WO2017148255A1 - 一种修复区稳固的复合软组织修复材料 - Google Patents

一种修复区稳固的复合软组织修复材料 Download PDF

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WO2017148255A1
WO2017148255A1 PCT/CN2017/073395 CN2017073395W WO2017148255A1 WO 2017148255 A1 WO2017148255 A1 WO 2017148255A1 CN 2017073395 W CN2017073395 W CN 2017073395W WO 2017148255 A1 WO2017148255 A1 WO 2017148255A1
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soft tissue
composite soft
crosslinked
tissue repairing
membranous
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PCT/CN2017/073395
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English (en)
French (fr)
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张剑
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上海卓阮医疗科技有限公司
中国人民解放军第二军医大学
卓阮医疗科技（苏州）有限公司
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Application filed by 上海卓阮医疗科技有限公司, 中国人民解放军第二军医大学, 卓阮医疗科技（苏州）有限公司 filed Critical 上海卓阮医疗科技有限公司
Priority to EP17759106.2A priority Critical patent/EP3424541A4/en
Priority to JP2018565448A priority patent/JP2019508206A/ja
Publication of WO2017148255A1 publication Critical patent/WO2017148255A1/zh
Priority to US16/117,772 priority patent/US11058529B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/0063—Implantable repair or support meshes, e.g. hernia meshes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A61L27/362—Skin, e.g. dermal papillae
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A61L27/3629—Intestinal tissue, e.g. small intestinal submucosa
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A61L27/3633—Extracellular matrix [ECM]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction

Definitions

  • the invention belongs to the field of soft tissue repair, and particularly relates to a composite soft tissue repairing material with a stable repairing area.
  • Soft tissue repair and reconstruction represented by abdominal wall defects, chest wall defects, meningeal defects and burn wounds is an important subject in surgical and regenerative medicine, and the repair of large-scale defects is a surgical problem.
  • Non-degradable synthetic materials are good carriers of bacteria. Once the bacteria adhere to them, they will form biofilms and are difficult to be immune to the body. The system is eliminated, even if the antibiotic dose is increased by 1000 times.
  • some synthetic patches such as expanded polytetrafluoroethylene patches, have their own defects such as inability to fuse with host tissues, fiber wrap around the material, and are less resistant to infection, and must be removed once infection occurs.
  • Acellular matrix biologic patch refers to the same or different kinds of extracellular matrix (cavitary submucosa, etc.) or inert tissue matrix (dermis, pericardium, peritoneum, etc.) as a material, with chemical detergent combined with other auxiliary reagents Remove all cells, antigens, lipids, soluble proteins and other substances, retain matrix components with intact appearance and histology and ultrastructure, including collagen, elastin, proteoglycan, glycosaminoglycan and non-collagen glycoprotein.
  • the acellular matrix bio-patch can not only maintain the normal configuration of the tissue, but also provide a scaffold for cell regeneration, stimulate and induce the growth of the host's own cells or collagen to repair the tissue defect; and at the same time, the immune response is removed.
  • the cellular component thus avoids the occurrence of rejection, which itself is completely absorbed and utilized by the body, and functions by machine weight plasticity.
  • the long-term loss of elasticity of the bio-repair area is due to the fact that the bio-patches undergo degradation and remodeling while undergoing endogenous biological healing. If the degradation of the implanted material and the remodeling of the new tissue do not reach equilibrium, the tension will not be transmitted intact and in a timely manner, resulting in inelasticity, bulging or recurrence of the repaired area of the bio-patches.
  • CN201664349U discloses a novel composite raft and body wall repair sheet.
  • the patch is composed of a polymer material mesh, a bio-derived material, a medical adhesive-bonded polymer mesh, and a biologically derived material.
  • the composite sputum patch can effectively isolate the direct contact between the intra-abdominal organ and the synthetic mesh.
  • the lightweight mesh can play the role of “reinforcing bar” in the repair zone in the long-term, optimize the overall tensile performance of the composite mesh, and significantly reduce ⁇ . Incidence and improved operational feel.
  • this composite patch there are still some problems with this composite patch:
  • the polymer material mesh covers the surface of the acellular matrix, and directly contacts the body tissue after implantation, which changes the type of host-material contact area of the acellular matrix (M2 type macrophage infiltration mainly ⁇ M1 type) Macrophage infiltration is the main);
  • CN102698318A discloses a biomaterial composite patch.
  • the patch is composed of a synthetic material as a base layer, an extracellular matrix/decellularized tissue matrix material bio-patch or a synthetic biomaterial or a synthetic material patch of the remaining synthetic degradable material as an additional layer.
