CN103800096A - Implantation fiber membrane used for pelvic floor dysfunction repair, preparation method and medical apparatus containing implantation fiber membrane used for pelvic floor dysfunction repair - Google Patents
Implantation fiber membrane used for pelvic floor dysfunction repair, preparation method and medical apparatus containing implantation fiber membrane used for pelvic floor dysfunction repair Download PDFInfo
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- CN103800096A CN103800096A CN201210457158.2A CN201210457158A CN103800096A CN 103800096 A CN103800096 A CN 103800096A CN 201210457158 A CN201210457158 A CN 201210457158A CN 103800096 A CN103800096 A CN 103800096A
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Abstract
The invention provides an implantation fiber membrane used for female pelvic floor dysfunction tissue repair. The implantation fiber membrane is characterized by comprising a fluffy fibrous layer (A), wherein the fluffy fibrous layer (A) is formed by interweaving cellosilks with the diameters of 10 nanometers-100 micrometers, and is of a porous structure, the filling power is 400-1500 cm<3>/g, and the softness is 50-500 millinewton. Preferably, the implantation fiber membrane further comprises a directed fibrous layer (B), and the directed fibrous layer (B) is a layer which is formed by the directional alignment of the cellosilks and is of a porous three-dimensional structure.
Description
Technical field
The present invention relates to implantation film, be particularly used for the treatment of implantation film, the preparation method of female pelvic functional disorder disease and the medical apparatus and instruments that contains it.
Background technology
Be subject to the impact of the factors such as fertility, disease, aging, pelvic floor soft tissue around weakens the supporting function of pelvic organ, causes occurring various pelvic floor dysfunction diseases.Pelvic floor dysfunction disease is women's commonly encountered diseases and frequently-occurring disease.Female pelvic floor functional disorder disease (Pelvic Floor Dysfunction diseas e, PFD), claim again pelvic floor defects or pelvic floor supporting tissue lax, main manifestations is prolapsus, bulging (the Pelvic OrganProlapse of pelvic cavity viscera (as bladder, uterus, rectum, vagina and small intestinal etc.), and stress incontinence (Stress Urinary Incontinence, SUI) POP).POP and SUI are closely related, and women's life and health are caused to serious impact.At present, be first-selected for moderate and above prolapsus person's operative treatment.In operation, apply pelvic floor patch treatment pelvic floor dysfunction disease, its effect obtains numerous medical personnel and patient's approval.And adopt that composite medical material carries out without tension force tape surgery managed (comprising TOT, TVT-O, SPARC, TVT) be treat at present PFD the most effectively, method the most thoroughly.
At the bottom of traditional basin, prothesis is all reinforced organizing repeatedly of weakness, does not solve root problem, and Postoperative recurrent rate is high, has the risk of operation again.This makes it possible to replace the synthetic or application of biomaterial sticking patch (suspender belt) in reconstruction at the bottom of basin of weak impaired pelvic floor fascia tissue more and more extensive.At present in pelvic floor repair product, most widely used is the non-degradable net sheet that mesh grid sheet, the especially polypropylene material of synthetic material made, and has occupied most market.But this net sheet exposes serious untoward reaction gradually, as problems such as erosion, exposure, shrinkage, hemorrhage, pain, sexual intercourse discomforts.2005-2007, reports hemorrhage 1000 routine bad use cases, from 2008 to 2010, has 2874 routine bad reports, has caused paying close attention to of society and FDA.FDA is just advising this series products to rise to the III class apparatus of supervision highest level from implanting II class medical apparatus and instruments, and has required relevant producer to provide complete clinical report and market to follow the tracks of report.In January, 2012, order 33 pelvic floor repair sticking patch manufacturers and 7 stress incontinence sticking patch manufacturers of FDA carry out the clinical research of going deep into of product.In June, 2012, Johson & Johnson issues bulletin, ends the first quarter in 2013, will suspend in the world all pelvic floor repair products of its company.J & J at present, American Me dical Systems, C.R.Bard, the companies such as Boston Scientific face the lawsuit that up to a hundred relevant issues cause.
Above untoward reaction come from many-side, be mainly due to the sensitivity of female pelvic organs and tissues, weakness (as, vaginal wall is made up of mucosa, flesh layer and fibrous tissue film, vaginal wall is rich in venous plexus, therefore Local Damaged wound is hemorrhage or formation hematoma easily), material itself, the technique of sticking patch (suspender belt), and modus operandi etc. causes.As hard in the net sheet quality that polypropylene material etc. is prepared by knitting skill, rough surface, though the continuous improvement of process manufacturer, but still thoroughly do not solve, because this is the limitation of knitting skill itself.This more firmly, more coarse material implants, patient will have comparatively significantly foreign body sensation, and there will be material shrinkage, displacement to cause even puncture of extruding to normal position tissue, friction at patient, there is serious complication, as infection, hemorrhage, abnormal flavour, abscess etc.Wherein modal is to corrode, and can cause that visceral organ injury, material expose, pain unbearably, affects even threat to life patient's orthobiosis.In later experiments, also confirm, the net sheet associativities such as tissue and polypropylene are also bad, take out after net sheet, find that tissue and material be not in conjunction with tight, substantially the parcel to material in tissue, can peel off tissue and net sheet relatively easily, has on long terms larger potential safety hazard.Clinical discovery corrodes and generally appears at postoperative 12-24 month, (Vaginal mesh erosion 7years after a sacral colpopexy, the Acta Obstet Gynecol Scand.2003Jul such as Deval; 82 (7): 674-5) once report has net sheet to implant the patient that the erosion of net sheet occurs for latter 7 years.This is also that mesh grid sheet easily occurs that displacement causes a reason of erosion.
No matter to corrode or shrinkage, once occur that this problem needs second operation reparation in most situations, or by net sheet and around infected tissue thoroughly remove.This will very seriously affect patient's orthobiosis, brings huge wound to patient's psychology, physiology, and a lot of patients can still not feel well and pain after net sheet removes, and affect love life, even normally sitting.
In order to solve the problem of the said goods, in prior art (as CN 101773689A), propose to replace traditional weaving method to prepare surgery biological patch with electrostatic spinning.Electrostatic spinning is that one is prepared the simple and effective processing method of polymer superfine fibre, because its superfine fibre preparing can reach nanoscale, nano bionic support can be simulated n cell epimatrix structure to a certain extent effectively, better suited microenvironment is provided to growth and the climbing of cell.This characteristic makes micro/nano fibrous membrane material prepared by electrospinning process be specially adapted to bio-medical field at present.But, at present, in the electrospinning film of research, major part there will be cell to be difficult to the slow deficiency of growing into or grow in it, and the mechanical strength of electrospinning film is poor and soft not, can only be used for clinically mechanical strength and comfort level and require lower position, as skin etc.
Desirable pelvic floor dysfunction disease reparation need possess following performance with implantation film: 1. certain intensity, can resist mechanical stress, and before not being completed into, wants health tissues to bear Intraabdominal pressure; 2. be convenient to cell and tissue and stick, creep and fast breeding, prevent that material from exposing or be subjected to displacement in vivo and rub; 3. preventing that antibacterial from hiding grows, and avoids the infection because using the braided materials such as polypropylene to cause; 4. after implant into body, can keep good dimensional stability, can not shrink and be out of shape; 5. Stability Analysis of Structures, is convenient to be cut into the shape needing and does not decoherence, and is convenient to and tissue apposition; 6. soft, for repairing at the bottom of basin, the vaginal wall tissue that the bottom that is characterized in diaphragm (sticking patch or suspender belt) is thin layer or be close to urethra, tissue is weak, if the material of diaphragm (sticking patch or suspender belt) is harder, easily cause material to pierce through fragile vaginal wall or urethra, cause the complication such as erosion, therefore desirable diaphragm need to have superior pliability; And the applicable pliability of material is convenient to molding, is increased the operability of operation, reduction patient's sense of discomfort, the effect of raising operation.But the tissue repair that existing braiding or electrospinning form is all undesirable by the performance of fibrous membrane.
Summary of the invention
the problem that invention will solve
The present invention makes in view of the problem of above-mentioned prior art.Object is to provide a kind of tissue repair implantation film, it has good mechanical strength, can support for enough mechanics for repairing prerequisite completely, and be conducive to the quick adhesion of cell and tissue and propagation, guiding cell differentiation, be conducive to fitting tightly between tissue, the diaphragm pliability of associated ideal simultaneously, can effectively reduce or avoid the generation of erosion, improves patient's comfort.
