WO2023060823A1 - 用于容置植入型医疗设备的生物套及其制备方法、用途 - Google Patents

用于容置植入型医疗设备的生物套及其制备方法、用途 Download PDF

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Publication number
WO2023060823A1
WO2023060823A1 PCT/CN2022/079071 CN2022079071W WO2023060823A1 WO 2023060823 A1 WO2023060823 A1 WO 2023060823A1 CN 2022079071 W CN2022079071 W CN 2022079071W WO 2023060823 A1 WO2023060823 A1 WO 2023060823A1
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film layer
biological
layer
biofilm
coating
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PCT/CN2022/079071
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English (en)
French (fr)
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喻学桥
吴文跃
赵博
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北京博辉瑞进生物科技有限公司
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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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/005—Ingredients of undetermined constitution or reaction products thereof
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials

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  • the disclosure belongs to the field of medical devices and biomedical materials, and in particular, the disclosure relates to a biological cover for accommodating implanted medical devices, a preparation method and an application thereof.
  • Cardiovascular Cardiac Implantable Electronic Device includes cardiac pacemaker (Cardiac Pacemaker, PM), cardioverter defibrillator (Implantable Cardioverter Defibrillator, ICD) and cardiac resynchronization therapy (Cardiac Resynchronization Therap, CRT) pacemaker and defibrillator, implantable cardiac event recorder (Insertable cardiac monitor, ICM) and implantable cardiovascular monitor are typical high-risk medical devices.
  • cardiac pacemaker Cardiac Pacemaker, PM
  • cardioverter defibrillator Implantable Cardioverter Defibrillator
  • CRT cardiac resynchronization therapy
  • ICM implantable cardiac event recorder
  • implantable cardiac monitor implantable cardiovascular monitor
  • CIED is mainly used for bradyarrhythmias (such as sick sinus syndrome, third-degree atrioventricular block), tachyarrhythmias (such as paroxysmal atrial fibrillation, long QT syndrome), and non-cardiac electrical disorders (such as refractory heart failure, nerve-mediated syncope, hypertrophic obstructive cardiomyopathy) treatment and monitoring.
  • bradyarrhythmias such as sick sinus syndrome, third-degree atrioventricular block
  • tachyarrhythmias such as paroxysmal atrial fibrillation, long QT syndrome
  • non-cardiac electrical disorders such as refractory heart failure, nerve-mediated syncope, hypertrophic obstructive cardiomyopathy
  • CIED is mainly composed of a pulse generator, electrodes and wires.
  • cardiovascular implants such as pacemakers and defibrillators are made of alloy materials (for example, Ni-Co-Cr alloy, Co-Cr-Mo alloy, Titanium and Ti-6A1-4V alloy, etc.), stainless steel and various biocompatible polymer materials, generally directly implanted in the cavity formed by the subcutaneous tissue in front of the pectoralis major.
  • the main complications during this process include infection, hematoma, ulceration, thrombus, fistula formation, electrode dislocation, electrode myocardial perforation, wire wear and tear, device displacement in the body, etc.
  • infection, hematoma, and ulceration are the main causes of CIED implantation. It is a common postoperative complication with an incidence rate of up to 7%, which has seriously affected patients and has become an important problem in the treatment of cardiovascular diseases.
  • the shell of the equipment is usually made of metal or polymer material, which is a foreign body to the human body, and rejection reaction will inevitably occur, thus causing infection, inflammation, etc.;
  • the present disclosure provides a biological cover.
  • the implantable medical device is placed in the cavity of the biological cover, which can avoid direct contact with the human body and reduce the occurrence of complications such as infection and inflammation; and, the integrated biological
  • the cover has a high tensile strength, which can avoid the possible risks of suture breakage or premature degradation of the suture in the sutured biological cover, and improve the stability of the wrapped implantable medical device.
  • the present disclosure provides a biological cover, wherein the biological cover is formed of sterilized and decellularized extracellular matrix material, and has an integrally formed bag structure; An accommodating cavity for placing the implantable medical device, and an opening for communicating the accommodating cavity with the outside world.
  • the accommodating cavity is surrounded by opposite first and second surfaces; wherein, the first and second surfaces are connected A portion of which forms the transition junction of the biological cover;
  • the length of the transition connection part along the length direction of the biological cover is 5-10 cm, and the length of the transition connection part along the width direction of the biological cover is 4-8 cm.
  • At least one micropore is opened on the first surface and/or the second surface; optionally, the diameter of the micropore is 1-3 mm; optionally, the spacing of the microholes is 10-15 mm.
  • the sterilized and decellularized extracellular matrix material is obtained from small intestinal submucosa tissue, which is subjected to virus inactivation treatment and decellularization treatment;
  • the step of virus inactivation treatment comprises: soaking the small intestinal submucosa tissue in a virus solution containing (0.1-5)% (v/v) peracetic acid and (5-40)% (v/v) ethanol In the inactivation solution, treat at 10-40°C for 2-4 hours;
  • the step of decellularization treatment comprises: soaking the small intestinal submucosa tissue in a decellularization solution containing 0.1-2wt% trypsin and 0.01-0.3wt% EDTA, at a temperature of 10-40°C, the ultrasonic power is Under the ultrasonic condition above 5000W, process for 10-60 minutes.
  • the following step is further included: washing the small intestinal submucosa tissue until the The detected electrical conductivity of the small intestinal submucosa tissue is reduced to below 10 ⁇ S/cm;
  • the following step is further included: washing the small intestinal submucosa tissue, until the detected electrical conductivity of the small intestinal submucosa tissue is reduced to below 1 ⁇ S/cm.
  • the present disclosure provides a method for preparing the biological kit according to the first aspect, wherein the preparation method includes the following steps:
  • the preparation step of the biofilm layer preparing the sterilized and decellularized small intestinal submucosa material as the biofilm layer for preparing the biological cover;
  • the coating step of the biofilm layer alternately coating the biofilm layer on the surfaces of both sides of the plate-shaped mold, so that the surfaces of the two sides are respectively coated with at least 2 layers of the biofilm layer; wherein, any The biofilm layer of the layer includes a coating film layer covering a partial area of one side surface, and an extended film layer continuously extending to the other side surface corresponding to the partial area;
  • Freeze-drying step freeze-dry the biofilm layer coated on the mold in a non-pressing environment, so that at least 2 layers of the biofilm layer are combined into one; wherein, the biofilm layer covering the two surfaces
  • the layers respectively form a first surface body and a second surface body, and the biofilm layer connecting the first surface body and the second surface body forms a transition connection part, and the side of the biofilm layer that does not cover the mold forms an opening, obtaining
  • the biological cover is integrally formed by the first face, the second face and the transition connection part.
  • the coating step of the biofilm layer comprises:
  • the first biofilm layer forms a coating film layer of the first biofilm layer covering the coating area and extends outwards
  • the stretched film layer of the first biofilm layer in the coating area is bent towards the direction of the second surface, so that the stretched film layer covers the coating area of the second surface;
  • the stretched film layer on the second surface is flattened, and the coating step of the first surface in the direction of the second surface is completed;
  • the second biofilm layer forms the coating film layer of the second biofilm layer covering the coating area and extends outwards
  • the extended film layer of the second biofilm layer in the coating area the extended film layer of the second biofilm layer is bent towards the first surface direction, so that the extended film layer of the second biofilm layer covers the The cladding area of the first surface; flattening the stretched film layer on the first surface to complete the cladding step of the second surface in the direction of the first surface;
  • the extended film layer of the first biofilm layer completely covers the covering area of the second surface; and/or, the first In the coating step facing the direction of the second surface, the extended film layer of the second biofilm layer completely covers the coating area of the first surface;
  • the step of wrapping the first face in the direction of the second face and the step of covering the first face in the direction of the second face are repeated at least once.
  • the step of freeze-drying treatment includes: placing the plate-shaped mold coated with the biofilm layer in a vacuum freeze dryer for non-compression freeze-drying;
  • the conditions for non-compressed freeze-drying include: pre-freeze to -45°C, keep warm for 1-2 hours; then adjust the temperature to -15°C, keep warm for 5-7 hours; then adjust the temperature to 0°C, keep warm for 2 hours ; Finally, adjust the temperature to 25° C. and keep it warm for 4 hours.
  • the preparation method further includes the following steps:
  • Punching step remove the biological cover from the mold, cut it to the required size, and then punch holes in the first surface and/or the second surface to form a hole in the first surface. At least one micropore on the surface body and/or the second surface body; preferably, the spacing of the microholes is 10-15 mm, and the diameter is 1-3 mm on the first surface body and/or the second surface body upper punch;
  • Sterilization step after heat preservation of the biological cover, use ethylene oxide to sterilize the biological cover, and then analyze the ethylene oxide to obtain a sterilized biological cover; preferably, the heat preservation treatment
  • the temperature is 20-40°C, the time is 2-4 hours, and the humidity is 30-70%; preferably, the concentration of the ethylene oxide is 300-1000mg/L, and the sterilization time is 4 -8 hours;
  • the step of analyzing ethylene oxide is carried out in a ventilated analysis room, the temperature is controlled at 10-30° C., and the time is 14-28 days.
  • the present disclosure provides an implantable medical device, wherein the implantable medical device includes:
  • An implantable medical device the implantable medical device is at least partially placed in the accommodating cavity of the biological cover;
  • the implantable medical device is selected from devices for the diagnosis, monitoring and/or treatment of cardiovascular diseases; optionally, the implantable medical device is selected from any of the following: pacemaker, implantable cardioverter defibrillator, cardiac resynchronization therapy pacemaker, implantable defibrillator, implantable ECG event recorder, implantable cardiovascular monitor.
  • the implantable medical device is selected from devices for the diagnosis, monitoring and/or treatment of cardiovascular diseases; optionally, the implantable medical device is selected from any of the following: pacemaker, implantable cardioverter defibrillator, cardiac resynchronization therapy pacemaker, implantable defibrillator, implantable ECG event recorder, implantable cardiovascular monitor.
  • the biological cover provided by the present disclosure can place an implanted medical device in its cavity, which can provide a physical barrier for the implanted medical device, avoid direct contact between the implanted medical device and the body, and reduce the Complications such as infection, inflammation, scarring, and calcification after implantation were prevented.
  • the integrally formed structure of the biological cover has high tensile strength, which can avoid bad use conditions such as suture breakage or premature degradation of the suture thread in the sutured biological cover, and achieve stable physical isolation of implantable devices.
  • the biological cover provided by the present disclosure is formed of sterilized and decellularized small intestinal submucosa material, which is safe to use and has good tissue repair ability, and can promote tissue repair at the implanted site, healing, speeding up post-operative recovery after implantation.
  • the submucosa material of the small intestine can be degraded under the action of enzymes in the body, and finally the new tissue surrounding the implanted medical device forms a cystic structure, which further strengthens the implanted medical device, maintains the normal operation of the device and prolongs the life of the device. usage time.
  • the biological cover provided by the present disclosure releases antimicrobial peptides after degradation, reducing the incidence of complications such as inflammation and infection after medical device implantation.
  • the preparation method of the biological cover provided in the present disclosure can prepare an integrated biological cover without using sutures to suture the cover body, which can reduce the preparation time and cost of the biological cover. And the risk of suture breakage and the risk of suture degradation earlier than the body is avoided.
  • Fig. 1 shows the structural representation of biological cover
  • Fig. 2 shows the structural representation of plate mold
  • Fig. 3 shows the structural representation of biofilm layer
  • Fig. 4-A shows the schematic diagram of the process of covering the biofilm layer from the first to the second surface
  • Fig. 4-B shows the schematic diagram of the process of covering the biofilm layer from the second side to the first surface
  • Figure 5 shows the physical map of the biological cover, wherein A is a schematic side view of the biological cover, B is a schematic view of the other side of the biological cover, C is a schematic view of the pocket of the biological cover, and D is a side oblique view of the biological cover .
  • Fig. 6 shows the statistical diagram of tensile strength of 4 samples.
  • sample 1 is a dry-sewn SIS biological cover
  • sample 2 is a dry-integrated SIS biological cover
  • sample 3 is a hydrated-sewn SIS biological cover
  • sample 4 is a hydrated-integrated SIS biological cover.