  • the base layer and the additional layer are integrally formed by medical suture or medical glue or other methods.
  • the basic principle and structure of the patch are the same as those of CN201664349U.
  • the patch has the following problems:
  • Biomaterials have a structure similar to that of natural tissues. Biomaterials used alone have certain tolerance to infection, but when used in combination with synthetic patches, infections are still inevitable due to exposure of synthetic patches to body tissues. The overall composite is not resistant to infection;
  • the polymer material tends to use the standard weight non-absorbable mesh sheet, and there may be a problem that the abdominal wall compliance is poor and the foreign body feeling in the body repairing area is strong during use in the patch.
  • the patch is formed by integrating the base layer and the additional layer of a specific size under the aseptic conditions during the operation, which is time-consuming and labor-intensive, inconvenient to use, and cannot guarantee the stability of the structure.
  • the technical problem to be solved by the present invention is to provide a composite soft tissue repairing material with a stable repairing area, which combines the advantages of a tissue-inducing regenerative stent and a non-absorbable or slow-absorbent patch, including high tissue compatibility and direct contact with the soil. It has good application prospects, such as tolerance to infection and mechanical stability of the repair area.
  • the invention relates to a composite soft tissue repairing material with stable repairing area, wherein a synthetic material or a cross-linked material is used as a central mechanical reinforcing layer, and a non-crosslinked membranous acellular matrix is used as the upper and lower layers; the upper and lower layers are completely coated with central mechanical strengthening.
  • the layers form a sandwich structure.
  • the synthetic material or cross-linking material is located inside the non-crosslinked membranous acellular matrix rather than attached to the surface of the non-crosslinked acellular matrix, and the non-crosslinked acellular matrix is isolated from the synthetic material or the crosslinked material and the body tissue after implantation Early direct contact does not alter the basic type of immune response in the host-material junction zone of the composite as a whole, and avoids bacterial colonization in non-absorbable components.
  • the edge of the central mechanical reinforcement layer is 2-15 mm from the edge of the upper surface layer. Ensure that no mechanical reinforcement layer is exposed to the surface of the composite; the non-crosslinked decellularized matrix acts as a surface layer to make the composite material highly compatible and directly contact the organ.
  • the tensile force of the central mechanical reinforcement layer is >16N/cm (the strength of the natural human abdominal wall fascia), the elasticity is slightly lower than the strength of the human abdominal wall fascia, and the mechanics are stable for a long time.
  • the mass ratio of the synthetic material or the crosslinked material in the central mechanical reinforcing layer to the non-crosslinked membranous acellular matrix in the surface layer is 1:20 to 1:1, so as to ensure a low content of the component to make up for the non-crosslinking in a special case.
  • the cell matrix induces inelasticity in the repair zone due to poor tissue regeneration.
  • the synthetic material or the cross-linked material both contain a certain amount of non-absorbent or slow-absorbing components, such as a mesh or a membrane made of a polymer material or a metal material; or a cross-linked membranous acellular matrix.
  • the central mechanical reinforcement layer can improve the overall bending resistance and handling feel, and the cross-linked membranous acellular matrix can be used as a mechanical reinforcement layer to achieve significant mechanical improvement while reducing overall hardness.
  • the non-absorbent polymer material is a medical polymer such as one or more of polypropylene, polyester, polyvinylidene fluoride and silica gel; and the non-absorbable metal material is titanium alloy or nickel-titanium alloy.
  • the slow-absorbing polymeric material is poly-4-hydroxybutyric acid, polylactic acid, polyglycolic acid, polytrimethylene carbonate, glycolide/lactide/polytrimethylene carbonate One or more of an ester or a silk protein; the slow-absorbing metal material is a degradable magnesium alloy.
  • the polymer material of the non-absorbent polymer material has a mass of ⁇ 60 g/m 2 , preferably ⁇ 40 g/m 2 , a large mesh structure, and a mesh diameter of >3 mm.
  • the crosslinked membranous acellular matrix is derived from the submucosa of the hollow organ of a human or mammal, the dermis, the pericardium, the peritoneum, the pleura or the amnion; the degree of cross-linking is 1-100%.
  • the degree of cross-linking is variable but the final long-term stability mechanics is required to meet the mechanical requirements of the central mechanical reinforcement layer.
  • the non-crosslinked membranous acellular matrix is derived from the submucosa, dermis, pericardium, peritoneum, pleura or amnion of a hollow organ of a human or mammal.
  • the crosslinked membranous acellular matrix or the non-crosslinked membranous acellular matrix may be a single layer or a multilayer structure, and the specific number of layers should be changed depending on the site of use.