Secondly, the present invention also provides a kind of tissue repair implantation film, and it has good pliability, good biocompatibility, is conducive to tissue and grows into form firmly reparation, further can have the characteristic of infection, hemostasis.
for the scheme of dealing with problems
The present invention relates to a kind of tissue repair implantation film that is used for the treatment of female pelvic functional disorder disease, it is characterized in that, described implantation film comprises fluffy fiber layer (A);
The cellosilk that described fluffy fiber layer (A) is 10nm ~ 100 μ m by diameter is interwoven, and has vesicular texture, and its loft is 400 ~ 1500cm
3/ g, its pliability is 50 ~ 500 milli newton.
Implantation film of the present invention, the average pore size of wherein said fluffy fiber layer (A) is 50 ~ 500 μ m.
Implantation film of the present invention, the thickness of wherein said fluffy fiber layer (A) is 0.2 ~ 2mm, tensile strength is 10 ~ 300N/cm.
Implantation film of the present invention, the loft of wherein said fluffy fiber layer (A) is 800 ~ 1300cm
3/ g.
Implantation film of the present invention, the pliability of wherein said fluffy fiber layer (A) is 200 ~ 450 milli newton.
Implantation film of the present invention, wherein said fluffy fiber layer (A) adopts and comprises that the method for electrostatic spinning step makes.
Implantation film of the present invention, wherein said implantation film further comprises directional fiber layer (B), described directional fiber layer (B) be by cellosilk align and form have cellular three dimensional structure layer.
Implantation film of the present invention, the filametntary diameter in wherein said directional fiber layer (B) is 10nm～20 μ m.
Implantation film of the present invention, passes through the mode combination of electrostatic spinning, ultrasonic fusion or stitching between each layer in wherein said implantation film.
Implantation film of the present invention, comprises the medicine of hemostasis class medicine, anti-infection drug, cell growth regulator, toxicity inhibitor, anesthetis micro-nano granules and/or treatment urinary incontinence in wherein said implantation film.
Implantation film of the present invention, the surface of wherein said implantation film comprises hemostatic layer.
Implantation film of the present invention, wherein said hemostatic layer comprises collagen, polyoxyethylene fibre, chitosan, fibrin, peptide and/or thrombin.
Implantation film of the present invention, wherein said hemostatic layer forms by the method for electrostatic spinning, lyophilization, forced air drying or vacuum drying.
Implantation film of the present invention, the fibrous material of wherein said implantation film is degradation material, non-degradable material or its combination.
Implantation film of the present invention, wherein said degradation material is selected one or more in the group of free polylactic acid, polycaprolactone, polyglycolic acid, Poly(D,L-lactide-co-glycolide, peptide polymer, chitosan and modification of chitosan composition to dioxy Ketohexamethylene, collagen protein, gelatin, fibrin, fibroin, elastin mimicry.
Implantation film of the present invention, wherein said non-degradable material selects one or more in the group of freely gathering fluorine material, polyolefin, polyurethane, polyamide, polyester and silicone rubber composition.
Implantation film of the present invention, wherein said implantation film has the through hole that runs through described implantation film upper and lower surface.
Implantation film of the present invention, the aperture of wherein said through hole is 0.2-4mm.
The preparation method that the invention still further relates to described implantation film, is characterized in that, the preparation method of described implantation film comprises the step of preparing fluffy fiber layer (A), and the described step of preparing fluffy fiber layer (A) comprises:
(1) by two kinds of different dissolution properties fibrous materials, be dissolved in respectively in corresponding solvent, obtain the fibrous material solution of two kinds of homogeneous;
(2) two kinds of homogeneous fibrous material solution that obtain in step (1) are respectively charged in different electrostatic spinning syringes, through electrostatic spinning, obtain the fibrous membrane of the different mutual crisscross intersection of cellosilk of two kinds of dissolution properties;
(3), according to the dissolution properties of cellosilk material, with solvent, by a kind of cellosilk dissolving in the fibrous membrane of manufacturing in step (2), another remains unchanged, and obtains described fluffy fiber layer (A).
The preparation method of implantation film of the present invention, is characterized in that, the preparation method of described implantation film comprises the step of preparing fluffy fiber layer (A), and the described step of preparing fluffy fiber layer (A) comprises:
(1) fibrous material is dissolved in solvent, obtains the fibrous material solution of homogeneous;
(2) the homogeneous fibrous material solution obtaining in step (1) is packed in electrostatic spinning syringe, carry out electrostatic spinning and obtain fiber, and fiber is received as to membrane structure, obtain fibrous membrane;
(3) fibrous membrane preparing in step (2), under the state after solvent supersonic is swelling, is carried out to pre-freeze, then carry out vacuum lyophilization, obtain described fluffy fiber layer (A).
In above-mentioned preparation method, in described step (3), after the ethanol water that is 50 volume % ~ 95 volume % infiltrates, then in water, carry out ultrasonic swelling by the fibrous membrane concentration preparing in step (2).
The preparation method of implantation film of the present invention, is characterized in that, the preparation method of described implantation film comprises the step of preparing fluffy fiber layer (A), and the described step of preparing fluffy fiber layer (A) comprises:
(1) fibrous material is dissolved in solvent, obtains the fibrous material solution of homogeneous;
(2) the homogeneous fibrous material solution obtaining in step (1) is packed in electrostatic spinning syringe, obtain fibrous membrane through electrostatic spinning;
(3) fibrous membrane of preparation in step (2) is stretched along the direction of one of the transverse axis of fibrous membrane or longitudinal axis, after stopping stretching, fibrous membrane is shaped under this extended state; Then fibrous membrane is stretched along the direction vertical with above-mentioned draw direction of fibrous membrane, after stopping stretching, fibrous membrane is shaped under this extended state, obtain described fluffy fiber layer (A).
Preparation method of the present invention, wherein in step (3), the draft temperature of the described fibrous membrane of stretching is the temperature lower than 0 ℃ ~ 30 ℃ of materials hot deformation temperature, rate of extension is 50 ~ 400mm/min, tensile elongation is original length 1.5 ~ 6.0 times, shaping time is 1h ~ 4h.
Preparation method of the present invention, wherein, described preparation method further comprises the step of preparing directional fiber layer (B) with electrostatic spinning.
The invention still further relates to a kind of implanted medical device that is used for the treatment of female pelvic functional disorder disease, it is characterized in that, described implanted medical device comprises implantation film of the present invention.
Implanted medical device of the present invention, wherein said implanted medical device is without tension force urinary incontinence suspender or pelvic floor sticking patch.
Implanted medical device of the present invention, wherein saidly comprises main part and end without tension force urinary incontinence suspender, and described main part is made up of implantation film of the present invention, and described end is for operating theater instruments traction and/or for fixing.
Implanted medical device of the present invention, wherein said main part has straight line or corrugated outline.
Implanted medical device of the present invention, wherein said corrugated concavo-convex stand out is 1mm-5mm.
Implanted medical device of the present invention, wherein said pelvic floor sticking patch comprises the prolapsus for repairing pelvic cavity viscera, the middle part bulk portion of bulging, described middle part bulk portion is made up of implantation film of the present invention.
Implanted medical device of the present invention, wherein said pelvic floor sticking patch comprises the arm shape structure that is positioned at middle part bulk portion periphery for suspending prolapsus pelvic cavity viscera in midair.
the effect of invention
Compared with prior art, the present invention has following beneficial effect:
(1) tissue repair implantation film of the present invention, has bigger serface, be conducive to quick adhesion and the propagation of cell and tissue, and the surface topology of fiber is also conducive to guide cell differentiation;
(2) tissue repair of the present invention has porous fluffy structure with implantation film, is more conducive to fibrocyte grows into rapidly than the electrospinning membrane structure of common material, plays the effect strengthening and fixing;
(3) implantation film improves the general performance of material for tissue repair of the present invention, and quality is light, soft, the female pelvic floor of not only fitting organs and tissues sensitivity, weak requirement, be more conducive to and organize between fit tightly, improve patient's comfort;
(4) tissue repair implantation film of the present invention, can reduce repair reuse artifacts shrinkage, cause infect and with the generation of the situation such as internal organs adhesion;
(5) tissue repair implantation film of the present invention, can provide good biocompatibility, is beneficial to tissue and grows into form firmly reparation, further has the characteristic of infection, hemostasis.
Above beneficial effect, can effectively reduce or avoid the generation of erosion, realizes the ideal reparation to pelvic floor functional disorder disease.
