WO2022170820A1 - 一种用于同步修复软硬组织缺损的仿生复合支架的3d打印成型方法 - Google Patents

一种用于同步修复软硬组织缺损的仿生复合支架的3d打印成型方法 Download PDF

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WO2022170820A1
WO2022170820A1 PCT/CN2021/133032 CN2021133032W WO2022170820A1 WO 2022170820 A1 WO2022170820 A1 WO 2022170820A1 CN 2021133032 W CN2021133032 W CN 2021133032W WO 2022170820 A1 WO2022170820 A1 WO 2022170820A1
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mold
scaffold
chitosan
ceramic skeleton
resin
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PCT/CN2021/133032
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English (en)
French (fr)
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张斌
殷晓红
洪忆榕
余晓雯
李琦
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浙江大学
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    • 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
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • 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
    • A61L27/02—Inorganic materials
    • A61L27/10—Ceramics or glasses
    • 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
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular 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
    • A61L27/36—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
    • A61L27/38—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 containing added animal cells
    • A61L27/3804—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 containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
    • 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
    • A61L27/38—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 containing added animal cells
    • A61L27/3804—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 containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
    • A61L27/3834—Cells able to produce different cell types, e.g. hematopoietic stem cells, mesenchymal stem cells, marrow stromal cells, embryonic stem cells
    • 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
    • A61L27/52—Hydrogels or hydrocolloids
    • 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
    • A61L27/56—Porous materials, e.g. foams or sponges
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C33/00—Moulds or cores; Details thereof or accessories therefor
    • B29C33/38—Moulds or cores; Details thereof or accessories therefor characterised by the material or the manufacturing process
    • B29C33/3842—Manufacturing moulds, e.g. shaping the mould surface by machining
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C33/00—Moulds or cores; Details thereof or accessories therefor
    • B29C33/38—Moulds or cores; Details thereof or accessories therefor characterised by the material or the manufacturing process
    • B29C33/40—Plastics, e.g. foam or rubber
    • 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 technical field of composite stents, in particular to a 3D printing and molding method for a bionic composite stent for synchronously repairing soft and hard tissue defects.
  • Cleft lip and palate is a common congenital malformation, about 1.7 per 1000 births with cleft lip and palate. Cleft lip and palate not only affects the patient's image, but also has negative effects on language learning, dental health, facial development, and mental health. There are many causes of cleft lip and palate, such as genetic defects, chromosomal mutations and environmental influences, which cannot be completely ruled out by prenatal examinations. Generally, cleft lip and palate are divided into four categories: simple cleft lip, simple cleft palate, unilateral cleft lip combined with cleft palate, and bilateral cleft lip combined with cleft palate. , making it difficult to repair.
  • Furlow double-reverse Z-shaped palatoplasty loosens the nasal and oral mucosa and moves it backward, which can lengthen the soft palate, which is more beneficial to the growth and development of the maxilla and language learning.
  • the above-mentioned palatoplasty repairs the cleft palate to a certain extent, it cannot repair the bone defect of the palate, and the surgical wound is large, the amount of bleeding is large, the postoperative complications are many, and the possibility of infection is high.
  • the production of bony surface scars has an impact on pronunciation.
  • the composite scaffold containing osteoblasts and fibroblasts which is consistent with the defect of patients with cleft lip and palate, will provide support for the bone defect and guide bone growth.
  • the soft tissue scaffold can cover the wound surface and promote soft tissue repair. Therefore, it is of great significance to prepare biomimetic composite scaffolds for simultaneous repair of soft and hard tissue defects.
  • the present invention provides a 3D printing molding method for a bionic composite stent for synchronously repairing soft and hard tissue defects.
  • the present invention relates to two kinds of scaffolds and a variety of intermediate molds, namely a first scaffold carrying fibroblasts, a second scaffold carrying bone marrow mesenchymal stem cells, and resin molds, chitosan molds and PDMS ( Dimethicone) mold.
  • the resin mold and the chitosan mold are printed by DLP (Digital Light Processing), and the PDMS mold is made of the resin mold and the chitosan mold as the molds for pouring and heat curing.
  • the composite scaffold is firstly made of TCP (tricalcium phosphate) photosensitive resin mixed slurry, then DLP light-cured, degreased and sintered to form a ceramic skeleton, and then layered on the TCP scaffold by means of PDMS molds, loaded with fibroblasts and bone marrow mesenchymal stem cells, respectively.
  • GelMA methacrylated hydrogel
  • the present invention provides a bionic composite scaffold for synchronously repairing soft and hard tissue defects, which is composed of a first scaffold carrying fibroblasts and a second scaffold carrying bone marrow mesenchymal stem cells. mesenchymal stem cells fill the inner pores of the second scaffold;
  • the second bracket is provided with a protruding edge for positioning, the first bracket is located on the upper and lower surfaces of the second bracket, and the first bracket and the second bracket are connected through a dovetail slot.
  • the first scaffold is a hydrogel scaffold loaded with fibroblasts
  • the second scaffold is a ceramic skeleton, and the ceramic skeleton is filled with water loaded with bone marrow mesenchymal stem cells gel.
  • the pore size of the upper and lower surfaces of the ceramic skeleton is 50-120 microns, and the inner pore size of the ceramic skeleton is 300-600 microns.
