Metal-reinforced porous composite membrane and its production method and application

Abstract

The present application relates to a metal-reinforced perforated composite membrane, comprising a first membrane layer, a second membrane layer and a metal bracket, wherein the metal bracket is located between the first membrane layer and the second membrane layer, and the first membrane layer and the second membrane layer cover the metal bracket inside; a plurality of through holes are arranged on the metal-reinforced perforated composite membrane, the through holes penetrate the first membrane layer and the second membrane layer, the plurality of through holes are arranged around the periphery of the membrane layer area covered with the metal bracket, and the positions of the through holes do not overlap with the metal bracket; the materials of the first membrane layer and the second membrane layer are independently selected from micro-stretched expanded polytetrafluoroethylene with a stretching amplitude of 20% to 100%, and the micro-stretched expanded polytetrafluoroethylene has a microporous structure; the formed metal-reinforced perforated composite membrane has micropores with an overall average pore size of 0.03μm to 0.50μm outside the through hole area; the material of the metal bracket includes implantable metal.

Description

Technical Field

[0001] The present application relates to the field of medical devices, and in particular to a metal-reinforced porous composite membrane and a manufacturing method and application thereof. Background Art

[0002] Guided Bone Regeneration (GBR) refers to placing a barrier membrane between soft tissue and bone defect to establish a biological barrier, preventing connective tissue cells and epithelial cells that interfere with bone formation and migrate faster from entering the bone defect area, allowing precursor osteoblasts with potential growth ability and slower migration speed to enter the bone defect area first to complete induction and growth. For large-area bone defects or vertical bone defects, especially in extreme vertical bone defects, when the vertical defect size is greater than 7mm, it is crucial to maintain the bone formation space and blood supply during the treatment process using guided bone regeneration. Since it is impossible to obtain the initial stability of the implant during bone grafting surgery, staged implantation is generally performed (i.e. bone grafting first, then implantation).

[0003] In traditional technology, traditional titanium mesh or 3D titanium mesh plus collagen membrane is usually used as a combined barrier membrane for large-area bone defect repair. However, titanium mesh has problems such as sharp edges that need to be trimmed, difficult to remove, and high exposure infection rate. Literature records that the exposure rate of titanium mesh is as high as 12-50%. In order to overcome the technical defects of using titanium mesh as a barrier membrane for guided bone regeneration to repair bone defects, many studies have attempted to improve this. For example, titanium-reinforced polytetrafluoroethylene membrane is used for treatment, but because the traditional titanium-reinforced polytetrafluoroethylene membrane blocks blood supply, it will cause wound dehiscence, making submembrane osteogenesis unsatisfactory. Summary of the invention

[0004] Based on this, it is necessary to provide a metal-reinforced porous composite membrane that does not require trimming of sharp edges, is easy to remove, has a low exposure rate, and can enhance the osteogenesis effect, as well as a preparation method and application thereof.

[0005] An embodiment of the present application provides a metal-reinforced perforated composite membrane, comprising a first membrane layer, a second membrane layer, and a metal bracket, wherein the metal bracket is located between the first membrane layer and the second membrane layer, and is covered by the first membrane layer and the second membrane layer;

[0006] A plurality of through holes are arranged on the metal reinforced perforated composite membrane, the through holes penetrate the first membrane layer and the second membrane layer, and the plurality of through holes are arranged around the periphery of the membrane layer area coated with the metal bracket, and the position of each through hole does not overlap with the metal bracket;

[0007] The materials of the first film layer and the second film layer are independently selected from micro-stretched expanded polytetrafluoroethylene with a stretching range of 20% to 100%, and the micro-stretched expanded polytetrafluoroethylene has a microporous structure; the formed metal-reinforced porous composite membrane has micropores with an overall average pore size of 0.03 μm to 0.50 μm outside the through-hole area;

[0008] The material of the metal stent includes implantable metal.

[0009] In one embodiment, each of the through holes satisfies one or more of the following properties (1) to (2):

[0010] (1) The pore size is 10 μm to 500 μm;

[0011] (2) The hole spacing is 50μm to 1000μm.

[0012] In one embodiment, the metal reinforced perforated composite membrane as a whole satisfies one or more of the following properties (1) to (3):

[0013] (1) The pore size of the micropores outside the through-hole region is in the range of 0.01 μm to 1.5 μm;

[0014] (2) The total thickness of the film layer area not coated with the metal bracket is 0.10 mm to 0.50 mm;

[0015] (3) The total thickness of the film layer area coated with the metal bracket is 0.20 mm to 0.80 mm.

[0016] In one embodiment, the average pore size of the micropores of the micro-stretched expanded polytetrafluoroethylene used to form the second film layer is smaller than the average pore size of the micropores of the micro-stretched expanded polytetrafluoroethylene used to form the first film layer.

[0017] In one embodiment, the micro-stretched expanded polytetrafluoroethylene used to form the first film layer satisfies one or more of the following properties (1) to (3):

[0018] (1) Thickness: 0.10mm~0.40mm;

[0019] (2) The pore size range of the micropores is 0.05 μm to 5.0 μm;

[0020] (3) The average pore size of the micropores is 0.2 μm to 1.0 μm.

[0021] In one embodiment, the micro-stretched expanded polytetrafluoroethylene used to form the second film layer satisfies one or more of the following properties (1) to (3):

[0022] (1) Thickness: 0.05mm~0.3mm;

[0023] (2) The pore size range of the micropores is 0.01 μm to 2.50 μm;

[0024] (3) The average pore size of the micropores is 0.1 μm to 0.5 μm.

[0025] In one embodiment, the implantable metal includes pure titanium, titanium alloy or stainless steel.

[0026] In one embodiment, the thickness of the metal bracket is 0.05 mm to 0.2 mm.

[0027] In one embodiment, the metal bracket is a prefabricated metal bracket;

[0028] Optionally, the metal support includes a metal center bar and a plurality of metal branch bars, the plurality of metal branch bars are distributed on both sides of the metal center bar, and each of the metal branch bars is respectively connected to the metal center bar.

[0029] In one embodiment, a surface of the first film layer facing away from the metal support has groove-shaped stripes.

[0030] In one embodiment, there are multiple stripes.

[0031] In one embodiment, each of the stripes includes a plurality of first stripes arranged along a first direction and a plurality of second stripes arranged along a second direction; the first direction and the second direction are perpendicular to each other;

[0032] Optionally, in each of the stripes, the first stripes and the second stripes are arranged alternately;

[0033] Further optionally, among the stripes, the length of each first stripe is greater than the length of each second stripe, and the width of each first stripe is the same as the width of each second stripe; a plurality of the first stripes are arranged in a straight line, and a plurality of the second stripes are arranged in parallel; and the depth of each first stripe and each second stripe independently decreases from the middle to both ends;

[0034] Optionally, the depth of each of the first stripes and the depth of each of the second stripes are independently 0 mm to 0.15 mm.

[0035] An embodiment of the present application further provides a method for manufacturing the metal-reinforced perforated composite membrane as described in any of the above embodiments, comprising the following steps:

[0036] Providing a mold, the mold comprising a mold bottom plate and a mold cover plate;

[0037] A first film, a metal bracket and a second film are sequentially stacked on the mold bottom plate, wherein the metal bracket does not extend beyond the outer edges of the first film and the second film; the materials of the first film and the second film are independently selected from micro-stretched expanded polytetrafluoroethylene with a stretching range of 20% to 100%, and the micro-stretched expanded polytetrafluoroethylene has a microporous structure;

[0038] Covering the mold cover plate on the second film;

[0039] hot pressing the mold containing the first film, the metal support and the second film;

[0040] After the hot pressing is finished, the mold is removed after cooling to obtain a hot pressed semi-finished product;

[0041] A plurality of through holes are punched on the hot-pressed semi-finished product, the through holes passing through the first film and the second film, and the plurality of through holes are arranged around the periphery of the film layer area coated with the metal support, and the positions of the through holes do not overlap with the metal support; the formed metal-reinforced perforated composite membrane has micropores with an overall average pore size of 0.03 μm to 0.50 μm outside the through hole area.

[0042] In one embodiment, the step further includes forming stripes on a surface of the first film facing away from the metal support;

[0043] Optionally, the step of forming stripes on a surface of the first film facing away from the metal support comprises:

[0044] A stripe template corresponding to the preset stripes is placed between the first film and the mold bottom plate.

[0045] In one embodiment, the step of heat pressing comprises:

[0046] The mold including the first film, the metal support and the second film is pressed, heated and kept warm in sequence;

[0047] Optionally, the clamping method is locking clamping, and the locking torque is 0.5N·m to 10N·m;

[0048] Optionally, the heating rate during heating is 30°C / min to 60°C / min, and the heating temperature is 300°C to 380°C;

[0049] Optionally, the insulation time is 1 h to 5 h.

[0050] In one embodiment, the cooling rate is 2°C / h to 10°C / h.

[0051] In one embodiment, the method of drilling a plurality of through holes on the semi-finished product after hot pressing is laser drilling;

[0052] Optionally, the laser light source for laser drilling is a picosecond ultraviolet laser or a nanosecond ultraviolet laser or a picosecond green laser;

[0053] Optionally, the wavelength of the laser drilling is 355nm to 532nm;

[0054] Optionally, the power of the laser drilling is 4W-30W, the frequency is 100kHz-800kHz, and the pulse width is 1ps-100ps.