  • 3-biofilm layer 31-coating film layer, 32-stretched film layer, 321-first stretched film layer, 322-second stretched film layer, 323-third stretched film layer.
  • references to “some specific/preferred embodiments”, “other specific/preferred embodiments”, “embodiments” and the like refer to the specific elements described in relation to the embodiments (for example, A feature, structure, property, and/or characteristic) is included in at least one embodiment described herein and may or may not be present in other embodiments.
  • references to “some specific/preferred embodiments”, “other specific/preferred embodiments”, “embodiments” and the like refer to the specific elements described in relation to the embodiments (for example, A feature, structure, property, and/or characteristic) is included in at least one embodiment described herein and may or may not be present in other embodiments.
  • the described elements may be combined in any suitable manner in the various embodiments.
  • numerical range represented by "numerical value A - numerical value B" means the range which includes numerical value A and B of an end point.
  • v/v is used to represent volume percentage content
  • wt% is used to represent mass percentage content
  • w/v is used to represent “g/ml” concentration
  • the temperature when “normal temperature” and “room temperature” are used, the temperature may be 10-40°C.
  • the first aspect of the present disclosure provides a biological cover, which is formed of sterilized and decellularized extracellular matrix material, and has an integrally formed bag structure 1; the bag structure 1 has a An accommodating cavity for placing the implantable medical device, and an opening 13 communicating the accommodating cavity with the outside world.
  • Placing the implantable medical device in the accommodation cavity of the biological sleeve can provide a physical barrier for the medical device and reduce the incidence of complications such as infection caused by the direct contact between the metal or polymer material of the device shell and the human body , and can reduce equipment failure and damage caused by equipment displacement.
  • biological covers can play the role of physical barriers, at present, most of the biological covers for implantable medical devices are sutured to form a bag-like structure. The suture process needs to control the sterile environment, which complicates the processing of biological covers. , increasing the processing cost and processing time of biological sets.
  • the bio-sleeve formed by suturing may cause risks such as suture breakage or suture degradation earlier than the sleeve body during use, which will adversely affect the implantation of medical devices in vivo.
  • the biological cover in the present disclosure has an integrally formed bag structure 1, which does not need to be sutured with sutures, effectively reducing adverse consequences such as separation and displacement of the bag due to breakage of sutures, premature degradation, etc.; and, Compared with the sutured biological cover, the one-piece biological cover in the present disclosure has higher tensile strength, and its use strength and stability are increased, which can further reduce the probability of complications after device implantation.
  • the accommodating chamber of the biological cover is surrounded by the first surface body 11 and the second surface body 12 .
  • the part where the first plane body 11 and the second plane body 12 meet forms the transitional connection part 14 of the biological cover.
  • the first face body 11 and the second face body 12 may have various shapes and sizes.
  • the first plane body 11 and the second plane body 12 may be triangles, quadrilaterals, pentagons, circles, etc. respectively.
  • the first plane body 11 and the second plane body 12 are configured to enclose an accommodating cavity for accommodating implantable medical devices, and the shapes and sizes of the first plane body 11 and the second plane body 12 can be determined according to implantation Adaptive adjustments to the shape and size of medical equipment.
  • the opposite faces of the first face body 11 and the second face body 12 are quadrilateral, and the first face body 11 and the second face body 12 respectively have a length direction (L1 direction) along the biological cover. Two side edges extending, and two side edges extending along the width direction (W1 direction) of the biological cover.
  • the length of any one of the first face body 11 and the second face body 12 is 5-10 cm, and the width is 4-8 cm.
  • the area of any one of the first plane 11 and the second plane 12 is configured as 5.4 ⁇ 5, 6.9 ⁇ 6.5, 6.9 ⁇ 8 or 6.9 ⁇ 9.5 (width ⁇ height, unit: cm).
  • first surface body 11 and the second surface body 12 are opposite and have the same shape and size. In some other embodiments, the first surface body 11 and the second surface body 12 may also be opposite, but have different shapes or sizes.
  • the transitional connection portion 14 is formed on the side where the first plane body 11 and the second plane body 12 meet, so that the first plane body 11 and the second plane body 12 enclose an area suitable for accommodating implantable medical devices.
  • an opening 13 is correspondingly formed between the unconnected sides of the first face body 11 and the second face body 12, and the implantable medical device can be partially or completely placed in the accommodating cavity through the opening 13 .
  • the opening 13 communicates the accommodating cavity of the biological cover with the outside world.
  • outside refers to the space outside the accommodating cavity of the biological cover, which may be the internal environment or the internal environment, depending on the use environment of the biological cover.
  • the first face body 11 and the second face body 12 are quadrilaterals extending along the length direction (L1 direction) and width direction (W1 direction) of the biological cover respectively.
  • the transition connection portion 14 is formed between any three opposite sides of the first body 11 and the second body 12 .
  • Openings 13 are correspondingly formed between the unconnected sides of the first surface body 11 and the second surface body 12 .
  • the transitional connection portion 14 is formed after the first surface body 11 and the second surface body 12 are joined together, which does not affect the integrally formed structure of the biological cover.
  • the transition connecting part 14 is as the joint part of the first surface body 11 and the second surface body 12, as long as the first surface body 11 and the second surface body 12 are made along the length direction (L1 direction) and the width direction (W1 direction) of the biological cover. It is only necessary to join the integrally formed structure.
  • the present disclosure only sets the length of the transitional connection portion 14 along the L1 direction and the W1 direction, and the cross section of the transitional connection portion 14 in the L1 direction or the W1 direction can have any shape, for example, a polygon, a circle, or even a point. status and so on.
  • the transition connection part 14 is formed on both sides of the first surface body 11 and the second surface body 12 extending along the width direction (W1 direction), and on one side extending along the length direction (L1 direction), so that the first The surface body 11 and the second surface body 12 enclose a bag structure 1 with an accommodating cavity.
  • the transition connection portion 14 includes a first transition connection portion 141 and a second transition connection portion 142 on both sides along the width direction (W1 direction), and a third transition connection portion 143 along the length direction (L1 direction),
  • the third transitional connection part 143 is connected to the opposite end of the first transitional connection part 141 and the second transitional connection part 142, so that the first surface body 11 and the second surface body 12 enclose an integrally formed bag body with an accommodating cavity Structure 1.
  • the opening 13 is formed on the opposite side of the third transitional connection portion 143 along the length direction.
  • first transition connection portion 141 and the second transition connection portion 142 may also exist on opposite sides along the length direction (L1 direction), and the third transition connection portion 143 exists on the width direction (L1 direction).
  • One side in the W1 direction), and the other side in the width direction (W1 direction) opposite to the third transition connection portion 143 forms an opening 13 .
  • the biological cover is formed of sterilized and decellularized extracellular matrix (ECM) material.
  • ECM extracellular matrix
  • the sterilized and decellularized ECM material has high biocompatibility, low immunogenicity, and high antibacterial performance. It is suitable for wrapping implantable medical devices and implanting them in the body to exert antibacterial effects, isolate wounds, and avoid direct contact between equipment and the body. , Reduce equipment displacement, etc., effectively reduce inflammation, infection, calcification and scarring.
  • the ECM material has a three-dimensional tissue structure, which can promote the migration and growth of cells at the implanted site, promote the growth of blood vessels, and promote the growth of new tissues.
  • the ECM material is a biodegradable biomaterial, which will degrade after being implanted in the body for a period of time.
  • the new tissue wraps the implanted device to form a cystic structure, which further stabilizes the implanted medical device and reduces infection, collapse, hematoma, etc.
  • the sterilized and decellularized ECM material is sterilized and decellularized small intestinal submucosa material.
  • Small Intestinal Submucosa (SIS) material has excellent ability to promote tissue repair and healing.
  • At least one micropore is opened on the first surface body 11 and/or the second surface body 12 .
  • opening micropores on the one hand, it can prevent body fluids from accumulating inside the bag, on the other hand, it can effectively combine the new blood vessels and tissues at the implantation site with the biological cover, and wrap the implanted medical device to form a cystic structure, which can play a role in stabilizing the device. effect.
  • the diameter of the microholes is 1-3 mm, and the distance between the microholes is 10-15 mm.
  • the antimicrobial peptides are released after the biological cover is degraded to play the role of antibacterial and anti-infection. Further, the antimicrobial peptide is selected from one or more of NK-lysin, LL-37, and PR-39. By releasing rich antimicrobial peptides, the risk of implantable medical devices causing infection in the body can be reduced.
  • the biological cover in the present disclosure provides a natural, low immunogenic and antibacterial material barrier for implantable medical devices through the integrally formed first surface body 11, second surface body 12 and transition connection part 14, avoiding The metal or polymer material of the equipment casing is in direct contact with the body.
  • the biological cover does not need sutures for suturing, and its processing cost is low and the processing technology is simple; and compared with the suture biological cover, the integrated biological cover in the present disclosure has higher tensile strength, which can avoid the damage caused by sutures. Risks caused by breakage or premature degradation, its use performance is further improved.
  • the sterilized and decellularized extracellular matrix material in the present disclosure is a sterilized and decellularized small intestinal submucosa material obtained by taking small intestinal submucosa tissue, virus inactivation treatment and decellularization treatment, and has high biocompatibility, immune Low originality, good antibacterial performance and other advantages, and can effectively promote tissue repair and healing.
  • the submucosa tissue of the small intestine is obtained by removing lymphoid tissue, washing until the surface is free of stains, and drying.
  • the small intestinal submucosa tissue is derived from porcine small intestinal submucosa tissue.
  • the small intestinal submucosa tissue is cut to a specified size, for example, the length of the cut small intestinal submucosa tissue is 2-20 cm, and the width is 2-10 cm.
  • the step of virus inactivation treatment includes: immersing the small intestinal submucosa tissue in a virus inactivation solution comprising peracetic acid and ethanol for virus inactivation.
  • concentration of peracetic acid in the virus inactivation solution is (0.1-5)% (v/v)
  • concentration of peracetic acid is 0.5% (v/v), 1% (v/v) , 2% (v/v), 3% (v/v), 4% (v/v) and so on.
  • the concentration of ethanol in the virus inactivation solution is (5-40)% (v/v), exemplary, the concentration of ethanol is 8% (v/v), 10% (v/v), 15% (v/v) v), 20% (v/v), 25% (v/v), 30% (v/v), 35% (v/v), etc.
  • the time for virus inactivation treatment is 2-4 hours, and the temperature is 10-40°C.
  • the volume ratio of the virus inactivation solution to the small intestinal submucosa tissue is (20-40):1, for example, 25:1, 30:1, 35:1, 38:1, etc.
  • the harmful components in the submucosa tissue of the small intestine can be effectively removed to ensure the biological safety of its prepared biological kit.
  • the step of decellularization comprises soaking the small intestinal submucosa tissue in a decellularization solution comprising trypsin and EDTA for decellularization.
  • a decellularization solution comprising trypsin and EDTA for decellularization.
  • the content of trypsin in the decellularized solution is 0.1-2wt%, for example, the content of trypsin is 0.5wt%, 0.8wt%, 1wt%, 1.2wt%, 1.5wt%, 1.8wt% and so on.
  • the content of EDTA in the decellularization solution is 0.01-0.3wt%.
  • the content of EDTA is 0.05wt%, 0.08wt%, 0.1wt%, 0.15wt%, 0.2wt%, 0.22wt%, 0.25wt%, 0.28wt% etc.
  • the decellularization solution is PBS buffer containing trypsin and EDTA, and its pH is 6-8.
  • the decellularization is performed under sonication.
  • the small intestinal submucosa tissue is placed in an ultrasonic cleaning machine for decellularization.
  • the ultrasonic power during the decellularization process is above 5000 W, the temperature is 10-40° C., and the ultrasonic time is 10-60 minutes.
  • the decellularization treatment can effectively remove immune source components such as nucleic acid, cell membrane, and nuclear fragments in the submucosa tissue of the small intestine, reduce the immunogenicity of the material, and make the biological sleeve prepared by it suitable for implantation in the body.
  • a washing step is also included: washing the small intestinal submucosa tissue, and detecting the conductivity of the small intestinal submucosa tissue Reduced to below 10 ⁇ S/cm.