  • the dovetail groove is arranged on the upper and lower surfaces of the ceramic skeleton, the width of the lower bottom of the dovetail groove is 200-400 microns, and the width of the upper bottom is 50-150 microns.
  • the above-mentioned 3D printing and molding method for a bionic composite scaffold for synchronously repairing soft and hard tissue defects includes the following steps:
  • Step 1 According to the existing hard tissue model, a ceramic skeleton is prepared, and the upper surface or the lower surface of the ceramic skeleton is left with a protruding edge for positioning;
  • Step 2 According to the existing soft and hard tissue model as the prototype, the resin mold, the first chitosan mold and the second chitosan mold are obtained by DLP printing, and the resin mold is consistent with the outer contour of the soft and hard tissue model, And the position corresponding to the ceramic skeleton is preset with a protruding edge of the same shape and size;
  • the first chitosan mold and the second chitosan mold are both formed by connecting a vertical part and a horizontal part, and have an L-shaped structure;
  • Step 3 Bond the chitosan mold on both sides of the resin mold, and the side corresponding to the protruding edge of the ceramic skeleton in the resin mold faces upward; the horizontal part of the first chitosan mold and the side of the resin mold The middle and lower positions of the wall are in contact, and the vertical part of the first chitosan mold is parallel to the thickness direction of the resin mold; the horizontal part of the second chitosan mold is in contact with the bottom of the side wall of the resin mold, and is flush with the lower surface of the resin mold , the vertical part of the second chitosan mold is parallel to the thickness direction of the resin mold;
  • Step 4 Mix PDMS and curing agent in proportion to form PDMS prepolymer, which is poured into a petri dish for vacuum defoaming; after defoaming, place the bonded resin mold and chitosan mold in a petri dish , due to buoyancy, there is a gap between the bottom of the resin mold and the bottom of the petri dish; it was cured at 55 °C overnight, then the mold was taken out from the petri dish, and the chitosan mold was removed by dissolving the acid solution to form the first A pour channel and a second pour channel, after which the resin mold is taken out, leaving the PDMS mold with the pour pipe;
  • Step 5 Place the ceramic skeleton prepared in step 1 in the PDMS mold, pour the hydrogel loaded with bone marrow mesenchymal stem cells through the first pouring channel, and pour the hydrogel loaded with fibroblasts through the second pouring channel , and the hydrogel loaded with fibroblasts is poured on the upper surface of the ceramic skeleton, so that the upper surface of the ceramic skeleton is flush with the PDMS mold; the blue light is used for cross-linking and curing;
  • Step 6 Cut the PDMS mold and take out the prepared composite scaffold.
  • a dovetail groove micro-lock structure is arranged at the connection between the first bracket and the second bracket, which improves the bonding strength between the first bracket and the second bracket, and the brackets will not be disengaged or misaligned with each other.
  • the second bracket of the present invention is designed with a protruding edge for positioning, which ensures the forming accuracy, and also plays a positioning role in the subsequent application of the bracket, and is suitable for various applications.
  • the present invention adopts the method of combining 3D printing and model casting to combine two materials with different properties and requiring different post-processing into a composite bracket, which not only ensures the strength but also has biocompatibility and can be used for Simultaneous repair of soft and hard tissue defects;
  • FIG. 1 is a schematic structural diagram of a bionic composite scaffold model in this embodiment
  • FIG. 2 is a schematic structural diagram of the biomimetic composite scaffold prepared in this example
  • FIG. 3 is a schematic diagram of the internal structure of the biomimetic composite stent in this embodiment
  • FIG. 5 is a schematic structural diagram of a chitosan mold in this embodiment
  • FIG. 6 is a schematic structural diagram of the PDMS mold in this embodiment.
  • the present invention involves two kinds of scaffolds and various intermediate molds, namely a first scaffold 1 carrying fibroblasts, a second scaffold 2 carrying bone marrow mesenchymal stem cells, and resin molds, chitosan molds and PDMS (polydimethylsiloxane) mold.
  • the resin mold and the chitosan mold are printed by DLP (Digital Light Processing), and the PDMS mold is made of the resin mold and the chitosan mold as the molds for pouring and heat curing.
  • a biomimetic composite scaffold for simultaneous repair of soft and hard tissue defects proposed by the present invention consists of a first scaffold carrying fibroblasts and a second scaffold carrying bone marrow mesenchymal stem cells. mesenchymal stem cells fill the inner pores of the second scaffold;
  • the second bracket is provided with a protruding edge 2-1 for positioning, the first bracket is located on the upper and lower surfaces of the second bracket, and the first bracket and the second bracket pass through the dovetail groove 2 -2 connections.
  • the first scaffold is a hydrogel scaffold loaded with fibroblasts, and the fibroblasts are used to promote tissue repair and play a biomimetic role;
  • the second scaffold The scaffold adopts a ceramic skeleton 3, and the interior of the ceramic skeleton is filled with a hydrogel 4 loaded with bone marrow mesenchymal stem cells.
  • the pore size of the upper and lower surfaces of the ceramic skeleton is 50-120 microns, and the inner pore size of the ceramic skeleton is 300-600 microns.