Accompanying drawing explanation
Fig. 1 is fluffy fiber layer (A) the tangent plane scanning electron microscope (SEM) photograph that embodiment 5 obtains;
Fig. 2 is the electrospinning film tangent plane scanning electron microscope (SEM) photograph that embodiment 5 steps (2) obtain;
Fig. 3 is an exemplary plot without tension force urinary incontinence suspender of the present invention;
Fig. 4 is another exemplary plot without tension force urinary incontinence suspender of the present invention;
Fig. 5 is the exemplary plot of the pelvic floor sticking patch for forepelvis of the present invention;
Fig. 6 is the exemplary plot of the pelvic floor sticking patch for rear pelvis of the present invention;
Fig. 7 is that in embodiment 9, IV group PVDF fluffy fiber layer is implanted 4 weeks rear design sketchs of dissecting between miniature pig vesicovaginal space;
Fig. 8 is that in embodiment 9, I group PP net sheet is implanted 4 weeks rear design sketchs between miniature pig vesicovaginal space.
description of reference numerals
1 main part
2 ends
3 outlines
4 through holes
5 sticking patch through holes
The bulk portion at 6 sticking patch middle parts
The arm shape structure of 7 sticking patch peripheries
The tractive part of 8 sticking patch arm shape structures
The specific embodiment
The present invention relates to be used for the treatment of the tissue repair implantation film of female pelvic functional disorder disease, described implantation film comprises fluffy fiber layer (A); The cellosilk that described fluffy fiber layer (A) is 10nm ~ 100 μ m by diameter is interwoven, and has vesicular texture, and its loft is 400 ~ 1500cm
3/ g, its pliability is 50 ~ 500 milli newton.Implantation film of the present invention can be single or multiple lift film, in the time that implantation film is monofilm, only comprises fluffy fiber layer (A).
In the time that implantation film is multilayer film, can comprise one or more layers fluffy fiber layer (A), be not particularly limited for the material of other layers, structure, preparation method etc., can use any material, structure and the preparation method that in prior art, can be used for treating female pelvic functional disorder disease.Preferably, described implantation film may further include directional fiber layer (B), described directional fiber layer (B) be by cellosilk align and form have cellular three dimensional structure layer.Between each layer of implantation film, can pass through the mode combinations such as electrostatic spinning, ultrasonic fusion or stitching.
< fluffy fiber layer (A) >
The cellosilk that fluffy fiber layer of the present invention (A) is 10nm ~ 100 μ m by diameter is interwoven, and has vesicular texture, and its loft is 400 ~ 1500cm
3/ g, its pliability is 50 ~ 500 milli newton.Described filametntary diameter is preferably 500nm ~ 5 μ m, and described loft is preferably 800-1300cm
3/ g, described pliability is preferably 200 ~ 450 milli newton.Further, fluffy fiber layer of the present invention (A) preferably average pore size is 50 ~ 500 μ m, and preferred thickness is 0.5 ~ 1.0mm, and preferably tensile strength is 20 ~ 80N/cm.
Loft of the present invention refers to the apparent thickness of fluffy fiber layer (A) and the ratio of surface density 1000 times,
Loft B=apparent thickness T
0/ surface density ω × 10
3,
Wherein, loft is with cm
3/ g represents, apparent thickness represents with mm, and surface density is with g/m
2represent.Apparent thickness T
0method of testing be to utilize FAST-1 compressibility Fabric Style instrument to test according to GB/T 7689.1-2001 method, be expressed as fluffy fiber layer (A) at 2cN/cm
2thickness under pressure (mm) and fluffy fiber layer (A) are at 100cN/cm
2thickness under pressure (mm) poor.The test mode of surface density ω is to ignore in the thickness situation of fluffy fiber layer (A), measures single the weight under unit are.
Pliability of the present invention refers to that newton represents with milli according to the maximum vector sum of the counter-bending power of diaphragm that in GB/T 8942-2002, method tests out and diaphragm and gap place frictional force, and more the bright film of novel is more soft for softness values.
The diameter of cellosilk described in the present invention is to measure by the method for scanning electron microscope; Described average pore size utilizes Capillary Flow pore analysis instrument to measure by bubble point method, with reference to ASTM D 6767-2002; Described tensile strength is to measure by GB/T3923.1-1997 " mensuration of fabric ultimate strength and elongation at break " method; Described thickness is measured according to GB/T7689.1-2001 method by compressibility Fabric Style instrument.
As the manufacture method of fluffy fiber layer of the present invention (A), comprise the method that has comprised electrostatic spinning step that adopts.
As a kind of preferable production process of this fluffy fiber layer (A), can adopt electrospinning to carry out in conjunction with dissolution with solvents method, specifically comprise the steps:
(1) by two kinds of fibrous materials that dissolution properties is different, be dissolved in respectively in corresponding solvent, obtain the fibrous material solution of two kinds of homogeneous;
(2) two kinds of homogeneous fibrous material solution that obtain in step (1) are respectively charged in different electrostatic spinning syringes, the corresponding nozzle needle of two kinds of fibrous materials is evenly distributed on high-tension electricity source plate, carry out electrostatic spinning, obtain the fibrous membrane of the different crisscross intersection of cellosilk of two kinds of dissolution properties;
(3) according to the dissolution properties of fibrous material, select suitable solvent that a kind of cellosilk in the fibrous membrane of preparation in step (2) is dissolved, another remains unchanged, and obtains described fluffy fiber layer (A).
In above-mentioned steps (2), preferably the rate adaptation of micro-injection pump is 0.1 ~ 15.0ml/ hour, more preferably 3 ~ 6ml/ hour.Preferably the voltage-regulation of high tension generator is 5 ~ 45KV, more preferably 20 ~ 36KV.Preferably the receiving range of receiving system is adjusted to 5.0 ~ 30.0cm, more preferably 15.0 ~ 20.0cm.
In the present invention, described two kinds of different fibrous materials of dissolution properties refer in two kinds of fibrous materials, to only have wherein a kind of fibrous material can be dissolved in a certain solvent.Preferred a kind of fibrous material is wherein: PCU(polycarbonate polyurethane) or PVDF(Kynoar).Preferred another kind of fibrous material is wherein: PLLA(L-polylactic acid) or PLGA(Poly(D,L-lactide-co-glycolide).
As another preferable production process of fluffy fiber layer of the present invention (A), comprise the steps:
(1) fibrous material is dissolved in solvent, obtains the fibrous material solution of homogeneous;
(2) the homogeneous fibrous material solution obtaining in step (1) is packed in electrostatic spinning syringe, carry out electrostatic spinning and obtain cellosilk, and cellosilk is received as to membrane structure, obtain fibrous membrane;
(3) fibrous membrane preparing in step (2), under the state after solvent supersonic is swelling, is carried out to pre-freeze under predetermined temperature, then carry out vacuum lyophilization, obtain fluffy fiber layer (A).
In above-mentioned steps (2), preferably the rate adaptation of micro-injection pump is 0.1 ~ 15.0ml/ hour, more preferably 3 ~ 6ml/ hour.Preferably the voltage-regulation of high tension generator is 5 ~ 45KV, more preferably 30 ~ 36KV.Preferably the receiving range of receiving system is adjusted to 5.0 ~ 30.0cm, more preferably 15.0 ~ 20.0cm.
In above-mentioned steps (3), be preferably water for injection for the solvent of ultrasonic swollen fiber film.After by the fibrous membrane concentration preparing in step (2) being preferably the ethanol water infiltration of 50 volume % ~ 95 volume %, put into the ultrasonic machine that fills water for injection, after ultrasonic swelling 5 ~ 15 minutes, leave standstill, change water for injection, ultrasonic swelling again, until being injected water, ethanol is replaced.Then the fibrous membrane under ultrasonic water for injection swelling rear state is put into freeze drying box and carried out precooling 2 ~ 5 hours in-50 ℃, then open vacuum and carry out vacuum lyophilization 20 ~ 26 hours, obtain described fluffy fiber layer (A).
As another preferable production process of fluffy fiber layer of the present invention (A), comprise the steps:
(1) fibrous material is dissolved in solvent, obtains the fibrous material solution of homogeneous;
(2) the homogeneous fibrous material solution obtaining in step (1) is packed in electrostatic spinning syringe, carry out electrostatic spinning and obtain cellosilk, and cellosilk is received as to membrane structure, obtain fibrous membrane;
(3) fibrous membrane of preparation in step (2) is stretched along the direction of one of the transverse axis of fibrous membrane or longitudinal axis, after stopping stretching, fibrous membrane is shaped under this extended state; Then fibrous membrane is stretched along the direction vertical with above-mentioned draw direction of fibrous membrane, after stopping stretching, fibrous membrane is shaped under this extended state, obtain fluffy fiber layer (A).