  • the cleaning solution for cleaning the small intestinal submucosa tissue once is PBS buffer solution with a pH of 6-8, the temperature of the cleaning solution is 10-40°C, and the volume ratio of the cleaning solution to the small intestinal submucosa tissue is (20-40): 1, for example, 25:1, 30:1, 35:1, 38:1, etc.
  • a cleaning step is performed in an ultrasonic cleaner.
  • the small intestinal submucosa is first washed with cleaning solution for 2-4 times, each time for 10-30 minutes, and then washed with water for injection at 10-40°C.
  • the volume ratio of water for injection to small intestinal submucosa is It is (20-40): 1, until the detection conductivity is below 10 ⁇ S/cm.
  • detection of electrical conductivity refers to the difference in electrical conductivity between the water for injection after cleaning the small intestinal submucosa tissue and the water for injection without cleaning the small intestinal submucosa tissue.
  • the detected electrical conductivity of the small intestinal submucosa tissue is reduced to below 10 ⁇ S/cm, and the residue of substances in the treatment solution is eliminated.
  • a second washing step is further included: washing the small intestinal submucosa tissue, and the detection conductivity of the small intestinal submucosa tissue is reduced to 1 ⁇ S/cm the following.
  • the cleaning solution for secondary cleaning of the small intestinal submucosa tissue is PBS buffer solution with a pH of 6-8, the temperature of the cleaning solution is 10-40°C, and the volume ratio of the cleaning solution to the small intestinal submucosa tissue is (20-40) : 1, for example, 25:1, 30:1, 35:1, 38:1, etc.
  • the small intestinal submucosa is first washed with cleaning solution for 2-4 times, each time for 10-30 minutes, and then washed with water for injection at 10-40°C.
  • the volume ratio of water for injection to small intestinal submucosa is (20-40): 1, until the detection conductivity is below 1 ⁇ S/cm.
  • the detected electrical conductivity of the small intestinal submucosa tissue is reduced to below 1 ⁇ S/cm, and the residue of substances in the treatment solution is eliminated.
  • the implantable medical device provided in the present disclosure includes the biological cover and the implantable medical device provided in the present disclosure, and the implantable medical device is at least partially placed in the accommodating cavity of the biological cover.
  • the biological cover in the present disclosure provides a layer of safe and stable physical barrier for the device implanted in the body, and can avoid the occurrence of various complications caused by the direct contact between the device and the body. Moreover, the integrally formed structure of the biological cover has high tensile strength, which avoids possible unstable factors such as suture breakage or premature degradation in suturing the biological cover, and has important clinical application prospects.
  • the implantable medical device is selected from devices used in the diagnosis, monitoring and/or treatment of cardiovascular diseases.
  • the implantable medical device is selected from any one of the following: cardiac pacemaker, implantable cardioverter defibrillator, cardiac resynchronization therapy pacemaker, implantable defibrillator Vibrators, implantable ECG event recorders, implantable cardiovascular monitors, etc.
  • the preparation method of the biological cover in the present disclosure comprises the following steps:
  • the preparation step of the biofilm layer 3 the biofilm layer 3 is formed from a sterilized and decellularized extracellular matrix material;
  • the coating step of the biofilm layer 3 alternately coating the biofilm layer 3 on the surfaces of both sides of the plate-shaped mold 2, so that the surfaces of the two sides are respectively coated with at least 2 layers of the biofilm layer 3;
  • the biofilm layer 3 of any layer includes a coating film layer 31 covering a partial area of one side surface, and an extended film layer continuously extending to the other side surface corresponding to the partial area. 32;
  • Freeze-drying step freeze-dry the biofilm layer 3 coated on the mold 2 in a non-pressing environment, so that at least two layers of the biofilm layer 3 are combined into one; wherein, two surfaces are coated
  • the biofilm layer 3 on the top forms a first face body 11 and a second face body 12 respectively, and the biofilm layer 3 connecting the first face body and the second face body forms a transition connection part 14, and the biofilm layer 3 is not
  • An opening 13 is formed covering one side of the mold 2 to obtain the biological cover.
  • the preparation method of the biological cover provided by the present disclosure can be used to prepare an integrally formed biological cover with high tensile strength. In the preparation process, it is not necessary to use suture thread to sew the cover body, which simplifies the preparation steps of the biological cover, reduces the preparation time and reduces the preparation cost.
  • the biofilm layer 3 is a biofilm layer 3 with a defined size formed from sterilized and decellularized extracellular matrix material. Further, the biofilm layer 3 is formed from sterilized and decellularized small intestinal submucosa material.
  • the coating step of biofilm layer 3 comprises:
  • S1 take the plate mold 2 whose two sides are respectively the first surface 21 and the second surface 22, as shown in Figure 2, along the length direction (L2 direction) of the mold 2, the first surface 21 and the second surface 22 are opposite
  • the top area is reserved as a non-clad area, and the rest of the area is used as a clad area.
  • the non-clad region of the first surface 21 is called the first non-clad region 211
  • the non-clad region of the second surface 22 opposite to the non-clad region of the first surface 21 is called the second non-clad region.
  • Covering region 221; the covering region of the first surface 21 is called the first covering region 212, and the covering region of the second surface 22 opposite to the covering region of the first surface 21 is called the second covering region 222 .
  • the plate-shaped mold 2 is a stainless steel bottom plate.
  • the size (width ⁇ height, in cm) of any one of the first surface 21 and the second surface 22 is 5.4 ⁇ 7; 6.9 ⁇ 8.5; 6.9 ⁇ 10; 6.9 ⁇ 11.5, etc. .
  • the biofilm layer 3 forms the coating film layer 31 coating the first coating area 212 and extends outward
  • the cladding step in the direction of two sides 22.
  • the first coating area 212 of the first surface 21 is coated with the biofilm layer 3, wherein the part of the biofilm layer 3 covering the first coating area 212 is used as the coating. coating layer 31 .
  • the biofilm layer 3 has a part extending beyond the first coating area 212 in the length direction (L2 direction) and the width direction (W2 direction) of the mold 2 , and this part is the stretched film layer 32 .
  • the stretched film layer 32 includes a first stretched film layer 321 and a second stretched film layer 322 located on opposite sides along the width direction of the mold 2, and the first stretched film layer 321 and the second stretched film layer are connected. 322 of the third stretched film layer 323 .
  • the stretched film layer 32 toward the second surface 22, specifically, as shown in FIG. Both are covered on the second cladding region 222 of the second surface 22 .
  • the first stretched film layer 321 and the third stretched film layer 323 are folded toward the second surface 22 at the part connecting the first stretched film layer 321 , so that the first stretched film layer 321 covers the second covering area 222 top; then the second stretched film layer 322 and the third stretched film layer 323 are folded towards the second surface 22 at the part connecting the second stretched film layer 323 so that the second stretched film layer 322 covers the coating area of the second surface 22 222 on.
  • the third stretched film layer 323 After the third stretched film layer 323 is folded twice, it forms a shape in which both sides are folded toward the middle, and the third stretched film layer 323 is folded toward the second surface 22 so that the third stretched film layer 323 covers the second coating area 222 . It should be noted that the present disclosure does not specifically limit the folding sequence of the first stretched film layer 321 , the second stretched film layer 322 and the third stretched film layer 323 , which can be set according to specific needs.
  • the first stretched film layer 321 and the second stretched film layer 322 completely cover the second cladding region 222 .
  • the area of the first stretched film layer 321+the area of the second stretched film layer 322 the area of the second cladding region 222, therefore, the first stretched film layer 321 and the second stretched film layer 322 completely cover the second surface 22
  • the cladding region 222 and the two do not overlap each other.
  • the first stretched film layer 321 and the second stretched film layer 322 do not completely cover the second cladding region 222, for example, the area of the first stretched film layer 321 + the area of the second stretched film layer 322 area ⁇ area of the second cladding region 222 . Therefore, after the first stretched film layer 321 and the second stretched film layer 322 are folded on the second covering area 222 , there is a certain gap between the first stretched film layer 321 and the second stretched film layer 322 .
  • first stretched film layer 321, the second stretched film layer 322 and the third stretched film layer 323 covering the second coating area 222 are flattened to form the first biofilm layer covering the second surface 22 3.
  • first stretched film layer 321 and the second stretched film layer 322 completely cover the second cladding region 222 or not, they together form the third stretched film layer 323 to cover the second surface. 22 layers of a biofilm layer 3 . That is, in one coating process, the extended film layer 32 forms a “one layer” of biofilm layer 3 covering the second coating area 222 . Therefore, after the coating step from the first surface 21 to the second surface 22 is completed, both the first surface 21 and the second surface 22 of the mold 2 are coated with a layer of biofilm layer 3 .
  • the biofilm layer 3 forms the coating film layer 31 covering the second coating area 222 and extends outwards out of the second coating area 222.
  • the stretched film layer 32 of the second cladding area 222; the stretched film layer 32 is bent toward the first surface 21, so that the stretched film layer 32 covers the first cladding area 212 of the first surface 21;
  • the stretched film layer 32 on the first surface 21 is flattened, so that the first surface 21 and the second surface 22 are respectively coated with two layers of biofilm layers 3, and the process from the second surface 22 to the first surface is completed. Coating step in the direction of surface 21.
  • the stretched film layer 32 includes a first stretched film layer 321 and a second stretched film layer 322 located on opposite sides along the width direction of the mold 2, and a third stretched film layer connecting the first stretched film layer 321 and the second stretched film layer 322 Layer 323.
  • the stretched film layer 32 is bent towards the first surface 21, and the first stretched film layer 321, the second stretched film layer 322 and the third stretched film layer 323 are all covered on the first coating area 212 by three times of folding, The specific folding process is shown in S2.
  • the first stretched film layer 321 and the second stretched film layer 322 completely cover the first cladding region 212 .
  • the area of the first stretched film layer 321+the area of the second stretched film layer 322 the area of the first cladding region 212, therefore, the first stretched film layer 321 and the second stretched film layer 322 completely cover the first cladding area. area 212 and the two do not overlap each other.
  • the first stretched film layer 321 and the second stretched film layer 322 do not completely cover the first cladding region 212, for example, the area of the first stretched film layer 321 + the area of the second stretched film layer 322 area ⁇ area of the first cladding region 212 . Therefore, after the first stretched film layer 321 and the second stretched film layer 322 are folded on the first covering area 212 , there is a certain gap between the first stretched film layer 321 and the second stretched film layer 322 .
  • first stretched film layer 321 , the second stretched film layer 322 and the third stretched film layer 323 coated on the first coating area 212 are flattened to form a second layer of biofilm covering the first surface 21 Layer 3.
  • first stretched film layer 321 and the second stretched film layer 322 completely cover the first covering region 212, they together form a layer covering the first surface with the third stretched film layer 323. 21 of a biofilm layer 3 . That is, in one coating process, the extended film layer 32 forms a “one layer” of biofilm layer 3 covering the first coating area 212 . Therefore, after the coating step from the second surface 22 to the first surface 21 is completed, both the first surface 21 and the second surface 22 of the mold 2 are coated with two layers of biofilm layers 3 .
  • the biofilm layer 3 coated on the mold 2 is freeze-dried in a non-pressing environment, so that at least two layers of the biofilm layer The layers 3 are integrated to obtain a biological cover integrally formed by the transitional connection part 14 , the first surface body 11 and the second surface body 12 .
  • the plate-shaped mold 2 coated with the biofilm layer 3 is placed in a vacuum freeze dryer for non-compression freeze-drying.
  • the conditions for non-compression freeze-drying include: pre-freezing the plate-shaped mold 2 coated with the biofilm layer 3 to -45°C, and keeping it warm for 1-2 hours; then adjusting the temperature to -15°C, and keeping it warm for 5-7 hours; Then adjust the temperature to 0°C and keep it warm for 2 hours; finally adjust the temperature to 25°C and keep it warm for 4 hours.
  • the biofilm layer 3 is freeze-dried and shaped by a freeze-drying process under non-pressing conditions to obtain an integrally formed biological cover with a bag structure 1 .