  • the dovetail groove is arranged on the upper and lower surfaces of the ceramic skeleton, the width of the lower bottom of the dovetail groove is 200-400 microns, and the width of the upper bottom is 50-150 microns.
  • the pore size of the upper and lower surfaces of the ceramic skeleton is 100 microns, and the inner pore size of the ceramic skeleton is 500 microns.
  • the dovetail groove is arranged on the upper and lower surfaces of the ceramic skeleton, the width of the lower bottom of the dovetail groove is 300 microns, and the width of the upper bottom is 100 microns.
  • the present invention also proposes a 3D printing-based molding method for preparing the above-mentioned composite scaffold.
  • a mixed slurry of TCP (tricalcium phosphate) photosensitive resin is used to form a ceramic skeleton through DLP photo-curing, degreasing and sintering to form a ceramic skeleton, and then a PDMS mold is used to form a ceramic skeleton.
  • GelMA (methacrylated hydrogel) hydrogels loaded with fibroblasts and bone marrow mesenchymal stem cells were cast in layers on the TCP scaffold and formed by photocuring.
  • the biomimetic composite scaffold proposed by the invention has biocompatibility and can be used to repair soft and hard tissue defects simultaneously.
  • the PDMS mold used in the present invention is based on a resin mold and a chitosan mold, and is obtained by pouring and thermosetting.
  • Step 1 According to the existing hard tissue model, a ceramic skeleton is prepared, and the upper surface or the lower surface of the ceramic skeleton is left with a protruding edge for positioning;
  • Step 2 According to the existing soft and hard tissue model as the prototype, the resin mold, the first chitosan mold and the second chitosan mold are obtained by DLP printing; the hard tissue model and the soft and hard tissue model are based on actual needs. , obtained by conventional technical means.
  • the outer contour of the resin mold is consistent with the soft and hard tissue model, and the positions corresponding to the ceramic skeleton are preset with protruding edges of the same shape and size; in this embodiment, the resin mold is used as the core of the present invention to assist in the manufacture of molds , its surface is smooth and solid structure, as shown in Figure 4.
  • the first chitosan mold and the second chitosan mold are formed by connecting a vertical part and a horizontal part, and have an L-shaped structure, as shown in FIG. 5 .
  • Step 3 Bond the chitosan mold on both sides of the resin mold, and the side corresponding to the protruding edge of the ceramic skeleton in the resin mold faces upward; the horizontal part of the first chitosan mold and the side of the resin mold The middle and lower positions of the wall are in contact, and the vertical part of the first chitosan mold is parallel to the thickness direction of the resin mold; the horizontal part of the second chitosan mold is in contact with the bottom of the side wall of the resin mold, and is flush with the lower surface of the resin mold , the vertical part of the second chitosan mold is parallel to the thickness direction of the resin mold;
  • Step 4 Mix PDMS and curing agent in proportion to form a PDMS prepolymer, which is poured into a petri dish for vacuum defoaming; in this embodiment, it is preferable to mix PDMS and curing agent in a mass ratio of 10:1.
  • the bonded resin mold and chitosan mold are placed in a petri dish, and resin can be used as a binder.
  • resin can be used as a binder.
  • a petri dish with a height of 150 mm is used; There is a gap between the bottom and the bottom of the petri dish.
  • the gap formed in this example is about 1mm, that is to say, there will still be a layer of PDMS with a thickness of about 1mm between the resin mold and the bottom of the petri dish; placed at 55°C After curing overnight, the mold was taken out from the petri dish, and the chitosan mold was removed by dissolving the acid solution to form a first pouring channel 6-1 and a second pouring channel 6-2, after which the resin mold was taken out, leaving a pouring pipe
  • the PDMS mold 5 as shown in Figure 6;
  • Step 5 As shown in Figure 7, place the ceramic skeleton prepared in Step 1 in the PDMS mold, pour the hydrogel loaded with bone marrow mesenchymal stem cells through the first pouring channel, and pour the hydrogel loaded with the bone marrow mesenchymal stem cells through the second pouring channel.
  • the hydrogel of fiber cells, and the hydrogel loaded with fibroblasts is poured on the upper surface of the ceramic skeleton, so that the upper surface of the ceramic skeleton is flush with the PDMS mold; the blue light is used for cross-linking and curing; in this example, the 0.5% w/v LAP (lithium phenyl-2,4,6-trimethylbenzoylphosphonate) was pre-added as a photo-crosslinking agent in the hydrogel of 2,4,6-trimethylbenzoylphosphonate, and the blue light cross-linking curing time was 30s.
  • LAP lithium phenyl-2,4,6-trimethylbenzoylphosphonate
  • Step 6 Cut the PDMS mold and take out the prepared composite scaffold.
  • the hydrogel mentioned above is preferably GelMA hydrogel.
  • the preparation method of the ceramic skeleton is:
  • TCP resin mixed slurry in this embodiment, the mass ratio of TCP powder, resin and dispersant is 66:29:5, the resin model is SP700, and the dispersant is The model number is BYK111.
  • the TCP resin mixed slurry is photo-cured by DLP. Since the curing time varies with the thickness of the model slice when using DLP photo-curing, in this embodiment, the stent uses a 20-micron layer. Thick slices, preferably the exposure power is 30mw/cm 2 , and the curing time is 1.2s;
  • the actual printed line diameter produced by DLP printing is slightly larger than the design diameter, which easily leads to the actual porosity of the scaffold being lower than the designed porosity.
