CN103800942B - Pelvic floor patch - Google Patents

Pelvic floor patch Download PDF

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Publication number
CN103800942B
CN103800942B CN201210457576.1A CN201210457576A CN103800942B CN 103800942 B CN103800942 B CN 103800942B CN 201210457576 A CN201210457576 A CN 201210457576A CN 103800942 B CN103800942 B CN 103800942B
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pelvic floor
layer
fibrous
floor patch
patch according
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CN103800942A (en
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赖奎霖
徐弢
袁玉宇
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SHENZHEN MEDPRIN REGENERATIVE MEDICAL TECHNOLOGIES Co Ltd
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SHENZHEN MEDPRIN REGENERATIVE MEDICAL TECHNOLOGIES Co Ltd
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Abstract

The invention provides a kind of pelvic floor patch, it comprises fibrous membrane, and described fibrous membrane at least comprises and has the first fibrous layer of directional orientation and the second fibrous layer of No yield point.This pelvic floor patch has good biocompatibility, good pliability and good tissue compliance, is beneficial to tissue and grows into be formed and firmly repair, can have the characteristic of infection, hemostasis further.Patch at the bottom of this basin also can be used for making no-station pole canopy suspender, in order to treat stress incontinence.

Description

Pelvic floor patch
Technical field
The present invention relates to a kind of patch of bio-medical technical field, particularly a kind of pelvic floor patch for pelvic floor disorders disease.
Background technology
Female pelvic is back-up system at the bottom of the basin of the complexity be made up of the multilamellar muscle, fascia, ligament etc. of semiclosed inferior pelvic aperture, by the impact of the factors such as fertility, disease, aging, the supporting function of soft tissue around pelvic floor to pelvic organ weakens, and causes occurring various pelvic floor disorders disease.Pelvic floor disorders disease is commonly encountered diseases and the frequently-occurring disease of women.Female pelvic floor obstacle disease (Pelvic Floor Dysfunction disease, PFD), relax also known as pelvic floor defects or pelvic floor supporting tissue, main manifestations is prolapsus, bulging (the Pelvic Organ Prolapse of pelvic cavity viscera (as bladder, uterus, rectum, vagina and small intestinal etc.), and stress incontinence (Stress Urinary Incontinence, SUI) POP).POP and SUI is closely related, and causes serious impact on the life of women with healthy.At present, be first-selected for moderate and above prolapsus person's operative treatment.Apply pelvic floor patch treatment pelvic floor disorders disease in operation, its effect obtains the accreditation of numerous medical personnel and patient.
Current employing pelvic floor patch when carrying out operative treatment needs sticking patch to be placed between fascia layer and vagina outer wall to provide certain mechanical support to prolapse to treat internal organs.Wherein fascia is one deck dense connective tissue running through health, and it surrounds muscle, muscle group, blood vessel, nerve etc.Fascia is divided into three-decker again, is respectively superficial fascia, deep fascia, interior visceral fascia.Muscle membrane is containing closely regularly arranged collagen fiber, and the direction of collagen fiber is along direction of pull, so fascia has very strong unidirectional tensile property.Vaginal wall is made up of mucosa, muscle layer and fibrous tissue film, has a lot of band pleat.Vaginal wall is rich in venous plexus, therefore Local Damaged wound easily hemorrhage or formation hematoma.So desirable pelvic floor repairing patch should have good biocompatibility, good tissue compliance, good pliability, meet fascia layer and vaginal wall and organize different structures and growth requirement, guide rapidly growing into, to recover the support to internal organs at the bottom of basin of corresponding tissue.
In current pelvic floor repair product, the non-degradable mesh sheet that the braided material based on polypropylene is made occupies most market, but this sticking patch exposes comparatively serious untoward reaction gradually, as problems such as erosion, shrinkage, hemorrhage, pain.2005-2007, reports hemorrhage 1000 routine bad use cases, from 2008 to 2010, has 2874 routine bad reports, has caused society and the paying close attention to of FDA.FDA is just advising this series products to rise to the III class apparatus of supervising highest level from implanting II class medical apparatus and instruments, and has required that relevant manufacturers provides complete clinical report and market to follow the tracks of report.In January, 2012, what FDA ordered that 33 pelvic floor repair sticking patch manufacturers and 7 stress incontinence sticking patch manufacturers carry out product gos deep into clinical research.In June, 2012, Johnson & Johnson (Johnson & Johnson) company issues bulletin, ends the first quarter in 2013, will suspend all pelvic floor repair products of company in the world.Current Johnson & Johnson, American Medical Systems, the companies such as C.R.Bard, Boston Scientific face the lawsuit that up to a hundred relevant issues cause.
Above untoward reaction from many-side, mainly because material itself, technique and modus operandi etc. cause.The mesh sheet quality prepared by knitting skill as materials such as polypropylene is comparatively hard, rough surface, poor with the implant site compliance goodness of fit.This more firmly, more coarse material implants, operative site has comparatively significantly foreign body sensation, and there will be dislodgment at some patient and cause even puncturing to the extruding of normal site tissue, occurs serious erosion.And the goodness of fit lower with implant site structure, tissue is grown into poor, is substantially in the parcel of tissue to material, is combined not tight, there is potential safety hazard in the long run with material.Also confirm in later experiments, tissue and mesh sheet associativity bad, after taking out material, can will organize relatively easily and mesh sheet stripping, this is also that polypropylene mesh easily occurs being shifted and causes a reason of erosion.
No matter be corrode or shrinkage, once occur that this problem needs second operation reparation in most cases, or mesh sheet thoroughly removed.This will very seriously affect the orthobiosis of patient, brings huge wound to the psychology of patient, physiology, and a lot of patient still can not feel well and pain after mesh sheet removes, even cannot normal sitting, or affects love life.