  • the size of the biological set (width ⁇ height, in cm) is 5.4 ⁇ 5; 6.9 ⁇ 6.5; 6.9 ⁇ 8; 6.9 ⁇ 9.5 and so on.
  • a punching step is further included after the freeze-drying step. Specifically, the biological cover is removed from the mold 2 and cut to a desired size. Then the biological cover is put into a mechanical punching machine, and punches holes on the first face body 11 and/or the second face body 12 to form a hole located on the first face body 11 and/or the second face body 12. at least one micropore.
  • the first face body 11 and/or the second face body 12 are perforated with a hole pitch of 10 mm and a hole diameter of 3 mm.
  • a hole pitch of 10 mm and a hole diameter of 3 mm are opened on both the first surface body 11 and the second surface body 12 .
  • a sterilization step is included after the aperturing step. Specifically, after the biological cover is kept warm, ethylene oxide is used to sterilize the biological cover, and then the ethylene oxide is decomposed to obtain a sterilized biological cover.
  • the temperature of the heat preservation treatment is 20-40° C.
  • the time is 2-4 hours
  • the humidity is 30-70%.
  • the concentration of ethylene oxide feeding is 300-1000mg/L
  • the time of sterilization treatment is 4-8 hours.
  • the step of decomposing ethylene oxide is carried out in a ventilated desorption chamber, the temperature is controlled at 10-30° C., and the time is 14-28 days.
  • a biological cover with high biological safety and suitable for wrapping medical equipment implanted in the body is obtained, so as to reduce the occurrence of complications such as infection and verification after the equipment is implanted in the body.
  • a gap of a certain length (1/4 to 1/2 of the height of various specifications of the product) is cut at one end of the biological cover, and then the CIED is taken out.
  • the preparation method of the biological cover provided by the present disclosure does not need to use sutures to suture the first surface body 11 and the second surface body 12, and can be used to prepare an integrally formed biological cover, which simplifies the preparation process and reduces the production cost of the biological cover. Moreover, compared with the sutured biological cover, the integrally formed biological cover has improved tensile strength, which can improve the stability of the device in vivo and reduce the probability of complications after the wrapped device is implanted in the body.
  • This embodiment provides a method for preparing small intestinal submucosa material, which specifically includes the following steps:
  • the specified size specifically refers to: width 2-10cm, length 2-20cm.
  • Adopt the virus inactivation solution that comprises 2% (v/v) peracetic acid, 20% (v/v) ethanol to soak pig small intestine submucosa tissue, carry out virus inactivation treatment; Virus inactivation solution and pig small intestine submucosa tissue
  • the volume ratio is 40:1
  • the inactivation time is 4 hours
  • the temperature range is 40°C.
  • the cleaning solution is a PBS solution with a pH of 6-8, the temperature of the cleaning solution is 30°C, the volume of the cleaning solution and the porcine small intestinal submucosa tissue
  • the ratio is 40:1.
  • the volume ratio of water for injection and porcine small intestinal submucosa tissue is 40:1, and stop until the detection conductivity is below 10 ⁇ S/cm; the cleaning process is performed under ultrasonic in the washing machine.
  • the decellularization solution is a solution of 1 wt% trypsin solution and 0.2 wt% EDTA, and the solvent is PBS solution with pH6-8.
  • the volume ratio of decellularization solution to porcine small intestinal submucosa tissue is 40:1.
  • the decellularization process is carried out in an ultrasonic cleaner with an ultrasonic power of at least 5000W.
  • the cleaning time of the decellularization process is 30 minutes and the temperature is 30°C.
  • the cleaning solution is a PBS solution with a pH of 6-8, the temperature of the cleaning solution is 30°C, and the volume of the cleaning solution and the porcine small intestinal submucosa tissue
  • the ratio is 40:1.
  • the volume ratio of water for injection to porcine small intestinal submucosa tissue is 40:1, and stop until the detection conductivity is 1 to below the detection conductivity to obtain sterilization. and decellularized small intestinal submucosa material.
  • the present embodiment provides the preparation method of biological cover, specifically comprises the following steps:
  • the small intestinal submucosa material prepared in Example 1 was used as the biofilm layer.
  • Carry out fixed molding on the mould, described mold is made up of stainless steel base plate of different sizes (type: 5.4*7; 15cm) of biofilm layer wraps around the bottom plate, and the remaining material at the bottom is about 5mm to 10mm, folded to one side, and scraped with a stainless steel scraper to complete the step of forward coating; in the opposite direction, wrap a new biofilm layer Make a circle around the base plate, with about 5mm to 10mm of material remaining at the bottom, fold it to the other side, scrape it flat, and complete the step of reverse coating. Repeat this process once, scrape it flat, and finally get a SIS biological cover with 2 sides and 4 layers, and the specification model is (5.4 ⁇ 5; 6.9 ⁇ 6.5; 6.9 ⁇ 8; 6.9 ⁇ 9.5; the unit of width ⁇ height is cm).
  • step drying (2) remove the freeze-dried biological cover from step drying (2) from the stainless steel base plate, cut it into a fixed size on a mold, then put it into a mechanical punching machine, and punch holes with a spacing of 10mm and a hole diameter of 3mm.