[0055] An embodiment of the present application further provides a barrier membrane for use in the field of guided bone regeneration, comprising the metal-reinforced porous composite membrane as described in any of the above embodiments.

[0056] The metal-reinforced porous composite membrane provided in the present application is used in the process of guided bone regeneration. Compared with the traditional titanium mesh, it does not require trimming of sharp edges and is easier to remove. It also has better soft tissue adhesion, can provide sufficient stable three-dimensional space for new bone regeneration, can reduce the exposure rate, and can increase the nutrient transport and material exchange capacity between the soft tissue and the bone formation area, significantly promoting osteogenesis. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 is a schematic structural diagram of a metal-reinforced porous composite membrane in an embodiment;

[0058] Figure 2 is a top view of a metal-reinforced porous composite membrane in one embodiment;

[0059] Figure 3 is a scanning electron microscope image of a surface of the first film layer facing away from the metal support in one embodiment;

[0060] Figure 4 is a scanning electron microscope image of the second film layer in one embodiment;

[0061] Figure 5 is a scanning electron microscope image of a cross-sectional position of a metal-reinforced porous composite membrane in an embodiment;

[0062] Figure 6 Schematic diagram of using the metal-reinforced porous composite membrane to repair a critical defect in a rabbit skull in Example 1;

[0063] Figure 7 A comparison of the volume and area ratio of new bone formation after the critical defect of rabbit skull was repaired using the composite membranes of Examples 1, 5, 6, 7 and Comparative Examples 1 and 2;

[0064] Figure 8A comparison diagram of bone heights at different observation points in a beagle mandibular vertical bone defect repair model using the composite membranes of Example 1 and Comparative Examples 2 and 3;

[0065] Fig. 9 The graph is a comparison of the bone formation rates of the beagle dog mandibular vertical bone defect repair model using the composite membranes of Example 1 and Comparative Examples 2 and 3.

[0066] Description of reference numerals:

[0067] 10: metal reinforced composite membrane with holes; 110: first membrane layer; 120: second membrane layer; 130: metal bracket; 140: through hole. DETAILED DESCRIPTION

[0068] For ease of understanding of the application, the application will be described more fully below in conjunction with embodiments and accompanying drawings. The application can be implemented in many different forms and is not limited to the embodiments described in the application. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the application more thorough and comprehensive.

[0069] Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application. The term "and / or" used in this application includes any and all combinations of one or more related listed items.

[0070] In the present application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0071] See also Figures 1 to 5 , an embodiment of the present application provides a metal-reinforced perforated composite membrane 10, comprising a first membrane layer 110, a second membrane layer 120 and a metal bracket 130, wherein the metal bracket 130 is located between the first membrane layer 110 and the second membrane layer 120, and is covered by the first membrane layer 110 and the second membrane layer 120;

[0072] A plurality of through holes 140 are provided on the metal reinforced perforated composite membrane 10, and the through holes 140 penetrate the first membrane layer 110 and the second membrane layer 120. The plurality of through holes 140 are arranged around the membrane layer area covered with the metal bracket 130, and the position of each through hole 140 does not overlap with the metal bracket 130.

[0073] The materials of the first film layer 110 and the second film layer 120 are independently selected from micro-stretched expanded polytetrafluoroethylene with a stretching range of 20% to 100%, and the micro-stretched expanded polytetrafluoroethylene has a microporous structure; the formed metal reinforced porous composite membrane 10 has micropores with an overall average pore size of 0.03μm to 0.50μm outside the through hole 140 area;

[0074] The material of the metal stent 130 includes implantable metal.

[0075] The metal reinforced perforated composite membrane 10 provided in one embodiment of the present application includes a first membrane layer 110 and a second membrane layer 120 of a micro-stretched expanded polytetrafluoroethylene material. The first membrane layer 110 and the second membrane layer 120 wrap a metal stent 130 made of an implantable metal material, and there is no need to trim the sharp edges of the metal reinforcement. The film made of the micro-stretched expanded polytetrafluoroethylene material has a microporous structure and has good adhesion to soft tissue. It is not easy to be exposed during clinical use and is easy to perform blunt peeling. The film made of the micro-stretched expanded polytetrafluoroethylene material has good biocompatibility with the metal stent 130. The formed metal reinforced perforated composite membrane 10 can construct a space for regeneration required for osteogenesis, can fix bones, and / or be used for other fixation and space maintenance functions. The formed metal-reinforced composite membrane with holes has micropores with an overall average pore size of 0.03 μm to 0.50 μm outside the through-hole area. The small pore size is conducive to reducing the soft tissue from adhering to the membrane, and can avoid the problem of difficult clinical removal. It can also completely block soft tissue cells, eliminate stimulation that may hinder bone formation, and provide a stable space required for bone regeneration. It can be used as a barrier membrane in guided bone regeneration, and is used in oral surgery, craniofacial surgery, and maxillofacial surgery for the treatment of periodontal tissue defects. Furthermore, since the metal-reinforced composite membrane with holes 10 also has through holes 140, it can increase the nutrient transport and material exchange capacity between the soft tissue and the bone formation area, promote bone formation, and does not destroy its barrier function.

[0076] It can be understood that the overall average pore size of the metal reinforced porous composite membrane 10 outside the through hole 140 area can be, for example, but not limited to, 0.03 μm, 0.04 μm, 0.05 μm, 0.06 μm, 0.07 μm, 0.08 μm, 0.09 μm, 0.10 μm, 0.11 μm, 0.12 μm, 0.13 μm, 0.14 μm, 0.15 μm, 0.16 μm, 0.17 μm, 0.18 μm, 0.19 μm, 0.20 μm, 0.21 μm, 0.22 μm, 0.23 μm, 0.24 μm, 0.25 μm, 0.26 μm, 0.27 μm, 0.28 μm, 0.29 μm, 0.30 μm, 0.31 μm, 0.32 μm, 0.33 μm, 0.34 μm, 0.36 μm, 0.37 μm, 0.38 μm, 0.39 μm, 0.40 μm, 0.41 μm, 0.42 μm, 0.43 μm, 0.44 μm, 0.45 μm, 0.46 μm, 0.47 μm, 0.48 μm, 0.49 μm, 0.50 μm, 0.51 μm, 0.52 μm, 0.53 μm, 0.54 μm, 0.55 μm, 0.56 μm, 0.57 μm, 0.58 μm, 0.59 μm, .24μm, 0.25μm, 0.26μm, 0.27μm, 0.28μm, 0.29μm, 0.30μm, 0.31μm, 0.32μm, 0.33μm, 0.34μm, 0.35μm, 0.36μm, 0.37μm m, 0.38μm, 0.39μm, 0.40μm, 0.41μm, 0.42μm, 0.43μm, 0.44μm, 0.45μm, 0.46μm, 0.47μm, 0.48μm, 0.49μm, 0.50μm, etc.

[0077] In one embodiment, the aperture of each through hole 140 is 10 μm to 500 μm. Controlling the aperture of the through hole within a suitable range can ensure that the nutrients of the soft tissue and the bone defect area are connected, while also ensuring that the composite membrane can have a good barrier effect. In one embodiment, the aperture of each through hole 140 is 50 μm to 500 μm.

[0078] In one embodiment, the hole spacing between each through hole 140 is 50 μm to 1000 μm. In one embodiment, the hole spacing between each through hole 140 is 100 μm to 500 μm.

[0079] It can be understood that the hole spacing refers to the shortest distance between the edges of adjacent through holes. If the through holes are circular holes and all through holes have the same diameter, the hole spacing is the distance between the centers of two adjacent holes minus the hole diameter.

[0080] In one embodiment, the overall pore size range of the micropores of the metal reinforced perforated composite membrane 10 outside the through hole 140 is 0.01 μm to 1.00 μm.

[0081] In one embodiment, the total thickness of the film layer area not coated with the metal bracket 130 in the metal reinforced perforated composite membrane 10 is 0.10 mm to 0.50 mm. It can be understood that the total thickness of the film layer area not coated with the metal bracket 130 in the metal reinforced perforated composite membrane 10 can be, for example but not limited to, 0.10 mm, 0.11 mm, 0.12 mm, 0.13 mm, 0.14 mm, 0.15 mm, 0.16 mm, 0.17 mm, 0.18 mm, 0.19 mm, 0.20 mm, 0.21 mm, 0.22 mm, 0.23 mm, 0.24 mm, 0.25 mm, 0.26 mm, 0.27 mm, 0.28 mm, 0.29 mm, 0.30 mm, 0.31 mm, 0.32 mm, 0.33 mm, 0.34 mm, 0.35 mm, 0.36 mm, 0.37 mm, 0.38 mm, 0.39 mm, 0.40 mm, 0.41 mm, 0.42 mm, 0.43 mm, 0.44 mm, 0.45 mm, 0.46 mm, 0.47 mm, 0.48 mm, 0.49 mm, 0.50 mm, 0.51 mm, 0.52 mm, 0.53 mm, 0.54 mm, 0.55 mm, 0.56 mm, 0.57 mm, 0.58 mm, 0.59 mm, 0.60 mm, 0.61 mm, 0.62 mm, 0.63 mm, 0.64 mm, 0.65 mm, 0.66 mm, 0.67 mm, 0.68 mm, 0 27mm, 0.28mm, 0.29mm, 0.30mm, 0.31mm, 0.32mm, 0.33mm, 0.34mm, 0.35mm, 0.36mm, 0.37mm, 0.38mm, 0.39mm, 0.40mm, 0.41mm, 0.42mm, 0.43mm, 0.44mm, 0.45mm, 0.46mm, 0.47mm, 0.48mm, 0.49mm, 0.50mm, etc. In one embodiment, the total thickness of the film layer area not covered with the metal support 130 in the metal reinforced porous composite membrane 10 is 0.10mm-0.30mm. In one embodiment, the total thickness of the film layer area not covered with the metal support 130 in the metal reinforced porous composite membrane 10 is 0.20mm-0.25mm.