  • the central mechanical reinforcement layer is fixed with the upper and lower layers in one or more of a medical adhesive bond, a stitching bundling, and a vacuum lamination.
  • Medical adhesives and sutures are preferably absorbable components.
  • the vacuum pressure of the vacuum lamination is -100 to -760 mmHg, and the action time is 0.5 to 72 h.
  • the composite soft tissue repairing material further comprises a hole penetrating the surface layer and the mechanical strengthening layer, the diameter is 1 to 5 mm, and the hole spacing is 1 to 5 mm; no synthetic material or crosslinked material is exposed to the hole. If the mechanical reinforcement layer is a large mesh mesh, the openings do not overlap with the mesh fibers, and the openings are in the mechanical reinforcement layer grid.
  • the cross-linking according to the present invention means that the collagen molecules in the non-crosslinked membranous acellular matrix are bound by covalent bonds between molecules or molecules, or between molecules or other components, by physical or chemical means.
  • the target of collagenase is such that the material does not degrade or only partially degrade after implantation, and has similar or even better biomechanical properties than the synthetic mesh, thereby achieving the purpose of permanently retaining part of the permanent implanted fiber and stabilizing the repaired area.
  • the repaired area of the present invention is stable in the long-term, without loss of elasticity, bulging or shrinkage: on the one hand, the three-dimensional collagen network scaffold structure of the acellular matrix on the surface of the early patch can induce rapid growth of host cells and blood vessels.
  • the non-degrading component ensures that the lowest point of the acellular matrix remodeling mechanics meets the needs of tissue repair mechanics and smoothly completes the transmission of tissue tension.
  • the acellular matrix is remodeled, and the permanent implant component is not absorbed to maintain the tension-free repair of the tissue for a long time.
  • the final repair zone achieves a long-term stable structural effect similar to that of "reinforced concrete-concrete".
  • the defect in the central zone tissue induces poor regeneration, and the permanent component can continue to provide a certain mechanical tension to avoid the loss of elasticity and tissue bulging in the repair zone.
  • the permanent implanted fiber can be used to repair the unabsorbed monofilament mesh into an ultra-lightweight, super-large mesh structure, and the long-term repair zone does not shrink.
  • the surface of the "sandwich" structure repairing material of the present invention is an extracellular matrix component, has good histocompatibility, can directly contact organs such as intestinal tubes, and has light adhesion and no vigorous tissue. reaction.
  • high-polymer fiber or high-strength cross-linked collagen fiber that is not absorbed or slowly absorbed is tightly wrapped in the extracellular matrix component, and its edge is 2-15 mm from the edge of the biomaterial (the margin of the surgical suture is generally 5 mm, The distance can be ensured to suture to the mechanical strengthening layer) to ensure that the surrounding tissue cannot be directly contacted at the initial stage of implantation, and the degradation of the exogenous extracellular matrix is basically synchronized with the growth of the autologous tissue, so that the organ can be effectively maintained and not absorbed.
  • the insulation of the fibers prevents the fibers from eroding into the tissue.
  • the pores of the entire "sandwich” material the growth of surrounding fibrous tissue is accelerated, which is conducive to the flow of tissue fluid, so the incidence of local complications such as seroma is low.
  • the surface of collagen fiber is negatively charged and has components such as laminin and glycosaminoglycan. It is easy to adhere to positively charged anti-infective particles such as nano-silver particles. After implantation, anti-infective components are continuously released to the surrounding area. In the extracellular matrix. Therefore, the "sandwich" structural repair material can easily develop a broad-spectrum, strong, and long-lasting anti-infective ability.
  • the two extracellular matrix biomaterials can provide at least 2 times higher mechanical strength than the human abdominal wall fascia, which can meet the load requirements during wound healing and wound healing, and the mechanical reinforcement layer can also provide A certain tension.
  • the composite patch is expected to have a tensile strength that is 3 times higher than that of the natural abdominal wall fascia.
  • Low-permanent implants do not affect abdominal wall compliance: the mass ratio of non-absorbed or slow-absorbing components to non-crosslinked acellular matrix in the central mechanical reinforcement layer of “sandwich” material is ⁇ 1:1. Because it does not absorb or absorb the non-early major stress components of the fiber, it mainly acts as a "reinforcing bar" in the repair zone in the long-term, and does not form a large scar. The patient can obtain high comfort and flexibility after surgery.
  • Figure 1 is a schematic view showing the structure of the present invention; wherein (2) is a central mechanical reinforcing layer; (1) and (3) are upper and lower layers.
  • the porcine small intestine submucosa was prepared by the Abraham method, and the monolithic membranous SIS was spliced into a larger area layer according to the interlaminar dislocation, and three layers were laid and bonded with medical chitosan.
