and after medicine carrying, healing process of tendons obviously not disturbed; Medicine can discharge lastingly, is 20 days release time, and after drug release, fibrous membrane can progressively be degraded.
Description of drawings
Fig. 1 is that the present invention prepares in the fibrous membrane method of preventing and treating the tissue adhesion, the electrostatic spinning schematic diagram;
Fig. 2 is the control tissue adhesion's of the load ibuprofen for preparing in first embodiment of the invention fibrous membrane SEM photo, wherein, A is the fibrous membrane of load ibuprofen not, B is that the ibuprofen load capacity is 2% fibrous membrane, C is that the ibuprofen load capacity is 6% fibrous membrane, and D is that the ibuprofen load capacity is 10 fibrous membrane;
Fig. 3 is the control tissue adhesion's for preparing in first embodiment fibrous membrane external degradation curve, and Fig. 3 a is maximum weight loss temporal evolution curve, and Fig. 3 b is fibrous membrane molecular weight temporal evolution curve;
Fig. 4 is the control tissue adhesion's for preparing in first embodiment fibrous membrane sustained drug release effect;
Fig. 5 is the control tissue adhesion's for preparing in first embodiment fibrous membrane experiment in vitro fibroblast cultivation effect; Wherein, Fig. 5 a is that mtt assay is measured the fibroblast cultivation effect, and Fig. 5 b is Live/dead cell dyeing method observed result;
Fig. 6 is the control tissue adhesion's for preparing in first embodiment of the invention fibrous membrane results of animal; Wherein, Fig. 6 a is semi-quantitative method evaluation of tissue adhesion situation, Fig. 6 b is histology tissue adhesion situation, Fig. 6 c is tissue adhesion's scoring, Fig. 6 d is the healing process of tendons scoring, and Fig. 6 e is the inflammatory cell infiltration reaction, and Fig. 6 f is the inflammatory cell infiltration scoring, Fig. 6 g is tendon flexing merit testing result, and Fig. 6 h is the maximum stretching resistance testing result of tendon.
The specific embodiment
In lactic acid and glycol copolymer (Mw=40 kDa), lactic acid and ethylene glycol monomer mol ratio are 10
:90.
Lactic acid and glycol copolymer, ibuprofen mixture (1g altogether) are dissolved in the solvent that contains 2.5g dichloromethane and 1.5g acetone, make spinning solution.
Carry out electrostatic spinning, as shown in Figure 1, mode stock solution 1 is placed in syringe 2, the voltage that high voltage power supply 3 applies surpasses in the situation of marginal value, after the charge repulsion of liquid surface surpasses its surface tension, will go out the polymer jet in the surperficial high velocity jet of the taylor cone of shower nozzle end; These jets finally are deposited on reception pole plate 4 shorter distance interior high-speed stretch, solvent evaporates and a curing through electric field force, form polymer fiber or fibrous membrane.
The electrostatic spinning parameter is specially: 1) voltage 15kV; 2) receiving range 15cm; 3) spinning solution feeding speed 3 ml/h.
According to the method described above, prepare respectively the fibrous membrane that the ibuprofen drug loading is 0 wt% (hereinafter referred to as PELA), 2 w%(hereinafter referred to as PELA-2%) fibrous membrane, 6 wt%(hereinafter referred to as PELA-6%) fibrous membrane and 10 wt%(hereinafter referred to as PELA-10%) fibrous membrane.
Under room temperature condition, vacuum drying is 24 hours.
1.1, the control tissue adhesion's of the load of the present embodiment preparation or not load ibuprofen fibrous membrane shape characteristic
Scanning electron microscope (SEM) is observed the form of electrospinning fibre and is taken pictures, as shown in Figure 1.Result shows that the fiber that consists of is evenly distributed.
Applies image analysis software I mage-J analyzes the SEM picture, calculates at random the diameter of 100 fibers, estimates average diameter and the diameter range of fiber.
Adopt liquid substitution method test porosity.Result such as table 1.
Table 1, the characteristics such as hydrophilic angle of load or not load ibuprofen PELA nanofiber Antiadhesive film
Load ibuprofen small-molecule substance can be so that the diameter of PELA fiber and porosity be on a declining curve, and hydrophilic angle and specific surface area are increase tendency.But, the monitor sample amount of just present drug loading, difference does not have statistical significance.