In order to solve the problem of the said goods, propose in prior art (as CN101773689A) to use electrostatic spinning to replace traditional weaving method to prepare surgery biological patch.Electrostatic spinning is that one prepares polymer superfine fibre simply effective processing method, because its superfine fibre prepared can reach micro/nano level, nano bionic rack surface is more smooth, can effectively simulate natural extracellular matrix structure to a certain extent, provide good microenvironment to the growth of cell and climbing.The micro/nano fibrous membrane material that this characteristic makes electrospinning process prepare at present is specially adapted to bio-medical field, as the timbering material etc. of biomembrane, drug conveying, organizational project etc.
But conventional electrospinning fiber alignment is out unordered loose, cause electrospinning film mechanical strength poor; Differ greatly with the ordered structure of some somas, as myofibrillar arrangement etc., superficial cell grows also No yield point, cannot meet the requirement of pelvic fascia tissue compliance coupling.The lower position of mechanical strength requirement can only be used for clinically, as skin at present.In order to improve mechanical property, usual method makes electrospinning film a little bit thicker (as being greater than 0.5mm), but visible internal capillary blood vessel connectivity is poor in growing animal experiment.
Therefore, the sticking patch obtained by braiding or general electrostatic spinning technique, its internal approach anisotropy, cannot give fibroblastic growth provider tropism when organizing self-regeneration.
Summary of the invention
the problem that invention will solve
For above-mentioned various problem of the prior art, the invention provides a kind of pelvic floor repair material, it has good biocompatibility, good tissue compliance and good pliability, quick, the orientation that are beneficial to biological cells and tissues are grown into be formed and are firmly repaired, and made of soft reduces or avoids postoperative foreign body sensation, can have the characteristic of infection, hemostasis further.
for the scheme of dealing with problems
The invention provides a kind of pelvic floor patch, it is characterized in that, described pelvic floor patch comprises fibrous membrane, and described fibrous membrane at least comprises and has the first fibrous layer of directional orientation and the second fibrous layer of No yield point.Intermediate layer can also be had between first fibrous layer of described fibrous membrane and the second fibrous layer.Described intermediate layer is preferably No yield point fibrous layer.
Pelvic floor patch of the present invention, is combined by the mode of electrostatic spinning, ultrasonic fusion or stitching between each layer of wherein said fibrous membrane.
Pelvic floor patch of the present invention, combines closely preferably by the mode of electrostatic spinning between each layer of wherein said fibrous membrane.Such as, when described fibrous membrane is duplicature, be directly transitioned into the second fibrous layer from the first fibrous layer by electrospinning, two-layer combination is closely not stratified.When described fibrous membrane also has intermediate layer, directly intermediate layer can be transitioned into from the first fibrous layer by electrospinning, then to the second fibrous layer.
Pelvic floor patch of the present invention, one or more the mode of wherein said fibrous membrane in drilling process, hyperthermic treatment and immersion treatment processes.
Pelvic floor patch of the present invention, wherein said drilling is treated to punching press drilling, laser punching, locally pressure found hole.
Pelvic floor patch of the present invention, wherein said pelvic floor patch comprises and the membrane-bound mesh grid of described fiber or memory metal.
Pelvic floor patch of the present invention, wherein said fibrous membrane tinsel or polymer fiber carry out sewing process.
Pelvic floor patch of the present invention, the first fibrous layer of wherein said fibrous membrane is that the cellosilk being 10nm ~ 20 μm by diameter aligns the layer with cellular three dimensional structure formed; Second fibrous layer of described fibrous membrane is the layer with cellular three dimensional structure that the unordered intertexture of cellosilk being 10nm ~ 20 μm by diameter is formed; When described fibrous membrane has intermediate layer, the layer with cellular three dimensional structure that the unordered intertexture of cellosilk that it is 10nm ~ 20 μm that described intermediate layer is preferably by diameter is formed.
Pelvic floor patch of the present invention, the thickness of wherein said pelvic floor patch is 0.25mm ~ 0.8mm, and the pore size of through hole is 0.4 ~ 2mm, and hot strength is 30 ~ 80N.
Pelvic floor patch of the present invention, the fibrous material wherein preparing described fibrous membrane is degradation material, non-degradable material or its combination.
Pelvic floor patch of the present invention, wherein said degradation material be selected from the group be made up of the peptide polymer of polylactic acid, polycaprolactone, polyglycolic acid, Poly(D,L-lactide-co-glycolide, 1,3-PD polymer, collagen protein, gelatin, fibrin, fibroin, elastin mimicry, chitosan and modification of chitosan one or more.
Pelvic floor patch of the present invention, wherein said non-degradable material be selected from poly-fluorine class material, polyolefin, polyurethane one or more.
Pelvic floor patch of the present invention, wherein said non-degradable material is polyvinylidene fluoride.
Pelvic floor patch of the present invention, containing anti-infection drug, hemostasis class medicine and/or micro-nano granules in wherein said pelvic floor patch.
Pelvic floor patch of the present invention, wherein said anti-infection drug comprises ampicillin class, spiramycin class, sulfonamides, quinolones and/or cephalosporins.
Pelvic floor patch of the present invention, wherein said hemostasis class medicine comprises 6-aminocaprolc acid, para-amino-methyl-benzoic acid, tranamic acid, Radix Notoginseng and/or YUNNAN BAIYAO.
Pelvic floor patch of the present invention, wherein said micro-nano granules comprises SiO 2, TiO 2, ZnO, Ag, Ni, quaternary ammonium salt, chitosan, calcium alginate, polyvinyl alcohol and/or natural macromolecular nanoparticle.
No-station pole canopy suspender of the present invention, is characterized in that, described no-station pole canopy suspender uses above-mentioned pelvic floor patch preparation.Preferably, it is used for the treatment of stress incontinence.
the effect of invention
Pelvic floor patch of the present invention has good biocompatibility, good organization's compliance, good pliability, be beneficial to tissue fast and orientation grow into be formed and firmly repair, effective minimizing or the damage avoiding vagina outer wall, and there is the characteristic of infection, hemostasis further.Described patch can also be used for making no-station pole canopy suspender, in order to treat stress incontinence.