  • the agent is bonded as a unit and is a non-crosslinked membranous acellular matrix.
  • the non-crosslinked membranous acellular matrix increased the number of penetrating pores with a pore spacing of 5 mm and a diameter of 1 mm.
  • the mesh gap of the large mesh polypropylene mesh sheet is 5 x 5 mm and the mass is 40 g/m 2 .
  • the non-crosslinked membranous acellular matrix was used as the upper and lower mesh polypropylene mesh as the intermediate mechanical reinforcement layer according to the "sandwich" structure, the quality of the non-crosslinked membranous acellular matrix and the large mesh polypropylene mesh The ratio is 10:1.
  • the edge of the polypropylene mesh is 5 mm from the edge of the non-crosslinked membranous acellular matrix, ensuring that no polypropylene fibers are exposed to the pores of the non-crosslinked membranous acellular matrix.
  • the three were bonded with a medical chitosan adhesive and pressed together at a pressure of -200 mm Hg over 18 h.
  • An animal model of canine rectus abdominis anterior sheath and rectus abdominis muscle defect with local hypertension was constructed, and the defect area was 10 ⁇ 5 cm 2 .
  • the composite soft tissue repair material was cut to a certain size. Repair, post-month water injection into the water bladder to increase the tension to 40mmHg, observed 24 months repair area without abdominal wall bulging; 24 months after surgery, remove the repair area tissue, determine the mechanical strength. The tensile strength of the measured material was 32 ⁇ 8 N/cm.
  • the SIS was prepared by the Abraham method, and the single-membrane SIS was spliced into a large-area layer in the manner of interlayer dislocation, and three layers were laid, and the medical chitosan adhesive was bonded as one.
  • the material is increased through the pores with a pore spacing of 5 mm and a diameter of 1 mm, which is a non-crosslinked membranous acellular matrix.
  • the high-strength cross-linked membranous acellular matrix biomaterial was prepared by treating SIS with 0.5% genipin aqueous solution for 72 hours, and the degree of crosslinking was 50% and the mass was 38 g/m 2 as measured by the ninhydrin method.
  • the non-crosslinked membranous acellular matrix is used as the upper and lower layers and the high-strength cross-linked membranous acellular matrix biomaterial as an intermediate mechanical reinforcement layer placed in a "sandwich" structure, a non-crosslinked membranous acellular matrix and a high-strength cross-linked membrane
  • the mass ratio of the acellular matrix material was 2:1.
  • the edge of the high-strength cross-linked membranous acellular matrix biomaterial is 5 mm from the edge of the non-crosslinked membranous acellular matrix, ensuring that no cross-linked material is exposed to the pores of the acellular matrix biomaterial.
  • the three were bonded with a medical chitosan adhesive.
  • the tensile strength of the material is estimated to be 50 ⁇ 5N/cm.
  • An animal model of canine rectus abdominis anterior sheath and rectus abdominis muscle defect with local hypertension was constructed, and the defect area was 10 ⁇ 5 cm 2 .
  • the composite soft tissue repair material was cut to a certain size. Repair, post-month water injection into the water bladder to increase the tension to 40mmHg, observed 24 months repair area without abdominal wall bulging; 24 months after surgery, remove the repair area tissue, determine the mechanical strength. The tensile strength of the measured material was 30 ⁇ 5 N/cm.