1.2, the control tissue adhesion's of the load ibuprofen of the present embodiment preparation fibrous membrane mechanical property
Use strength tester and study its stretching mechanical character, and measure the load-deformation curve of nano fibrous membrane, the wide 5mm of batten, rate of extension 50mm/min, test result is averaged, result such as table 2.
Table 2, the mechanical characteristic of load or not load ibuprofen PELA nanofiber Antiadhesive film
Load ibuprofen small-molecule substance can be so that the elastic modelling quantity of PELA fiber be increase tendency.But difference does not have statistical significance.
1.3, the control tissue adhesion's of the load of the present embodiment preparation or not load ibuprofen fibrous membrane external degradation
At PH=7.2, temperature is 37
oCSoak described control tissue adhesion's fibrous membrane under condition with phosphate buffer, changed a solution in every four days, in the 1st, 2,4,6,8,10 and 12 weeks, this fabric is carried out dried and weighs, the calculated weight loss is measured the degraded situation of nanofiber and is drawn degradation curve.
As shown in Fig. 3 a, the maximum weight loss of the PELA of load ibuprofen control tissue adhesion's fibrous membrane is respectively 45%(PELA-2%), 60%(PELA-6%) and 72%(PELA-10%), as shown in Fig. 3 b, along with degradation time extends, control tissue adhesion's fibrous membrane is degraded gradually, reaches 30% to 50% degradation rate after 6 weeks.
1.4, the control tissue adhesion's of the load of the present embodiment preparation or not load ibuprofen the external slow release of fibrous membrane
Get respectively each 6 fritters of above-mentioned four kinds of Absorbable membranes, put into the PBS buffer, carry out external slow release test in 37 degree incubators, get its supernatant in different time sections, with the drug level of rp-hplc determination celecoxib, draw corresponding release profiles such as Fig. 4.Fig. 4 shows, the control tissue adhesion's of the load ibuprofen of the present embodiment preparation fibrous membrane can be completed the lasting release of medicine, discharge a few days ago, ibuprofen is respectively 38%(PELA-2% from prominent the releasing on the nanofiber Antiadhesive film), 47%(PELA-6%) and 62%(PELA-10%).
1.5, the control tissue adhesion's of the load of the present embodiment preparation or not load ibuprofen fibrous membrane in-vitro evaluation
24 orifice plates are put in the load of diameter 15mm or the nano fibrous membrane of not load ibuprofen, after sterilization with fibroblast according to 1 * 10
4The density in/hole is inoculated on material, add to contain 10% hyclone and 1% pair of anti-DMEN culture fluid is cultivated, respectively at quantity (OD) value of measuring living cells in 1,4,7 day with mtt assay, with 2% dimethyl sulfoxide solution as blank.Result such as Fig. 5 a, the control tissue adhesion's of relative not load ibuprofen fibrous membrane, the control tissue adhesion's of load ibuprofen fibrous membrane has the effect of better inhibition cell proliferation.And along with the rising of ibuprofen medicine carrying concentration, inhibition increases gradually.
Utilize the live/dead cell dyeing to observe cell adhesion and vigor situation on control tissue adhesion's the fibrous membrane of load or not load ibuprofen, result such as Fig. 5 b.Cultivate and find under scanning electron microscope after 1 day that cell adhesion propagation has obvious difference, in Fig. 5 b, A, B, C, D, E are for after cultivating the 1st day, and F, G, H, I, J are for after cultivating 4 days.A, F are culture plate, and B, G are the PELA film, and C, H are load 2% ibuprofen control tissue adhesion's fibrous membrane; D, I are load 6% ibuprofen control tissue adhesion's fibrous membrane; E, J are load 10% ibuprofen control tissue adhesion's fibrous membrane.As seen, the control tissue adhesion's of relative not load ibuprofen fibrous membrane, the control tissue adhesion's of load ibuprofen fibrous membrane has the effect of better inhibition cell adhesion.And along with the rising of ibuprofen medicine carrying concentration, inhibition increases gradually.