  • Stainless steel scissors cut a gap of a certain length (about 1/2z of the height of various specifications of the product) at one end of the biological cover, which is convenient for taking out the CIED, and then pack it in a Tyvek packaging bag.
  • the sterilization conditions are: temperature 20-40 °C for 2-4 hours, humidity 30-70%, then pass through concentration 300-1000mg/L ethylene oxide, sterilization 4 -8 hours; the analysis process is carried out in a ventilated analysis room, the temperature is controlled between 10-30°C, and the time is 14-28 days.
  • Prepare sample 1 use the small intestinal submucosa material prepared in Example 1 as the biofilm layer, and after vacuum freeze-drying, use a sewing machine (JH9870, Brother (China) Commercial Co., Ltd.) to suture according to the needle spacing of 2mm to make a dry- Stitched SIS biological set.
  • a sewing machine JH9870, Brother (China) Commercial Co., Ltd.
  • Preparation sample 2 The integrated SIS biological kit prepared in Example 2 was used as the dry-integrated SIS biological kit.
  • sample 3 The small intestinal submucosa material prepared in Example 1 was used as the biofilm layer, and after vacuum freeze-drying, it was sutured using a sewing machine (JH9870, Brother (China) Commercial Co., Ltd.) with a needle spacing of 2 mm. Place in PBS solution for 2-5 minutes for hydration to make a hydration-suture SIS biological cover.
  • a sewing machine JH9870, Brother (China) Commercial Co., Ltd.
  • Samples 1, 2, 3, and 4 were tested for tensile strength. Cut the material into samples with a width of 20 mm and a length of 30 mm. The distance between the fixtures is 15mm, and samples 1-4 are respectively clamped to the fixtures, and the maximum force value of the samples is measured by a pharmaceutical packaging performance tester (model: MED-1, Jinan Languang Electromechanical Technology Co., Ltd.).
  • sample 1 and sample 2 are statistical diagrams of the tensile strength of the dry integrated and sutured SIS biological cover, wherein sample 1 and sample 2 have a statistical difference of ###, and the p value ⁇ 0.001, indicating that the biological cover is dry In the state, the tensile strength of the suture biological cover is much smaller than that of the integrated biological cover.
  • Sample 3 and sample 4 in the figure are statistical charts of the tensile strength of the integrated and sutured SIS biological cover after hydration, among which there is a statistical difference between sample 3 and sample 4, and the p value is less than 0.01, indicating that the biological cover after hydration , the tensile strength of the suture biological cover is less than that of the integrated biological cover.
  • the results show that the tensile strength of the sutured biological cover is lower than that of the integrated biological cover, no matter in the dry state or the hydrated state of the SIS biological cover, which indicates that the integrated biological cover has better tensile strength when implanted in the body. strength.

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Abstract

一种用于容置植入型医疗设备的生物套及其制备方法、用途。生物套由灭菌且脱细胞的细胞外基质材料形成，并且具有一体成型的袋体结构（1）。生物套的容置腔内放置植入型医疗设备，可为植入型医疗设备提供物理屏障，避免植入型医疗设备与机体直接接触，降低了植入后感染、炎症、瘢痕化及钙化等并发症的发生。

Description

用于容置植入型医疗设备的生物套及其制备方法、用途 技术领域
本公开属于医疗器械和生物医用材料领域，具体来说，本公开涉及用于容置植入型医疗设备的生物套及其制备方法、用途。
背景技术
植入型医疗设备是治疗心脑血管疾病和骨科疾病等最有效的手段之一。其中，心血管植入型电子器械(Cardiovascular Cardiac Implantable Electronic Device，CIED)包括心脏起搏器(Cardiac Pacemaker，PM)、心律转复除颤器(Implantable Cardioverter Defibrillator，ICD)及心脏再同步治疗(Cardiac Resynchronization Therap，CRT)起搏器和除颤器、植入型心电事件记录仪(Insertable cardiac monitor，ICM)以及植入型心血管监测器等，是典型的高风险医疗器械。近些年，又涌现出全皮下ICD(Subcutaneous ICD，S-ICD)、无导线起搏器及磁共振兼容器械等新型的治疗设备。
CIED主要应用于缓慢性心律失常，(如病态窦房结综合征、III度房室传导阻滞)，快速性心律失常(如阵发性心房颤动、长QT综合征)，以及非心电疾患(如顽固性心力衰竭、神经介导性晕厥、肥厚梗阻型心肌病)的治疗和监测等。近年来，随着心血管疾病患病率的不断增加，人口老龄化和临床适应症的扩大，CIED的植入数量也呈现出逐渐上升的趋势。
由于植入量的增加，CIED植入后的并发症日益严重。CIED主要由脉冲发生器、电极及导线组成，通常情况下，起搏器、除颤器等心血管植入物是由合金材料(例如，Ni-Co-Cr合金、Co-Cr-Mo合金、钛和Ti-6A1-4V合金等)、不锈钢和各种生物相容性聚合物材料制成，一般直接植入胸大肌前皮下组织形成的空腔中。在此过程中发生的主要并发症包括感染、血肿、破溃、血栓、瘘道形成、电极脱位、电极心肌穿孔、导线磨损断裂、设备体内移位等，其中感染、血肿、破溃是CIED植入术后常见的并发症，发生率可达7％，对患者造成了严重影响，已成为心血管疾病治疗面临的重要难题。
设备导致植入后并发症发生的主要因素有：
(1)设备的外壳为常为金属或高分子材料，这对于人体是异物，不可避免的发生排斥反应，从而引发感染、炎症等；
(2)由于植入设备尺寸不能与空腔完全契合，或者不恰当的肢体运动等方面原因，会引起植入设备不断移动，导致摩擦出血、血肿、破溃后血凝块形成血栓等；
(3)由于植入设备后排斥反应，炎症等疾病的发生，可导致组织结构发生变化，附近组织发生移位，最后可引起瘘管形成；
(4)导线磨损断裂及设备体移位等均有可能导致植入设备过早失效，从而引发二次手术及更为严重的并发症。
这些并发症的出现不只增加了患者的经济负担，同时也降低了患者的生活质量，尤其对于那些依赖CIED等植入型医疗设备的患者，更是同时增加了死亡率。因此，如何降低感染发生率，降低设备植入后并发症的发生，是当前亟需解决的重要问题。
发明内容
发明要解决的问题
鉴于现有技术中存在的问题，例如，植入型医疗设备在植入患者体内后，易发生感染等并发症，导致患者的生存质量降低、死亡率提高。为此，本公开提供了一种生物套，植入型医疗设备放置于生物套的容置腔内，可避免与人体直接接触，减少感染、炎症等并发症的发生；并且，一体成型的生物套具有高的抗拉强度，可避免缝合生物套可能存 在的缝合线断裂或缝合线过早降解等风险，提高包裹植入型医疗设备的稳固性。
用于解决问题的方案
第一方面，本公开提供了一种生物套，其中，所述生物套由灭菌且脱细胞的细胞外基质材料形成，并且具有一体成型的袋体结构；所述袋体结构具有用于容置植入型医疗设备的容置腔，以及将所述容置腔与外界连通的开口。
在一些实施方式中，根据本公开所述的生物套，其中，所述容置腔由相对的第一面体和第二面体围成；其中，所述第一面体和第二面体相接的部分形成所述生物套的过渡连接部；
可选地，所述过渡连接部沿所述生物套的长度方向的长度为5～10cm，所述过渡连接部沿所述生物套的宽度方向的长度为4～8cm。
在一些实施方式中，根据本公开所述的生物套，其中，所述第一面体和/或所述第二面体上开设有至少一个微孔；可选地，所述微孔的直径为1～3mm；可选地，所述微孔的间距为10～15mm。
在一些实施方式中，根据本公开所述的生物套，其中，所述灭菌且脱细胞的细胞外基质材料是取小肠粘膜下层组织，经病毒灭活处理和脱细胞处理得到；
优选地，所述病毒灭活处理的步骤包括：将小肠粘膜下层组织浸泡于包含(0.1-5)％(v/v)过氧乙酸和(5-40)％(v/v)乙醇的病毒灭活溶液中，在10-40℃温度下，处理2-4小时；
优选地，所述脱细胞处理的步骤包括：将小肠粘膜下层组织浸泡于包含0.1-2wt％胰蛋白酶和0.01-0.3wt％EDTA的脱细胞溶液中，在10-40℃温度下，超声波功率为5000W以上的超声条件下，处理10-60分钟。
在一些实施方式中，根据本公开所述的生物套，其中，在所述病毒灭活处理和脱细胞处理的步骤之间，还包括如下步骤：对所述小肠粘膜下层组织进行清洗，至所述小肠粘膜下层组织的检测电导率降低为10μS/cm以下；
优选地，在所述脱细胞处理的步骤之后，还包括如下步骤：对所述小肠粘膜下层组织进行清洗，至所述小肠粘膜下层组织的检测电导率降低为1μS/cm以下。
第二方面，本公开提供了一种根据第一方面所述的生物套的制备方法，其中，所述制备方法包括如下步骤：
生物膜层的制备步骤：制备灭菌且脱细胞的小肠粘膜下层材料，作为用于制备生物套的生物膜层；
生物膜层的包覆步骤：在板状模具的两侧的表面上交替包覆生物膜层，使所述两侧的表面上分别包覆至少2层的所述生物膜层；其中，任一层的所述生物膜层包括覆盖于一侧表面的部分区域上的包覆膜层，以及连续延伸至与所述部分区域相对应的另一侧表面上的延伸膜层；
冻干步骤：在非压制环境下对包覆于所述模具上的生物膜层进行冷冻干燥处理，使至少2层的所述生物膜层结合为一体；其中，包覆两个表面的生物膜层分别形成第一面体和第二面体，连接所述第一面体和第二面体的生物膜层形成过渡连接部，所述生物膜层未包覆所述模具的一侧形成开口，得到由第一面体、第二面体和过渡连接部一体成型的生物套。