[0082] In one embodiment, the total thickness of the film layer region of the metal-reinforced perforated composite film 10 coated with the metal support 130 is 0.20 mm to 0.80 mm. It can be understood that the total thickness of the membrane layer area coated with the metal bracket 130 in the metal reinforced perforated composite membrane 10 can be, for example but not limited to, 0.20mm, 0.22mm, 0.24mm, 0.25mm, 0.28mm, 0.30mm, 0.31mm, 0.35mm, 0.38mm, 0.39mm, 0.40mm, 043mm, 0.45mm, 0.46mm, 0.48mm, 0.50mm, 0.53mm, 0.55mm, 0.58mm, 0.59mm, 0.60mm, 0.62mm, 0.65mm, 0.66mm, 0.67mm, 0.70mm, 0.71mm, 0.73mm, 0.75mm, 0.77mm, 0.78mm, 0.80mm and the like. In one embodiment, the total thickness of the film layer area of ​​the metal reinforced perforated composite membrane 10 coated with the metal support 130 is 0.30 mm to 0.50 mm. In one embodiment, the total thickness of the film layer area of ​​the metal reinforced perforated composite membrane 10 coated with the metal support 130 is 0.40 mm.

[0083] In one embodiment, the stretching amplitude of the micro-stretched expanded polytetrafluoroethylene used to form the second film layer is smaller than the stretching amplitude of the micro-stretched expanded polytetrafluoroethylene used to form the first film layer.

[0084] In one embodiment, the average pore size of the micropores of the micro-stretched expanded polytetrafluoroethylene used to form the second film layer is smaller than the average pore size of the micropores of the micro-stretched expanded polytetrafluoroethylene used to form the first film layer.

[0085] In one embodiment, the thickness of the micro-stretched expanded polytetrafluoroethylene used to form the first film layer is 0.10 mm to 0.40 mm. It can be understood that the thickness of the micro-stretched expanded polytetrafluoroethylene used to form the first film layer can be, for example, but not limited to, 0.1 mm, 0.11 mm, 0.12 mm, 0.13 mm, 0.14 mm, 0.15 mm, 0.16 mm, 0.17 mm, 0.18 mm, 0.19 mm, 0.20 mm, 0.21 mm, 0.22 mm, 0.23 mm, 0.24 mm, 0.25 mm, 0.26 mm, 0.27 mm, 0.28 mm, 0.29 mm, 0.30 mm, 0.31 mm, 0.32 mm, 0.33 mm, 0.34 mm, 0.35 mm, 0.36 mm, 0.37 mm, 0.38 mm, 0.39 mm, 0.40 mm, etc. In one embodiment, the thickness of the slightly stretched expanded polytetrafluoroethylene used to form the first film layer is 0.15 mm to 0.25 mm. In one embodiment, the thickness of the slightly stretched expanded polytetrafluoroethylene used to form the first film layer is 0.20 mm to 0.22 mm.

[0086] In one embodiment, the pore size of the micropores of the micro-stretched expanded polytetrafluoroethylene used to form the first film layer ranges from 0.05 μm to 5.0 μm.

[0087] In one embodiment, the micropores of the micro-stretched expanded polytetrafluoroethylene used to form the first film layer have a pore size range of 0.1 μm to 5.0 μm.

[0088] In one of the embodiments, the average pore size of the micropores of the micro-stretched expanded polytetrafluoroethylene used to form the first film layer is 0.2μm to 1.0μm. The micro-stretched expanded polytetrafluoroethylene used to form the first film layer has a microporous structure, which is conducive to promoting the adhesion of the film to the soft tissue. It can be understood that the average pore size of the micropores of the micro-stretched expanded polytetrafluoroethylene used to form the first film layer can be, for example, but not limited to, 0.2μm, 0.3μm, 0.4μm, 0.5μm, 0.6μm, 0.7μm, 0.8μm, 0.9μm, 1.0μm, etc. In one of the embodiments, the average pore size of the micropores of the micro-stretched expanded polytetrafluoroethylene used to form the first film layer is 0.5μm to 0.8μm.

[0089] In one embodiment, the thickness of the micro-stretched expanded polytetrafluoroethylene used to form the second film layer is 0.05mm to 0.3mm. It can be understood that the thickness of the micro-stretched expanded polytetrafluoroethylene used to form the second film layer can be, for example, but not limited to, 0.05mm, 0.06mm, 0.07mm, 0.08mm, 0.09mm, 0.10mm 0.11mm, 0.12mm, 0.13mm, 0.14mm, 0.15mm, 0.16mm, 0.17mm, 0.18mm, 0.19mm, 0.20mm, 0.21mm, 0.22mm, 0.23mm, 0.24mm, 0.25mm, 0.26mm, 0.27mm, 0.28mm, 0.29mm, 0.30mm, etc. In one embodiment, the thickness of the micro-stretched expanded polytetrafluoroethylene used to form the second film layer is 0.05mm to 0.2mm. In one embodiment, the thickness of the micro-stretched expanded polytetrafluoroethylene used to form the second film layer is 0.1 mm to 0.15 mm.

[0090] In one embodiment, the micropores of the micro-stretched expanded polytetrafluoroethylene used to form the second film layer have a pore size range of 0.01 μm to 2.5 μm. In one embodiment, the micropores of the micro-stretched expanded polytetrafluoroethylene used to form the second film layer have a pore size range of 0.03 μm to 1.0 μm.

[0091] In one embodiment, the average pore size of the micropores of the micro-stretched expanded polytetrafluoroethylene used to form the second film layer is 0.1μm to 0.5μm. The micropores of the micro-stretched expanded polytetrafluoroethylene used to form the second film layer are small microporous structures. On the whole, the average pore size of the micropores of the micro-stretched expanded polytetrafluoroethylene used to form the second film layer is smaller than the average pore size of the micropores of the micro-stretched expanded polytetrafluoroethylene used to form the first film layer, which can completely block the growth of connective tissue or fibrous tissue into the bone formation area, which is conducive to reducing the stimulation factors that may hinder bone formation. It can be understood that the average pore size of the micropores of the micro-stretched expanded polytetrafluoroethylene used to form the second film layer can be, for example, but not limited to, 0.1μm, 0.15μm, 0.2μm, 0.25μm, 0.3μm, 0.35μm, 0.4μm, 0.45μm, 0.5μm, etc. In one embodiment, the average pore size of the micropores of the micro-stretched expanded polytetrafluoroethylene used to form the second film layer is 0.25 μm to 0.3 μm.

[0092] In one embodiment, the implantable metal includes pure titanium, titanium alloy or stainless steel.

[0093] In one embodiment, the implantable metal includes TA1 medical pure titanium or TC4 titanium alloy.

[0094] In one embodiment, the thickness of the metal bracket 130 is 0.05 mm to 0.2 mm. It is understandable that the thickness of the metal bracket 130 can be, for example, but not limited to, 0.05 mm, 0.06 mm, 0.07 mm, 0.08 mm, 0.09 mm, 0.10 mm, 0.11 mm, 0.12 mm, 0.13 mm, 0.14 mm, 0.15 mm, 0.16 mm, 0.17 mm, 0.18 mm, 0.19 mm, 0.20 mm, etc. In one embodiment, the thickness of the metal bracket 130 is 0.10 mm to 0.15 mm.

[0095] In one embodiment, the metal bracket 130 is a prefabricated metal bracket. The prefabricated metal bracket can be prefabricated into a corresponding shape in advance according to the shape and size of the bone defect so that the metal bracket 130 can better match it, which is more conducive to fixing the bone filler under the membrane, and the metal bracket 130 has better support against gingival pressure, which is conducive to protecting the bone filler under the membrane and facilitating new bone formation in the defect area. It can be understood that the metal bracket 130 can be a conventional prefabricated metal bracket for conventional defect types; it can also be made into a special personalized metal bracket through 3D printing and finite element analysis technology according to the patient's special defect size and shape. When the final product is used, trimming of the titanium bracket is avoided, reducing the probability of membrane exposure due to sharp edges, and membrane nail fixing holes can be set on the metal bracket 130 to optimize membrane nail fixation during surgery.

[0096] In one embodiment, the metal bracket 130 is shaped as follows: including a metal center bar and a plurality of metal branch bars, wherein the plurality of metal branch bars are distributed on both sides of the metal center bar, and each metal branch bar is connected to the metal center bar respectively.

[0097] In one embodiment, the shape of the metal bracket 130 is: composed of an H-shaped metal support bar in the middle and symmetrical K-shaped metal support bars on both sides, wherein the vertical metal support bars on both sides of the H-shaped overlap with the two K-shaped vertical metal support bars, and the metal bracket 130 has a symmetrical structure.