Accompanying drawing explanation
Fig. 1 (A) implants experiment operation for rabbit subcutaneous abdomen Musclar layer and shines
Fig. 1 (B) implants to dissect after March for rabbit subcutaneous abdomen Musclar layer and shines
Fig. 2 dissects after rabbit subcutaneous abdomen Musclar layer implants June to shine
Fig. 3 (A) implants experiment operation for vaginal wall and shines
Fig. 3 (B) implants to dissect after January for vaginal wall and shines
The vaginal wall that Fig. 4 (A) is double layer fibre film (experimental group) implants laboratory sample pathology figure
The vaginal wall that Fig. 4 (B) is single layer fibre film (matched group 1) implants laboratory sample pathology figure
The vaginal wall that Fig. 4 (C) is polypropylene mesh (matched group 2) implants laboratory sample pathology figure
Fig. 5 is the structural representation of double layer fibre film of the present invention
Fig. 6 is the structural representation that the second fibrous layer of No yield point in double layer fibre film of the present invention contains medicine
Fig. 7 is the enlarged drawing of I part in Fig. 6
Fig. 8 is the structural representation all containing medicine in the first and second fibrous layers of double layer fibre film of the present invention
Fig. 9 is the structural representation of multi-layer fiber film of the present invention
Figure 10 be in the second fibrous layer of No yield point in multi-layer fiber film of the present invention and intermediate layer all containing medicine structural representation
Figure 11 is the enlarged drawing of II part in Figure 10
description of reference numerals
In Fig. 1 and 2, (1), (2), (3) are double layer fibre film (experimental group), single layer fibre film (matched group 1) and polypropylene mesh (matched group 2) respectively.
In Fig. 3, white arrow is depicted as double layer fibre membrane sample.
Fig. 5,6, A in 8-10 is the second fibrous layer of No yield point, B is first fibrous layer with directional orientation, and the C in Fig. 9 and 10 is intermediate layer.
In Fig. 7 and 11 1 refers to first fibrous layer with directional orientation, and the second fibrous layer of 2 finger No yield point, 3 refer to medicines.In Figure 11 4 refers to intermediate layer, and 5 refer to medicine.
Detailed description of the invention
The invention provides a kind of pelvic floor patch, it is characterized in that, described pelvic floor patch comprises fibrous membrane, and described fibrous membrane at least comprises and has the first fibrous layer of directional orientation, the second fibrous layer of No yield point, it meets tissue characteristic, is beneficial to better reparation.Described fibrous membrane may further include intermediate layer.
Pelvic floor patch of the present invention comprises fibrous membrane, and it can be duplicature or multilayer film.Its top layer is first fibrous layer with directional orientation, contacts fascia layer during operation; Bottom is the second fibrous layer of No yield point, contacts vagina outer wall during operation.The intermediate layer be made up of fiber can also be added between top layer and bottom, preferably wherein comprise medicine and play hemostasis, anti-infective effect.First fibrous layer has regular fiber orientation, arrangement of collagen fibers direction in simulation Muscle membrane extracellular matrix, can Growth of Cells be guided, for the extracellular matrix of cell and new secretion thereof provides directed skeleton, structure, imitate the organizational structure of body self as far as possible.Good postoperative repairing effect can be realized, reduce relapse rate.Second fibrous layer is No yield point fibrous layer, meets the architectural feature of vaginal wall outer layer fiber layer, is beneficial to the combination of vaginal wall and product.Intermediate layer is preferably No yield point fibrous layer, according to different clinical needs, as hemostasis, infection, antiinflammatory etc., can load different pharmaceutical.According to different clinical needs, the first fibrous layer and second fibrous layer of top layer and bottom also can load medicine.
Described fibrolaminar fibrous material can be 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), thermoplastic polyurethane (TPU), 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); The peptide polymer of collagen protein, gelatin, fibrin, fibroin, elastin mimicry and natural macromolecular material; Chitosan, modification of chitosan.Wherein, pelvic floor patch prepared by preferred polyvinylidene fluoride material, it has good histocompatibility and durability, and mechanical strength is good.The fibrous material used in described first fibrous layer, the second fibrous layer and intermediate layer can be the same or different.
Oriented fiber layers described in the present invention refers to that the fiber in this fibrous layer has single orientation, and described No yield point fibrous layer refers to that the fiber in this fibrous layer does not have single orientation, comprises the situations such as the orientation of random orientation and braiding formation.First fibrous layer of the present invention, the second fibrous layer and intermediate layer can use above-mentioned fibrous material, by Weaving method preparation existing in prior art, and such as spunbond non-woven technology and loop bonding non-woven technology.Preferably the first fibrous layer by the method for electrostatic spinning prepare have Single Fiber towards oriented fiber layers, the second fibrous layer and intermediate layer prepare the fibrous layer of No yield point preferably by the method for electrostatic spinning.Directly can be combined by electrostatic spinning between each layer of fibrous membrane of the present invention, also can the modes such as ultrasonic fusion or stitching be used to combine after obtaining each layer respectively.
The present invention preferably uses the method for electrostatic spinning to prepare described first fibrous layer, the second fibrous layer and intermediate layer.Electrostatic spinning can make the timbering material with enough mechanical strengths, close to or reach existing commercial polypropylene braiding mesh sheet, reliable physical support effect can be provided in reparation.More importantly, this electrospun scaffolds is very soft, organizes compliance fairly good.Foreign body sensation is in vivo very low, and can not produce wear phenomenon to surrounding tissue.Meanwhile, tissue and cell can be grown into material internal very soon, and later experiments confirms that normal structure and material tight are fitted together to, and bond strength is very high, cannot both completely to separate.The animal experiment in vivo of six months shows, material and neighbouring organize grow into as a whole.First fibrolaminar structural simulation extra-cellular matrix structure of the present invention, is extremely beneficial to growing into of fibroblast and blood capillary, plays a key effect to the self-regeneration of muscle, fascia, repairing effect stable when can realize long.Patch of the present invention for guarantee is had good biocompatibility and histocompatibility by both above, and avoid the erosion occurring braiding mesh sheet, this is the change of the essence to traditional product.