In above-mentioned steps (2), preferably the rate adaptation of micro-injection pump is 0.1 ~ 15.0ml/ hour, more preferably 3 ~ 6ml/ hour.Preferably the voltage-regulation of high tension generator is 5 ~ 45KV, more preferably 30 ~ 36KV.Preferably the receiving range of receiving system is adjusted to 5.0 ~ 30.0cm, more preferably 15.0 ~ 20.0cm.
In above-mentioned steps (3), horizontal and vertical rate of extension is preferably 50 ~ 400mm/min, more preferably 50mm/min ~ 200mm/min independently of one another.Horizontal and vertical tensile elongation is preferably 1.5 ~ 6.0 times of original length independently of one another.
In above-mentioned steps (3), preferably, with the both sides of the fibrous membrane making in clamp clamps above-mentioned steps (2), temperature setting is set to the temperature lower than 0 ℃ ~ 30 ℃ of fibrous material heat distortion temperatures, speed with 50 ~ 400mm/min at the uniform velocity stretches, after making fibrous membrane be elongated 1.5 ~ 6.0 times to original length, stop stretching, make at normal temperatures the fibrous membrane 1h ~ 4h that shapes under this extended state, then take off and by the other both sides clamp clamps of fibrous membrane, temperature setting is set to the temperature lower than 0 ℃ ~ 30 ℃ of materials hot deformation temperature, along at the uniform velocity stretching with the speed of 50 ~ 400mm/min with the direction that draw direction is vertical before, after making fibrous membrane be elongated 1.5 ~ 6.0 times to original length, stop stretching, make at normal temperatures the fibrous membrane 1h ~ 4h that shapes under this extended state, obtain fluffy fiber layer (A).
Fig. 1 is the tangent plane Electronic Speculum figure of the fluffy fiber layer (A) that obtains according to said method in the embodiment of the present invention 5, Fig. 2 be in the embodiment of the present invention 5 according to said method after step (2), the electrospinning film obtaining.Shown in Fig. 1 and Fig. 2, can find out, the electrospinning film that fluffy fiber layer of the present invention (A) obtains from common electrospinning is different on the fibre structure of microcosmic, and in macroscopic view, shows as the difference such as loft, pliability, by 130cm
3the loft of/g and 870 milli newton's pliability becomes 1100cm
3the loft of/g and 400 milli newton's pliability.Visible fluffy fiber layer of the present invention (A) has better bulkiness and flexibility.
< directional fiber layer (B) >
The cellosilk that directional fiber layer (B) is is 10nm～20 μ m by diameter aligns the layer with cellular three dimensional structure forming.It has regular fiber orientation, can simulate the arrangement of collagen fibers direction in fascia inner cell epimatrix, can guide Growth of Cells, for the extracellular matrix of cell and new secretion thereof provides directed skeleton, structure, imitate as far as possible the organizational structure of body self, extremely be beneficial to growing into of fibroblast and blood capillary, the self-regeneration of muscle, fascia is played a key effect, can realize repairing effect stable when long.Thereby can realize good postoperative repairing effect, reduce relapse rate.
In the present invention, preferably use electrostatic spinning to prepare directional fiber layer (B), its operating condition is that the speed of adjusting micro-injection pump is 0.1～15.0 ml/hour, regulating the voltage of high tension generator is 5～45kV, regulating the receiving range of receiving system is 5.0～30.0 centimetres, regulate translational speed 1～20 cel of electrospinning syringe needle, receive roller rotating speed and be 2000～6000 circles/point.
< fibrous material >
The material of implantation film of the present invention comprises non-degradable material, degradation material or its combination.Described non-degradable material mainly comprises poly-fluorine class material, as polyvinylidene fluoride (PVDF), polytetrafluoroethylene (PTFE) etc.; Polyolefin, as polyethylene, polypropylene etc.; Polyurethane material, as polyurethanes (PU), polycarbonate polyurethane (PCU), polyether based polyurethanes, silicane-modified polyurethane (SPU) etc.Described degradation material mainly comprises the synthetic materials such as polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA), Poly(D,L-lactide-co-glycolide (PLGA), 1,3-PD polymer (PDO); With natural macromolecular materials such as the peptide polymers of collagen protein, gelatin, fibrin, fibroin, elastin mimicry; Chitosan, modification of chitosan.The fibrous material of fluffy fiber layer (A), directional fiber layer (B) and other layer of use can be identical or different, wherein, preferably polyvinylidene fluoride material is prepared directional fiber layer (B), and it has good histocompatibility and durability, and mechanical strength is good.Preferably polyvinylidene fluoride (PVDF), polycarbonate polyurethane (PCU), polylactic acid (PLA) are prepared fluffy fiber layer (A).
Other layer of > of <
Implantation film of the present invention can also contain fluffy fiber layer (A) and directional fiber layer (B) layer in addition, fibrous layer (C), woven mesh layer (D) or memory metal layer (E) without orientation that it can be prepared for common electrospinning.
Implantation film of the present invention can also contain the layer that comprises anti-infection drug, hemostasis class medicine and/or micro-nano granules, wherein said anti-infection drug, hemostasis class medicine and/or micro-nano granules can be arranged in the fibrous layer (C) of fluffy fiber layer (A), directional fiber layer (B), nothing orientation, also can be positioned at other layer outside above-mentioned each layer, also can be adsorbed in the surface of implantation film.
Described anti-infection drug comprises ampicillin class, spiramycin class, sulfonamides, quinolones and/or cephalosporins.Described hemostasis class medicine comprises 6-aminocaprolc acid, para-amino-methyl-benzoic acid, tranamic acid, Radix Notoginseng and/or YUNNAN BAIYAO.Described micro-nano granules comprises SiO
2, TiO
2, ZnO, Ag, Ni, quaternary ammonium salt, chitosan, calcium alginate, polyvinyl alcohol and/or natural macromolecular nanoparticle.
< post processing >
Implantation film of the present invention can further pass through post processing modification, for example, can process through one or more the mode in drilling processing, hyperthermic treatment and immersion treatment.Described fibrous membrane can also be with the processing of sewing of tinsel or polymer fiber.
Described drilling processing can be used punching press drilling, laser punching, local pressure to found the methods such as hole to form the through hole of perforating fiber film upper and lower surface.Wherein preferred laser punching, by regulating and parameters optimization, after cut pore-forming, hole periphery can, by a high temperature moment melting part, become compact texture, and the width of hole periphery puddle is about 0.02 ~ 0.05mm.This puddle can play fixation holes size, maintains the effect of product entirety mechanical property.In the time using electrostatic spinning preparation to implant sticking patch, can be by adopting metal, insulation staggered-mesh dash receiver, the Coulomb repulsion lines that receives strip tool patterning carrys out drilling.
At the bottom of long-term basin, repair system research shows, the aperture of implantation film is most important to therapeutic effect.And brace aperture rate prepared by traditional electrical spinning process is high, but aperture is very little; And general forming hole method can greatly affect the mechanical property of electrospinning support.The present invention is by research and more different aftertreatment technologys, and through biological experiment in external, body in a large number, draws good, the more soft and good diaphragm material of therapeutic effect of mechanical strength through repeatedly optimizing, and possesses suitable pore size and hole and arranges.As the mode that the hole that adopts certain size is staggered or different size hole combines can be beneficial to better tissue and grow into, in exchanging inside and outside improving material, the quick eliminating of metabolite while being also beneficial to tissue, Growth of Cells.Meanwhile, hole, for tissue growth provides more spaces, is more conducive to penetrating of blood capillary.
In order to keep mechanical strength, prepared by the mode that can adopt macropore and aperture to combine: the macropore of stamping 0.8～1.6mm diameter according to 0.5～1cm spacing; Between every four macropores, evenly stamp the aperture of 2～4 0.4～0.6mm diameters.When can keeping patch mechanical strength like this, increase pore quantity, be more conducive to organize quick perforation growth.
< implanted medical device >
The implanted medical device that is used for the treatment of female pelvic functional disorder disease of the present invention, comprises implantation film of the present invention.Concrete, described implanted medical device can be without tension force urinary incontinence suspender or pelvic floor repair sticking patch.