[0098] In one embodiment, the metal bracket 130 is manufactured by laser cutting or stamping, wherein the laser cutting needs to be protected by an inert gas to avoid burns.

[0099] It can be understood that the ends of the metal branches in the metal bracket 130 can also be semi-circular to avoid sharp angles.

[0100] In one embodiment, the metal bracket 130 is a personalized bracket, which is prepared by the following method: three-dimensional scanning of the patient's oral and maxillary conditions, defect modeling, confirming the defect size and shape, using finite element analysis of the force distribution of the defect site according to the patient's special defect size and shape, designing a special personalized metal bracket, and then using 3D printing technology to make a special personalized metal bracket. When the final product is used, trimming of the titanium bracket is avoided to reduce the probability of membrane exposure caused by sharp edges. In addition, a membrane nail fixing hole can be set on the metal bracket 130 to optimize the membrane nail fixation during the operation.

[0101] In one embodiment, please refer to Figure 3 The surface of the first film layer 110 facing away from the metal bracket 130 has groove-shaped stripes. The groove-shaped stripes are conducive to promoting the adhesion of the metal-reinforced perforated composite film 10 to the soft tissue, and can further overcome the problem of poor adhesion between the film layer and the soft tissue, resulting in soft tissue cracking and film exposure, but will not cause the soft tissue to adhere too deeply, avoiding the problem of inconvenient removal.

[0102] In one embodiment, there are multiple stripes.

[0103] In one embodiment, each stripe includes a plurality of first stripes arranged along a first direction and a plurality of second stripes arranged along a second direction; the first direction and the second direction are perpendicular to each other.

[0104] Optionally, in each stripe, the first stripe and the second stripe are arranged alternately.

[0105] Optionally, among the stripes, the length of each first stripe is greater than the length of each second stripe, and the width of each first stripe is the same as the width of each second stripe; a plurality of first stripes are arranged in a straight line, and a plurality of second stripes are arranged in parallel; and the depth of each first stripe and each second stripe decreases independently from the middle to both ends. This stripe structure enables the first film layer 110 to better adhere to the soft tissue fibers.

[0106] In one embodiment, the depth of each first stripe and the depth of each second stripe are independently 0 mm to 0.15 mm.

[0107] It is understandable that the metal reinforced composite membrane with holes 10 can be cut into various shapes according to the needs, such as but not limited to rectangular, square, semicircular, circular, racetrack, etc. In one embodiment, the metal reinforced composite membrane with holes 10 is rectangular, 15mm to 50mm long, and 15mm to 40mm wide. It is understandable that in order to avoid sharp corners when the metal reinforced composite membrane with holes 10 is rectangular or square, chamfering can be performed, and the chamfer radius can be, for example, but not limited to, 2mm to 6mm.

[0108] An embodiment of the present application further provides a method for manufacturing a metal-reinforced perforated composite membrane as in any of the above embodiments, comprising the following steps S1 to S6.

[0109] Step S1: providing a mold, wherein the mold comprises a mold bottom plate and a mold cover plate.

[0110] Step S2: stacking a first film, a metal bracket and a second film in sequence on the mold bottom plate, wherein the metal bracket does not extend beyond the outer edges of the first film and the second film; the materials of the first film and the second film are independently selected from micro-stretched expanded polytetrafluoroethylene with a stretching range of 20% to 100%, and the micro-stretched expanded polytetrafluoroethylene has a microporous structure.

[0111] Step S3: Covering the mold cover plate on the second film.

[0112] Step S4: hot pressing the mold containing the first film, the metal support and the second film.

[0113] Step S5: After the hot pressing is completed, the mold is removed after cooling to obtain a hot pressed semi-finished product.

[0114] Step S6: drilling a plurality of through holes on the semi-finished product after hot pressing, the through holes penetrating the first film and the second film, the plurality of through holes being arranged around the periphery of the film layer area coated with the metal support, and the through holes and the metal support not overlapping; the formed metal-reinforced perforated composite membrane has micropores with an overall average pore size of 0.03 μm to 0.50 μm outside the through hole area.

[0115] It can be understood that in the above embodiment, the first film and the second film are respectively the aforementioned micro-stretched expanded polytetrafluoroethylene for forming the first film layer 110 and the micro-stretched expanded polytetrafluoroethylene for forming the second film layer 120. After the above method is used to produce the first film layer 110 and the second film 120, respectively, the first film and the second film are subjected to processes such as hot pressing to form the first film layer 110 and the second film layer 120.

[0116] In one embodiment, the stretching degree of the second film is smaller than the stretching degree of the first film.

[0117] In one embodiment, the average pore size of the micropores of the second film is smaller than the average pore size of the micropores of the first film.

[0118] In one embodiment, the thickness of the first film is 0.10 mm to 0.40 mm. It is understandable that the thickness of the first film can be, for example, but not limited to, 0.1 mm, 0.11 mm, 0.12 mm, 0.13 mm, 0.14 mm, 0.15 mm, 0.16 mm, 0.17 mm, 0.18 mm, 0.19 mm, 0.20 mm, 0.21 mm, 0.22 mm, 0.23 mm, 0.24 mm, 0.25 mm, 0.26 mm, 0.27 mm, 0.28 mm, 0.29 mm, 0.30 mm, 0.31 mm, 0.32 mm, 0.33 mm, 0.34 mm, 0.35 mm, 0.36 mm, 0.37 mm, 0.38 mm, 0.39 mm, 0.40 mm, etc. In one embodiment, the thickness of the first film is 0.15 mm to 0.25 mm. In one embodiment, the thickness of the first film is 0.20 mm to 0.22 mm.

[0119] In one embodiment, the pore size of the micropores of the first film ranges from 0.05 μm to 5.0 μm.

[0120] In one embodiment, the pore size of the micropores of the first film ranges from 0.1 μm to 5.0 μm.

[0121] In one embodiment, the average pore size of the micropores of the first film is 0.2 μm to 1.0 μm. The first film made of micro-stretched expanded polytetrafluoroethylene has a microporous structure, which is conducive to promoting the adhesion of the film to the soft tissue. It can be understood that the average pore size of the micropores of the first film can be, for example, but not limited to, 0.2 μm, 0.3 μm, 0.4 μm, 0.5 μm, 0.6 μm, 0.7 μm, 0.8 μm, 0.9 μm, 1.0 μm, etc. In one embodiment, the average pore size of the micropores of the first film is 0.5 μm to 0.8 μm.

[0122] In one embodiment, the thickness of the second film is 0.05mm-0.3mm. It is understandable that the thickness of the second film can be, for example, but not limited to, 0.05mm, 0.06mm, 0.07mm, 0.08mm, 0.09mm, 0.10mm 0.11mm, 0.12mm, 0.13mm, 0.14mm, 0.15mm, 0.16mm, 0.17mm, 0.18mm, 0.19mm, 0.20mm, 0.21mm, 0.22mm, 0.23mm, 0.24mm, 0.25mm, 0.26mm, 0.27mm, 0.28mm, 0.29mm, 0.30mm, etc. In one embodiment, the thickness of the second film is 0.05mm-0.2mm. In one embodiment, the thickness of the second film is 0.1mm-0.15mm.

[0123] In one embodiment, the pore size of the micropores of the second film ranges from 0.01 μm to 2.5 μm. In one embodiment, the pore size of the micropores of the second film ranges from 0.03 μm to 1.0 μm.

[0124] In one embodiment, the average pore size of the micropores of the second film is 0.1μm to 0.5μm. The micropores of the second film made of micro-stretched expanded polytetrafluoroethylene are small microporous structures. On the whole, the average pore size of the micropores of the second film is smaller than the average pore size of the micropores of the first film, which can completely block the growth of connective tissue or fibrous tissue into the osteogenic area, which is conducive to reducing the stimulation factors that may hinder bone formation. It can be understood that the average pore size of the micropores of the second film can be, for example, but not limited to, 0.1μm, 0.15μm, 0.2μm, 0.25μm, 0.3μm, 0.35μm, 0.4μm, 0.45μm, 0.5μm, etc. In one embodiment, the average pore size of the micropores of the second film is 0.25μm to 0.3μm.

[0125] In one embodiment, the metal reinforced perforated composite film further comprises a step of forming stripes on the surface of the first film on the side away from the metal support.

[0126] Optionally, the step of forming stripes on the surface of the first film facing away from the metal support comprises:

[0127] A stripe template corresponding to the preset stripes is placed between the first film and the mold bottom plate.

[0128] Furthermore, the stripe template may be, for example but not limited to, a metal mesh.

[0129] In one embodiment, in step S4, the step of hot pressing comprises:

[0130] The mold containing the first film, the metal support and the second film is pressed, heated and kept warm in sequence.

[0131] In one embodiment, the clamping method is locking and clamping, and the locking torque is 0.5N·m to 10N·m. It can be understood that the locking torque can be, for example, but not limited to, 0.5N·m, 1N·m, 1.5N·m, 2N·m, 2.5N·m, 3N·m, 3.5N·m, 4N·m, 4.5N·m, 5N·m, 5.5N·m, 6N·m, 6.5N·m, 7N·m, 7.5N·m, 8N·m, 8.5N·m, 9N·m, 9.5N·m, 10N·m, etc. It can be understood that the locking and clamping method can be, for example, but not limited to, a fixing clamp, a fixing screw, etc.