For human body autologous tissue structure of more fitting, be beneficial to cell attachment, growth and tissue repair, multistage process can be adopted in preparation process to prepare the fibrous membrane of tool two kinds of surfaces characteristic simultaneously.When this and operation, modes of emplacement matches, and can reach good result.
Classes of anti-infective, hemostasis class medicine or micro-and nano-particles can be contained in described sticking patch.Described anti-infection drug comprises and is not limited to ampicillin class, spiramycin class, sulfonamides, quinolones, the antibiotic such as cephalo-type.Described hemostasis class medicine includes but not limited to 6-aminocaprolc acid, para-amino-methyl-benzoic acid, tranamic acid, Radix Notoginseng, YUNNAN BAIYAO.Described micro-nano granules comprises SiO 2, TiO 2, ZnO, Ag, Ni, quaternary ammonium salt, chitosan, calcium alginate, polyvinyl alcohol, natural macromolecular nanoparticle.Preferred micro-nano granules is chitosan, can play the effect of hemostasis simultaneously.
Pelvic floor patch of the present invention, wherein said fibrous membrane further across post processing modification, such as, can one or more the mode in drilling process, hyperthermic treatment and immersion treatment can process.If product is by density and the elastic performance that can change material of stretching.
Described drilling process can use 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, and become compact texture, the width of hole periphery puddle is about 0.02 ~ 0.05mm.This puddle can play fixation holes size, maintains the effect of Total Product mechanical property.When using electrostatic spinning to prepare fibrous membrane, by adopting metal, insulation staggered-mesh dash receiver, the Coulomb repulsion lines receiving strip tool patterning carrys out drilling.
Repair system research at the bottom of long-term basin shows, the aperture of sticking patch is most important to therapeutic effect.And brace aperture rate prepared by conventional electrospinning process is high, but aperture is very little; And the mechanical property of general forming hole method meeting extreme influence electrospun scaffold.The present invention by research and more different aftertreatment technology, and in external, body in a large number biological experiment, drawing good, the more soft and good diaphragm material of therapeutic effect of mechanical strength through repeatedly optimizing, possessing suitable pore size and hole arrangement.The mode that the hole of certain size is staggered or different size hole combines as adopted can be beneficial to tissue better and grow into, and while exchanging, is also beneficial to the quick eliminating of metabolite when tissue, Growth of Cells inside and outside raising material.Meanwhile, hole provides more spaces for tissue growth, is more conducive to penetrating of blood capillary.
The top layer of fibrous membrane of the present invention be the cellosilk being 10nm ~ 20 μm by diameter align there is cavernous three dimensional structure.The bottom of described fibrous membrane be by diameter be the cellosilk of 10nm ~ 20 μm unordered be interwoven there is cavernous three dimensional structure.The thickness of described fibrous membrane is preferably 0.25mm ~ 0.8mm, and the pore size of through hole is 0.4 ~ 2mm, and the hot strength of fibrous membrane is 30 ~ 80N.More preferably the thickness of fibrous membrane is 0.25 ~ 0.4mm.For keeping mechanical strength, prepared by the mode that macropore and aperture can be adopted to combine: as stamped the macropore of 0.8 ~ 2.0mm diameter according to 4 ~ 8mm spacing; The wrong aperture stamping 0.4 ~ 0.6mm diameter between around macropore.Increase pore quantity while can keeping patch mechanical strength like this, be more conducive to organize quick through growth.
Described pelvic floor patch can also comprise and the membrane-bound mesh grid of described fiber or memory metal.Sewing process can also be carried out with tinsel or polymer fiber in described fibrous membrane surface.
In a specific embodiments of the present invention, electrostatic spinning is used to prepare the first fibrolaminar operating condition for regulating the speed of micro-injection pump to be 0.1 ~ 15.0 ml/hour, the voltage regulating high tension generator is 15 ~ 45kV, the receiving range regulating receiving system is 15.0 ~ 30.0 centimetres, regulate translational speed 1 ~ 20 cel of electrospinning syringe needle, receive roller rotating speed be 2000 ~ 6000 circles/point, thus obtained first fibrous layer.
In a specific embodiments of the present invention, electrostatic spinning is used to prepare the second fibrolaminar operating condition for regulating the speed of micro-injection pump to be 0.1 ~ 15.0 ml/hour, the voltage regulating high tension generator is 15 ~ 45kV, the receiving range regulating receiving system is 15.0 ~ 30.0 centimetres, regulate translational speed 1 ~ 20 cel of electrospinning syringe needle, dash receiver motionless (receive roller rotating speed be 50 ~ 1000 circles/point), thus obtained second fibrous layer.
In a specific embodiments of the present invention, high polymer and anti-infection drug can be dissolved in different solvents respectively, the solution that each self-forming is homogeneous, stable.Then be respectively charged in different electrostatic spinning syringes by above-mentioned homogeneous macromolecular solution and drug solution, electrospinning obtains the second fibrous layer.Then, change condition, the second fibrous layer is formed the first fibrous layer, thus obtained double layer fibre film.In another embodiment, can first prepare the first fibrous layer, then form the second fibrous layer thereon.Also can not add anti-infection drug in the first fibrous layer and the second fibrous layer in such scheme, and add anti-infection drug in the intermediate layer.
In another specific embodiments of the present invention, electrostatic spinning can be used to prepare the first fibrous layer and the second fibrous layer respectively, then use ultrasound wave fusion method, the first fibrous layer and the second fibrous layer are combined, form double layer fibre film.
In addition, in another specific embodiments of the present invention, high polymer is dissolved and makes uniform solution in a solvent, then, take out after polypropylene or other are not degraded or degradation material is made braiding mesh sheet are infiltrated in above-mentioned high polymeric solution, drying.Then, above-mentioned mesh sheet is twisted in reception roller surface.Above-mentioned high polymeric solution is loaded in electrostatic spinning syringe, thus obtain the first fibrous layer in described braiding mesh sheet.After electrospinning terminates, the mesh sheet of surface with electrospinning layer is taken off, thus obtain double layer fibre film of the present invention.