  • 56% of the designed porosity rate, and finally a 50% porosity scaffold can be obtained.
  • the present invention adopts the method of model compensation to increase the porosity in advance, which solves the problem of low porosity in DLP printing.
  • the porosity of DLP printing is set to be 5%-15% higher than the actual porosity.
  • the printed porosity is 10% higher than the actual porosity.
  • the threshold is set to 2%.
  • Degreasing and sintering first heat up to 400-500°C at a rate of 0.5-1.2°C/min at room temperature, keep at 400-500°C for 20-40min, and then from 400-500°C at a rate of 1.5-2.5°C/min The temperature is increased to 1100-1300°C at a rate of 1100-1300°C, and the temperature is kept at 1100-1300°C for 100-150min, and the ceramic skeleton is taken out for air cooling.
  • the length of the vertical part of the first chitosan mold is 50%-95% of the thickness of the resin mold, and the length of the vertical part of the second chitosan mold is the same as the thickness of the resin mold Consistent.
  • the biomimetic composite stent prepared above can be used in combination with auxiliary connecting equipment for clinical repair of cleft lip and palate in patients with cleft lip and palate.
  • auxiliary connecting equipment for clinical repair of cleft lip and palate in patients with cleft lip and palate.
  • the operations and treatment methods involved in the clinical repair process are not covered by the present invention.
  • the biomimetic composite scaffold applied to the clinical repair of cleft palate needs to be customized in combination with the actual defect tissue model of the patient, and the actual defect tissue model can be obtained by conventional technical means in the field, such as CT scanning of the cleft palate.
  • the prepared bionic composite scaffold is consistent with the soft and hard tissue defects of patients with cleft lip and palate, which can reduce the surgical wound area and blood loss, and reduce the possibility of facial developmental deformities after surgery.
  • the composite stent is sutured to the defect and fixed by other auxiliary connecting devices to reduce the possibility of loosening.