Describedly comprise main part and end without tension force urinary incontinence suspender (hereinafter to be referred as suspender belt), described main part is made up of implantation film of the present invention, and described end is for operating theater instruments traction and/or for fixing.
Exemplarily, suspender belt of the present invention can have the outward appearance as Fig. 3-4, suspender belt comprises main part 1 and end 2, after suspender belt implant into body, main part 1 contacts with anterior vaginal wall and urethra interbed, thereby main part 1 embeds obturator fascia and make it keep tensioning state to apply support force upwards to urethra, and end 2 is for operating theater instruments traction and/or for fixing.Suspender belt width is preferably 5mm-30mm, and thickness is preferably 0.1mm-2mm.The main part of suspender belt can have the outline 3 of straight line (as Fig. 3) or corrugated (as Fig. 4), and described corrugated concavo-convex stand out is preferably 1mm-5mm.Also can have and the same or analogous corrugated outline of main part a specific embodiments medial end portions.Preferably use the suspender belt with corrugated outline, it can make more firm being fixed among pelvis obturator membrane of suspender belt.Preferably, in the main part 1 of suspender belt, having diameter is the through hole 4 of 0.1mm-3mm, and the upper and lower surface that it runs through suspender belt main part, is conducive to tissue and grows between hole, plays the effect of further grappling net sheet.More preferably the diameter of described through hole 4 is 1.2mm-3mm.
Described pelvic floor sticking patch comprises the prolapsus for repairing pelvic cavity viscera (as bladder, uterus, rectum, vagina and small intestinal etc.), the mid-section body part of bulging, and described mid-section body part is made up of implantation film of the present invention.The implantation film using in described pelvic floor sticking patch preferably comprises directional fiber layer (B).Exemplarily, pelvic floor sticking patch of the present invention can be if Fig. 5 (for forepelvis) and 6(are for rear pelvis) as shown in shape, described pelvic floor sticking patch comprises the arm shape structure 7 that is positioned at middle part bulk portion 6 and periphery for suspending prolapsus pelvic cavity viscera in midair, the end of described arm shape structure 7 is tractive parts 8 of arm shape structure, preferably in the arm shape structure 7 of the middle part of sticking patch bulk portion 6 and periphery, has the through hole 5 that runs through upper and lower surface.Described middle part bulk portion 6 is adjusted according to the shape of the pelvic cavity viscera for repairing, and the shape of arm shape structure 7 and quantity also can specifically be adjusted according to the internal organs that will repair.
The implanted medical device of being made up of implantation film of the present invention can be for the treatment of female pelvic floor functional disorder disease.Of the present invention can be for the treatment of female incontinence without tension force urinary incontinence suspender, pelvic floor sticking patch can be for repairing prolapsus, the bulging of pelvic cavity viscera.
Embodiment
Embodiment 1
(1) polyvinylidene fluoride (PVDF) is dissolved in to the mixed solvent that volume ratio is DMF/acetone of 4:6, making the concentration of PVDF in solution is 18g/100mL, obtains the fibrous material solution A of homogeneous; PLLA (PLLA) is dissolved in hexafluoroisopropanol (HFIP) solution, and making the concentration of PLLA in solution is 5g/100mL, obtains the fibrous material solution B of homogeneous.
(2) the fibrous material solution A of above-mentioned two kinds of homogeneous and B are respectively charged in five electrostatic spinning syringes to wherein 4 syringe dress PVDF solution, a syringe dress PLLA solution.1 nozzle needle that 4 nozzle needles that PVDF solution is corresponding and PLLA are corresponding is evenly distributed on high-tension electricity source plate, regulating the speed of micro-injection pump is 5mL/ hour, regulating the voltage of high tension generator is 30KV, regulating the receiving range of receiving system is 25cm, by bi-material time, static cospinning is prepared the fibrous membrane of the different crisscross intersection of cellosilk material of two kinds of dissolution properties, stops electrostatic spinning after reaching 0.5mm thickness.
(3) by the film taking off, put into hexafluoroisopropanol solvent ultrasonic swelling, dissolve 6 hours, wherein PLLA material is dissolved completely, make fluffy fiber layer (A1).
The average fibre diameter of described fluffy fiber layer (A1) is 3 μ m, and film thickness is 0.5mm, and average pore size is 350 μ m, and tensile strength is 60N/cm, and loft is 420cm
3/ g, pliability is 470 milli newton.
(1) DMF/acetone mixed solvent that is 4:6 by PVDF material dissolves in volume ratio, making the concentration of PVDF in solution is 20g/100mL; Prepare the fibrous material solution of homogeneous.
(2) the fibrous material solution obtaining in step (1) is packed in electrostatic spinning syringe, regulating the speed of micro-injection pump is 6mL/ hour, regulating the voltage of high tension generator is 30KV, regulating the receiving range of receiving system is 25cm, carry out electrostatic spinning and obtain cellosilk, and cellosilk is received as to membrane structure, and spin after thicknesses of layers is about 0.5mm and stop electrostatic spinning, obtain fibrous membrane.
The average fibre diameter of the fibrous membrane herein obtaining is 2 μ m, and film thickness is 0.5mm, and average pore size is 150 μ m, and tensile strength is 32N/cm, and loft is 110cm
3/ g, pliability is 740 milli newton.
(3) be complete wetting in the alcoholic solution of 95 volume % by the fibrous membrane making in step (2) in concentration, then take out the fibrous membrane after alcoholic solution infiltrates, put into the ultrasonic container that fills water for injection, fibrous membrane is fully immersed in water for injection, open ultrasonic, power 90W, ultrasonic 10 minutes, leave standstill after 5 ~ 10 minutes, change the water for injection in ultrasonic container, then open ultrasonic, power 90W, ultrasonic 10 minutes, repeat operation 7 ~ 8 times, replaced complete to ethanol in solution.Then take out the ultrasonic fibrous membrane after swelling of water for injection, be put in the freeze drying box of-50 ℃ and carry out precooling 4 hours, then open vacuum lyophilization, make the fibrous membrane vacuum lyophilization 24 hours of precooling, obtain fluffy fiber layer (A2).
The average fibre diameter of described fluffy fiber layer (A2) is 2 μ m, and film thickness is 0.6mm, and average pore size is 380 μ m, and tensile strength is 37N/cm, and loft is 1105cm
3/ g, pliability is 400 milli newton.
(1) DMF/acetone mixed solvent that is 4:6 by PVDF material dissolves in volume ratio, making the concentration of PVDF in solution is 18g/100mL; Prepare the fibrous material solution of homogeneous;
(2) the fibrous material solution obtaining in step (1) is packed in electrostatic spinning syringe, regulating the speed of micro-injection pump is 6mL/ hour, regulating the voltage of high tension generator is 30KV, regulating the receiving range of receiving system is 20cm, carry out electrostatic spinning and obtain cellosilk, and cellosilk is received as to membrane structure, and spin after thicknesses of layers is about 0.5mm and stop electrostatic spinning, obtain fibrous membrane.
The average fibre diameter of the fibrous membrane herein obtaining is 2 μ m, and film thickness is 0.5mm, and average pore size is 190 μ m, and tensile strength is 43N/cm, and loft is 170cm
3/ g, pliability is 930 milli newton.
(3) then use the both sides of clamp clamps fibrous membrane, be at the uniform velocity to stretch with the speed of 100mm/min under 95 ℃ of conditions in temperature, after making fibrous membrane be elongated 3.0 times to original length, stop stretching, make at normal temperatures the fibrous membrane 4h that shapes under this extended state, then take off fibrous membrane the other both sides with clamp clamps fibrous membrane, be under 95 ℃ of conditions in temperature, along at the uniform velocity stretching with the speed of 100mm/min with the direction that draw direction is vertical before, after making fibrous membrane be elongated 3.0 times to original length, stop stretching, make at normal temperatures the fibrous membrane 4h that shapes under this extended state, obtain fluffy fiber layer (A3).
The average fibre diameter of described fluffy fiber layer (A3) is 2 μ m, and film thickness is 0.6mm, and average pore size is 400 μ m, and tensile strength is 65N/cm, and loft is 1410cm
3/ g, pliability is 400 milli newton.
Embodiment 4
(1), by polycarbonate polyurethane (PCU), be dissolved in the mixed solvent of DMF and oxolane, the concentration that makes PCU in solution is 12g/100mL, the mixed proportion (volume ratio) of DMF and oxolane is 1:1, obtains the fibrous material solution A of homogeneous.