As shown in Figure 5, double layer fibre film of the present invention exemplarily can comprise and has the first fibrous layer B of directional orientation and the second fibrous layer A of No yield point.Wherein can as shown in Figure 6,7, the second fibrous layer A(2 of No yield point) containing medicine 3, and there is the first fibrous layer B(1 of directional orientation) and containing medicine, or the bilayer of double layer fibre film is as shown in Figure 8 respectively containing identical or different medicine.In addition, as shown in Figure 9, fibrous membrane of the present invention can be multi-layer fiber film, also arranges intermediate layer C having between the first fibrous layer B of directional orientation and the second fibrous layer A of No yield point.As shown in Figure 10,11, the second fibrous layer A(2 of No yield point) and intermediate layer C(4) respectively containing identical or different medicine 3 and 5.
In order to better the present invention is described, be described in the mode of specific embodiment below, but the present invention is not limited in the concrete mode of embodiment.In the present invention, when not particularly pointing out, described percentage ratio is mass percent.
Embodiment
The preparation > of < fibrous membrane
The preparation of the double-deck electrospinning film of embodiment 1()
Be dissolved in by polyvinylidene fluoride (PVDF) in dimethyl acetylamide (DMAc) solvent, the concentration forming polyvinylidene fluoride is the uniform solution of 20g/100mL.
Then load in electrostatic spinning syringe by above-mentioned solution, the speed regulating micro-injection pump is 3 mls/hour, and the voltage regulating high tension generator is 22kV, and the receiving range regulating receiving system is 20 centimetres.Receiving system uses live-rollers, translational speed 10 cel of electrospinning syringe needle, receive roller rotating speed be 4000 circles/point, two pins carry out electrospinning 8 hours simultaneously, thus the first fibrous layer of preparation directional orientation.Then, rotating speed is turned down to 80 circles/point, same use two pins to carry out electrospinning 8 hours, thus prepare the second fibrous layer of No yield point.Taken off from reception roller by film after end, in vacuum drying oven, solvent is removed in 50 DEG C of insulations.
The preparation of embodiment 2(tri-layers of fibrous membrane)
Polyglycolic acid, polylactic acid are dissolved in respectively hexafluoroisopropanol (HFIP) and obtain solution a, wherein the concentration of polyglycolic acid is 8g/100mL, and the concentration of polylactic acid is 10g/100mL.
Polyglycolic acid, polylactic acid, medicine Radix Notoginseng are dissolved in hexafluoroisopropanol and obtain solvent b, and wherein the concentration of polyglycolic acid is 6g/100mL, and the concentration of polylactic acid is 8g/100mL, and the concentration of medicine Radix Notoginseng is 10g/100mL.
Then load in electrostatic spinning syringe by above-mentioned solution a, the speed regulating micro-injection pump is 2 mls/hour, and the voltage regulating high tension generator is 15kV, and the receiving range regulating receiving system is 20 centimetres.Receiving system uses live-rollers, translational speed 3 cel of electrospinning syringe needle, receive roller rotating speed be 2000 circles/point, two pins carry out electrospinning 3 hours simultaneously, thus the first fibrous layer of preparation directional orientation.Then, change the solution in electrostatic spinning syringe into above-mentioned solution b, rotating speed is turned down to 80 circles/point, same use two pins to carry out electrospinning 5 hours, thus electrospinning prepares the intermediate layer of No yield point.Then, change the solution in electrostatic spinning syringe into above-mentioned solution a, keep receiving roller rotating speed 80 to enclose/point, use two pins to carry out electrospinning 8 hours, thus electrospinning prepare the second fibrous layer of No yield point.Taken off from reception roller by film after end, in vacuum drying oven, solvent is removed in 50 DEG C of insulations.
The preparation of embodiment 3(tri-layers of fibrous membrane)
High polymer polycarbonate polyurethane (PCU) is dissolved in dimethyl formamide (DMF) and obtains solution a, wherein the concentration of PCU is 12g/100mL.
Be dissolved in DMAc and obtain solution b in PCU, medicine ampicillin, wherein the concentration of PCU is 12g/100mL, and the concentration of medicine ampicillin is 15g/100mL.
Then load in electrostatic spinning syringe by above-mentioned solution a, the speed regulating micro-injection pump is 12 mls/hour, and the voltage regulating high tension generator is 42kV, and the receiving range regulating receiving system is 15 centimetres.Receiving system uses live-rollers, translational speed 26 cel of electrospinning syringe needle, receive roller rotating speed be 4000 circles/point, two pins carry out electrospinning 2 hours simultaneously, thus the first fibrous layer of preparation directional orientation.Then, change the solution in electrostatic spinning syringe into above-mentioned solution b, rotating speed is turned down to 300 circles/point, regulates the speed of micro-injection pump to be 6 mls/hour, use two pins to carry out electrospinning 3 hours equally, thus electrospinning prepares the intermediate layer of No yield point.Then, change the solution in electrostatic spinning syringe into above-mentioned solution a, keep receiving roller rotating speed 300 to enclose/point, the speed regulating micro-injection pump is 12 mls/hour, use two pins to carry out electrospinning 4 hours, thus electrospinning prepares the second fibrous layer of No yield point.Taken off from reception roller by film after end, in vacuum drying oven, solvent is removed in 50 DEG C of insulations.
The preparation of the two-layer fibrous membrane of embodiment 4()
Polycaprolactone (PCL) is dissolved in hexafluoroisopropanol and obtains solution a, wherein the concentration of PCL is 15g/100mL.
In above-mentioned solution a, add nanometer silver (diameter 10 ~ 20nm) obtain suspension b, wherein the concentration of nanometer silver is 10g/100mL.