Utilize the method for MTT, the cytotoxicity of the control tissue adhesion's of in vitro study load or not load ibuprofen fibrous membrane.First extract lixiviating solution, cultivated 24 hours at 37 ° of C.According to 1x10
4Cell/200 μ l divide the L929 cell breeding to cultivate in box in 96 holes.After 24 hours, 100%, 50%, 10%, 1% and 0% gradient adds lixiviating solution, at 37 ° of C and 5% CO
2Cultivated again 24 hours.Microplate reader detects the absorption photometric value.Result shows that the absorption photometric value is respectively 0.407(PELA), 0.398(PELA-2%), 0.394(PELA-6%), 0.387(PELA-10%), according to national standard, the control tissue adhesion's of the present embodiment preparation fibrous membrane is defined as does not have cytotoxicity.
In sum, the control tissue adhesion's of the load ibuprofen of the present embodiment accounting fibrous membrane obviously strengthens in external inhibitory action to fibroblast adhesion and propagation.
1.6, the control tissue adhesion's of the load of the present embodiment preparation or not load ibuprofen fibrous membrane interior evaluating
Select experiment with 12 all Leghorn chickens, cut off the middle toe toe and stretch flexor tendon, kesseler closes skin incision after sewing up, and postoperative uses the self-control brace to fix.Be divided at random four groups: (matched group, control), the B group is PELA-6%, every group of 10 samples for PELA group, C group to the A group for blank group.
Appear in 3 weeks of postoperative and repair the position, observe the reaction of skin incision and surrounding tissue, tendon joint portion healing, adhesion and false sheath formational situation, the adhesion of A group is obvious; B organizes a small amount of adhesion; The C group does not have adhesion substantially, and effect is best.
Adopt the semiquantitative method of the practicalities such as Zeng to be used for scoring substantially: 1 grade of expression does not have adhesion; 2 grades of slight adhesions of expression, adhesion organization can separate with surrounding tissue; 3 grades represent that adhesion organization can not separate with surrounding tissue; 4 grades of 35-60% that account for damage field for the adhesion area; The ratio that 5 grades of expression adhesion areas account for the damage field area is greater than 60%, result such as Fig. 6 a, and clinical follow shows that (matched group) adhesion of A group is obvious, is rated more than 4 grades; The a small amount of adhesion grading of B group (PELA group) is below 3 grades, and C group (PELA-6% group) effect is best, below 2 grades.
Structure observation
The modeling group: in 3 weeks of postoperative, visible granulation tissue is opened into the tendon broken ends of fractured bone, and the edge has collagenocyte to form, the inflammatory cell infiltration significant reaction.The broken ends of fractured bone and a large amount of dense connective tissuies generation on every side, tendon and paratenon's boundary are unclear, and fibroblast proliferation is active.Matched group: in 3 weeks of postoperative, the tendon injury zone is covered by granulation tissue is local, visible obviously inflammatory cell infiltration.The gap portion of tendon and paratenon exists.Treatment group: in 3 weeks of postoperative, the tendon perivascular granulation tissue generates, and has film layer sample thing between tendon, visible a small amount of inflammatory cell infiltration.The gap of tendon and paratenon still exists.Fibroblast proliferation, collagen contents increases, but relative with matched group less than modeling.The broken ends of fractured bone has collagenous tissue hypertrophy, orientation more regular.Histology result (Fig. 6 b) shows: (matched group) adhesion of A group is obvious, a small amount of adhesion of B group (PELA group), and C group (PELA-6% group) effect is best.And histological score is shown preventing adhesiving effect obviously and is had the inflammation-inhibiting effect, and healing process of tendons is not obviously disturbed.
Adopt the methods of marking of the application such as G ü demez and Tang to carry out tissue adhesion and healing process of tendons scoring.
Tissue adhesion's scoring: 1 grade of expression does not have adhesion; 2 grades of expression adhesion areas account for the ratio of damage field area less than 30%; 2 grades of 33-66% that account for damage field for the adhesion area; The ratio that level expression adhesion area accounts for the damage field area is greater than 66%, result such as Fig. 6 c.
The healing process of tendons scoring: 1 grade of expression healing process of tendons is good, and smooth surface does not have adhesion; 2 grades represent that tendon broken ends of fractured bone seriality is good but brilliance is owed on the surface; 3 grades represent that arrangement of collagen fibers is irregular or partly rupture; 4 grades of granulation tissuies that represent tendon disunion or hypertrophy cause extensive adhesion, result such as Fig. 6 d.
Fig. 6 c and Fig. 6 d show, A group (matched group) grading is near 4 grades, and B group (PELA group) grading is in the 2-3 level, and C group (PELA-6% group) effect is best, that is, the medicine carrying control tissue adhesion's of the present embodiment preparation fibrous membrane has better preventing adhesiving effect and healing process of tendons effect.