[0132] In one embodiment, the heating rate during heating is 30°C / min to 60°C / min, and the heating temperature is 300°C to 380°C. It is understandable that the heating rate during heating can be, for example, but not limited to, 30°C / min, 35°C / min, 40°C / min, 45°C / min, 50°C / min, 55°C / min, 60°C / min, etc. It is understandable that, for example, but not limited to, the heating temperature can be 300°C, 310°C, 320°C, 330°C, 340°C, 350°C, 360°C, 370°C, 380°C, etc.

[0133] In one embodiment, the insulation time is 1 hour to 5 hours. It can be understood that the insulation time can be, for example but not limited to, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, etc.

[0134] In one embodiment, the cooling rate is 2°C / h to 10°C / h. It is understandable that the cooling rate may be, for example but not limited to, 2°C / h, 3°C / h, 4°C / h, 5°C / h, 6°C / h, 7°C / h, 8°C / h, 9°C / h, 10°C / h, etc.

[0135] In one embodiment, in step S6, a plurality of through holes are punched on the semi-finished product after hot pressing by laser drilling.

[0136] Optionally, the laser light source for laser drilling is a picosecond ultraviolet laser or a nanosecond ultraviolet laser or a picosecond green laser.

[0137] Optionally, the wavelength of the laser drilling is 355nm to 532nm.

[0138] Optionally, the power of the laser drilling is 4W-30W, the frequency is 100kHz-800kHz, and the pulse width is 1ps-100ps.

[0139] An embodiment of the present application further provides a barrier membrane for use in the field of guided bone regeneration, including the metal-reinforced porous composite membrane as described in any of the above embodiments.

[0140] In one embodiment, the barrier membrane used in the field of guided bone regeneration further comprises a collagen membrane.

[0141] An embodiment of the present application also provides a use of the barrier membrane in the above embodiment in guided bone regeneration.

[0142] In one embodiment, the first film layer of the barrier film contacts the soft tissue surface, and the second film layer contacts the bone graft.

[0143] The metal reinforced porous composite membrane and its preparation method and application of the present application are further described in detail below through specific examples. It can be understood that in the following specific examples, unless otherwise specified, all raw materials can be sourced from commercial sources.

[0144] Example 1

[0145] A metal-reinforced porous composite membrane 10:

[0146] The metal reinforced perforated composite membrane 10 comprises a first membrane layer 110, a second membrane layer 120 and a metal support 130. The metal support 130 is located between the first membrane layer 110 and the second membrane layer 120 and is covered by the first membrane layer 110 and the second membrane layer 120.

[0147] A plurality of through holes 140 are arranged on the metal reinforced perforated composite membrane 10 , and the through holes 140 penetrate the first membrane layer 110 and the second membrane layer 120 . The plurality of through holes 140 are arranged around the membrane layer area coated with the metal bracket 130 , and the positions of the through holes 140 do not overlap with the metal bracket 130 .

[0148] Regarding the first film layer 110:

[0149] The material of the first film layer 110 is slightly stretched expanded polytetrafluoroethylene, and the stretching range is 80%.

[0150] The surface of the first film layer 110 facing away from the metal support 130 includes a plurality of groove-shaped stripes arranged in parallel.

[0151] Each stripe includes a plurality of first stripes arranged along a first direction and a plurality of second stripes arranged along a second direction, and the first direction and the second direction are perpendicular to each other; in each stripe, the first stripes and the second stripes are arranged alternately.

[0152] Each first stripe is deepest in the middle, with a depth of 0.1 mm, and gradually becomes shallower to a depth of 0 mm toward both ends. Each first stripe is 0.1 mm wide and 0.5 mm long.

[0153] Each second stripe is deepest in the middle, with a depth of 0.1 mm, and gradually becomes shallower to a depth of 0 mm toward both ends. Each second stripe is 0.1 mm wide and 0.3 mm long.

[0154] The distance between every two adjacent first stripes is 0.4 mm, and the distance between every two adjacent second stripes is 0.6 mm.

[0155] Regarding the second film layer 120:

[0156] The material of the second film layer 120 is slightly stretched expanded polytetrafluoroethylene, and the stretching range is 30%.

[0157] About Metal Bracket 130:

[0158] The metal stent 130 is made of TA1 medical pure titanium stent with a thickness of 0.15 mm and a surface roughness of less than 0.08 μm.

[0159] The metal support 130 includes a metal center bar and a plurality of metal branch bars. The plurality of metal branch bars are symmetrically distributed on both sides of the metal center bar, and each metal branch bar is connected to the metal center bar respectively.

[0160] The metal bracket 130 is processed by laser cutting or stamping, wherein the laser cutting needs to be protected by inert gas to avoid burns. The end of the metal bracket is semi-circular to avoid sharp angles.

[0161] About the metal reinforced porous composite membrane 10 as a whole:

[0162] The diameter of the through hole 140 is 200 μm, and the hole spacing is 500 μm.

[0163] The pore size range of the micropores outside the through hole area is 0.01μm to 0.8μm, the average pore size of the micropores outside the through hole area is 0.15μm, the total thickness of the film layer area not coated with the metal bracket 130 is 0.25mm, and the total thickness of the film layer area coated with the metal bracket 130 is 0.40mm.

[0164] The first film layer 110 , the metal support 130 and the second film layer 120 are combined by heat pressing without any other additives in between.

[0165] The formed metal-reinforced perforated composite membrane 10 is rectangular in shape.

[0166] The method for making the metal reinforced porous composite membrane 10 comprises the following steps:

[0167] (1) Two micro-stretched expanded polytetrafluoroethylene membranes with stretching amplitudes of 80% and 30% were cut into 5 cm × 6 cm films as the first film and the second film, respectively. They were ultrasonically cleaned three times using purified water, alcohol and injection water as cleaning agents, respectively, and placed in a 60°C oven for drying for 3 hours. The TA1 medical pure titanium stent used as a metal stent was cleaned in the same way; the pore size range of the micropores of the first film was 0.1 μm to 5.0 μm, the average pore size of the micropores was 0.5 μm, and the thickness was 0.22 mm. The pore size range of the micropores of the second film was 0.01 μm to 2.50 μm, the average pore size of the micropores was 0.25 μm, and the thickness was 0.1 mm;

[0168] (2) providing a mold for hot pressing, the mold comprising a mold base plate and a mold cover plate; stacking a metal mesh, a first film, a metal bracket and a second film corresponding to the preset stripes on the mold base plate in sequence, wherein the metal bracket does not extend beyond the outer edges of the first film and the second film; covering the mold cover plate on the second film; clamping the mold base plate and the mold cover plate with a fixing clamp around the mold, and using a torque wrench to fix the clamping torque to 2.5 Nm;

[0169] (3) Place the assembled mold in a high-temperature oven and set the temperature control program. First, set the program to heat up at a rate of 50°C / min until the temperature reaches 360°C and maintain heating for 2 hours. Then set the program to cool down at a rate of 5°C / h until the temperature reaches 100°C. Take out the mold and cool it to room temperature. Open the mold and take out the semi-finished product.

[0170] (4) The semi-finished product after hot pressing is fixed on the mold of the laser drilling equipment, and a visual positioning system is used to avoid the position of the metal bracket and set a drilling matrix around the film layer area coated with the metal bracket. The laser light source is a picosecond ultraviolet laser with a wavelength of 355nm, a power of 20w, a repetition frequency of 400kHz, and a pulse width of 10ps for drilling;

[0171] (5) Cut the punched semi-finished product into products, and ensure that the TA1 titanium metal bracket is centered through visual positioning or mold positioning, and the position deviation is controlled within ±0.5mm;

[0172] (6) The cut products are ultrasonically cleaned three times using purified water, alcohol, and injection water, respectively, and dried in an oven at 60°C for 3 h before inner and outer packaging and sterilization to produce finished products.

[0173] Example 2

[0174] A metal-reinforced porous composite membrane 10:

[0175] The metal reinforced perforated composite membrane 10 comprises a first membrane layer 110, a second membrane layer 120 and a metal support 130. The metal support 130 is located between the first membrane layer 110 and the second membrane layer 120 and is covered by the first membrane layer 110 and the second membrane layer 120.

[0176] A plurality of through holes 140 are arranged on the metal reinforced perforated composite membrane 10 , and the through holes 140 penetrate the first membrane layer 110 and the second membrane layer 120 . The plurality of through holes 140 are arranged around the membrane layer area coated with the metal bracket 130 , and the positions of the through holes 140 do not overlap with the metal bracket 130 .

[0177] Regarding the first film layer 110:

[0178] The material of the first film layer 110 is slightly stretched expanded polytetrafluoroethylene, and the stretching range is 100%.

[0179] The surface of the first film layer 110 facing away from the metal support 130 includes a plurality of groove-shaped stripes arranged in parallel.

[0180] Each stripe includes a plurality of first stripes arranged along a first direction and a plurality of second stripes arranged along a second direction, and the first direction and the second direction are perpendicular to each other; in each stripe, the first stripes and the second stripes are arranged alternately.