Then load in electrostatic spinning syringe by above-mentioned solution a, the speed regulating micro-injection pump is 6 mls/hour, and the voltage regulating high tension generator is 25kV, and the receiving range regulating receiving system is 16 centimetres.Receiving system uses live-rollers, translational speed 10 cel of electrospinning syringe needle, receive roller rotating speed be 3000 circles/point, two pins carry out electrospinning 5 hours simultaneously, thus the first fibrous layer of preparation directional orientation.Then, change the solution in electrostatic spinning syringe into above-mentioned suspension b, reception roller rotating speed is down to 200 circles/point, use two pins to carry out electrospinning 6 hours, thus prepare the second fibrous layer of No yield point.Taken off from reception roller by film after end, in vacuum drying oven, solvent is removed in 50 DEG C of insulations.
The ultrasonic fusion method of embodiment 5(prepares three layers of fibrous membrane)
Thermoplastic polyurethane (TPU) is dissolved in DMF and obtains the solution that TPU concentration is 14g/100mL.Then above-mentioned solution is loaded in electrostatic spinning syringe,
The speed regulating micro-injection pump is 4 mls/hour, and the voltage regulating high tension generator is 20kV, and the receiving range regulating receiving system is 15 centimetres.Receiving system uses live-rollers, translational speed 10 cel of electrospinning syringe needle, receive roller rotating speed be 3000 circles/point, two pins carry out electrospinning 6 hours simultaneously, thus the first fibrous layer of preparation directional orientation.
Thermoplastic polyurethane (TPU) is dissolved in DMF and obtains the solution that TPU concentration is 14g/100mL.Then load in electrostatic spinning syringe by above-mentioned solution, the speed regulating micro-injection pump is 3 mls/hour, and the voltage regulating high tension generator is 25kV, and the receiving range regulating receiving system is 16 centimetres.Receiving system uses live-rollers, translational speed 10 cel of electrospinning syringe needle, receive roller rotating speed be 300 circles/point, two pins carry out electrospinning 8 hours simultaneously, thus prepare the second fibrous layer of No yield point.
Be dissolved in HFIP by Poly(D,L-lactide-co-glycolide (PLGA) and chitosan, wherein the concentration of PLGA is 12g/100mL, and the concentration of chitosan is 10g/100mL.Then load in electrostatic spinning syringe by above-mentioned solution, the speed regulating micro-injection pump is 2 mls/hour, and the voltage regulating high tension generator is 30kV, and the receiving range regulating receiving system is 18 centimetres.Receiving system uses live-rollers, translational speed 15 cel of electrospinning syringe needle, receive roller rotating speed be 200 circles/point, two pins carry out electrospinning 4 hours simultaneously, thus the intermediate layer of obtained No yield point.
By above-mentioned, first fibrous layer, intermediate layer and the second fibrous layer are stacked together in order, then 20000Hz frequency ultrasound (Fu Tan plant equipment company limited is used, model JT-200-S), every the mode of the distances of 10 centimetres by the ultrasonic fusion of point, above-mentioned each layer is linked together.
Embodiment 6(mesh grid is combined with electrospinning)
Polylactic acid (PLA) is dissolved in HFIP and obtains the solution that concentration is 20g/100mL.Politef is woven mesh sheet in above-mentioned high polymeric solution, infiltrate rear taking-up, drying.Then, above-mentioned mesh sheet is twisted in reception roller surface.To mesh sheet surface sprinkling solvent, make its slight moistening rear beginning electrospinning.
Be in the hexafluoroisopropanol solution loading electrostatic spinning syringe of 12g/100mL by the concentration of polylactic acid (PLA), the speed regulating micro-injection pump is 10 mls/hour, the voltage regulating high tension generator is 26kV, and the receiving range regulating receiving system is 20 centimetres.Receiving system uses live-rollers, translational speed 10 cel of electrospinning syringe needle, receive roller rotating speed be 2000 circles/point, two pins carry out electrospinning 4 hours simultaneously, thus as the first fibrous layer directional orientation preparing by the second fibrolaminar mesh sheet.After end, solvent is removed in compound film sheet 50 DEG C of insulations in vacuum drying oven.
Embodiment 7(memory metal)
Patterning prepared by embodiment 3 is become shape of product, and peripherally the Nitinol line of upper diameter 0.1mm sewed up by a circle with sutures.Product can be carried out folding (as doubling) under-10 ~ 0 DEG C of low temperature.Under being placed on 37 DEG C of environment, product can recover shape automatically.
Embodiment 8(laser punching)
(large aperture combination)
By three layers of obtained for embodiment 5 fibrous membrane, carry out laser punching, laser power is 50W, cutting speed 10cm/s.According to distance of center circle from calculating, stamp every 8mm laser the macropore that diameter is 2mm, evenly stamping 4 diameters between each macropore is the aperture of 0.5mm.
(staggered hole)
By three layers of obtained for embodiment 5 fibrous membrane, according to distance of center circle from calculating, level stamps every 5mm laser the hole that diameter is 1.2mm, and at a distance of 0.5cm between row and row, and the hole between two row is staggered, horizontal displacement 2.5mm distance.Wherein, laser power is 40W, and cutting speed is 8cm/s.
< prepares no-station pole canopy suspender >
The fibrous membrane of above-described embodiment 1-8 is cut into 40cm × 1.5cm rectangular, may be used for after sterilizing treating stress incontinence.
< drug release experiment in vitro >
Fibrous membrane obtained for embodiment 2 is cut into 2cm × 2cm square piece, amounts to 20, be divided into 4 groups, use ethylene oxide sterilizing.Every sheet is immersed in (pH=7.4) in 10mL sterile phosphate buffer, is placed in 37 DEG C of cell culture incubators, detected respectively at 1 week, 2 weeks, 4 weeks, 8 weeks, adopt high-efficient liquid phase chromatogram technique measuring drug concentration in solution.Experimental result (see table 1) shows medicine slow releasing from after 1 week, discharges the medicine of in diaphragm 35% ± 4% by 8 weeks.