  • the ceramic skeleton in the composite scaffold can provide suitable support and osteoconductive regeneration.
  • the hydrogel bionic soft tissue scaffold covers the wound surface, which can effectively promote wound healing, reduce external infection, and play a protective role.

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Abstract

本发明公开了一种用于同步修复软硬组织缺损的仿生复合支架的3D打印成型方法，属于复合支架技术领域。本发明的仿生复合支架由载有成纤维细胞的第一支架、以及载有骨髓间充质干细胞的第二支架构成，所述的骨髓间充质干细胞填充在第二支架的内部孔隙中；所述的第二支架上设有起定位作用的凸出边缘，第一支架位于第二支架的上下表面，第一支架与第二支架通过燕尾槽连接。复合支架首先采用TCP光敏树脂混合浆料经DLP光固化成型、脱脂烧结形成陶瓷骨架，然后借助PDMS模具在TCP支架上分层浇筑分别载有成纤维细胞与骨髓间充质干细胞的GelMA水凝胶并光固化形成。本发明提出的仿生复合支架具有生物相容性，可用于同步修复软硬组织缺损。

Description

一种用于同步修复软硬组织缺损的仿生复合支架的3D打印成型方法 技术领域
本发明属于复合支架技术领域，具体为一种用于同步修复软硬组织缺损的仿生复合支架的3D打印成型方法。
背景技术
唇腭裂是常见的先天性畸形，每1000个新生儿中约有1.7个唇腭裂患者。唇腭裂不仅影响患者的形象，而且对语言学习、牙齿健康、面容发育以及心理健康等多个方面具有负面影响。导致唇腭裂的原因有很多，例如基因缺陷、染色体变异以及环境影响等，目前尚不能完全通过产检排除。一般地，唇腭裂分为单纯唇裂、单纯腭裂、单侧唇裂合并腭裂以及双侧唇裂合并腭裂四类，其中单纯腭裂、单侧唇裂合并腭裂以及双侧唇裂合并腭裂同时具有软组织与骨组织的缺损，给修复带来困难。
目前，唇腭裂修复方式称为腭成形术。第一位能够完全修复腭裂的学者是Von Langenbeck，其术式被称为Von Langenbeck腭成形术，该术式通过松动双侧黏骨膜瓣来闭合硬腭。这项技术适合于修复单纯腭裂，现在经常与其他术式一起使用。Veau-Wardill-Kilner腭成形术由于可以增加腭的长度而被广泛使用，该术式向后翻转黏骨膜瓣，可以改善腭咽功能。Furlow双反Z形腭成形术松动鼻、口粘膜并向后移动，可以延长软腭，对上颌生长发育和语言学习更有利。以上腭成形术虽然在一定程度上修复了腭裂，却不能修复腭部的骨缺损，且手术创面大、出血量大，术后并发症多，感染可能性高。此外，骨面瘢痕的产生对发音造成影响。
采用与唇腭裂患者缺损相一致的载有成骨细胞与成纤维细胞的复合支架将为骨缺损处提供支撑，并引导骨生长，软组织支架部分可以覆盖创面，促进软组织修复。因此，制备用于同步修复软硬组织缺损的仿生复合支架具有重要意义。
发明内容
本发明为了解决现有的同步修复软硬组织缺损技术的不足，提供一种用于同步修复软硬组织缺损的仿生复合支架的3D打印成型方法。本发明涉及到了两种支架和多种中间模具，即载有成纤维细胞的第一支架、载有骨髓间充质干细胞的第二支架以及成型时使用的树脂模具、壳聚糖模具与PDMS(聚二甲基硅氧烷)模具。树脂模具、壳聚糖模具采用DLP(数字光处理)打印而成，PDMS模具由树脂模具、壳聚糖模具作为模具浇筑热固化而成。
复合支架首先采用TCP(磷酸三钙)光敏树脂混合浆料经DLP光固化成型、脱脂烧结形成陶瓷骨架，然后借助PDMS模具在TCP支架上分层浇筑分别载有成纤维细胞与骨髓间充质干细胞的GelMA(甲基丙烯酸化水凝胶)水凝胶并光固化形成。本发明提出的仿生复合支架具有生物相容性，可用于同步修复软硬组织缺损。
为了实现上述目的，本发明采用如下技术方案：
本发明的提供了一种用于同步修复软硬组织缺损的仿生复合支架，由载有成纤维细胞的第一支架、以及载有骨髓间充质干细胞的第二支架构成，所述的骨髓间充质干细胞填充在第二支架的内部孔隙中；
所述的第二支架上设有起定位作用的凸出边缘，第一支架位于第二支架的上下表面，第一支架与第二支架通过燕尾槽连接。
作为本发明的优选，所述的第一支架采用载有成纤维细胞的水凝胶支架；所述的第二支架采用陶瓷骨架，所述的陶瓷骨架内部填充载有骨髓间充质干细胞的水凝胶。
作为本发明的优选，所述的陶瓷骨架上下表面孔隙尺寸为50-120微米，陶瓷骨架的内部孔隙尺寸为300-600微米。
作为本发明的优选，所述的燕尾槽设置在陶瓷骨架的上下表面，燕尾槽的下底宽度为200-400微米，上底宽度为50-150微米。
上述的用于同步修复软硬组织缺损的仿生复合支架的3D打印成型方法，包括如下步骤：
步骤1：根据已有的硬组织模型，制备陶瓷骨架，所述陶瓷骨架的上表面或者下表面留有起定位作用的凸出边缘；
步骤2：根据已有的软硬组织模型为原型，通过DLP打印得到树脂模具、第一壳聚糖模具和第二壳聚糖模具，所述的树脂模具与软硬组织模型的外轮廓一致，且与陶瓷骨架相对应的位置预设有形状、大小一致的凸出边缘；