PLLA is dissolved in hexafluoroisopropanol (HFIP) solution, and making the concentration of PLLA in solution is 5g/100mL, obtains the fibrous material solution B of homogeneous.
(2) the fibrous material solution A of above-mentioned two kinds of homogeneous and B are respectively charged in 4 electrostatic spinning syringes to wherein 3 syringe dress PCU solution, a syringe dress PLLA solution.1 nozzle needle that 3 nozzle needles that PCU solution is corresponding and PLLA are corresponding is evenly distributed on high-tension electricity source plate, regulating the speed of micro-injection pump is 6mL/ hour, regulating the voltage of high tension generator is 28KV, regulating the receiving range of receiving system is 22cm, by bi-material time, static cospinning is prepared the fibrous membrane of the different crisscross intersection of cellosilk material of two kinds of dissolution properties, stops electrostatic spinning after reaching 0.5mm thickness.
(3) by the film taking off, put into hexafluoroisopropanol solvent ultrasonic swelling, dissolve 6 hours, make PLLA material dissolves complete, PCU material remains unchanged, and takes out not dissolved material from solvent, obtains fluffy fiber layer (A4).
The average fibre diameter of gained fluffy fiber layer (A4) is 2 μ m herein, and film thickness is 0.5mm, and average pore size is 300 μ m, and tensile strength is 25N/cm, and loft is 830cm
3/ g, pliability is 230 milli newton.
(1) PLLA (PLLA) material is dissolved in hexafluoroisopropanol solvent, making PLLA concentration in solution is 6g/100mL, prepares the fibrous material solution of homogeneous.
(2) the fibrous material solution making in step (1) is packed in electrostatic spinning syringe, regulating the speed of micro-injection pump is 6mL/ hour, regulating the voltage of high tension generator is 20KV, regulating the receiving range of receiving system is 15cm, carry out electrostatic spinning and obtain cellosilk, and cellosilk is accepted as to membrane structure, and spin after thicknesses of layers is about 0.5mm and stop electrostatic spinning, obtain fibrous membrane.
The average fibre diameter of the fibrous membrane herein obtaining is 2 μ m, and film thickness is 0.5mm, and average pore size is 115 μ m, and tensile strength is 33N/cm, and loft is 130cm
3/ g, pliability is 870 milli newton.
(3) then use the both sides of clamp clamps fibrous membrane, be at the uniform velocity to stretch with the speed of 100mm/min under 60 ℃ of conditions in temperature, after making fibrous membrane be elongated 3 times to original length, stop stretching, make at normal temperatures the fibrous membrane 4h that shapes under this extended state, then take off fibrous membrane the other both sides with clamp clamps fibrous membrane, be under 60 ℃ of conditions in temperature, along at the uniform velocity stretching with the speed of 100mm/min with the direction that draw direction is vertical before, after making fibrous membrane be elongated 3 times to original length, stop stretching, make at normal temperatures the fibrous membrane 4h that shapes under this extended state, obtain fluffy fiber layer (A5).
The average fibre diameter of described fluffy fiber layer (A5) is 2 μ m, and film thickness is 0.6mm, and average pore size is 450 μ m, and tensile strength is 50N/cm, and loft is 1100cm
3/ g, pliability is 400 milli newton.
DMF/the acetone mixed solvent that is 4:6 in volume ratio by PVDF material dissolves, making the concentration of PVDF in solution is 20g/100mL; Prepare the fibrous material solution of homogeneous.
Fluffy fiber layer (A2) prepared by embodiment 2 covers and receives roller surface, aforementioned PVDF solution is packed in electrostatic spinning syringe, regulating the speed of micro-injection pump is 4mL/ hour, regulating the voltage of high tension generator is 28KV, regulating the receiving range of receiving system is 20cm, translational speed 10 cels of electrospinning syringe needle, receive roller rotating speed and be 4000 circles/point, carry out electrostatic spinning, at fluffy fiber layer (A2) upper formation directional fiber layer (B1), thereby obtain the double-deck fibrous membrane that comprises fluffy fiber layer (A2) and directional fiber layer (B1).
Embodiment 7
(1) DMF/acetone mixed solvent that is 4:6 by PVDF material dissolves in volume ratio, making the concentration of PVDF in solution is 20g/100mL; Prepare the fibrous material solution of homogeneous.
Aforementioned solution is packed in electrostatic spinning syringe, regulating the speed of micro-injection pump is 4mL/ hour, regulating the voltage of high tension generator is 28KV, regulating the receiving range of receiving system is 20cm, translational speed 10 cels of electrospinning syringe needle, receive roller rotating speed and be 4000 circles/point, carry out electrostatic spinning.Spin after thicknesses of layers is about 0.3mm and close electrostatic spinning, obtain the directional fiber layer (B2) of orderly aligned single-layer.
(2) the directional fiber layer (B2) of step (1) and two kinds of fibrous membranes of fluffy fiber layer (A3) prepared by embodiment 3 are stacked together, then use ultrasonic (the Fu Tan plant equipment company limited of 20000Hz frequency, model JT-200-S), above-mentioned each layer is linked together by the mode of putting ultrasonic fusion every the distances of 10 centimetres, obtain the double-deck fibrous membrane that comprises fluffy fiber layer (A3) and directional fiber layer (B2).
Embodiment 8
< is containing surperficial hemostatic layer >
By 0.9g sodium chloride, 1.79g 12 Heshui sodium hydrogen phosphates are dissolved in 70mL aqueous solution, and after fully dissolving, adding 1.5mL concentration is that acetic acid solution and the 20mL ethanol of 36 volume % stirs, and obtains solution A.
The II Collagen Type VI heating for dissolving of 2g oxidized cellulose and 2g, in above-mentioned solution A, and is treated to it is cooling, obtain solution B.
It is 350 units/mL that the thrombin lyophilized powder of lyophilizing is made to concentration, and the thrombin solution of 10mL is joined to B in above-mentioned solution, obtains solution C.
The fluffy fiber layer making in embodiment 1,2,3,4,5 (A 1-5) is immersed in above-mentioned solution C 10 minutes, the diaphragm fully soaking is carried out to lyophilizing and spend the night.Be cropped to the specification needing, obtain repairing at the bottom of a basin that contains hemostatic function composition oxidized cellulose diaphragm and without tension force suspender.
Embodiment 9
The application > of < fibrous membrane in repairing at the bottom of basin
Adopt the polypropylene mesh (3DMAX of existing clinical employing
tMmesh, the sample being provided by No.2 Hospital Attached to Zhongshan Univ) (I group) as a control group, reduced fibrous membrane (the II group) as a control group obtaining by the electrospinning film making in embodiment 1 step (2), reduced the implantation film 1(III group obtaining by the PVDF fluffy fiber layer (A1) making in embodiment 1), the PVDF fluffy fiber layer (A2) being made by embodiment 2 is reduced the implantation film 2(IV group obtaining), the PVDF fluffy fiber layer (A3) being made by embodiment 3 is reduced the implantation film 3(V group obtaining), the PCU fluffy fiber layer (A4) being made by embodiment 4 is reduced the implantation film 4(VI group obtaining), the PLLA fluffy fiber layer (A5) being made by embodiment 5 is reduced the implantation film 5(VII group obtaining) carry out miniature pig experiment as experimental group.Above-mentioned material is all cut into 2cm × 2cm size diaphragm.Select 20kg～25kg, 28 of health adult female miniature pigs, are divided into 7 groups at random, 4 every group.
Miniature pig is implemented to general anesthesia, face upward Baoding.Through hypogastric region stomach wall approach, expose bladder, uterus and vagina epimere.Diaphragm is inserted respectively between vesicovaginal space, and silk thread is fixed.Postoperative animal is carried out to conventional nursing and observation.The generations such as in all laboratory animal observation periods, all performance is good, and wound healing is good,, exposure outstanding without implant, art portion is without redness.Postoperative and the mental status are normal, give enough spaces for activities, and all survival is to the time of drawing materials.
Postoperative 4 weeks, put to death two animals for every group, cut including the vesicovaginal space tissue specimen of repairing sticking patch.The pliability that touches embedded material with hands, the obvious hardening of polypropylene mesh of contrast groups I group, has foreign body sensation; Contrast groups II group pliability is taken second place, and experimental group sticking patch pliability all has greatly improved, and particularly, with IV, V, VII group pliability optimum, flexible, approaches autologous tissue.