Table 1 drug release data table
Time (week) 1 2 4 8
Drug accumulation percentage ratio burst size 10% 12% 20% 35%
Error ±2% ±2% ±3% ±4%
< cell experiment >
Fibrous membrane obtained for embodiment 1 is cut into the disk that diameter is 3cm, uses ethylene oxide sterilizing.Disk is put into cell culture six orifice plate by aseptic operating platform, and directional orientation layer is experimental group upward, and No yield point layer is matched group upward.Add 2mL people's muscle fibroblast (C2C12) cell suspension, put into 37 DEG C of cell culture incubators and cultivate.Take out basis of microscopic observation after cultivating 1 week, the visible a large amount of cell of experimental group grows along machine direction, and cellular control unit growth is unordered.
< zoopery example >
A. implant between subcutaneous and Musclar layer and test (biocompatibility and the new tissue growth situation of sample are tested) (see Fig. 1, Fig. 2)
Laboratory animal selects new zealand rabbit, body weight 2.2-2.6Kg, age 6-12 month, totally 12.Experimental rabbit is divided into 2 groups at random, often organizes 6 laboratory animals, respectively the et al. Ke of correspondence 3 and 6 months observation periods.Material experiment group is aseptic diaphragm (embodiment 1), and matched group 1 is monolayer Random fiber film, and matched group 2 is polypropylene mesh (Johson & Johnson), and material is all cut to 1cm × 4cm.Implant rabbit subcutaneous abdomen Musclar layer respectively, in 3 months after operation, within 6 months, observe materials microstructure growing state.
Method for implantation: remove rabbit abdominal part by hair, sterilization, scalpel cuts skin gently, do not cut muscle, gently carry the other fascia of ventrimeson with Smooth forceps, cut fascia with scalpel along ventrimeson, not muscle injury simultaneously, subcutaneous fascia is separated with muscle by blade holder passivity, exposes suitable material transplanting scope.All laboratory animals, implant the sample (Figure 1A (2), (3)) of experimental group sample (Figure 1A (1)), matched group 1 and matched group 2 between subcutaneous fascia and Musclar layer.Material No. 4 lines are fixed on corresponding position, sew up.
3 months after operation, dissects the 1st group of laboratory animal, and 3 groups of sample biocompatibility are better as seen from Figure 1, and naked eyes are visible, and experimental group superficial capillary vessels enriches, and the two sides of all samples has cambium (Figure 1B) all as seen.Observe two-layer diaphragm, have obvious fiber alignment texture above its oriented layer, omnidirectional layer is then without obvious fiber alignment texture.And single layer fibre layer and the equal random growth of polypropylene mesh two covering weave.
Postoperative 6 months, dissect the 2nd group of laboratory animal (Fig. 2).The associativity of tissues observed and material, on polypropylene material and single layer fibre film, cambium does not find directed texture, and polypropylene material easily and cambium peel off, material internal has no cambium; The visible cambium of single layer fibre film is grown into diaphragm inside, diaphragm and the more difficult stripping of cambium, but grows unordered.Double layer fibre film is grown into completely by cambium, can not peel off, and the directed texture of obvious visible cambium on oriented fiber layers.
B. vaginal wall implants experiment (see Fig. 3 and 4)
The implantation of capable for above-mentioned reparation sticking patch new zealand rabbit vaginal wall is tested.New zealand rabbit, body weight 2.2-2.6Kg, age 6-12 month, totally 18.Experimental rabbit is divided into 2 groups at random, often organizes 9, respectively the et al. Ke of correspondence 1 and 3 months observation periods.Material experiment group is double layer fibre film (embodiment 1), and matched group 1 is unordered electrospinning diaphragm, and matched group 2 is polypropylene mesh (Johson & Johnson), and size is 1cm × 1cm.Laboratory animal is anaesthetized, preserved skin, lying on the back is bound on plank; Sterilization paving is single, in abdominal part center, cuts skin and Musclar layer with No. 4 scalpels along rabbit hunter's line, find bladder, gently draw proposition, with the mesentery between bladder root and uterus for stitch, with No. 0 line, material is fixed (Fig. 3 A), bladder is sent into abdominal cavity gently, close abdomen.With the muscle interrupted suture of No. 0 silk thread by sticking patch and surrounding.With No. 4 wire discontinuous sewing skins.
Postoperative rabbit each intramuscular injection penicillin 400,000 morning and afternoon every day unit, continuously injection 5 days, every day observes the rabbit mental status and appetite while feeding grass, and whether occurs other diseases.Within postoperative 7th ~ 10 days, take out stitches, detailed observation experiment animal health condition and art portion changes in material in feeding process.Put to death laboratory animal when postoperative 1,3 month, cut muscle and expose art portion (Fig. 3 B), tissues observed growing state also takes out sample and does pathological section.
Month after operation, after anatomy experiment animal, the material surface of observation experiment group and matched group 1 all has one deck cambium to cover, and in cambium, blood capillary is high-visible, and cambium is combined with material closely; Face complied with by experimental group material, and new tissue growth orientation texture is obviously visible.The nascent membrane that matched group 2 material surface has one deck very thin covers, and few blood capillary is grown in nascent membrane, nascent membrane and material easily openable.
3 months after operation, experimental result (see table 2) shows, experimental group fibrous membrane is integrated with tissue is long, and cannot distinguish, be as good as with normal surrounding tissue in appearance, alignment layer surface has fiber grain, meets expection rational design (pathological effects is as Fig. 4 A).Experimental group fibrous membrane implant part and surrounding tissue entirety thereof are taken out, sample is soft, without hard object sense.Pathological section shows that sample inflammatory reaction is comparatively light, and foreign-body giant cell < 3/HPF, has no inflammatory granuloma tissue, do not form fibers encapsulation.Matched group 1 sample is integrated with the basic length of tissue, and there is a small amount of blood capillary on surface, but tissue growth is unordered, and pathological section shows sample inflammatory reaction general (pathological effects is as Fig. 4 B).Matched group polypropylene mesh surface grows (pathological effects is as Fig. 4 C) in a organized way, but tissue growth is unordered, mesh sheet with organize layering, both can be peeled off, inflammatory reaction is general.