在一些实施方式中，根据本公开所述的制备方法，其中，所述生物膜层的包覆步骤包括：
取两侧分别为第一面和第二面的板状模具，沿所述模具的长度方向，将所述第一面和第二面相对的顶部区域预留为非包覆区，其余区域作为包覆区；
在所述第一面的包覆区上包覆第一生物膜层，所述第一生物膜层形成覆盖所述包覆区的第一生物膜层的包覆膜层和向外延伸出所述包覆区的第一生物膜层的延伸膜层；将 所述延伸膜层朝向第二面的方向弯折，使所述延伸膜层覆盖所述第二面的包覆区；将位于所述第二面上的延伸膜层压平，完成第一面向第二面方向的包覆步骤；
在所述第二面的包覆区上包覆第二生物膜层，所述第二生物膜层形成覆盖所述包覆区的第二生物膜层的包覆膜层和向外延伸出所述包覆区的第二生物膜层的延伸膜层；将所述第二生物膜层的延伸膜层朝向第一面方向弯折，使所述第二生物膜层的延伸膜层覆盖所述第一面的包覆区；将位于所述第一面上的延伸膜层压平，完成第二面向第一面方向的包覆步骤；
优选地，所述第一面向第二面方向的包覆步骤中，所述第一生物膜层的延伸膜层完整包覆所述第二面的包覆区；和/或，所述第一面向第二面方向的包覆步骤中，所述第二生物膜层的延伸膜层完整包覆所述第一面的包覆区；
优选地，至少重复一次所述第一面向第二面方向的包覆步骤，和所述第一面向第二面方向的包覆步骤。
在一些实施方式中，根据本公开所述的制备方法，其中，所述冷冻干燥处理的步骤包括：将包覆生物膜层的板状模具置于真空冷冻干燥机中进行非压制冻干；
优选地，所述非压制冻干的条件包括：预冻至-45℃，保温1-2小时；然后调节温度至-15℃，保温5-7小时；再调节温度至0℃，保温2小时；最后调节温度至25℃，保温4小时。
在一些实施方式中，根据本公开所述的制备方法，其中，所述制备方法还包括如下步骤：
打孔步骤：将所述生物套从所述模具上取下，裁切为所需尺寸，然后在所述第一面体和/或所述第二面体上打孔，形成位于所述第一面体和/或所述第二面体上的至少一个微孔；优选地，以微孔的间距为10-15mm，直径为1-3mm在所述第一面体和/或所述第二面体上打孔；
灭菌步骤：将所述生物套保温处理后，采用环氧乙烷对所述生物套进行灭菌处理，然后解析环氧乙烷，得到灭菌处理的生物套；优选地，所述保温处理的温度为20-40℃，时间为2-4小时，湿度30-70％；优选地，所述环氧乙烷通入的浓度为300-1000mg/L，所述灭菌处理的时间为4-8小时；优选地，所述解析环氧乙烷的步骤在在通风的解析室中进行，温度控制为10-30℃，时间为14-28天。
第三方面，本公开提供了一种植入型医疗装置，其中，所述植入型医疗装置包括：
根据第一方面所述的生物套，或根据第二方面所述的方法制备的生物套；
植入型医疗设备，所述植入型医疗设备至少部分地放置于所述生物套的容置腔内；
可选地，所述植入型医疗设备选自用于心血管疾病的诊断、监测和/或治疗的设备；可选地，所述植入型医疗设备选自下述任一种：心脏起搏器、植入型心律转复除颤器、心脏再同步治疗起搏器、植入型除颤器、植入型心电事件记录仪、植入型心血管监测器。
在一些实施方式中，根据本公开所述的生物套，或根据本公开所述的方法制备的生物套在容置植入型医疗设备中的用途；
可选地，所述植入型医疗设备选自用于心血管疾病的诊断、监测和/或治疗的设备；可选地，所述植入型医疗设备选自下述任一种：心脏起搏器、植入型心律转复除颤器、心脏再同步治疗起搏器、植入型除颤器、植入型心电事件记录仪、植入型心血管监测器。
发明的效果
在一些实施方式中，本公开提供的一种生物套，其容置腔内放置植入型医疗设备，可为植入型医疗设备提供物理屏障，避免植入型医疗设备与机体直接接触，降低了植入后感染、炎症、瘢痕化及钙化等并发症的发生。并且，生物套一体成型的结构具有抗拉伸强度高，能够避免缝合生物套存在的缝合线断裂或缝合线过早降解等不良使用状况，实现对植入型设备稳固的物理隔离。
在一些实施方式中，本公开提供的生物套，由灭菌且脱细胞的小肠粘膜下层材料形成，其使用安全性高，并具有良好的组织修复能力，能够促进植入位置处组织的修复、愈合，加速植入后的术后恢复。
进一步地，小肠粘膜下层材料在体内酶的作用下可发生降解，最终使植入型医疗设备的外部包裹新生组织形成囊状结构，进一步加固植入型医疗设备，维持设备的正常运行并延长设备的使用时间。
在一些实施方式中，本公开提供的生物套，降解后释放抗菌肽，降低医疗设备植入后炎症、感染等并发症的发生概率。
在一些实施方式中，本公开提供的生物套的制备方法，可制备得到一体化成型的生物套，无需使用缝合线进行套体的缝合，能够减少生物套的制备时间，降低制备成本。并且避免了缝合线断裂的风险，以及缝合线早于套体发生降解的风险。
附图说明
图1示出了生物套的结构示意图；
图2示出了板状模具的结构示意图；
图3示出了生物膜层的结构示意图；
图4-A示出了由第一面向第二面包覆生物膜层的过程示意图；
图4-B示出了由第二面向第一面包覆生物膜层的过程示意图；
图5示出了生物套的实物图，其中，A为生物套的一个侧面示意图，B为生物套的另一侧面示意图，C为生物套的袋口示意图，D为生物套的侧方斜视图。
图6示出了4种样品的抗拉强度统计图。其中，样品1为干燥-缝合SIS生物套，样品2为干燥-一体化SIS生物套，样品3为水合-缝合SIS生物套，样品4为水合-一体化SIS生物套。
附图标记说明：
1-袋体结构，11-第一面体，12-第二面体，13-开口，14-过渡连接部，141-第一过渡连接部，142-第二过渡连接部，143-第三过渡连接部；
2-模具，21-第一面，211-第一非包覆区，212-第一包覆区，22-第二面，221-第二非包覆区，222-第二包覆区；
3-生物膜层，31-包覆膜层，32-延伸膜层，321-第一延伸膜层，322-第二延伸膜层，323-第三延伸膜层。
具体实施方式
以下将详细说明本发明的各种示例性实施例、特征和方面。在这里专用的词“示例性”意为“用作例子、实施例或说明性”。这里作为“示例性”所说明的任何实施例不必解释为优于或好于其它实施例。
另外，为了更好地说明本发明，在下文的具体实施方式中给出了众多的具体细节。本领域技术人员应当理解，没有某些具体细节，本发明同样可以实施。在另外一些实例中，对于本领域技术人员熟知的方法、手段、器材和步骤未作详细描述，以便于凸显本发明的主旨。
如无特殊声明，本说明书中所使用的单位均为国际标准单位，并且本发明中出现的数值，数值范围，均应当理解为包含了工业生产中所不可避免的系统性误差。
本说明书中，使用“可以”表示的含义包括了进行某种处理以及不进行某种处理两方面的含义。
本说明书中，所提及的“一些具体/优选的实施方式”、“另一些具体/优选的实施方式”、“实施方式”等是指所描述的与该实施方式有关的特定要素(例如，特征、结构、性质和/或特性)包括在此处所述的至少一种实施方式中，并且可存在于其它实施方式中或者可不存在于其它实施方式中。另外，应理解，所述要素可以任何合适的方式组合在各种实施方式中。
本说明书中，使用“数值A～数值B”表示的数值范围是指包含端点数值A、B的范围。
本说明书中，使用“v/v”表示体积百分比含量，使用“wt％”表示质量百分比含量，使用“w/v”表示“克/毫升”浓度。
本说明书中，使用“常温”、“室温”时，其温度可以是10-40℃。
生物套
本公开的第一方面提供了一种生物套，所述生物套由灭菌且脱细胞的细胞外基质材料形成，并且具有一体成型的袋体结构1；所述袋体结构1具有用于容置植入型医疗设备的容置腔，以及将所述容置腔与外界连通的开口13。
将植入型医疗设备放置于生物套的容置腔内，可为医疗设备提供一层物理屏障，降低由于设备的外壳的金属或高分子材料与人体直接接触导致的感染等并发症的发生率，并且可以减少由于设备移位等导致的设备失效、损坏。生物套的使用虽然可以发挥物理屏障的作用，但是目前容置植入型医疗设备的生物套多采用缝合的方式形成袋状结构，缝合过程需要控制无菌环境，使生物套的加工过程复杂化，增加了生物套的加工成本和加工时间。并且，通过缝合方式形成的生物套，在使用过程中，可能发生缝合线断裂或缝合线早于套体降解等风险，对医疗设备的体内植入带来不利影响。而本公开中的生物套具有一体成型的袋体结构1，无需使用缝合线进行缝合，有效减少了由于缝合线的断裂、过早降解等导致的袋体分离、移位等不良后果；并且，与缝合生物套相比，本公开中一体成型的生物套具有更高的抗拉伸强度，其使用强度和稳固性增加，可进一步减少设备植入后发生并发症的概率。
在一些实施方式中，生物套的容置腔由第一面体11和第二面体12围成。其中，第一面体11和第二面体12相接的部分形成生物套的过渡连接部14。
在本公开中，第一面体11和第二面体12可以具有各种不同的形状和尺寸。示例性的，第一面体11和第二面体12分别可以是三角形、四边形、五边形、圆形等等。具体地，第一面体11和第二面体12被配置为围成用于容置植入型医疗设备的容置腔，第一面体11和第二面体12的形状及尺寸可依据植入型医疗设备的形状和尺寸进行适应性的调整。
在一些实施方式中，如图1所示，第一面体11和第二面体12相对的面呈四边形，第一面体11和第二面体12分别具有沿生物套的长度方向(L1方向)延伸的两个侧边，和沿生物套的宽度方向(W1方向)延伸的两个侧边。
在一些实施方式中，第一面体11和第二面体12中任一者的长度为5～10cm，宽度为4～8cm。示例性的，第一面体11和第二面体12中任一者的面积被配置为5.4×5，6.9×6.5，6.9×8或6.9×9.5(宽×高，单位：cm)。
在一些实施方式中，相对的第一面体11和第二面体12两者相对且具有相同的形状和尺寸。在另外一些实施方式中，第一面体11和第二面体12也可以是相对，但具有不同的形状或尺寸。
在本公开中，过渡连接部14形成于第一面体11和第二面体12的部分相接的侧边，使第一面体11和第二面体12围成适于容置植入型医疗设备的容置腔，第一面体11和第二面体12的未连接的侧边之间对应形成开口13，植入型医疗设备通过开口13可部分地或全部地被放置于容置腔内。
在本公开中，开口13将生物套的容置腔与外界连通。其中，“外界”是指生物套的容置腔以外的空间，可以是体内环境也可以是体内环境，具体依据生物套的使用环境决定。
在一些实施方式中，如图1所示，第一面体11和第二面体12分别呈沿生物套的长度方向(L1方向)和宽度方向(W1方向)延伸的四边形。其中，过渡连接部14形成于第一面体11和第二面体12的任意三个相对的侧边之间。第一面体11和第二面体12未相接的侧边之间对应形成开口13。
需要说明的是，本公开中过渡连接部14是由于第一面体11和第二面体12相接合后形成，其不影响生物套的一体成型结构。并且，过渡连接部14作为第一面体11和第二面体12的接合部分，只要使第一面体11和第二面体12沿生物套的长度方向(L1方向)和宽度方向(W1方向)接合为一体成型的结构即可。因此，本公开仅对过渡连接部14沿L1方向和W1方向的长度进行设定，过渡连接部14在L1方向或W1方向的截面可以具有任意的形状，例如，多边形、圆形、甚至为点状等等。
在一些实施方式中，过渡连接部14形成于第一面体11和第二面体12沿宽度方向(W1方向)延伸的两侧，和沿长度方向(L1方向)延伸的一侧，使第一面体11和第二面体12围成具有容置腔的袋体结构1。更具体地，过渡连接部14包括沿宽度方向(W1方向)的两侧的第一过渡连接部141和第二过渡连接部142，以及沿长度方向(L1方向)的第三过渡连接部143，第三过渡连接部143与第一过渡连接部141和第二过渡连接部142相对的一个端部连接，使第一面体11和第二面体12围成具有容置腔的一体成型的袋体结构1。其中，第三过渡连接部143沿长度方向相对的另一侧形成开口13。
在另外一些实施方式中，第一过渡连接部141和第二过渡连接部142也可以是存在于沿长度方向(L1方向)的相对的两侧，第三过渡连接部143存在于沿宽度方向(W1方向)的一侧，与第三过渡连接部143相对的沿宽度方向(W1方向)的另一侧形成开口13。
在本公开中，生物套由灭菌且脱细胞的细胞外基质(Extracellular matrix，ECM)材料形成。
灭菌且脱细胞的ECM材料具有高的生物相容性、低免疫原性，以及高抗菌性能，适合包裹植入型医疗设备植入体内，发挥抗菌、创面隔离、避免设备与机体的直接接触、减少设备移位等作用，有效减少炎症、感染、钙化及瘢痕化的产生。
进一步地，ECM材料具有三维立体的组织结构，可以促进植入位置处细胞的迁移、生长，促进血管生长，促进新生组织的生长。而ECM材料是可降解的生物材料，在植入体内一段时间后会发生降解，新生组织包裹植入的设备形成囊状结构，进一步稳固了植入的医疗设备，减少感染、溃败、血肿等各种并发症的发生，并且保证了医疗设备的正常运行，增加了设备的使用寿命。
在一些实施方式中，灭菌且脱细胞的ECM材料为灭菌且脱细胞的小肠粘膜下层材料。小肠粘膜下层(Small Intestinal Submucosa，SIS)材料具有优异的促进组织修复、愈合能力。
在一些实施方式中，所述第一面体11和/或所述第二面体12上开设有至少一个微孔。通过开设微孔，一方面可以防止体液在袋内部积累，另一方面可以使植入位置处新生的血管、组织与生物套有效结合，包裹植入的医疗设备形成囊状结构，发挥稳固设备的作用。在一些优选的实施方式中，微孔的直径为1～3mm，微孔的间距为10～15mm。
在一些实施方式中，生物套降解后释放抗菌肽，发挥抗菌、抗感染的作用。进一步地，抗菌肽选自NK-lysin、LL-37、PR-39中的一种或多种。通过释放丰富的抗菌肽，可降低植入型医疗设备在体内引发感染的风险。
本公开中的生物套，通过一体成型的第一面体11、第二面体12和过渡连接部14， 为植入型医疗设备提供了一种天然、低免疫原性且抗菌的物质屏障，避免设备外壳的金属或高分子材料与机体直接接触。同时，生物套不需要缝合线进行缝合，其加工成本低、加工工艺简单；并且与缝合生物套相比，本公开中一体成型的生物套具有更高的抗拉伸强度，能够避免由于缝合线断裂或过早降解导致的风险，其使用性能进一步提升。