The inflammatory cell statistics
Modeling group: visible inflammatory cell infiltration significant reaction; Matched group is visible obviously inflammatory cell infiltration also, and the modeling group slightly raises relatively; Treatment group: visible a small amount of inflammatory cell infiltration, front two groups of minimizings.
Inflammatory cell is divided into: 1 grade of indivedual inflammatory cell infiltration; 2 grades of slight inflammatory cell infiltrations; 3 grades of moderate inflammatory cellular infiltrations; 4 grades of severe inflammatory cell infiltrations.
Fig. 6 e has provided A group (matched group), B group (PELA group), C organizes (PELA-6% group) inflammatory cell infiltration reaction detection result; Fig. 6 f has provided A group (matched group), B group (PELA group), C group (PELA-6% group) inflammatory cell scoring contrast.The inflammatory cell infiltration scoring of modeling group and matched group obviously increases, and the scoring of the treatment group of the control tissue adhesion's of year ibuprofen fibrous membrane is less.
Biomechanics checks
After chicken was put to death, right pawl the 3rd metatarsophalangeal joints of row was from disconnected, but kept the flexor digitorum profundus muscle tendon, and dissected to the ankle plane to near-end and cut off, and cut off all the other toes branch of flexor digitorum profundus muscle tendon.By fixture, chicken toe nearside phalanx is fixed in the lower end fixture of machanics instrument (BTC-FR020TN.A50, Zwick/Roell company, Germany), chicken toe point is fixed in the near-end of flexor digitorum profundus muscle tendon the upper end-fixture of instrument down.Fixedly tie up the chicken toe outward with 2.0 mm draw points, its distally interphalangeal joint is fixed in stretches the position, and as preload traction chicken toe straight down, make the nearside toe ask that the joint range of flexion is 0
oMachanics instrument is returned to zero.
Flexing merit: after the tendon sliding distance is measured, first machanics instrument is restored (pulling force and sliding distance are all to zero-bit), then begin test, reach 40 in nearside interphalangeal joint flexing
oIn time, stop, and measures the flexing merit.Result is as shown in Fig. 6 g.
The maximum stretching resistance of tendon: restart test after will machanics instrument restoring, required pulling force when measuring tendon and being broken is observed the healing process of tendons situation.Result is as shown in Fig. 6 h.
Fig. 6 g and Fig. 6 h show: the flexing merit of the control tissue adhesion's of year ibuprofen fibrous membrane treatment group obviously reduces, and maximum stretching resistance shows the healing that there is no obviously to affect tendon.
In sum, the control tissue adhesion's of load ibuprofen fibrous membrane, than the control tissue adhesion's of medicine carrying fibrous membrane not, preventing adhesiving effect is better, and can obviously reduce inflammatory cell infiltration; Simultaneously, the healing of tendon do not had obvious inhibitory action.
1g polylactic acid (Mw=50 kDa, Mw/Mn=1.6) is dissolved in the 3.5g dichloromethane; 0.04g, 0.08g and 0.12g Nano silver grain be scattered in 1.5g DMF (DMF), the Nano silver grain dispersion liquid joins in the solution of described polylactic acid, obtains spinning solution.
With reference to the described method of embodiment 1, electrostatic spinning prepares polylactic acid and the Nano silver grain weight ratio is 100
:4 control tissue adhesion's fibrous membrane (hereinafter referred to as PLLA/Ag4%), 100
:8 control tissue adhesion's fibrous membrane (hereinafter referred to as PLLA/Ag8%), 100
:12 control tissue adhesion's fibrous membrane (hereinafter referred to as PLLA/Ag12%) and the fibrous membrane (hereinafter referred to as PLLA) that does not carry the control tissue adhesion of silver.
2.1, the fibrous membrane that carries the control tissue adhesion of silver characterizes
SEM and TEM electron microscope observation gained fibrous membrane, find: fiber be circle, without microballon, and random arranging, fibrous membrane is multi-cellular structure, almost can't see Nano silver grain at fiber surface.
In PLLA/Ag4%, PLLA/Ag8%, PLLA/Ag12%, average fibre diameter is respectively 0.85 ± 0.21 μ m, 0.89 ± 0.38 μ m, 0.95 ± 0.42 μ m and 1.08 ± 0.32 μ m.