[0181] Each first stripe is deepest in the middle, with a depth of 0.05 mm, and gradually becomes shallower to a depth of 0 mm toward both ends. Each first stripe is 0.05 mm wide and 0.25 mm long.

[0182] Each second stripe is deepest in the middle, with a depth of 0.05 mm, and gradually becomes shallower to a depth of 0 mm toward both ends. Each second stripe is 0.05 mm wide and 0.15 mm long.

[0183] The spacing between every two adjacent first stripes is 0.3 mm. The spacing between every two adjacent second stripes is 0.3 mm.

[0184] Regarding the second film layer 120:

[0185] The material of the second film layer 120 is slightly stretched expanded polytetrafluoroethylene, and the stretching range is 30%.

[0186] About Metal Bracket 130:

[0187] The metal bracket 130 is made of TC4 titanium alloy prefabricated bracket with a thickness of 0.10 mm and a surface roughness of less than 0.05 μm.

[0188] The shape of the metal bracket 130 is composed of an H-shaped metal support bar in the middle and symmetrical K-shaped metal support bars on both sides, wherein the vertical metal support bars on both sides of the H-shaped metal support bars overlap with the two K-shaped vertical metal support bars, and the metal bracket 130 has a symmetrical structure.

[0189] The metal support 130 is processed by laser cutting or stamping, wherein the laser cutting needs to be protected by inert gas to avoid burns. The end of the metal support bar is semi-circular to avoid sharp angles.

[0190] About the metal reinforced porous composite membrane 10 as a whole:

[0191] The through holes 140 have a diameter of 50 μm and a hole pitch of 200 μm.

[0192] The pore size range of the micropores outside the through hole area is 0.02μm to 0.5μm, the average pore size of the micropores outside the through hole area is 0.2μm, the total thickness of the film layer area not coated with the metal bracket 130 is 0.2mm, and the total thickness of the film layer area coated with the metal bracket 130 is 0.40mm.

[0193] The first film layer 110 , the metal support 130 and the second film layer 120 are combined by heat pressing without any other additives in between.

[0194] The formed metal-reinforced perforated composite membrane 10 is rectangular in shape.

[0195] The method for making the metal reinforced porous composite membrane 10 comprises the following steps:

[0196] (1) Two micro-stretched expanded polytetrafluoroethylene membranes with stretching amplitudes of 100% and 30% were cut into 4 cm × 5 cm films as the first film and the second film, respectively. They were ultrasonically cleaned three times using purified water, alcohol and injection water as cleaning agents, respectively, and placed in a 60°C oven for drying for 5 hours. The TC4 titanium alloy prefabricated stent used as the metal stent was cleaned in the same way. The pore size range of the micropores of the first film was 0.5 μm to 5.0 μm, the average pore size of the micropores was 0.8 μm, and the thickness was 0.20 mm. The pore size range of the micropores of the second film was 0.03 μm to 1.0 μm, the average pore size of the micropores was 0.30 μm, and the thickness was 0.15 mm.

[0197] (2) providing a mold for hot pressing, the mold comprising a mold base plate and a mold cover plate; stacking a metal mesh, a first film, a metal bracket and a second film corresponding to the preset stripes on the mold base plate in sequence, wherein the metal bracket does not extend beyond the outer edges of the first film and the second film; covering the mold cover plate on the second film; using fixing screws and nuts in threaded holes provided in the mold to lock the mold base plate and the mold cover plate, and using a torque wrench to fix the screws, with the torque set to 10 N.m;

[0198] (3) Place the assembled mold in a high-temperature oven and set the temperature control program. First, set the program to heat up at a rate of 60°C / min until the temperature reaches 380°C and maintain heating for 1 hour. Then set the program to cool down at a rate of 10°C / h until the temperature drops to 80°C. Take out the mold and cool it to room temperature. Open the mold and take out the semi-finished product.

[0199] (4) The semi-finished product after hot pressing is fixed on the mold of the laser drilling equipment, and a visual positioning system is used to avoid the position of the metal bracket and set a drilling matrix around the film layer area coated with the metal bracket. The laser light source is a picosecond green laser with a wavelength of 532nm, a power of 10W, a repetition frequency of 200kHz, and a pulse width of 1.5ps for drilling;

[0200] (5) Cut the punched semi-finished product into products, and ensure that the TC4 titanium alloy prefabricated bracket is centered through visual positioning or mold positioning, and the position deviation is controlled within ±0.5mm;

[0201] (6) The cut products are ultrasonically cleaned three times using purified water, alcohol, and injection water, respectively, and dried in an oven at 80°C for 2 h before inner and outer packaging and sterilization to produce finished products.

[0202] Example 3

[0203] Example 3 is substantially the same as Example 2, except that the metal bracket is made of a high-nitrogen stainless steel prefabricated bracket.

[0204] Example 4

[0205] Embodiment 4 is substantially the same as Embodiment 1, except that the metal bracket 130 is customized. The specific preparation method of the metal bracket 130 is as follows:

[0206] (1) Obtaining a model of the patient's alveolar bone defect by performing a CT scan on the patient, and then designing a titanium stent model that matches the defect model. The titanium stent model includes the design of the membrane pin fixing point and the shape design of the main load-bearing area;

[0207] (2) Conduct finite element analysis on the titanium stent, import finite element analysis software, determine the fixed points, set the load conditions, perform mechanical analysis and solve, determine the distribution of the load-bearing capacity of the personalized titanium stent, thicken the main load-bearing area, perform transition processing between different thicknesses, and finally obtain a better titanium stent design model;

[0208] (3) Through additive manufacturing technology, personalized titanium stents are prepared, and annealing and surface treatment are performed to obtain the final titanium stent.

[0209] Example 5

[0210] Embodiment 5 is substantially the same as Embodiment 1, except that the through hole diameter is 500 μm.

[0211] Example 6

[0212] Example 6 is substantially the same as Example 1, except that: the stretching amplitude of the micro-stretched expanded polytetrafluoroethylene used to form the first membrane layer is 30%, and the stretching amplitude of the micro-stretched expanded polytetrafluoroethylene used to form the second membrane layer is 20%; the pore diameter of the through hole 140 is 100 μm, and the pore spacing is 500 μm; the pore diameter range of the micropores outside the through hole area is 0.01 μm to 0.5 μm, and the average pore diameter of the micropores outside the through hole area is 0.03 μm.

[0213] Example 7

[0214] Example 7 is substantially the same as Example 1, except that: the stretching amplitude of the micro-stretched expanded polytetrafluoroethylene used to form the first membrane layer is 100%, and the stretching amplitude of the micro-stretched expanded polytetrafluoroethylene used to form the second membrane layer is 90%; the pore diameter of the through hole 140 is 50 μm, and the pore spacing is 500 μm; the pore diameter range of the micropores outside the through hole area is 0.2 μm to 1.5 μm, and the average pore diameter of the micropores outside the through hole area is 0.5 μm.

[0215] Comparative Example 1

[0216] Comparative Example 1 is substantially the same as Example 1, except that there is no through hole.

[0217] Comparative Example 2

[0218] Comparative Example 2 is a commercially available titanium-reinforced dense polytetrafluoroethylene membrane with through holes, the through hole diameter is 667 μm, the spacing is about 500 μm, and the surface of the dense polytetrafluoroethylene is smooth and almost free of micropores.

[0219] Comparative Example 3

[0220] Comparative Example 3 is a commercially available titanium-reinforced expanded polytetrafluoroethylene membrane, the average pore size of the micropores reaches 30 μm, and the stretching amplitude of the expanded polytetrafluoroethylene is greater than 200%.

[0221] Comparative Example 4

[0222] Comparative Example 4 is a commercially available titanium-reinforced dense polytetrafluoroethylene membrane with no through holes, and the surface of the dense polytetrafluoroethylene is smooth and has almost no micropores.

[0223] Test Example 1

[0224] The adhesion of the metal reinforced perforated polytetrafluoroethylene membranes prepared in Examples 1 to 7 and Comparative Examples 1 to 4 was compared. The adhesion between 11 membranes and the wound surface was evaluated using the standard YY / T 1477.4-2017 in vitro model. The specific test method is:

[0225] (1) Remove the metal brackets from the above 11 membranes and cut them into 30 mm × 40 mm test pieces, 2 pieces for each test. Place the wound model (fibrin clot) between the two test pieces, with the wound model in contact with the soft tissue contact surface of the product. Place it on a horizontal tray, apply a 98 g block, and transfer it to a constant temperature and humidity chamber at (37 ± 2) ° C and a relative humidity of 85% for 24 h.

[0226] (2) Take out the above samples, put them into a drying oven at (37±2)℃ and dry them for 3h~4h, take them out and let them cool to room temperature;

[0227] (3) The above samples were subjected to a peel test in a 90° hand-held manner according to Figure A.2b) of standard YY / T 1477.4. The initial distance between the clamps was about 40 mm. The samples were stretched at a tensile rate of 100 mm / min until they were completely peeled off from the wound model. The potential soft tissue adhesion of the samples was evaluated and the maximum peeling force required for peeling was recorded.

[0228] (4) Repeat the above experimental steps 6 times.

[0229] The test results are shown in Table 1 below.