灭菌且脱细胞的细胞外基质材料
本公开中灭菌且脱细胞的细胞外基质材料是取小肠粘膜下层组织，经病毒灭活处理和脱细胞处理得到的灭菌且脱细胞的小肠粘膜下层材料，具有生物相容性高、免疫原性低、抗菌性能好等优势，且能够有效促进组织的修复、愈合。
在一些实施方式中，小肠粘膜下层组织是剔除了淋巴组织，冲洗至表面无污渍，滤干后得到。在一些具体的实施方式中，小肠粘膜下层组织来源于猪小肠粘膜下层组织。在一些具体的实施方式中，小肠粘膜下层组织被裁切为规定的尺寸，例如，裁切后的小肠粘膜下层组织的长度为2-20cm，宽度为2-10cm。
在一些实施方式中，病毒灭活处理的步骤包括：将小肠粘膜下层组织浸泡于包含过氧乙酸和乙醇的病毒灭活溶液中进行病毒灭活。其中，病毒灭活溶液中过氧乙酸的浓度为(0.1-5)％(v/v)，示例性的，过氧乙酸的浓度为0.5％(v/v)、1％(v/v)、2％(v/v)、3％(v/v)、4％(v/v)等等。病毒灭活溶液中乙醇的浓度为(5-40)％(v/v)，示例性的，乙醇的浓度为8％(v/v)、10％(v/v)、15％(v/v)、20％(v/v)、25％(v/v)、30％(v/v)、35％(v/v)等等。
在一些具体的实施方式中，病毒灭活处理的时间为2-4小时，温度为10-40℃。在一些具体的实施方式中，病毒灭活溶液与小肠粘膜下层组织的体积比为(20-40)︰1，例如，25:1、30:1、35:1、38:1等等。
通过病毒灭活处理，有效去除小肠粘膜下层组织中的有害成分，保证其制备生物套的生物安全性。
在一些实施方式中，脱细胞处理的步骤包括将小肠粘膜下层组织浸泡于包含胰蛋白酶和EDTA的脱细胞溶液中，进行脱细胞处理。其中，脱细胞溶液中胰蛋白酶的含量为0.1-2wt％，示例性的，胰蛋白酶的含量为0.5wt％、0.8wt％、1wt％、1.2wt％、1.5wt％、1.8wt％等等。脱细胞溶液中EDTA的含量为0.01-0.3wt％，示例性的，EDTA的含量为0.05wt％、0.08wt％、0.1wt％、0.15wt％、0.2wt％、0.22wt％、0.25wt％、0.28wt％等等。
进一步地，脱细胞溶液是包含胰蛋白酶和EDTA的PBS缓冲液，其pH为6-8。在一些具体的实施方式中，脱细胞处理在超声条件下进行。进一步地，是将小肠粘膜下层组织置于超声波清洗机中进行脱细胞处理。
作为优选地，脱细胞处理过程中的超声波功率为5000W以上，温度为10-40℃，超声时间为10-60分钟。
通过脱细胞处理，可有效去除小肠粘膜下层组织中的核酸、细胞膜、细胞核碎片等免疫源成分，降低材料的免疫原性，使其制备的生物套适合植入体内。
在一些实施方式中，在所述病毒灭活处理和脱细胞处理的步骤之间，还包括一次清洗的步骤：对所述小肠粘膜下层组织进行清洗，至所述小肠粘膜下层组织的检测电导率降低为10μS/cm以下。
进一步地，对小肠粘膜下层组织进行一次清洗的清洗液是pH6-8的PBS缓冲液，清洗液的温度为10-40℃，清洗液与小肠粘膜下层组织的体积比为(20-40)︰1，例如，25:1、30:1、35:1、38:1等等。
在一些具体的实施方式中，一次清洗步骤在超声波清洗机中进行。
在一些具体的实施方式中，首先以清洗液对小肠粘膜下层清洗2-4次，每次10-30分钟，然后采用10-40℃的注射用水清洗，注射用水与小肠粘膜下层组织的体积比为(20-40)︰1，至检测电导率为10μS/cm以下终止。
在本公开中，检测电导率是指清洗小肠粘膜下层组织后的注射用水，与未清洗小肠 粘膜下层组织的注射用水之间的电导率的差值。
通过一次清洗步骤，将小肠粘膜下层组织的检测电导率降低至10μS/cm以下，消除处理液中物质的残留。
在一些实施方式中，在所述脱细胞处理的步骤之后，还包括二次清洗的步骤：对所述小肠粘膜下层组织进行清洗，至所述小肠粘膜下层组织的检测电导率降低为1μS/cm以下。
进一步地，对小肠粘膜下层组织进行二次清洗的清洗液是pH6-8的PBS缓冲液，清洗液的温度为10-40℃，清洗液与小肠粘膜下层组织的体积比为(20-40)︰1，例如，25:1、30:1、35:1、38:1等等。
在一些具体的实施方式中，首先以清洗液对小肠粘膜下层清洗2-4次，每次10-30分钟，然后采用10-40℃的注射用水清洗，注射用水与小肠粘膜下层组织的体积比为(20-40)︰1，至检测电导率为1μS/cm以下终止。
通过二次清洗步骤，将小肠粘膜下层组织的检测电导率降低至1μS/cm以下，消除处理液中物质的残留。
植入型医疗装置
本公开提供的植入型医疗装置包括本公开提供的生物套和植入型医疗设备，所述植入型医疗设备至少部分地放置于所述生物套的容置腔内。
本公开中的生物套为植入体内的设备提供了一层安全、稳定的物理屏障，能够避免设备与机体直接接触导致的各种并发症的发生。并且，生物套一体成型的结构使其具有高的抗拉伸强度，避免了缝合生物套可能存在的缝合线断裂或过早降解等不稳定因素，具有重要的临床应用前景。
在一些可选的实施方式中，植入型医疗设备选自用于心血管疾病的诊断、监测和/或治疗的设备。在一些优选的实施方式中，所述植入型医疗设备选自下述任一种：心脏起搏器、植入型心律转复除颤器、心脏再同步治疗起搏器、植入型除颤器、植入型心电事件记录仪、植入型心血管监测器等。
生物套的制备方法
本公开中生物套的制备方法包括如下步骤：
生物膜层3的制备步骤：所述生物膜层3由灭菌且脱细胞的细胞外基质材料形成；
生物膜层3的包覆步骤：在板状模具2的两侧的表面上交替包覆生物膜层3，使所述两侧的表面上分别包覆至少2层的所述生物膜层3；其中，任一层的所述生物膜层3包括覆盖于一侧表面的部分区域上的包覆膜层31，以及连续延伸至与所述部分区域相对应的另一侧表面上的延伸膜层32；
冻干步骤：在非压制环境下对包覆于所述模具2上的生物膜层3进行冷冻干燥处理，使至少2层的所述生物膜层3结合为一体；其中，包覆两个表面上的所述生物膜层3分别形成第一面体11和第二面体12，连接所述第一面体和第二面体的生物膜层3形成过渡连接部14，所述生物膜层3未包覆所述模具2的一侧形成开口13，得到所述生物套。
本公开提供的生物套的制备方法，可用于制备高抗拉强度的一体化成型的生物套。其制备过程中无需使用缝合线进行套体的缝合，简化了生物套的制备步骤，减少制备时间，降低了制备成本。
在一些实施方式中，生物膜层3是由灭菌且脱细胞的细胞外基质材料形成的具有规定尺寸的生物膜层3。进一步的，生物膜层3由灭菌且脱细胞的小肠粘膜下层材料形成。
在一些实施方式中，生物膜层3的包覆步骤包括：
S1，取两侧分别为第一面21和第二面22的板状模具2，如图2所示，沿模具2的长度方向(L2方向)，将第一面21和第二面22相对的顶部区域预留为非包覆区，其余区域作为包覆区。为便于表述，将第一面21的非包覆区称为第一非包覆区211，与第一 面21的非包覆区相对的第二面22的非包覆区称为第二非包覆区221；将第一面21的包覆区称为第一包覆区212，与第一面21的包覆区相对的第二面22的包覆区称为第二包覆区222。
在一些具体的实施方式中，板状模具2为不锈钢底板。在一些具体的实施方式中，第一面21和第二面22中任一者的尺寸(宽×高，单位为cm)为5.4×7；6.9×8.5；6.9×10；6.9×11.5等等。
S2，在所述第一面21的第一包覆区212上包覆生物膜层3，所述生物膜层3形成包覆第一包覆区212的包覆膜层31和向外延伸出所述第一包覆区212的延伸膜层32；将所述延伸膜层32朝向第二面22方向弯折，使所述延伸膜层32覆盖所述第二面22的第二包覆区222；将位于所述第二面22上的延伸膜层32压平，使所述第一面21和第二面22分别包覆一层的生物膜层3，完成从第一面21向第二面22方向的包覆步骤。
具体来说，如图4-A所示，取生物膜层3对第一面21的第一包覆区212进行包覆，其中，生物膜层3覆盖第一包覆区212的部分作为包覆膜层31。并且，生物膜层3在沿模具2的长度方向(L2方向)和宽度方向(W2方向)上，均具有超出第一包覆区212且向外延伸的部分，该部分为延伸膜层32。如图3所示，延伸膜层32包括沿模具2的宽度方向位于相对两侧的第一延伸膜层321和第二延伸膜层322，以及连接第一延伸膜层321和第二延伸膜层322的第三延伸膜层323。
将延伸膜层32朝向第二面22方向弯折，具体地，如图4-A所示，通过三次折叠，使第一延伸膜层321、第二延伸膜层322和第三延伸膜层323均覆盖于第二面22的第二包覆区222上。示例性的，首先将第一延伸膜层321及第三延伸膜层323连接第一延伸膜层321的部分朝向第二面22折叠，使第一延伸膜层321覆盖于第二包覆区222上；然后将第二延伸膜层322及第三延伸膜层323连接第二延伸膜层322的部分朝向第二面22折叠，使第二延伸膜层322覆盖于第二面22的包覆区222上。第三延伸膜层323经过两次折叠后，形成两侧向中间折叠的形状，将第三延伸膜层323朝向第二面22折叠，使第三延伸膜层323包覆第二包覆区222。需要说明的是，本公开对第一延伸膜层321、第二延伸膜层322及第三延伸膜层323的折叠顺序不作具体限定，可按具体需要进行设置。
在一些实施方式中，第一延伸膜层321和第二延伸膜层322完整包覆第二包覆区222。示例性的，第一延伸膜层321的面积+第二延伸膜层322的面积＞第二包覆区222的面积，因此，覆盖于第二包覆区222上的第一延伸膜层321与第二延伸膜层322存在相互重叠的区域。或者，第一延伸膜层321的面积+第二延伸膜层322的面积＝第二包覆区222的面积，因此，第一延伸膜层321和第二延伸膜层322完整覆盖第二面22的包覆区222且两者互不重叠。
在一些实施方式中，第一延伸膜层321和第二延伸膜层322未完整包覆第二包覆区222，示例性的，第一延伸膜层321的面积+第二延伸膜层322的面积＜第二包覆区222的面积。因此，第一延伸膜层321和第二延伸膜层322折叠于第二包覆区222上后，第一延伸膜层321和第二延伸膜层322之间存在一定的间隙。
最后，将包覆第二包覆区222的第一延伸膜层321、第二延伸膜层322和第三延伸膜层323压平，形成包覆第二面22的第一层的生物膜层3。
需要说明的是，在本公开中，无论第一延伸膜层321和第二延伸膜层322是否完整包覆第二包覆区222，均与第三延伸膜层323共同形成包覆第二面22的一层生物膜层3。也即，在一次包覆过程中，由延伸膜层32形成包覆第二包覆区222的“一层”的生物膜层3。因此，在完成第一面21向第二面22的包覆步骤后，模具2的第一面21和第二面22上均包覆一层的生物膜层3。
S3，在所述第二面22的第二包覆区222上包覆生物膜层3，所述生物膜层3形成覆盖第二包覆区222的包覆膜层31和向外延伸出第二包覆区222的延伸膜层32；将所述延 伸膜层32朝向第一面21方向弯折，使所述延伸膜层32覆盖所述第一面21的第一包覆区212；将位于所述第一面21上的延伸膜层32压平，使所述第一面21和所述第二面22分别包覆两层的生物膜层3，完成从第二面22向第一面21方向的包覆步骤。
具体地，如图4-B所示，在完成从第一面21向第二面22方向的包覆后，另取一生物膜层3对第二包覆区222进行包覆，其中，生物膜层3覆盖第二包覆区222的部分作为包覆膜层31，连接包覆膜层31且向外延伸的部分为延伸膜层32。延伸膜层32包括沿模具2的宽度方向位于相对两侧的第一延伸膜层321和第二延伸膜层322，以及连接第一延伸膜层321和第二延伸膜层322的第三延伸膜层323。
将延伸膜层32朝向第一面21方向弯折，通过三次折叠，使第一延伸膜层321、第二延伸膜层322和第三延伸膜层323均覆盖于第一包覆区212上，具体折叠过程如S2中所示。
在一些实施方式中，第一延伸膜层321和第二延伸膜层322完整包覆第一包覆区212。示例性的，第一延伸膜层321的面积+第二延伸膜层322的面积＞第一包覆区212的面积，因此，覆盖于第一包覆区212上的第一延伸膜层321与第二延伸膜层322存在相互重叠的区域。或者，第一延伸膜层321的面积+第二延伸膜层322的面积＝第一包覆区212的面积，因此，第一延伸膜层321和第二延伸膜层322完整覆盖第一包覆区212且两者互不重叠。
在一些实施方式中，第一延伸膜层321和第二延伸膜层322未完整包覆第一包覆区212，示例性的，第一延伸膜层321的面积+第二延伸膜层322的面积＜第一包覆区212的面积。因此，第一延伸膜层321和第二延伸膜层322折叠于第一包覆区212上后，第一延伸膜层321和第二延伸膜层322之间存在一定的间隙。
最后，将包覆于第一包覆区212的第一延伸膜层321、第二延伸膜层322和第三延伸膜层323压平，形成包覆第一面21的第二层的生物膜层3。
需要说明的是，在本公开中，无论第一延伸膜层321和第二延伸膜层322是否完整包覆第一包覆区212，均与第三延伸膜层323共同形成包覆第一面21的一层生物膜层3。也即，在一次包覆过程中，由延伸膜层32形成包覆第一包覆区212的“一层”的生物膜层3。因此，在完成第二面22向第一面21的包覆步骤后，模具2的第一面21和第二面22上均包覆两层的生物膜层3。
S4，重复步骤S2和S3至少一次，使模具2的第一面21和第二面22上均包覆至少4层的生物膜层3。
在一些实施方式中，完成生物膜层3的包覆步骤后，在非压制环境性对包覆于所述模具2上的生物膜层3进行冷冻干燥处理，使至少2层的所述生物膜层3结合为一体，得到由过渡连接部14、第一面体11和第二面体12一体成型的生物套。