2.2, silver-colored slow release research
Initial 2 days, in PLLA/Ag4%, PLLA/Ag8%, PLLA/Ag12%, prominent the releasing of silver ion was respectively 28%, 35% and 41%; Release concentration is respectively 13.4,17.6 and 19.5 ppm.
In ensuing 10 days, the silver ion sustained release is until discharge fully.
2.3, analysis of cell proliferation
Mice fibroblast C3h 10 1/2 is used to estimate the cultivation effect on year silver for preparing in the present embodiment and the fibrous membrane that does not carry silver-colored control tissue adhesion.Described cell is at DMEM(GIBCO, Grand Island, NY, USA) cultivate, and add 10% hyclone (FBS) and antibiotic (penicillin 100U/ml, streptomycin 100g/ml), temperature is 37 ℃, carbon dioxide 5%.
Described cell is inoculated in culture hole, observation of cell propagation situation after 1 and 4 day, and by SEM observation of cell quantity.
Cell is at all samples surface growth, still, do not compare with the fibrous membrane that carries silver, carries cell that silver-colored fibrous membrane surface detects still less, 1 day with 4 days after observe similar trend, and cell is better at PLLA fibrous membrane surface growth.
Year silver-colored fibrous membrane that the present embodiment preparation is described can better be prevented and treated the tissue adhesion.
2.4, cytotoxicity
According to ISO (1992) 10993-5 standard, the mice fibroblast is that L929 is used to detect carrying silver or not carrying the cytotoxicity that silver is prevented and treated tissue adhesion's fibrous membrane of the present embodiment preparation.
By the MTT method, the trap of test 490nm, the relative activity of PLLA, PLLA/Ag 4%, PLLA/Ag 8%, PLLA/Ag 12% is respectively 99.31 ± 3.22%, 97.2 ± 6.31%, 96.25 ± 8.29% and 93.12 ± 9.35%.Therefore, carry silver and all there is no cytotoxicity with the fibrous membrane that does not carry silver-colored control tissue adhesion.
2.5, bacteriostatic experiment
At 37 ℃ of temperature, S.epidermidis(ATCC12228), S.aureus(ATCC25923) and P.aeruginosa(ATCC27853) overnight incubation in pancreas casein peptone soy agar (TSA) culture medium, then individual plant was cultivated 12 hours in BBL pancreas casein peptone soy agar.Adjust concentration to 1 * 10
6CFUs/ml, sample is cultivated at 24 well culture plates.
After dyeing, observe the adhesion of antibacterial by laser confocal scanning microscope (CLSM), PLLA fibrous membrane surface bacteria adheres to density maximum (P＜0.05), the CLSM photo is presented at the PLLA surface can obviously see green visible antibacterial, and it is surperficial at year silver-colored fibrous membrane, bacterial number obviously descends, and illustrates that carrying silver-colored fibrous membrane has better anti-microbial property.
And silver-colored fibrous membrane was surperficial in three kinds years, and above-mentioned three kinds of bacterial adhesion results do not have difference (P＞0.05).
SEM observes after three kinds of antibacterial culturing 24h the adhesion at different surfaces, photo shows, PLLA fibrous membrane surface bacteria density is maximum, carry silver-colored fibrous membrane surface sparse, carry silver-colored fibrous membrane surface bacteria quantity and obviously be less than PLLA fibrous membrane surface ((P＜0.05)), illustrate that carrying silver-colored fiber has better anti-microbial property.
Silver-colored fibrous membrane was surperficial in three kinds years, and bacterial number does not have difference (P＞0.05).
Above specific embodiments of the invention are described in detail, but it is just as example, the present invention is not restricted to specific embodiment described above.To those skilled in the art, any equivalent modifications that the present invention is carried out and substituting also all among category of the present invention.Therefore, not breaking away from impartial conversion and the modification of doing under the spirit and scope of the present invention, all should contain within the scope of the invention.
Claims (15)
1. material of preventing and treating the tissue adhesion, it is characterized in that, the base material of described control tissue adhesion's material is fibrous membrane, and the basic material of described fibrous membrane is selected from: any one or a few in hydroxy carboxylic acid homopolymer or multiple hydroxy carboxylic acid copolymer, hydroxy carboxylic acid and polyol copolymer, polyhydroxycarboxyliacid acid and polyvalent alcohol mixture.