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  • Life Sciences & Earth Sciences (AREA)
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  • Oral & Maxillofacial Surgery (AREA)
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Abstract

一种修复区稳固的复合软组织修复材料，包括以合成材料或交联材料作为中央力学加强层（2），以及非交联膜状脱细胞基质作为上下表层（1、3）。该上下表层（1、3）完全包覆中央力学加强层（2）形成三明治结构，从而综合了组织诱导再生支架和不可吸收或慢吸收补片的优点，包括组织相容性高、可直接接触脏器、耐受感染以及修复区力学稳定。

Description

一种修复区稳固的复合软组织修复材料 技术领域
本发明属于软组织修复领域，特别涉及一种修复区稳固的复合软组织修复材料。
背景技术
以腹壁缺损、胸壁缺损、脑膜缺损、烧伤创面为代表的软组织修复重建是外科和再生医学的一个重要课题，而其中大范围缺损的修复更是外科的难题。
近年来，各类合成修补材料，包括聚丙烯类补片、聚酯类补片、膨化聚四氟乙烯补片、羟基乙酸补片等的应用实现了无张力修补，降低了复发率。合成补片的修复过程是在合成纤维的慢性炎症刺激下，宿主的炎性细胞、纤维母细胞及胶原增殖到不可降解的网片网孔中形成“钢筋-混凝土”结构的瘢痕组织，修复区的远期力学强度维持良好。但不可降解纤维是对宿主的长期慢性炎症刺激，补片排出、慢性疼痛、肠粘连、肠梗阻甚至肠瘘等并发症仍时有发生。这些并发症常导致更复杂、需更高治疗费用的外科问题，也易导致疝形成/复发。对细菌定植的易感性及由此而导致的慢性感染是合成材料的另一个潜在问题，不降解合成材料都是细菌的良好载体，细菌一旦粘附其上就会形成生物被膜而难以被机体免疫系统消灭，即使抗生素剂量增大1000倍也无法去除。此外，一些合成补片如膨化聚四氟乙烯类补片植入后本身存在不能与宿主组织融合、材料周围纤维包裹形成等缺陷，抗感染性更差、一旦发生感染必须移除。
脱细胞基质类生物补片指以同种或异种的细胞外基质(空腔脏器粘膜下层等)或惰性组织基质(真皮、心包、腹膜等)为材料，用化学除垢剂联合其他辅助试剂脱去所有细胞、抗原、脂质、可溶性蛋白质等物质，保留具有完整外观形态和组织学及超微结构的基质成分，主要包括胶原、弹性蛋白、蛋白多糖、糖胺多糖和非胶原糖蛋白。因此，脱细胞基质生物补片不仅可以维持组织的正常构型，还可以为细胞再生提供支架，刺激和诱导宿主自身的细胞或胶原的长入，来修复组织缺损；同时因为除去了引起免疫反应的细胞成分，因而避免了排斥反应的发生，其自身完全可被机体吸收和利用，并通过机体重塑而发挥作用。
不过，脱细胞基质生物补片的远期疗效目前仍存在争议，主要是部分病例的修复区远期出现了失弹性(lose of laxity)、脏器膨出(Eventration/Bulge)甚至疝复发，特别是应用生物补片桥接法修复复杂、巨大的腹壁缺损时。有研究发现>50％的病例术后1年修复区有腹壁膨出，严重的病例因此而再次手术植入合成补片加强修复区。已有的预防措施仅有部分生产厂家建议在使用生物补片如脱细胞真皮补片时，材料水化后尽量拉伸超过原始面积50％再用于缺损修补，因为不预先拉伸，远期腹壁膨出发生率会增加。经过长期研究发现生物补片修复区远期易失弹性的原因是生物补片植入体内后经历降解和重塑同时进行(内源性生物愈合)的过 程，如果植入材料降解与新生组织重塑没有达到平衡，将不能完整并适时的传递承受张力，导致生物补片的修复区失弹性、膨出或疝复发。
为使植入组织-新生组织承受组织张力的过程平稳交递，研究者考虑引入不可降解成分或缓慢降解成分。CN201664349U公开了一种新型复合疝和体壁修补片。该补片是由高分子材料网片、生物衍生材料、医用粘合剂粘合高分子网片和生物衍生材料组成。这种复合疝修补片可有效隔离腹腔内脏器与合成网片的直接接触，轻量网片可以在远期起到修复区“钢筋”作用，优化复合网片的整体抗拉性能，显著降低疝发生率并提升操作手感。但这种复合疝补片仍存在一定问题：
(1)高分子材料网片覆盖于脱细胞基质表面，植入后直接与机体组织接触，改变了脱细胞基质的宿主-材料接触区免疫反应类型(M2型巨噬细胞浸润为主→M1型巨噬细胞浸润为主)；