The tissue of contrast material inside grow into situation and with cambium growing state around, gross examination of skeletal muscle, the tissue of experimental group (III-VII) the diaphragm situation and more excellent compared with I group polypropylene mesh and contrast groups II group diaphragm with the combination firmness of cambium around of growing into, show as experimental group membrane surface and all cover the newborn epithelial tissue of one deck, vascularization degree is higher, not easily openable of diaphragm and cambium; Wherein IV group PVDF material is implanted rear dissection effect after 4 weeks as Fig. 7, visible implant site cambium and surrounding tissue zero difference.I group polypropylene mesh and contrast groups II group membrane surface are also coated with one deck cambium, but capillary tube on cambium is sparse; And I group polypropylene mesh is easy and sticking patch is peeled off, as Fig. 8, material and cambium are still the harder rack of quality after peeling off, and new life does not grow into; Visible experimental group has better cell and the tissue effect of growing into, stronger with the compatibility and the laminating ability of cambium.
Pathological examination demonstration, all there are a large amount of fibroblasts and collagen fiber hypertrophy in III-VII group implantation film surface and inside, and there is more blood capillary (3-5/HPF) sticking patch inside; Wherein, there are a large amount of blood capillaries (5-10/HPF) V group sticking patch inside.The visible cambium diaphragm inside of having grown into, vascularization degree is high, and it is very fast to grow into, and growing into fast that higher loft is creeped, bred and organize cell is more favourable.II group fiber membrane surface has more fibroblast and collagen fiber, inner visible a small amount of fibroblast and the collagen fiber hypertrophy of sticking patch, minority lymphocytic infiltration (<5/HPF), a small amount of blood capillary proliferation (2-3/HPF), the visible cambium diaphragm of growing into is inner but grow into slowlyer, and has slight immune inflammation reaction.I group polypropylene networking sheet has a large amount of fibroblasts and collagen around, small amount blood capillary (<2/HPF), a small amount of foreign-body giant cell (≤3/HPF), visible cambium cannot grow up to one with diaphragm, repair slowlyer, and have foreign material repulsion reaction.
Continue to observe causing 12 weeks after operation, implant during this time the miniature pig of I group polypropylene net sheet material, have irritated performance, have friction on house interior walls and railing, tail biting performance, and the mental status is not good.All the other test miniature pig, movable normal, raise place put in a suitable place to breed in broadness.
12 weeks after operation, puts to death two animals for every group, cuts including repairing vagina and the bladder specimen implant at the bottom of basin.Touch with hands, when relatively postoperative 4 weeks of I group polypropylene net sheet material, still keep suitable hardness, and have obvious foreign body sensation; II group fiber diaphragm is softer, but touches between implant site and surrounding tissue, still has obvious differentiation; The pliability of experimental group III-VII implantation film is basic to be approached with autologous tissue, and between embedded material position and surrounding tissue, does not substantially have obvious feel to distinguish; Wherein the sense of touch of V group material is almost consistent with autologous tissue.
Perusal, III-VII group implantation film material is integrated with being organized into of growing, and cannot differentiate and peel off, integral plaster person of modern times soma, blood vessel is high-visible.Microscopic observation result shows, III-VII group implantation film is around combined closely with collagen fiber, fibrocyte, cannot distinguish cambium and diaphragm material, inner visible a large amount of collagen fiber, visible cambium completely and diaphragm grow up to one, realize rebuild repair; Pathological examination shows, material surface and inside is visible a large amount of fibroblasts and collagen all, has no foreign-body giant cell and lymphocyte, and material combines together with newborn tissue, is difficult to differentiation.Visible higher loft is more conducive to that inducing cell is grown into and tissue regeneration, applicable pliability is to being more conducive to the laminating of implant site cambium and surrounding tissue, and apparently, cambium does not cause foreign body sensation in vivo, or new life or autologous tissue are caused to frictionally damage.
Perusal, II group fiber diaphragm and cambium can be peeled off, the visible more blood capillary in surface; Microscopic observation result shows, around II group fiber diaphragm, is combined with obvious boundary line with collagen fiber, fibrocyte, is easy to distinguish cambium and diaphragm material, and surface has a large amount of collagen fiber, blood capillary to enrich, and inside is visible material still; Pathological examination shows, material surface has more fibroblast and a large amount of angiogenesis (5-10/HPF), inner visible a small amount of blood capillary (≤3/HPF), 1/HPF of foreign-body giant cell, the visible cambium diaphragm inside of growing into, but cambium is relatively less, and there is slight foreign body reaction.I group polypropylene mesh, repairs position and surrounding tissue and produces level Four (adopting Nari adhesion point system 1) adhesion, and material and organizing more easily of growing are peeled off, and polypropylene material is clearly visible, and material internal has no cambium and grows into, penetrates; Pathological examination shows, only material has a small amount of fibroblast and collagen to form around, the visible more blood capillary proliferation in surface (3-5/HPF), a large amount of foreign-body giant cells and lymphocytic infiltration, foreign body reaction and immunologic rejection are serious, visible cambium cannot grow up to one with diaphragm, and repairing effect is poor.The reason of simultaneously inferring the irritated performance of the corresponding experiment pig of observation process may be foreign body sensation and tissue infection strong reaction.
Embodiment 10
The fibrous layer (C) without orientation and fluffy fiber layer (A3) film that embodiment 3 obtains that adopt conventional electrospinning to obtain are made double-deck fibrous membrane (being called for short unordered fluffy film) by the method for embodiment 7 steps (2).
With above-mentioned unordered fluffy film as a control group, the double-deck fibrous membrane of embodiment 7 (being called for short orderly fluffy film) is experimental group, carries out zoopery, to verify the effect of ordered structure.
Laboratory animal is selected 12 healthy new zealand rabbits, body weight 2.0-2.5Kg, and male and female are not limit, rabbit about 6-12 in age month.Experimental rabbit is divided into 3 groups at random, 4 every group.Experimental group and matched group are all cut out as 1cm × 4cm rectangular, implant respectively rabbit subcutaneous abdomen, observe material surface tissue growth situation in postoperative 2 weeks, 3 months.
Method for implantation: by standby rabbit abdominal part hair, sterilization, along midline incision skin of abdomen, blunt separation subcutaneous fascia and muscle, expose suitable material transplanting scope.Between subcutaneous and fascia, the experimental group sample of 3 1cm × 4cm is implanted in interlayer left side, and the control sample of 3 1cm × 4cm is implanted on right side.Material is fixed on to corresponding position with No. 4 lines, sews up respectively subcutaneous fascia layer and skin layer.
After 2 weeks, fluffy of experimental group and matched group all has slim fibers encapsulation, and implant site blood capillary is abundant.After taking out part dyeing material, observe, above the oriented layer in experimental group, have obvious Growth of Cells and the orientation of creeping, and the omnidirectional confluent monolayer cells growth of matched group is at random.After three months, two groups of samples take out Partial Observation, have the directed texture of obvious fibrous tissue above experimental group directional fiber layer, and the omnidirectional fibrous layer of matched group does not have.Visible directional orientation fibrous layer (B) is more conducive to guide cell to be creeped and tissue compliance growth, the repair tissue fascia tissue that more gets close to nature.
Claims (31)
1. a tissue repair implantation film that is used for the treatment of female pelvic functional disorder disease, is characterized in that, described implantation film comprises fluffy fiber layer (A);
The cellosilk that described fluffy fiber layer (A) is 10nm ~ 100 μ m by diameter is interwoven, and has vesicular texture, and its loft is 400 ~ 1500cm
3/ g, its pliability is 50 ~ 500 milli newton.
2. implantation film according to claim 1, the average pore size of wherein said fluffy fiber layer (A) is 50 ~ 500 μ m.
3. implantation film according to claim 1 and 2, the thickness of wherein said fluffy fiber layer (A) is 0.2 ~ 2mm, tensile strength is 10 ~ 300N/cm.
4. according to the implantation film described in claim 1-3 any one, the loft of wherein said fluffy fiber layer (A) is 800 ~ 1300cm
3/ g.
5. according to the implantation film described in claim 1-4 any one, the pliability of wherein said fluffy fiber layer (A) is 200 ~ 450 milli newton.
6. according to the implantation film described in claim 1-5 any one, wherein said fluffy fiber layer (A) adopts and comprises that the method for electrostatic spinning step makes.
7. according to the implantation film described in claim 1-6 any one, wherein said implantation film further comprises directional fiber layer (B), described directional fiber layer (B) be by cellosilk align and form have cellular three dimensional structure layer.