Table 2. is pathological examination after three months
Experimental group Matched group 1 Matched group 2
Inflammation Gently Generally Generally
Foreign-body giant cell quantity < 3/HPF 3 ~ 5/HPF 5 ~ 8/HPF
Tissue growth order Have Nothing Nothing
Fissility Difficult Difficult Easily

Claims (22)

1. a pelvic floor patch, is characterized in that, described pelvic floor patch comprises fibrous membrane, and described fibrous membrane at least comprises and has the first fibrous layer of directional orientation and the second fibrous layer of No yield point; Second fibrous layer of wherein said fibrous membrane is the layer with cellular three dimensional structure that the unordered intertexture of cellosilk being 10nm ~ 20 μm by diameter is formed.
2. pelvic floor patch according to claim 1, also has intermediate layer between the first fibrous layer of wherein said fibrous membrane and the second fibrous layer.
3. pelvic floor patch according to claim 1 and 2, is combined by the mode of electrostatic spinning, ultrasonic fusion or stitching between each layer of wherein said fibrous membrane.
4. pelvic floor patch according to claim 1 and 2, is combined closely by the mode of electrostatic spinning between each layer of wherein said fibrous membrane.
5. pelvic floor patch according to claim 2, wherein said intermediate layer is No yield point fibrous layer.
6. pelvic floor patch according to claim 1 and 2, one or more the mode of wherein said fibrous membrane in drilling process, hyperthermic treatment and immersion treatment processes.
7. pelvic floor patch according to claim 6, wherein said drilling is treated to punching press drilling, laser punching, locally pressure found hole.
8. the pelvic floor patch according to any one of claim 1-7, wherein said pelvic floor patch comprises and the membrane-bound mesh grid of described fiber or memory metal further.
9. the pelvic floor patch according to any one of claim 1-7, wherein said fibrous membrane tinsel or polymer fiber carry out sewing process.
10. the pelvic floor patch according to any one of claim 1-7, the first fibrous layer of wherein said fibrous membrane is that the cellosilk being 10nm ~ 20 μm by diameter aligns the layer with cellular three dimensional structure formed.
11. pelvic floor patch according to claim 2, wherein said intermediate layer is the layer with cellular three dimensional structure that the unordered intertexture of cellosilk being 10nm ~ 20 μm by diameter is formed.
12. pelvic floor patch according to any one of claim 1-7, the thickness of wherein said pelvic floor patch is 0.25mm ~ 0.8mm, and the pore size of through hole is 0.4 ~ 2mm, and hot strength is 30 ~ 80N.
13. pelvic floor patch according to any one of claim 1-7, the fibrous material wherein preparing described fibrous membrane is degradation material, non-degradable material or its combination.
14. pelvic floor patch according to claim 13, wherein said degradation material be selected from the group be made up of the peptide polymer of polylactic acid, polycaprolactone, polyglycolic acid, Poly(D,L-lactide-co-glycolide, 1,3-PD polymer, collagen protein, gelatin, fibrin, fibroin, elastin mimicry, chitosan and modification of chitosan one or more.
15. pelvic floor patch according to claim 13, wherein said non-degradable material be selected from poly-fluorine class material, polyolefin, polyurethane one or more.
16. pelvic floor patch according to claim 13, wherein said non-degradable material is polyvinylidene fluoride.
17. pelvic floor patch according to any one of claim 1-7, containing anti-infection drug, hemostasis class medicine and/or micro-nano granules in wherein said pelvic floor patch.
18. pelvic floor patch according to claim 17, wherein said anti-infection drug comprises ampicillin class, spiramycin class, sulfonamides, quinolones and/or cephalosporins.
19. pelvic floor patch according to claim 17, wherein said hemostasis class medicine comprises 6-aminocaprolc acid, para-amino-methyl-benzoic acid, tranamic acid, Radix Notoginseng and/or YUNNAN BAIYAO.
20. pelvic floor patch according to claim 17, wherein said micro-nano granules comprises SiO 2, TiO 2, ZnO, Ag, Ni, quaternary ammonium salt, chitosan, calcium alginate, polyvinyl alcohol and/or natural macromolecular nanoparticle.
21. 1 kinds of no-station pole canopy suspenders, is characterized in that, described no-station pole canopy suspender uses the pelvic floor patch preparation described in claim 1-20.
22. no-station pole canopy suspenders according to claim 21, it is in order to treat stress incontinence.
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CN104225683B (en) * 2014-07-09 2016-07-06 广州迈普再生医学科技有限公司 Load hemostasis tissue repair film of Radix Notoginseng and preparation method thereof
CN104323871A (en) * 2014-10-22 2015-02-04 首都医科大学附属北京妇产医院 Grid-shaped bracket composite membrane of pelvic floor repairing belt and use method thereof
CN104963097A (en) * 2015-06-17 2015-10-07 广州迈普再生医学科技有限公司 Reinforced electrospun mat and preparation method thereof
CN106480607A (en) * 2015-08-24 2017-03-08 上海微创医疗器械(集团)有限公司 Static spinning membrane, the preparation method of static spinning membrane and composite membrane
CN105536071B (en) * 2016-01-21 2018-10-23 东华大学 A kind of polylactic acid and caprolactone/polypropylene composite materials basin bottom sticking patch and preparation method thereof
CN106310389A (en) * 2016-10-19 2017-01-11 爱美客技术发展股份有限公司 Bacterial cellulose patch used for gynecology and preparation method thereof
CN108771573B (en) * 2018-06-26 2020-10-13 柏为(武汉)医疗科技股份有限公司 Completely degradable and absorbable drug eluting stent and application thereof
CN114681106B (en) * 2020-12-30 2024-02-13 诺一迈尔(苏州)医学科技有限公司 Implant for promoting wound repair of endometrium
CN114681671A (en) * 2020-12-30 2022-07-01 广州迈普再生医学科技股份有限公司 Tissue repair membrane
CN113209384B (en) * 2021-05-08 2022-03-25 宁波市第一医院 Pelvic floor patch for gynecology and preparation method thereof
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