(2)由于生物材料大多数是应用于带有污染的损伤表面，而高分子材料为细菌良好的黏附载体，细菌粘于其上后即可产生使其免受宿主免疫防御机制和抗生素作用的生物被膜，从而得以在局部长期生长繁殖并可导致伤口的慢性感染。
CN102698318A公开了一种生物材料复合补片。该补片由人工合成材料作为基层、细胞外基质/脱细胞组织基质材料生物补片或人工合成生物材料或其余人工合成可降解材料的合成材料补片作为附加层构成。用医用缝合线或医用胶或其他方法将基层和附加层制成一体。该补片基本原理、结构与CN201664349U相同，除存在上述高分子材料暴露于组织中，炎症反应强烈和耐感染性较差共性问题外，该补片还存在以下问题：
(1)发明内容中提及的防粘连及耐受感染的描述是不准确的。生物材料拥有与天然组织相近的结构，单独使用的生物材料具有一定的耐受感染性，但联合合成补片使用时，由于合成补片暴露于机体组织中，仍然会不可避免的引起感染，因此整体复合材料不具有耐受感染性；
(2)高分子材料作为基层，则拥有与单纯合成材料相同的脏器粘连效果。
(3)高分子材料作为基层，倾向使用标准重量不可吸收网片，则该种补片中使用过程中可能存在腹壁顺应性较差、机体修复区异物感较强的问题。
(4)该种补片是在术中无菌条件下，将特定尺寸的基层和附加层制成一体，制备费时费力，使用不便，同时不能保证结构的稳定性。
发明内容
本发明所要解决的技术问题是提供一种修复区稳固的复合软组织修复材料，该材料综合了组织诱导再生支架和不可吸收或慢吸收补片的优点，包括组织相容性高、可直接接触脏器、耐受感染、修复区力学稳定等，具有良好的应用前景。
本发明的一种修复区稳固的复合软组织修复材料，以合成材料或交联材料作为中央力学加强层，以非交联膜状脱细胞基质作为上下表层；所述上下表层完全包覆中央力学加强层形成三明治结构。
所述合成材料或交联材料位于非交联膜状脱细胞基质内部而不是附加于非交联脱细胞基质表面，非交联脱细胞基质隔绝合成材料或交联材料与机体组织在植入后早期的直接接触，不改变复合材料整体的宿主-材料交界区免疫反应基本类型、避免细菌定植于不可吸收成分。
所述中央力学加强层的边缘距上下表层的边缘2-15mm。确保无力学加强层暴露于复合材料表面；非交联脱细胞基质作为表层使得复合材料组织相容性高，可直接接触脏器。中央力学加强层的拉断力>16N/cm(天然人体腹壁筋膜强度)，弹性略低于人体天然腹壁筋膜强度，力学长期稳定。
所述中央力学加强层中合成材料或交联材料与表层中非交联膜状脱细胞基质的质量比1:20～1:1，以保证较低的成分含量弥补特殊情况下非交联脱细胞基质诱导组织再生不佳而致的修复区失弹性。
所述合成材料或交联材料均含有一定量不吸收或慢吸收成分，如高分子材料或金属材料制成的网片或膜片；或者为交联膜状脱细胞基质。中央力学加强层可提高整体的抗弯曲度和操作手感，交联膜状脱细胞基质作为力学加强层可实现显著提高力学同时降低整体硬度。
所述不吸收的高分子材料为聚丙烯、聚酯、聚偏氟乙烯、硅胶中的一种或几种等医用高分子聚合物；所述不吸收的金属材料为钛合金、镍钛合金的一种或两种；所述慢吸收的高分子材料为聚-4-羟基丁酸、聚乳酸、聚羟基乙酸、聚三亚甲基碳酸酯、乙交酯/丙交酯/聚三亚甲基碳酸酯、丝蛋白中的一种或几种；所述慢吸收的金属材料为可降解镁合金。
所述不吸收的高分子材料制成的网片中高分子材料质量<60g/m2，优选<40g/m2，大网孔结构，网孔直径>3mm。
所述交联膜状脱细胞基质来源于人或哺乳动物的空腔脏器粘膜下层、真皮、心包、腹膜、胸膜或羊膜；交联度1-100％。交联程度可变但要求最终长期稳定力学符合中央力学加强层的力学要求。
所述非交联膜状脱细胞基质来源于人或哺乳动物的空腔脏器粘膜下层、真皮、心包、腹膜、胸膜或羊膜。
交联膜状脱细胞基质或非交联膜状脱细胞基质可为单层或多层结构，具体层数应根据使用部位的不同而更改。
所述中央力学加强层与上下表层以医用粘合剂粘合、缝合捆扎、真空层压中的一种或几种方式固定。
医用粘合剂、缝合线优选可吸收成分。真空层压的真空压力为-100～-760mmHg，作用时间为0.5～72h。
所述复合软组织修复材料还包括贯穿表层与力学加强层的孔洞，直径1～5mm，孔间距1～5mm；无合成材料或交联材料暴露于孔洞中。若力学加强层为大网孔网片，开孔不与网片纤维重叠，开孔处为力学加强层网格中