8. implantation film according to claim 7, the filametntary diameter in wherein said directional fiber layer (B) is 10nm～20 μ m.
9. according to the implantation film described in claim 1-8 any one, in wherein said implantation film, between each layer, pass through the mode combination of electrostatic spinning, ultrasonic fusion or stitching.
10. according to the implantation film described in claim 1-9 any one, in wherein said implantation film, comprise the medicine of hemostasis class medicine, anti-infection drug, cell growth regulator, toxicity inhibitor, anesthetis micro-nano granules and/or treatment urinary incontinence.
11. according to the implantation film described in claim 1-9 any one, and the surface of wherein said implantation film comprises hemostatic layer.
12. implantation films according to claim 11, wherein said hemostatic layer comprises collagen, polyoxyethylene fibre, chitosan, fibrin, peptide and/or thrombin.
13. according to the implantation film described in claim 11 or 12, and wherein said hemostatic layer forms by the method for electrostatic spinning, lyophilization, forced air drying or vacuum drying.
14. according to the implantation film described in claim 1-13 any one, and the fibrous material of wherein said implantation film is degradation material, non-degradable material or its combination.
15. implantation films according to claim 14, wherein said degradation material is selected one or more in the group of free polylactic acid, polycaprolactone, polyglycolic acid, Poly(D,L-lactide-co-glycolide, peptide polymer, chitosan and modification of chitosan composition to dioxy Ketohexamethylene, collagen protein, gelatin, fibrin, fibroin, elastin mimicry.
16. implantation films according to claim 14, wherein said non-degradable material selects one or more in the group of freely gathering fluorine material, polyolefin, polyurethane, polyamide, polyester and silicone rubber composition.
17. according to the implantation film described in claim 1-16 any one, and wherein said implantation film has the through hole that runs through described implantation film upper and lower surface.
18. implantation films according to claim 17, the aperture of wherein said through hole is 0.2-4mm.
The preparation method of the implantation film described in 19. claim 1-18, is characterized in that, the preparation method of described implantation film comprises the step of preparing fluffy fiber layer (A), and the described step of preparing fluffy fiber layer (A) comprises:
(1) by two kinds of different dissolution properties fibrous materials, be dissolved in respectively in corresponding solvent, obtain the fibrous material solution of two kinds of homogeneous;
(2) two kinds of homogeneous fibrous material solution that obtain in step (1) are respectively charged in different electrostatic spinning syringes, through electrostatic spinning, obtain the fibrous membrane of the different mutual crisscross intersection of cellosilk of two kinds of dissolution properties;
(3), according to the dissolution properties of cellosilk material, with solvent, by a kind of cellosilk dissolving in the fibrous membrane of manufacturing in step (2), another remains unchanged, and obtains described fluffy fiber layer (A).
The preparation method of the implantation film described in 20. claim 1-18, is characterized in that, the preparation method of described implantation film comprises the step of preparing fluffy fiber layer (A), and the described step of preparing fluffy fiber layer (A) comprises:
(1) fibrous material is dissolved in solvent, obtains the fibrous material solution of homogeneous;
(2) the homogeneous fibrous material solution obtaining in step (1) is packed in electrostatic spinning syringe, carry out electrostatic spinning and obtain fiber, and fiber is received as to membrane structure, obtain fibrous membrane;
(3) fibrous membrane preparing in step (2), under the state after solvent supersonic is swelling, is carried out to pre-freeze, then carry out vacuum lyophilization, obtain described fluffy fiber layer (A).
21. preparation methoies according to claim 20 in wherein said step (3), after the ethanol water that is 50 volume % ~ 95 volume % infiltrates, then are carried out ultrasonic swelling by the fibrous membrane concentration preparing in step (2) in water.
The preparation method of the implantation film described in 22. claim 1-18, is characterized in that, the preparation method of described implantation film comprises the step of preparing fluffy fiber layer (A), and the described step of preparing fluffy fiber layer (A) comprises:
(1) fibrous material is dissolved in solvent, obtains the fibrous material solution of homogeneous;
(2) the homogeneous fibrous material solution obtaining in step (1) is packed in electrostatic spinning syringe, obtain fibrous membrane through electrostatic spinning;
(3) fibrous membrane of preparation in step (2) is stretched along the direction of one of the transverse axis of fibrous membrane or longitudinal axis, after stopping stretching, fibrous membrane is shaped under this extended state; Then fibrous membrane is stretched along the direction vertical with above-mentioned draw direction of fibrous membrane, after stopping stretching, fibrous membrane is shaped under this extended state, obtain described fluffy fiber layer (A).
23. preparation methoies according to claim 22, wherein in step (3), the draft temperature of the described fibrous membrane of stretching is the temperature lower than 0 ℃ ~ 30 ℃ of materials hot deformation temperature, rate of extension is 50 ~ 400mm/min, tensile elongation is original length 1.5 ~ 6.0 times, shaping time is 1h ~ 4h.
24. according to the preparation method described in claim 19-23 any one, and wherein, described preparation method further comprises the step of preparing directional fiber layer (B) with electrostatic spinning.
25. 1 kinds are used for the treatment of the implanted medical device of female pelvic functional disorder disease, it is characterized in that, described implanted medical device comprises the implantation film described in claim 1-18.
26. implanted medical devices according to claim 25, wherein said implanted medical device is without tension force urinary incontinence suspender or pelvic floor sticking patch.
27. implanted medical devices according to claim 26, wherein saidly comprise main part and end without tension force urinary incontinence suspender, described main part is made up of the implantation film described in claim 1-18, and described end is for operating theater instruments traction and/or for fixing.
28. implanted medical devices according to claim 27, wherein said main part has straight line or corrugated outline.
29. implanted medical devices according to claim 28, wherein said corrugated concavo-convex stand out is 1mm-5mm.
30. implanted medical devices according to claim 26, wherein said pelvic floor sticking patch comprises the prolapsus for repairing pelvic cavity viscera, the middle part bulk portion of bulging, described middle part bulk portion is made up of the implantation film described in claim 1-18.
31. implanted medical devices according to claim 30, wherein said pelvic floor sticking patch comprises the arm shape structure that is positioned at middle part bulk portion periphery for suspending prolapsus pelvic cavity viscera in midair.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210457158.2A CN103800096B (en) | 2012-11-14 | 2012-11-14 | Pelvic floor dysfunction disease reparation is with implanting fiber diaphragm, preparation method and the medical apparatus and instruments containing it |
| IN1362DEN2015 IN2015DN01362A (en) | 2012-11-14 | 2013-11-14 | |
| BR112015009502-0A BR112015009502B1 (en) | 2012-11-14 | 2013-11-14 | FIBROUS MEMBRANE, COMPOSITE FIBROUS MEMBRANE, FIBROUS MEMBRANE PREPARATION METHOD, IMPLANTABLE MEMBRANE, IMPLANTABLE MEMBRANE PREPARATION METHOD, IMPLANTABLE MEDICAL DEVICE, ANTI-ADHESION FIBROUS MEMBRANE, FIBROUS MEMBRANE MEMBRANE PREPARATION METHOD |
| EP13854718.7A EP2921136B1 (en) | 2012-11-14 | 2013-11-14 | Fiber membranes for repairing tissue and products and preparation method thereof |
| KR1020157005750A KR101853283B1 (en) | 2012-11-14 | 2013-11-14 | Fibrous Membrane Used for Tissue Repair and Products and Preparation Methods Thereof |
| PCT/CN2013/001387 WO2014075388A1 (en) | 2012-11-14 | 2013-11-14 | Fiber membranes for repairing tissue and products and preparation method thereof |
| US14/377,665 US20160045296A1 (en) | 2012-11-14 | 2013-11-14 | Fiber membranes for repairing tissue and products and preparation method thereof |
| JP2015540990A JP6140295B2 (en) | 2012-11-14 | 2013-11-14 | Tissue repair fiber membrane and its product and manufacturing method |
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| CN201210457158.2A CN103800096B (en) | 2012-11-14 | 2012-11-14 | Pelvic floor dysfunction disease reparation is with implanting fiber diaphragm, preparation method and the medical apparatus and instruments containing it |
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| CN103800096A true CN103800096A (en) | 2014-05-21 |
| CN103800096B CN103800096B (en) | 2016-12-21 |
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| CN201210457158.2A Active CN103800096B (en) | 2012-11-14 | 2012-11-14 | Pelvic floor dysfunction disease reparation is with implanting fiber diaphragm, preparation method and the medical apparatus and instruments containing it |
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