所述的第一壳聚糖模具和第二壳聚糖模具均由垂直部和水平部连接构成，呈L型结构；
步骤3：将壳聚糖模具粘结在树脂模具的两侧，所述的树脂模具中对应于陶瓷骨架凸出边缘的一面朝上；第一壳聚糖模具的水平部与树脂模具的侧壁中下位置抵接，第一壳聚糖模具的垂直部平行于树脂模具的厚度方向；第二壳聚糖模具的水平部与树脂模具的侧壁底部抵接，与树脂模具下表面平齐，第二壳聚糖模具的垂直部平行于树脂模具的厚度方向；
步骤4：将PDMS与固化剂按比例混合，形成PDMS预聚物，浇筑在培养皿中进行真空脱泡；脱泡后，将粘结在一起的树脂模具与壳聚糖模具置于培养皿中，由于浮力作用，树脂模具的底部与培养皿的底部之间留有间隙；置于55℃条件下固化过夜，然后将模具从培养皿中取出，通过酸溶液溶解去除壳聚糖模具，形成第一浇筑通道和第二浇筑通道，之后将树脂模具取出，留下具有浇筑管道的PDMS模具；
步骤5：将步骤1制备得到的陶瓷骨架置于PDMS模具中，通过第一浇筑通道浇筑载有骨髓间充质干细胞的水凝胶，通过第二浇筑通道浇筑载有成纤维细胞的水凝胶，并且在陶瓷骨架上表面浇筑载有成纤维细胞的水凝胶，使陶瓷骨架上表面与PDMS模具平齐；采用蓝光交联固化成型；
步骤6：切开PDMS模具，取出制备好的复合支架。
与现有技术相比，本发明的优势在于：
(1)本发明在第一支架和第二支架的连接处设置了燕尾槽微锁结结构，提高了第一支架与第二支架之间的结合强度，支架之间不会相互脱开或错动。
(2)本发明的第二支架设计有起定位作用的凸出边缘，保证了成型精度，并且在后续的支架应用中也起到了定位作用，适用于多种应用场合。
(3)本发明采用3D打印与模型浇筑相结合的方法，将具有不同性质、需要不同后处理的两种材料结合成复合支架，在保证强度的同时还兼具有生物相容性，可用于同步修复软硬组织缺损；
(4)传统的DLP打印技术由于光散射作用，实际打印线条的直径略大，容易导致支架实际孔隙率低于设计孔隙率的问题，本发明采用模型补偿的方式，预先提高孔隙率，解决了DLP打印中孔隙率偏低的问题。
附图说明
图1为本实施例中的仿生复合支架模型结构示意图；
图2为本实施例中制备得到的仿生复合支架结构示意图；
图3为本实施例中的仿生复合支架内部结构示意图
图4为本实施例中的树脂模具结构示意图；
图5为本实施例中的壳聚糖模具结构示意图；
图6为本实施例中的PDMS模具结构示意图；
图7为本实施例中的成型过程示意图；
图中：1第一支架，2第二支架，2-1凸出边缘，2-2燕尾槽，3陶瓷骨架，4水凝胶，5PDMS模具，6-1第一浇筑通道，6-2第二浇筑通道。
具体实施方式
这里将详细地对示例性实施例进行说明，其示例表示在附图中。下面的描述及附图时，除非另有表示，不同附图中的相同数字表示相同或相似的要素。以下示例性实施例中所描述的实施方式并不代表与本申请相一致的所有的实施方式。相反，它们仅是与如所附中权利要求书中所详述的，本申请的一些方面相一致的装置的例子。
需要说明，本申请实施例中所有方向性指示(诸如上、下、左、右、前、后……)仅用于解释在某一特定姿态(如附图所示)下各部件之间的相对位置关系、运动情况等，如果该特定姿态发生改变时，则该方向性指示也相应地随之改变。
另外，在本申请中涉及“第一”、“第二”等的描述仅用于描述目的，而不能理解为指示或暗示其相对重要性或者隐含指明所指示的技术特征的数量。由此，限定有“第一”、“第二”的特征可以明示或者隐含地包括至少一个该特征。另外， 各个实施例之间的技术方案可以相互结合，但是必须是以本领域普通技术人员能够实现为基础，当技术方案的结合出现相互矛盾或无法实现时应当认为这种技术方案的结合不存在，也不在本申请要求的保护范围之内。
本发明涉及到了两种支架和多种中间模具，即载有成纤维细胞的第一支架1、载有骨髓间充质干细胞的第二支架2以及成型时使用的树脂模具、壳聚糖模具与PDMS(聚二甲基硅氧烷)模具。树脂模具、壳聚糖模具采用DLP(数字光处理)打印而成，PDMS模具由树脂模具、壳聚糖模具作为模具浇筑热固化而成。
具体的，本发明提出的一种用于同步修复软硬组织缺损的仿生复合支架由载有成纤维细胞的第一支架、以及载有骨髓间充质干细胞的第二支架构成，所述的骨髓间充质干细胞填充在第二支架的内部孔隙中；
如图1-3所示，所述的第二支架上设有起定位作用的凸出边缘2-1，第一支架位于第二支架的上下表面，第一支架与第二支架通过燕尾槽2-2连接。
在本发明的一项具体实施中，所述的第一支架采用载有成纤维细胞的水凝胶支架，所述的成纤维细胞用于促进组织修复，起到仿生作用；所述的第二支架采用陶瓷骨架3，所述的陶瓷骨架内部填充载有骨髓间充质干细胞的水凝胶4。所述的陶瓷骨架上下表面孔隙尺寸为50-120微米，陶瓷骨架的内部孔隙尺寸为300-600微米。所述的燕尾槽设置在陶瓷骨架的上下表面，燕尾槽的下底宽度为200-400微米，上底宽度为50-150微米。
在本实施例中，所述的陶瓷骨架上下表面孔隙尺寸为100微米，陶瓷骨架的内部孔隙尺寸为500微米。所述的燕尾槽设置在陶瓷骨架的上下表面，燕尾槽的下底宽度为300微米，上底宽度为100微米。