本发明涉及的交联，是指非交联膜状脱细胞基质中的胶原分子在物理或化学方法作用下，分子内部或分子间、或胶原分子与其他成分间通过共价键结合，以封闭胶原酶作用靶点，使材料植入后不降解或仅部分降解、具有类似甚至优于合成网片的生物力学特性，从而达到远期保留部分永久植入纤维、起到稳定修复区的目的。
有益效果
(1)本发明修复区远期稳固，无失弹性、膨出或皱缩：一方面，在修复早期补片表面的脱细胞基质的三维胶原网状支架结构可以诱导宿主细胞、血管快速长入，不降解成分可确保脱细胞基质重塑力学最低点符合组织修复力学需要、平稳完成组织张力的传递。修复中后期，脱细胞基质完成重塑，联合不吸收永久性植入成分可以长时间维持组织的无张力修复，最终修复区达到与“钢筋-混凝土”类似的长期稳定结构效果。在特殊情况下如大面积修复时缺损中央区组织诱导再生不佳，永久性成分可以持续提供一定的机械张力以避免修复区失弹性、组织膨出。此外，永久性植入纤维可以修复区中不吸收单纤维网片为超轻量、超大网孔结构，远期修复区不会皱缩。
(2)组织相容性佳：本发明涉及的“三明治”结构修复材料表面为细胞外基质成分，具有良好的组织相容性，能直接接触肠管等脏器，脏器粘连轻，无剧烈组织反应。此外，不吸收或慢吸收的高分子聚合物纤维或高强度交联胶原纤维被严密包裹在细胞外基质成分中，其边缘距生物材料边缘2-15mm(外科缝合时的边距一般5mm，本距离可确保缝合到力学加强层)可以保证植入初期无法直接接触到周围组织，而外源性细胞外基质的降解与自体组织的长入是基本同步的，故可有效维持脏器与不吸收纤维的隔离，防止纤维侵蚀到组织。贯穿整个“三明治”材料的孔洞，加速周围纤维组织长入，利于组织液流动，故血清肿等局部并发症发生率低。
(3)耐受感染：鉴于生物补片目前主要应用在污染或感染创面，增加的力学加强层应满足两个要求：避免植入后早期被细菌定植。不吸收或微量吸收纤维或交联胶原纤维被严密包裹在细胞外基质成分中，无论是在材料边缘还是孔洞处，其均难以直接接触到细菌；合成网片为单股、超大网孔、超轻量网片，不易隐藏细菌。故整体而言本“三明治”应与单纯细胞外基质生物材料拥有类似的耐受感染能力。此外，细胞外基质主要成分为I、III型胶原纤维，高 孔隙率，胶原纤维表面带负电荷并且附带层连蛋白、糖胺聚糖等成分，易于粘附带正电荷的各种抗感染微粒如纳米银微粒等，植入后抗感染成分持续释放到周围细胞外基质中。故本“三明治”结构修复材料可方便的发展出广谱、强效、持久的抗感染能力。
(4)高强度：两块细胞外基质生物材料可提供高于人体天然腹壁筋膜至少2倍的机械强度，能满足伤口愈合过程中和伤口愈合后的负荷需要，且力学加强层也可以提供一定的张力。预计该复合补片的抗张强度超过天然腹壁筋膜3倍。
(5)低永久性植入物，不影响腹壁顺应性：“三明治”材料中央力学加强层中不吸收成分或慢吸收成分与表层非交联脱细胞基质的质量比≤1：1。因不吸收或慢吸收纤维非早期主要受力成分而主要在远期起修复区“钢筋”作用，不形成大块疤痕，患者术后可获得高舒适度和身体灵活性。
(6)良好的记忆性、操作手感好：真空层压、线装订避免了补片脱散，便于外科医生在手术过程中根据手术创口随意裁剪补片的形状。此外，中央的力学加强层可赋予补片一定的弹性和柔韧性，便于外科医师在腹腔镜下使用。
附图说明
图1为本发明的结构示意图；其中，(2)为中央力学加强层；(1)、(3)为上下表层。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明讲授的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1
如图1所示，以Abraham法制备猪小肠粘膜下层(SIS)，将单片膜状SIS按照层间错位的方式拼接为较大面积片层，平铺三层，以医用壳聚糖粘合剂粘合为一体，为非交联膜状脱细胞基质。非交联膜状脱细胞基质增加贯穿的孔洞，孔间距为5mm，直径为1mm。大网孔聚丙烯网片的网孔间隙为5×5mm，质量为40g/m2。将非交联膜状脱细胞基质作为上下表层和大网孔聚丙烯网片作为中间力学加强层依“三明治”结构放置，非交联膜状脱细胞基质与大网孔聚丙烯网片的质量比为10:1。聚丙烯网片的边缘距非交联膜状脱细胞基质边缘5mm，确保无聚丙烯纤维暴露于非交联膜状脱细胞基质的孔洞。以医用壳聚糖粘合剂将三者粘合，再以-200mm Hg的压力经过18h将其压为一体。