[0230] Table 1 Maximum peel force test results

[0231]

[0232] The test results are shown in Table 1. Examples 1 to 7 and Comparative Example 1 can contact the wound model, have a certain adhesion force, and are relatively easy to peel off, and there is no significant difference in peeling force; the maximum peeling force of Comparative Example 3 is (2.74±0.22)N / 30mm, and the barrier film can contact the wound model, but the adhesion force is large and peeling is difficult, indicating that the barrier film will have the risk of adhering to soft tissue during use; the maximum peeling forces of Comparative Examples 2 and 4 are (0.18±0.07)N / 30mm and (0.14±0.04)N / 30mm, and there is no significant difference between the two groups, but there is a significant difference with other groups, indicating that Comparative Examples 2 and 4 can contact the wound model but not firmly, and separation occurs naturally without peeling during the test process, indicating that the barrier film is basically not in contact with the wound model. During use, there is a risk of exposure due to the incompatibility between the barrier film and soft tissue.

[0233] Test Example 2

[0234] Compare the metal reinforced composite membranes with holes in Examples 1, 5, 6 and 7, the composite membrane without through holes in Comparative Example 1 and the commercially available titanium reinforced dense polytetrafluoroethylene membrane with through holes in Comparative Example 2 for the repair effect on the critical defect of the rabbit skull. Figure 6 , the specific method is as follows:

[0235] (1) Eighteen 3 kg New Zealand rabbits were selected, and two 8 mm defect models were made for each rabbit, with a total of 36 sites. Six of each of the six barrier membrane products were randomly assigned.

[0236] (2) Animals were fasted but not watered for 12 h one day before surgery. On the day of the experiment, the animals were weighed and anesthetized with an intramuscular injection of Zotal 0.15-0.2 ml / kg to induce anesthesia.

[0237] (3) Shaving: Shave the hair on the rabbit's head.

[0238] (4) Disinfection: Place the animal in lateral recumbency and disinfect the head and face with 2% iodine tincture, then cover with a sterile sheet.

[0239] (5) Local anesthesia: 2% lidocaine hydrochloride (1:100,000 epinephrine) is used for local infiltration anesthesia in the surgical area to reduce bleeding during surgery.

[0240] (6) Modeling: Make a 3.0-4.0 cm incision along the middle of the skull, carefully pull apart the scalp and subcutaneous tissue to facilitate drilling and grinding with a grinder and a bending machine, and drill with a 7 mm diameter hollow drill bit to create an 8 mm defect on each side of the rabbit skull. Use a large amount of saline to cool the rabbit during the drilling process, and be careful not to damage the dura mater. After the modeling is completed, remove the skull at the modeling site.

[0241] (7) Material placement: Use sterile instruments to clamp the 12 mm diameter barrier membrane product, carefully apply medical glue 1-2 mm around the membrane, and be careful not to apply it in the center area. Then, cover the product on the rabbit skull defect.

[0242] (8) Suture: Use interrupted sutures to completely close the wound.

[0243] (9) Record any abnormal conditions and solutions during surgery.

[0244] (10) Postoperatively: intramuscular injection of penicillin (400,000 U / d) and tolfenamic acid for anti-inflammatory and analgesic purposes.

[0245] (11) After surgery, the animals were kept warm and their vital signs were monitored until they fully woke up.

[0246] (2) Anti-infection and analgesia. Anti-infection: intramuscular injection of penicillin (400,000 U / d), once a day for 3 consecutive days; analgesia: tolfenamic acid sodium 0.1 ml / kg, once a day for 3 consecutive days.

[0247] (13) Twelve weeks after surgery, the animals were killed, and the whole skull specimen was removed and fixed in 4% neutral formalin / 1% calcium chloride solution. Three-dimensional CT was performed to analyze the new bone volume (NBV) (mm3) of the defect area, and then H&E staining was performed to analyze the proportion of new bone (NBA%) by tissue morphometry. p<0.05 indicated a significant difference, indicated by *.

[0248] The test results are shown in Table 2 and Figure 7 .

[0249] Table 2 Test results of new bone volume and new bone area ratio

[0250] Test samples Number of tests <![CDATA[New bone volume (NBV, mm 3 )]]> New bone area ratio (NBA,%) Example 1 6 43.30±2.48 50.11±2.27 Example 5 6 39.48±1.41 47.53±0.91 Example 6 6 38.62±2.57 45.48±1.32 Example 7 6 37.57±0.71 43.48±2.34 Comparative Example 1 6 35.20±2.17 39.51±1.45 Comparative Example 2 6 32.60±1.83 38.89±2.06

[0251] Table 2 and Figure 7The new bone volume and new bone area ratio after the critical defect of the rabbit skull was repaired by using Examples 1, 5, 6, 7 and Comparative Examples 1 and 2. It can be seen that 12 weeks after implantation, after the metal-reinforced porous composite membranes of Examples 1, 5, 6, and 7 were used for treatment, the volume and area ratio of the new bone tissue in the rabbit skull were significantly greater than those of Comparative Examples 1 and 2. It is shown that the metal-reinforced porous composite membrane provided by the present application adopts the structural combination of "through hole + micropores on the composite membrane" to improve the connectivity of nutrients between soft tissue and bone defect areas, effectively promote osteogenesis, and at the same time prevent soft tissue from growing into the defect area to protect the osteogenesis environment. However, the barrier membrane of Comparative Example 1 has no through holes, and the connectivity of nutrients between soft tissue and bone defect areas is poor, and the effect of promoting osteogenesis is weak. Comparative Example 2 has soft tissue growing into the defect area due to the excessively large through hole diameter, and there are almost no micropores on the dense polytetrafluoroethylene membrane, which is not conducive to the penetration of nutrients through the membrane, and the overall osteogenesis effect is poor.

[0252] Test Example 3

[0253] A beagle mandibular vertical defect model was established to compare the osteogenesis, soft tissue adhesion and exposure of the metal reinforced polytetrafluoroethylene membrane prepared in Example 1, the commercially available titanium reinforced dense polytetrafluoroethylene membrane with through holes in Comparative Example 2 and the commercially available titanium reinforced expanded polytetrafluoroethylene membrane in Comparative Example 3. Design: Six male beagle dogs, aged 9-12 months and weighing 10-12 kg, were selected. Mandibular P2-M1 was extracted respectively to create a saddle-shaped defect of 8 mm (mesiodistal) × 8 mm (crown-root) × (5-7) mm (buccally and lingually). Each dog had 2 points on the left and right sides of the mandible, and was divided into 4 groups: Example 1, Comparative Example 2, Comparative Example 3 and blank group. Bone powder was then implanted and fixed with the three membranes mentioned above, while there was no membrane fixation. CT tests were performed immediately after surgery, 13 weeks, and 26 weeks to measure the bone formation height H and the bone formation rate (26W bone formation height H / postoperative bone formation height H×100%), and the product exposure was observed. After the CT test was completed at 26 weeks, the mucosa was opened to remove the material, and the adhesion between the membrane and soft tissue was evaluated using the Rydell scoring standard.

[0254] The specific method is as follows:

[0255] (1) Disinfection: Use 2% iodine to disinfect the oral cavity and face, and lay a sterile drape.

[0256] (2) Local anesthesia: 2% lidocaine hydrochloride (1:100,000 epinephrine) was used for local infiltration anesthesia in the surgical area to reduce bleeding during surgery.

[0257] (3) Gingival incision: Use a bone elevator to peel the gums, turn over the mucoperiosteal flap, and use a spacer to increase the space between the tooth root and the alveolar bone and loosen the tooth root.

[0258] (4) Crown division: Use a tungsten carbide fissure drill to divide the second, third, and fourth premolars and the first molar (P2-M1) on both sides of the mandible into two mesiodistal halves at the root bifurcation.

[0259] (5) Tooth extraction: Extract the tooth, scrape the extraction socket to form a recipient bed with rich blood supply, and rinse with sterile saline.

[0260] (6) Modeling: Use a drill bit for drilling and grinding, and use a large amount of physiological saline to cool down during the drilling and grinding process. Use a 3mm diameter drill bit to drill and expand, and control the speed within 1500rpm. Use a circular saw to prepare a saddle-shaped alveolar bone defect with the same depth, degree, and range in the extraction socket, with a mesiodistal width of 8mm, a vertical width of 10mm, and a buccal-lingual width of 5-7mm (the width of the mandibular bone of a beagle dog).

[0261] (7) Implantation of bone material: In a sterile container, pre-soak artificial bone powder: beagle dog autologous bone (1:1) and sterile saline to form a mixture, fill the mixture into the alveolar defect, squeeze with a filler, and fill loosely to avoid crushing the trabeculae until the bone powder is flush with the lateral ridge of the alveolar bone.

[0262] (8) Covering film: Under sterile conditions, the barrier film was cut into a suitable size, about 15×32 mm in size, and covered on the corresponding sites in Example 1, Comparative Example 2 and Comparative Example 3 using the corresponding barrier film product on the buccal and lingual sides of the filling part, fixed with film pins, and then covered with a layer of collagen film. The other groups were not covered with collagen film, and the blank group did not use a film.

[0263] (9) Suture: All sites are turned back to the mucoperiosteal flap, and after the skin flap is fully loosened, double-layer suture (such as horizontal suture + interrupted suture) is used to completely close the wound.

[0264] (10) After the tooth extraction on one side is completed, the animal is placed in a lateral position and the tooth extraction on the other side is performed in the same manner as above to complete the operation. The experimental animal is then returned to the breeding cage.