进一步的，将包覆生物膜层3的板状模具2置于真空冷冻干燥机中进行非压制冻干。作为优选，非压制冻干的条件包括：将包覆生物膜层3的板状模具2预冻至-45℃，保温1-2小时；然后调节温度至-15℃，保温5-7小时；再调节温度至0℃，保温2小时；最后调节温度至25℃，保温4小时。
通过非压制条件下的冷冻干燥工艺，使生物膜层3冷冻干燥成型，得到具有袋体结构1的一体成型的生物套。
在一些具体的实施方式中，生物套的尺寸(宽×高，单位为cm)为5.4×5；6.9×6.5；6.9×8；6.9×9.5等等。
在一些实施方式中，在冻干步骤之后还包括打孔步骤。具体的，将生物套从所述模具2上取下，裁切为所需尺寸。然后将生物套放入机械打孔机中，在所述第一面体11和/或所述第二面体12上打孔，形成位于第一面体11和/或所述第二面体12上的至少一个微孔。
在一些具体的实施方式中，以孔间距10mm、孔直径3mm对第一面体11和/或第二面体12进行打孔。作为优选，在第一面体11和第二面体12上均开设有孔间距10mm、孔直径3mm的微孔。
在一些实施方式中，在打孔步骤后还包括灭菌步骤。具体地，将所述生物套保温处理后，采用环氧乙烷对所述生物套进行灭菌处理，然后解析环氧乙烷，得到灭菌处理的生物套。作为优选，保温处理的温度为20-40℃，时间为2-4小时，湿度30-70％。环氧乙烷通入的浓度为300-1000mg/L，灭菌处理的时间为4-8小时。在一些优选的实施方式中，所述解析环氧乙烷的步骤在在通风的解析室中进行，温度控制为10-30℃，时间为14-28天。
通过灭菌步骤，得到生物安全性高，适合包裹医疗设备植入体内的生物套，以降低设备植入体内后感染、验证等并发症的发生。
在一些实施方式中，在灭菌步骤之前，在生物套的一端剪切出一定长度的豁口(为产品各种规格高度的1/4～1/2)，便放取CIED。
本公开提供的生物套的制备方法，无需使用缝合线进行第一面体11和第二面体12的缝合，可用于制备一体成型的生物套，简化了制备过程，降低了生物套的制作成本。并且，一体成型的生物套与缝合生物套相比，具有提高的抗拉强度，在包裹设备植入体内后可提高设备在体内使用的稳定性，降低并发症发生的概率。
实施例
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1
本实施例提供小肠粘膜下层材料的制备方法，具体包括如下步骤：
(1)原料的初处理
取猪小肠粘膜下层组织分割成规定尺寸，剔除淋巴组织，冲洗至表面无污渍，将水滤干；其中，规定尺寸具体是指：宽2-10cm，长2-20cm。
(2)病毒灭活处理
采用包含2％(v/v)过氧乙酸、20％(v/v)乙醇的病毒灭活溶液浸泡猪小肠粘膜下层组织，进行病毒灭活处理；病毒灭活溶液与猪小肠粘膜下层组织的体积比为40︰1，灭活时间4小时，温度范围为40℃。
(3)一次清洗
采用清洗液清洗猪小肠粘膜下层组织，至检测电导率为10μS/cm以下终止；其中，清洗液为pH6-8的PBS溶液，清洗液温度为30℃，清洗液与猪小肠粘膜下层组织的体积比为40︰1。使用清洗3次，每次20分钟，然后采用30℃的注射用水清洗，注射用水与猪小肠粘膜下层组织的体积比为40︰1，至检测电导率为10μS/cm以下终止；清洗过程在超声波清洗机中进行。
(4)脱细胞处理
脱细胞溶液为采用1wt％的胰蛋白酶溶液、0.2wt％EDTA的溶液，溶剂为pH6-8的PBS溶液。脱细胞溶液与猪小肠粘膜下层组织混合体积比为40：1，脱细胞过程在超声波清洗机中进行，超声波功率至少在5000W以上；脱细胞过程的清洗时间为30分钟，温度30℃。
(5)二次清洗
采用清洗液清洗猪小肠粘膜下层组织，至检测电导率为1μS/cm以下终止；其中， 清洗液为pH6-8的PBS溶液，清洗液温度为30℃，清洗液与猪小肠粘膜下层组织的体积比为40：1。使用清洗3次，每次20分钟，然后采用30℃的注射用水清洗，注射用水与猪小肠粘膜下层组织的体积比为40：1，至检测电导率为1至检测电导以下终止，得到灭菌且脱细胞的小肠粘膜下层材料。
实施例2
本实施例提供生物套的制备方法，具体包括如下步骤：
(1)固定成型
采用实施例1制备的小肠粘膜下层材料作为生物膜层。在模具上进行固定成型，所述模具由不同尺寸不锈钢底板(型号：5.4×7；6.9×8.5；6.9×10；6.9×11.5；单位为cm)、不锈钢刮板组成，将一定尺寸(12cm或者15cm)的生物膜层缠绕底板一圈，底端留存材料大约5mm～10mm，折向一面，用不锈钢刮板刮平，完成正向包覆的步骤；反方向再用一块新的生物膜层缠绕底板一圈，底端留存材料大约5mm～10mm，折向另一面，刮平，完成反向包覆的步骤。重复此过程一次，刮平，最后得到2面4层的SIS生物套，规格型号为(5.4×5；6.9×6.5；6.9×8；6.9×9.5；宽×高单位为cm)。
(2)真空冷冻干燥
在真空冷冻干燥机中进行非压制冻干，将模具连同包裹的生物膜层预冻至-45℃，保温1-2小时，然后调节温度至-15℃，保温5-7小时，再调节温度至0℃，保温2小时，最后调节温度至25℃，保温4小时，真空冷冻干燥完成。
(3)打孔包装
具体为：将步骤干燥(2)冻干的生物套从不锈钢底板上取下来，在模具上切切割成固定大小，然后放入机械打孔机中，以间距10mm进行打孔，孔直径3mm。
不锈钢剪刀在生物套的一端剪切出一定长度(为产品各种规格高度的1/2z左右)的豁口，方便放取CIED，然后采用特卫强包装袋包装。
(4)灭菌
采用环氧乙烷进行灭菌，灭菌条件为：先温度20-40℃保温时间2-4小时，湿度30-70％，然后通入浓度300-1000mg/L环氧乙烷，灭菌4-8小时；解析过程在通风的解析室中进行，温度控制在10-30℃之间，时间14-28天。
性能测试
制备样品1：采用实施例1制备的小肠粘膜下层材料作为生物膜层，进行真空冷冻干燥后，使用缝纫机(JH9870，兄弟(中国)商业有限公司)，按照针间距2mm进行缝合，制成干燥-缝合SIS生物套。
制备样品2：采用实施例2制备的一体化SIS生物套作为干燥-一体化SIS生物套。
制备样品3：采用实施例1制备的小肠粘膜下层材料作为生物膜层，进行真空冷冻干燥后，使用缝纫机(JH9870，兄弟(中国)商业有限公司)，按照针间距2mm进行缝合。置于PBS溶液中2-5分钟，进行水合作用，制成水合-缝合SIS生物套。
制备样品4：将实施例2制备的-一体化SIS生物套，置于PBS溶液中2-5分钟，进行水合作用，制成水合-一体化SIS生物套。
对样品1、2、3、4进行抗拉强度测试。将材料裁剪成宽度20mm，长度30mm的样品。夹具间的距离为15mm，再分别将样品1-4夹到夹具上，利用医药包装性能测试仪(型号：MED-1，济南兰光机电技术有限公司)测量样品的最大力值。
图6中样品1和样品2为干燥的一体化及缝合SIS生物套的抗拉强度统计图，其中样品1与样品2有###的统计学差异，p值＜0.001，说明生物套在干燥状态下，缝合生物套的抗拉强度远小于一体化生物套。图中样品3和样品4为水合后的一体化及缝合SIS生物套的抗拉强度统计图，其中样品3与样品4有$$的统计学差异，p值＜0.01，说明水 合后的生物套，缝合生物套的抗拉强度小于一体化生物套。总之，结果说明无论在SIS生物套在干燥的情况下或者水合后的状态，缝合生物套的抗拉强度均小于一体化生物套，从而说明一体化生物套在体内植入具有较好的抗拉强度。

Claims (11)

  1. 一种生物套，其中，所述生物套由灭菌且脱细胞的细胞外基质材料形成，并且具有一体成型的袋体结构；所述袋体结构具有用于容置植入型医疗设备的容置腔，以及将所述容置腔与外界连通的开口。
  2. 根据权利要求1所述的生物套，其中，所述容置腔由相对的第一面体和第二面体围成；其中，所述第一面体和第二面体相接的部分形成所述生物套的过渡连接部；
    可选地，所述过渡连接部沿所述生物套的长度方向的长度为5～10cm，所述过渡连接部沿所述生物套的宽度方向的长度为4～8cm。
  3. 根据权利要求2所述的生物套，其中，所述第一面体和/或所述第二面体上开设有至少一个微孔；可选地，所述微孔的直径为1～3mm；可选地，所述微孔的间距为10～15mm。
  4. 根据权利要求1-3任一项所述的生物套，其中，所述灭菌且脱细胞的小肠粘膜下层是取小肠粘膜下层组织，经病毒灭活处理和脱细胞处理得到；
    优选地，所述病毒灭活处理的步骤包括：将小肠粘膜下层组织浸泡于包含(0.1-5)％(v/v)过氧乙酸和(5-40)％(v/v)乙醇的病毒灭活溶液中，在10-40℃温度下，处理2-4小时；
    优选地，所述脱细胞处理的步骤包括：将小肠粘膜下层组织浸泡于包含0.1-2wt％胰蛋白酶和0.01-0.3wt％EDTA的脱细胞溶液中，在10-40℃温度下，超声波功率为5000W以上的超声条件下，处理10-60分钟。
  5. 根据权利要求4所述的生物套，其中，在所述病毒灭活处理和脱细胞处理的步骤之间，还包括如下步骤：对所述小肠粘膜下层组织进行清洗，至所述小肠粘膜下层组织的检测电导率降低为10μS/cm以下；
    优选地，在所述脱细胞处理的步骤之后，还包括如下步骤：对所述小肠粘膜下层组织进行清洗，至所述小肠粘膜下层组织的检测电导率降低为1μS/cm以下。
  6. 一种根据权利要求1-5任一项所述的生物套的制备方法，其中，所述制备方法包括如下步骤：
    生物膜层的制备步骤：制备灭菌且脱细胞的小肠粘膜下层材料，作为用于制备生物套的生物膜层；
    生物膜层的包覆步骤：在板状模具的两侧的表面上交替包覆生物膜层，使所述两侧的表面上分别包覆至少2层的所述生物膜层；其中，任一层的所述生物膜层包括覆盖于一侧表面的部分区域上的包覆膜层，以及连续延伸至与所述部分区域相对应的另一侧表面上的延伸膜层；
    冻干步骤：在非压制环境下对包覆于所述模具上的生物膜层进行冷冻干燥处理，使至少2层的所述生物膜层结合为一体；其中，包覆两个表面的生物膜层分别形成第一面体和第二面体，连接所述第一面体和第二面体的生物膜层形成过渡连接部，所述生物膜层未包覆所述模具的一侧形成开口，得到由第一面体、第二面体和过渡连接部一体成型的生物套。
  7. 根据权利要求6所述的制备方法，其中，所述生物膜层的包覆步骤包括：
    取两侧分别为第一面和第二面的板状模具，沿所述模具的长度方向，将所述第一面和第二面相对的顶部区域预留为非包覆区，其余区域作为包覆区；
    在所述第一面的包覆区上包覆第一生物膜层，所述第一生物膜层形成覆盖所述包覆区的第一生物膜层的包覆膜层和向外延伸出所述包覆区的第一生物膜层的延伸膜层；将所述延伸膜层朝向第二面的方向弯折，使所述延伸膜层覆盖所述第二面的包覆区；将位于所述第二面上的延伸膜层压平，完成第一面向第二面方向的包覆步骤；
    在所述第二面的包覆区上包覆第二生物膜层，所述第二生物膜层形成覆盖所述包覆区的第二生物膜层的包覆膜层和向外延伸出所述包覆区的第二生物膜层的延伸膜层；将所述第二生物膜层的延伸膜层朝向第一面方向弯折，使所述第二生物膜层的延伸膜层覆盖所述第一面的包覆区；将位于所述第一面上的延伸膜层压平，完成第二面向第一面方 向的包覆步骤；
    优选地，所述第一面向第二面方向的包覆步骤中，所述第一生物膜层的延伸膜层完整包覆所述第二面的包覆区；和/或，所述第一面向第二面方向的包覆步骤中，所述第二生物膜层的延伸膜层完整包覆所述第一面的包覆区；
    优选地，至少重复一次所述第一面向第二面方向的包覆步骤，和所述第一面向第二面方向的包覆步骤。
  8. 根据权利要求6所述的制备方法，其中，所述冷冻干燥处理的步骤包括：将包覆生物膜层的板状模具置于真空冷冻干燥机中进行非压制冻干；
    优选地，所述非压制冻干的条件包括：预冻至-45℃，保温1-2小时；然后调节温度至-15℃，保温5-7小时；再调节温度至0℃，保温2小时；最后调节温度至25℃，保温4小时。
  9. 根据权利要求6-8任一项所述的制备方法，其中，所述制备方法还包括如下步骤：
    打孔步骤：将所述生物套从所述模具上取下，裁切为所需尺寸，然后在所述第一面体和/或所述第二面体上打孔，形成位于所述第一面体和/或所述第二面体上的至少一个微孔；优选地，以微孔的间距为10-15mm，直径为1-3mm在所述第一面体和/或所述第二面体上打孔；
    灭菌步骤：将所述生物套保温处理后，采用环氧乙烷对所述生物套进行灭菌处理，然后解析环氧乙烷，得到灭菌处理的生物套；优选地，所述保温处理的温度为20-40℃，时间为2-4小时，湿度30-70％；优选地，所述环氧乙烷通入的浓度为300-1000mg/L，所述灭菌处理的时间为4-8小时；优选地，所述解析环氧乙烷的步骤在在通风的解析室中进行，温度控制为10-30℃，时间为14-28天。
  10. 一种植入型医疗装置，其中，所述植入型医疗装置包括：
    根据权利要求1-5任一项所述的生物套，或根据权利要求6-9任一项所述的方法制备的生物套；
    植入型医疗设备，所述植入型医疗设备至少部分地放置于所述生物套的容置腔内；
    可选地，所述植入型医疗设备选自用于心血管疾病的诊断、监测和/或治疗的设备；可选地，所述植入型医疗设备选自下述任一种：心脏起搏器、植入型心律转复除颤器、心脏再同步治疗起搏器、植入型除颤器、植入型心电事件记录仪、植入型心血管监测器。
  11. 根据权利要求1-5任一项所述的生物套，或根据权利要求6-9任一项所述的方法制备的生物套在容置植入型医疗设备中的用途；
    可选地，所述植入型医疗设备选自用于心血管疾病的诊断、监测和/或治疗的设备；可选地，所述植入型医疗设备选自下述任一种：心脏起搏器、植入型心律转复除颤器、心脏再同步治疗起搏器、植入型除颤器、植入型心电事件记录仪、植入型心血管监测器。
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