本发明还提出了一种用于制备上述复合支架的基于3D打印的成型方法，首先采用TCP(磷酸三钙)光敏树脂混合浆料经DLP光固化成型、脱脂烧结形成陶瓷骨架，然后借助PDMS模具在TCP支架上分层浇筑分别载有成纤维细胞与骨髓间充质干细胞的GelMA(甲基丙烯酸化水凝胶)水凝胶并光固化形成。本发明提出的仿生复合支架具有生物相容性，可用于同步修复软硬组织缺损。
本发明采用的PDMS模具是以树脂模具、壳聚糖模具为基础，浇筑热固化成型得到的。
下面对具体的成型过程进行介绍，主要步骤如下：
步骤1：根据已有的硬组织模型，制备陶瓷骨架，所述陶瓷骨架的上表面或者下表面留有起定位作用的凸出边缘；
步骤2：根据已有的软硬组织模型为原型，通过DLP打印得到树脂模具、第一壳聚糖模具和第二壳聚糖模具；所述的硬组织模型、软硬组织模型是根据实际需求，由常规技术手段获得的。
所述的树脂模具与软硬组织模型的外轮廓一致，且与陶瓷骨架相对应的位置预设有形状、大小一致的凸出边缘；本实施例中，树脂模具作为本发明的核心辅助制造模具，其表面光滑，为实心结构，如图4所示。
所述的第一壳聚糖模具和第二壳聚糖模具均由垂直部和水平部连接构成，呈L型结构，如图5所示。
步骤3：将壳聚糖模具粘结在树脂模具的两侧，所述的树脂模具中对应于陶瓷骨架凸出边缘的一面朝上；第一壳聚糖模具的水平部与树脂模具的侧壁中下位置抵接，第一壳聚糖模具的垂直部平行于树脂模具的厚度方向；第二壳聚糖模具的水平部与树脂模具的侧壁底部抵接，与树脂模具下表面平齐，第二壳聚糖模具的垂直部平行于树脂模具的厚度方向；
步骤4：将PDMS与固化剂按比例混合，形成PDMS预聚物，浇筑在培养皿中进行真空脱泡；在本实施例中，优选为PDMS与固化剂按照10:1的质量比混合。
脱泡后，将粘结在一起的树脂模具与壳聚糖模具置于培养皿中，可采用树脂作为粘结剂，本实施例中，采用高度为150mm培养皿；由于浮力作用，树脂模具的底部与培养皿的底部之间留有间隙，本实施例中形成的间隙约1mm，也就是说，会在树脂模具与培养皿底部仍存在一层约1mm厚的PDMS；置于55℃条件下固化过夜，然后将模具从培养皿中取出，通过酸溶液溶解去除壳聚糖模具，形成第一浇筑通道6-1和第二浇筑通道6-2，之后将树脂模具取出，留下具有浇筑管道的PDMS模具5，如图6所示；
步骤5：如图7所示，将步骤1制备得到的陶瓷骨架置于PDMS模具中，通过第一浇筑通道浇筑载有骨髓间充质干细胞的水凝胶，通过第二浇筑通道浇筑载 有成纤维细胞的水凝胶，并且在陶瓷骨架上表面浇筑载有成纤维细胞的水凝胶，使陶瓷骨架上表面与PDMS模具平齐；采用蓝光交联固化成型；在本实施例中，所述的水凝胶中预添加0.5％w/v LAP(苯基-2,4,6-三甲基苯甲酰基膦酸锂)作为光交联剂，蓝光交联固化的时间为30s。
步骤6：切开PDMS模具，取出制备好的复合支架。
上述中的水凝胶优选GelMA水凝胶。
在本实施例中，陶瓷骨架制备方法为：
1.1)将TCP粉末、树脂、分散剂按比例混合，得到TCP树脂混合浆料；本实施例中，TCP粉末、树脂、分散剂的质量比为66:29:5，树脂型号为SP700，分散剂型号为BYK111。
1.2)根据已有的硬组织模型，利用DLP将TCP树脂混合浆料光固化成型，由于使用DLP光固化成型时，固化时间因模型切片层厚而异，本实施例中，支架使用20微米层厚切片，优选为曝光功率为30mw/cm 2，固化时间为1.2s；
在光固化成型过程中，由于光散射作用，DLP打印产生实际打印线条直径略大于设计直径，易导致支架实际孔隙率低于设计孔隙率，在本发明的预实验中，采用56％的设计孔隙率，最终可获得50％孔隙率支架。本发明采用模型补偿的方式，预先提高孔隙率，解决了DLP打印中孔隙率偏低的问题，设置DLP打印的孔隙率高于实际孔隙率的5％-15％；本实施例中，设置DLP打印的孔隙率高于实际孔隙率的10％。
在一项具体实施中，若打印得到的孔隙率与实际孔隙率之间的误差低于阈值，则进入下一步骤；否则，降低设置的DLP打印的孔隙率，重复进行光固化成型过程。本实施例中，阈值设置2％。
1.3)脱脂烧结：首先在室温下以0.5-1.2℃/min的速率升温至400-500℃，在400-500℃下保温20-40min，随后从400-500℃以1.5-2.5℃/min的速率升温至1100-1300℃，在1100-1300℃下保温100-150min，取出陶瓷骨架空冷。本实施例中，优选为首先在室温下以1℃/min的速率升温至480℃，在480℃下保温30min，随后从480℃以2℃/min的速率升温至1240℃，在1240℃下保温2h，取出陶瓷骨架空冷。
为了顺利实现图7的基于3D打印的成型方法，所述第一壳聚糖模具的垂直部长度为50％-95％的树脂模具厚度，第二壳聚糖模具的垂直部长度与树脂模具厚度一致。
在本发明的一项具体应用中，可以将上述制备得到的仿生复合支架结合辅助连接设备应用于唇腭裂患者的腭裂临床修复，在临床修复过程中涉及到的手术及治疗方法不在本发明的保护范围内，为了使本领域技术人员对本发明的研究意义有更清晰的认知，下面对腭裂临床修复过程进行一下简要说明。