2. control tissue adhesion's according to claim 1 material, is characterized in that, described homopolymer or copolymer weight average molecular weight are 10-1000 kDa respectively independently; Molecular weight distribution (Mw/Mn) is 1-3 respectively independently.
3. control tissue adhesion's according to claim 1 material, is characterized in that, described hydroxy carboxylic acid is alpha-hydroxy carboxylic acid compounds, and described alpha-hydroxy carboxylic acid compounds molecular structure is R
1-C (R
2) (OH)-COOH, wherein R
1Be selected from the alkyl of H or C-C10; Described polyhydric alcohol is α-dihydroxylic alcohols, and described α-dihydroxylic alcohols molecular structure is R
3-C (R
4) (OH)-C (R
5) (OH)-R
6, wherein, R
3, R
4, R
5, R
6Be independently selected from respectively the alkyl of H or C1-C10.
4. the described control of any one tissue adhesion's material according to claim 1-3, is characterized in that, in described copolymer, alpha-hydroxy carboxylic acid compounds and α-dihydroxylic alcohols monomer mole ratio is preferably 1
:(0.1-20).
5. control according to claim 4 tissue adhesion's material, is characterized in that, described fibrous membrane basic material is any one or its mixture in polylactic acid homopolymer, lactic acid and glycol copolymer.
6. control tissue adhesion's according to claim 1 material, is characterized in that, wherein, average fibre diameter is 0.1-10 μ m.
7. control tissue adhesion's according to claim 1 material, is characterized in that, porosity is 50-98 %.
8. a medicine carrying material of preventing and treating the tissue adhesion, is characterized in that, comprise control tissue adhesion's claimed in claim 1 material, and load has drug component; Described drug component is selected from any one or a few in anti-inflammatory drug, antibacterials, somatomedin.
9. control tissue adhesion's according to claim 8 medicine carrying material, is characterized in that, described anti-inflammatory drug is non-steroidal drug; Described antibacterials are that silver is antibacterials.
10. according to claim 8 or 9 described control tissue adhesions' medicine carrying material, is characterized in that, in described control tissue adhesion's medicine carrying material, anti-inflammatory drug quality content is 0.1-30 %; And/or
In every 100 g basic materials, contain antibacterials 0.1-30 g.
11. a method for preparing the material of preventing and treating as claimed in claim 1 the tissue adhesion is characterized in that described method comprises the steps:
Step 1 provides the spinning material of the basic material that comprises the described fibrous membrane of claim 1;
Step 2 is dissolved in described spinning material in solvent, is mixed with spinning solution;
Step 3, electrostatic spinning is made fibrous membrane, the control tissue adhesion material of then making.
12. method according to claim 11 is characterized in that, described electrostatic spinning parameter is: voltage 5-30 kV; Receiving range 5-50 cm; Spinning solution feeding speed 0.5-10 ml/h.
13. a method for preparing the medicine carrying material of preventing and treating as claimed in claim 8 the tissue adhesion is characterized in that described method comprises the steps:
Step 1 provides spinning material; Described spinning material comprises the basic material of fibrous membrane as claimed in claim 1 and the medicine of required load;
Step 2 is dissolved in described spinning material in solvent, is mixed with spinning solution;
Step 3, electrostatic spinning are made the drug-loading fibre film, then make control tissue adhesion's medicine carrying material.
14. method according to claim 13 is characterized in that, step comprises:
Step 1 provides spinning material, and spinning material comprises polylactic acid, ibuprofen;
Step 2 is dissolved in described spinning material in the solvent that contains dichloromethane and acetone, is mixed with spinning solution;
Step 3, electrostatic spinning are made the fibrous membrane that carries ibuprofen, then make the control tissue adhesion's of carrying ibuprofen material.
15. method according to claim 13 is characterized in that, step comprises:
Step 1 provides spinning material, and spinning material comprises lactic acid and glycol copolymer, silver nano-grain;
Step 2 is dissolved in described spinning material in the solvent that contains dichloromethane and acetone, is mixed with spinning solution, wherein lactic acid and glycol copolymer are dissolved in dichloromethane, silver nano-grain is scattered in DMF, then the silver nano-grain dispersion liquid is joined in dichloromethane;
Step 3, electrostatic spinning are made and are carried silver-colored fibrous membrane, then make the control tissue adhesion's of carrying silver material.
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