[0265] (11) During the operation, any abnormal conditions and solutions should be recorded.

[0266] (12) Postoperatively: intramuscular injection of penicillin (800,000 U / d) and tolfenamic acid for anti-inflammatory and analgesic purposes, and observation of exposure.

[0267] Suture removal: The surgical sutures of all animals were uniformly removed around 21 days after surgery.

[0268] Immediately after surgery, 13 weeks, and 26 weeks after surgery, CBCT was taken under anesthesia to analyze the bone height and bone formation rate, and statistical analysis was performed. p < 0.05, there was a statistical difference between the groups, indicated by *; p < 0.01, there was a significant difference between the groups, indicated by **; p < 0.001, there was an extremely significant difference between the groups, indicated by ***. After taking the CT film 26 weeks after surgery, the gums were cut open and the implanted products were removed. When removing the implants, the adhesion degree was divided into 4 levels for scoring according to the Rydell scoring standard. Level 0: There is no obvious adhesion between the product and the soft tissue; Level I: The product is easy to be bluntly separated from the soft tissue; Level II: The product is easy to be bluntly separated from the soft tissue with great resistance, and the soft tissue remains intact after separation; Level III: The product cannot be bluntly separated from the soft tissue, and the soft tissue cannot remain intact after sharp separation.

[0269] The test results are shown in Tables 3 and 4. Figure 8 , 9 .

[0270] Table 3 Test results of soft tissue adhesion and exposure

[0271] Grouping Exposure quantity (exposure rate) Rydell score Example 1 0 I, I, I, I, I, I Comparative Example 2 1(16.7％) 0， / ，0，I，0，0 Comparative Example 3 0 II, I, II, II, III, III blank 0 /

[0272] Table 4 Osteogenesis effect test results

[0273]

[0274]

[0275] As can be seen from Table 3, the metal reinforced perforated polytetrafluoroethylene membrane prepared in Example 1 was implanted in the oral cavity of beagle dogs for guided bone regeneration without membrane exposure, while one case of exposure occurred in the commercially available product in Example 2, with an exposure rate of 16.7%. This may be due to the fact that the dense structure of the product in Example 2 did not adhere to the soft tissue, resulting in wound dehiscence. With reference to the Rydell scoring rule, Example 1, Comparative Example 2, and Comparative Example 3 were removed after 26 weeks of implantation to evaluate the adhesion to soft tissue. Six samples of each polytetrafluoroethylene membrane were tested. Example 1 was able to easily achieve blunt separation, and the soft tissue was intact after separation; in Comparative Example 3, there were 3 cases in which there was a certain resistance during blunt separation, and the soft tissue remained intact after separation, and in 2 cases, sharp separation was required, and the mucosal tissue was damaged. Due to the larger micropore size structure of Comparative Example 3, the soft tissue grew into the product, was tightly combined with the product, was difficult to remove, and damaged the mucosal tissue; Comparative Example 2 had no obvious adhesion to the soft tissue, and only 1 case required blunt separation, mainly because Comparative Example 2 was a dense polytetrafluoroethylene membrane with a smooth surface and almost no micropores, and poor affinity with soft tissue. Although there were 667μm through holes, and the soft tissue grew into the through holes, the number of through holes was limited, and the soft tissue and the membrane had basically no adhesion.

[0276] From Table 4, Figure 8 and Fig. 9 It can be seen that in the vertical bone defect model, the products of Example 1, Comparative Example 2, and Comparative Example 3 can all effectively form bones, and the bone formation height is statistically different from the blank group. After 26 weeks of implantation, the bone formation height of Example 1 is significantly greater than that of Comparative Example 2 and Comparative Example 3, and the bone formation rate of the product of Example 1 is significantly greater than that of Comparative Example 2 and Comparative Example 3. The superiority of Example 1 is due to the through-holes of the product and the microporous structure of the material itself, which is conducive to the attachment of soft tissue, but will not adhere to the soft tissue, and is conducive to the penetration of nutrients and bone formation. Although the product of Comparative Example 2 has a through-hole structure and the surgical process is covered with a collagen membrane, the through-hole aperture is too large, resulting in the growth of soft tissue, affecting the final bone formation effect. Similarly, Comparative Example 3 has a larger microporous aperture structure, which also causes soft tissue to grow into the product and affects the final bone formation effect. The through-holes and microporous structures with appropriate apertures in Example 1 can effectively shield the soft tissue, protect the bone formation area, and are conducive to the penetration of nutrients, and the final bone formation effect is better.

[0277] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0278] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of this application. Therefore, the protection scope of the patent of this application shall be subject to the attached claims.

Claims

1. A metal-reinforced porous composite membrane, characterized in that: It comprises a first film layer, a second film layer and a metal bracket, wherein the metal bracket is located between the first film layer and the second film layer and is covered by the first film layer and the second film layer; A plurality of through holes are arranged on the metal reinforced perforated composite membrane, the through holes penetrate the first membrane layer and the second membrane layer, and the plurality of through holes are arranged around the periphery of the membrane layer area coated with the metal bracket, and the position of each through hole does not overlap with the metal bracket; The materials of the first film layer and the second film layer are independently selected from micro-stretched expanded polytetrafluoroethylene with a stretching range of 20% to 100%, and the micro-stretched expanded polytetrafluoroethylene has a microporous structure; the formed metal-reinforced porous composite membrane has micropores with an overall average pore size of 0.03 μm to 0.50 μm outside the through-hole area; The material of the metal stent includes implantable metal; The shape of the metal bracket is: comprising a metal center bar and a plurality of metal branches, the plurality of metal branches are distributed on both sides of the metal center bar, and each metal branch is connected to the metal center bar respectively; The through hole has a diameter of 10 μm to 500 μm.

2. The metal reinforced perforated composite membrane according to claim 1, characterized in that: Each of the through holes meets the following properties: the hole spacing is 50 μm to 1000 μm.

3. The metal reinforced perforated composite membrane according to claim 1, characterized in that: The metal reinforced perforated composite membrane as a whole satisfies one or more of the following properties (1) to (3): (1) The pore size of the micropores outside the through-hole region is in the range of 0.01 μm to 1.00 μm; (2) The total thickness of the film layer area not coated with the metal bracket is 0.10 mm to 0.50 mm; (3) The total thickness of the film layer area coated with the metal bracket is 0.20 mm to 0.80 mm.

4. The metal reinforced perforated composite membrane according to claim 1, characterized in that: The average pore size of the micropores of the micro-stretched expanded polytetrafluoroethylene used to form the second film layer is smaller than the average pore size of the micropores of the micro-stretched expanded polytetrafluoroethylene used to form the first film layer.

5. The metal reinforced perforated composite membrane according to claim 4, characterized in that: The micro-stretched expanded polytetrafluoroethylene used to form the first film layer satisfies one or more of the following properties (1) to (3): (1) Thickness: 0.10mm~0.40mm; (2) The pore size range of the micropores is 0.05 μm to 5.0 μm; (3) The average pore size of the micropores is 0.2 μm to 1.0 μm.

6. The metal reinforced perforated composite membrane according to claim 4, characterized in that: The micro-stretched expanded polytetrafluoroethylene used to form the second film layer satisfies one or more of the following properties (1) to (3): (1) Thickness: 0.05mm~0.3mm; (2) The pore size range of the micropores is 0.01 μm to 2.50 μm; (3) The average pore size of the micropores is 0.1 μm to 0.5 μm.

7. The metal reinforced perforated composite membrane according to any one of claims 1 to 6, characterized in that: The implantable metal includes pure titanium, titanium alloy or stainless steel.

8. The metal reinforced perforated composite membrane according to claim 7, characterized in that: The thickness of the metal bracket is 0.05 mm to 0.2 mm.

9. The metal reinforced perforated composite membrane according to claim 7, characterized in that: The metal bracket is a prefabricated metal bracket.

10. The metal reinforced perforated composite membrane according to any one of claims 1 to 6, characterized in that: The surface of the first film layer facing away from the metal support has groove-shaped stripes.

11. A method for producing a metal-reinforced porous composite membrane according to any one of claims 1 to 10, characterized in that: The steps include: Providing a mold, the mold comprising a mold bottom plate and a mold cover plate; A first film, a metal bracket and a second film are sequentially stacked on the mold bottom plate, wherein the metal bracket does not extend beyond the outer edges of the first film and the second film; the materials of the first film and the second film are independently selected from micro-stretched expanded polytetrafluoroethylene with a stretching range of 20% to 100%, and the micro-stretched expanded polytetrafluoroethylene has a microporous structure; Covering the mold cover plate on the second film; hot pressing the mold containing the first film, the metal support and the second film; After the hot pressing is finished, the mold is removed after cooling to obtain a hot pressed semi-finished product; A plurality of through holes are punched on the hot-pressed semi-finished product, the through holes passing through the first film and the second film, and the plurality of through holes are arranged around the periphery of the film layer area coated with the metal support, and the positions of the through holes do not overlap with the metal support; the formed metal-reinforced perforated composite membrane has micropores with an overall average pore size of 0.03 μm to 0.50 μm outside the through hole area.

12. A barrier membrane for use in the field of guided bone regeneration, characterized in that: It comprises the metal reinforced perforated composite membrane as described in any one of claims 1 to 10.

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