应用于腭裂临床修复的仿生复合支架需要结合患者的实际缺损组织模型进行个性化定制，实际缺损组织模型可采用本领域常规的技术手段即可获得，例如对腭裂处进行CT扫描等。制备得到的仿生复合支架与唇腭裂患者的软硬组织缺损形态相符，可以减少手术创口面积与出血量，减少术后面部发育畸形的可能性，此外还需结合临床上的其他常规技术手段将仿生复合支架缝合在缺损部位，通过其他辅助连接设备固定，降低松动可能。复合支架中的陶瓷骨架可以提供合适的支撑作用与骨引导再生作用，水凝胶仿生的软组织支架覆盖创面，可以有效促进创面愈合，减少外部感染，起到保护作用。
上述只是对本发明的其中一个应用场景的介绍，说明其具备临床意义，但实现上述目的还需结合所应用领域的一些常规技术手段和设备。
附图和实施例中展示的复合支架的结构或者基于3D打印的成型方法的过程只是若干优选实施方式中的一种，应当指出，本发明不限于上述结构和基于3D打印的成型方法。对于本领域的普通技术人员来说，依然可以对前述的技术方案进行修改，或者对其中部分技术特征进行等同替换。而这些修改或替换，在不脱离本发明技术方案本质的前提下，均应认为是本发明的保护范围。

Claims (6)

  1. 一种用于同步修复软硬组织缺损的仿生复合支架的3D打印成型方法，所述的仿生复合支架由载有成纤维细胞的第一支架(1)、以及载有骨髓间充质干细胞的第二支架(2)构成，所述的骨髓间充质干细胞填充在第二支架(2)的内部孔隙中；
    所述的第二支架上设有起定位作用的凸出边缘(2-1)，第一支架位于第二支架的上下表面，第一支架与第二支架通过燕尾槽(2-2)连接；
    所述的第一支架采用载有成纤维细胞的水凝胶支架；所述的第二支架采用陶瓷骨架(3)，所述的陶瓷骨架内部填充载有骨髓间充质干细胞的水凝胶(4)；
    其特征在于，所述的成型方法包括如下步骤：
    步骤1：根据已有的硬组织模型，制备陶瓷骨架，所述陶瓷骨架的上表面或者下表面留有起定位作用的凸出边缘；
    步骤2：根据已有的软硬组织模型为原型，通过DLP打印得到树脂模具、第一壳聚糖模具和第二壳聚糖模具，所述的树脂模具与软硬组织模型的外轮廓一致，且与陶瓷骨架相对应的位置预设有形状、大小一致的凸出边缘；
    所述的第一壳聚糖模具和第二壳聚糖模具均由垂直部和水平部连接构成，呈L型结构；
    步骤3：将壳聚糖模具粘结在树脂模具的两侧，所述的树脂模具中对应于陶瓷骨架凸出边缘的一面朝上；第一壳聚糖模具的水平部与树脂模具的侧壁中下位置抵接，第一壳聚糖模具的垂直部平行于树脂模具的厚度方向；第二壳聚糖模具的水平部与树脂模具的侧壁底部抵接，与树脂模具下表面平齐，第二壳聚糖模具的垂直部平行于树脂模具的厚度方向；
    步骤4：将PDMS与固化剂按比例混合，形成PDMS预聚物，浇筑在培养皿中进行真空脱泡；脱泡后，将粘结在一起的树脂模具与壳聚糖模具置于培养皿中，由于浮力作用，树脂模具的底部与培养皿的底部之间留有间隙；置于55℃条件下固化过夜，然后将模具从培养皿中取出，通过酸溶液溶解去除壳聚糖模具，形成第一浇筑通道(6-1)和第二浇筑通道(6-2)，之后将树脂模具取出，留下具有浇筑管道的PDMS模具(5)；
    步骤5：将步骤1制备得到的陶瓷骨架置于PDMS模具中，通过第一浇筑通道浇筑载有骨髓间充质干细胞的水凝胶，通过第二浇筑通道浇筑载有成纤维细胞的水凝胶，并且在陶瓷骨架上表面浇筑载有成纤维细胞的水凝胶，使陶瓷骨架上表面与PDMS模具平齐；采用蓝光交联固化成型；
    步骤6：切开PDMS模具，取出制备好的复合支架。
  2. 根据权利要求1所述的3D打印成型方法，其特征在于，所述的陶瓷骨架制备方法为：
    1.1)将TCP粉末、树脂、分散剂按比例混合，得到TCP树脂混合浆料；
    1.2)根据已有的硬组织模型，利用DLP将TCP树脂混合浆料光固化成型，曝光功率为30mw/cm 2，固化时间为1.2s；在光固化成型过程中，设置DLP打印的孔隙率高于实际孔隙率的5％-15％；
    1.3)脱脂烧结：首先在室温下以0.5-1.2℃/min的速率升温至400-500℃，在400-500℃下保温20-40min，随后从400-500℃以1.5-2.5℃/min的速率升温至1100-1300℃，在1100-1300℃下保温100-150min，取出陶瓷骨架空冷。
  3. 根据权利要求2所述的3D打印成型方法，其特征在于，在所述的步骤1.2)之后还包括检测固化成型后的支架孔隙率的步骤，若打印得到的孔隙率与实际孔隙率之间的误差低于阈值，则进入下一步骤；否则，降低设置的DLP打印的孔隙率，重复进行光固化成型过程。
  4. 根据权利要求1所述的3D打印成型方法，其特征在于，所述第一壳聚糖模具的垂直部长度为50％-95％的树脂模具厚度，第二壳聚糖模具的垂直部长度与树脂模具厚度一致。
  5. 根据权利要求1所述的3D打印成型方法，其特征在于，步骤5中所述的水凝胶中预添加0.5％w/v LAP作为光交联剂。
  6. 根据权利要求5所述的3D打印成型方法，其特征在于，步骤5中所述的蓝光交联固化的时间为30s。
PCT/CN2021/133032 2021-02-09 2021-11-25 一种用于同步修复软硬组织缺损的仿生复合支架的3d打印成型方法 WO2022170820A1 (zh)

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