根据国家标准GB/T528-2009，取3个样品制作成4cm×1cm的哑铃状，用材料力学试验机固定样品两端，以10mm/min速度拉伸，测算材料抗张强度为52±8N/cm。
构建犬腹直肌前鞘和腹直肌缺损伴局部高压(腹直肌后鞘与修复材料间添加水囊)动物模型，缺损面积为10×5cm2，将复合软组织修复材料裁剪至一定大小进行修复，术后逐月水囊内注水提高张力至40mmHg，观察24个月修复区无腹壁膨出；术后24月取出修复区组织，测定力学强度。测算材料的抗张强度为32±8N/cm。
实施例2
如图1所示，以Abraham法制备SIS，将单片膜状SIS按照层间错位的方式拼接为较大面积片层，平铺三层，以医用壳聚糖粘合剂粘合为一体，材料增加贯穿的孔洞，孔间距为5mm，直径为1mm，为非交联膜状脱细胞基质。高强度交联膜状脱细胞基质生物材料是由SIS经0.5％京尼平水溶液处理72h制得，经茚三酮法测得交联度为50％，质量为38g/m2。将非交联膜状脱细胞基质作为上下表层和高强度交联膜状脱细胞基质生物材料作为中间力学加强层依“三明治”结构放置，非交联膜状脱细胞基质与高强度交联膜状脱细胞基质生物材料的质量比为2:1。高强度交联膜状脱细胞基质生物材料的边缘距非交联膜状脱细胞基质边缘5mm，确保无交联材料暴露于脱细胞基质生物材料孔洞。以医用壳聚糖粘合剂将三者粘合。
根据国家标准GB/T528-2009，测算材料抗张强度为50±5N/cm。
构建犬腹直肌前鞘和腹直肌缺损伴局部高压(腹直肌后鞘与修复材料间添加水囊)动物模型，缺损面积为10×5cm2，将复合软组织修复材料裁剪至一定大小进行修复，术后逐月水囊内注水提高张力至40mmHg，观察24个月修复区无腹壁膨出；术后24月取出修复区组织，测定力学强度。测算材料的抗张强度为30±5N/cm。

Claims (10)

  1. 一种修复区稳固的复合软组织修复材料，其特征在于：以合成材料或交联材料作为中央力学加强层，以非交联膜状脱细胞基质作为上下表层；所述上下表层完全包覆中央力学加强层形成三明治结构。
  2. 根据权利要求1所述的一种修复区稳固的复合软组织修复材料，其特征在于：所述中央力学加强层的边缘距上下表层的边缘2-15mm；中央力学加强层的拉断力>16N/cm。
  3. 根据权利要求1所述的一种修复区稳固的复合软组织修复材料，其特征在于：所述中央力学加强层中合成材料或交联材料与表层中非交联膜状脱细胞基质的质量比1:20～1:1。
  4. 根据权利要求3所述的一种修复区稳固的复合软组织修复材料，其特征在于：所述合成材料或交联材料均含有一定量不吸收或慢吸收成分，如高分子材料或金属材料制成的网片或膜片；或者为交联膜状脱细胞基质。
  5. 根据权利要求4所述的一种修复区稳固的复合软组织修复材料，其特征在于：所述不吸收的高分子材料为聚丙烯、聚酯、聚偏氟乙烯、硅胶中的一种或几种；所述不吸收的金属材料为钛合金、镍钛合金的一种或两种；所述慢吸收的高分子材料为聚-4-羟基丁酸、聚乳酸、聚羟基乙酸、聚三亚甲基碳酸酯、乙交酯/丙交酯/聚三亚甲基碳酸酯、丝蛋白中的一种或几种；所述慢吸收的金属材料为可降解镁合金。
  6. 根据权利要求4所述的一种修复区稳固的复合软组织修复材料，其特征在于：所述不吸收的高分子材料制成的网片中高分子材料质量<60g/m2，网孔直径>3mm。
  7. 根据权利要求4所述的一种修复区稳固的复合软组织修复材料，其特征在于：所述交联膜状脱细胞基质来源于人或哺乳动物的空腔脏器粘膜下层、真皮、心包、腹膜、胸膜或羊膜；多层材料层数为1～10层，交联度1-100％。
  8. 根据权利要求1所述的一种修复区稳固的复合软组织修复材料，其特征在于：所述非交联膜状脱细胞基质来源于人或哺乳动物的空腔脏器粘膜下层、真皮、心包、腹膜、胸膜或羊膜。
  9. 根据权利要求1所述的一种修复区稳固的复合软组织修复材料，其特征在于：所述中央力学加强层与上下表层以医用粘合剂粘合、缝合捆扎、真空层压中的一种或几种方式固定。
  10. 根据权利要求1所述的一种修复区稳固的复合软组织修复材料，其特征在于：所述复合软组织修复材料还包括贯穿材料的孔洞，直径1～5mm，孔间距1～5mm；无合成材料或交联材料暴露于孔洞中。
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