CN103405811A - Anti-adhesion biological membrane and preparation method thereof - Google Patents

Anti-adhesion biological membrane and preparation method thereof Download PDF

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CN103405811A
CN103405811A CN2013103580485A CN201310358048A CN103405811A CN 103405811 A CN103405811 A CN 103405811A CN 2013103580485 A CN2013103580485 A CN 2013103580485A CN 201310358048 A CN201310358048 A CN 201310358048A CN 103405811 A CN103405811 A CN 103405811A
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anti
adhesion
sis
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biological membrane
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CN103405811B (en
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陈岚
刘博武
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西安组织工程与再生医学研究所
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Abstract

The invention provides an anti-adhesion biological membrane and a preparation method thereof. The anti-adhesion biological membrane is a dry membrane which is formed by SIS (styrene isoprene styrene block copolymer) as a support material, compound hyaluronic acid, functional proteins and anti-inflammotary medicines. The anti-adhesion biological membrane is semi-transparent from light white to faint yellow. The thickness of the anti-adhesion biological membrane is 0.01-0.5mm. Compared with the prior art, the anti-adhesion biological membrane has very good biocompatibility, good physical barrier anti-adhesion effect and the effects of resisting inflammatory, stopping bleeding and promoting fiber degradation. The effects of the anti-adhesion biological membrane are obviously superior to those of existing anti-adhesion biological membrane products. Animal experiments prove that the effective rate of the anti-adhesion biological membrane prepared by the method for preventing the adhesion after abdominal surgery reaches above 90%, the effective rate for preventing the adhesion after pelvic cavity surgery reaches above 80%, and the effective rate for preventing the adhesion after tendon surgery reaches above 70%.

Description

一种防粘连生物膜及其制备方法 One kind of adhesion and biofilm prevention method for preparing

技术领域 FIELD

[0001] 本发明属于组织工程学医用生物材料技术领域,具体涉及一种防粘连生物膜及其制备方法。 [0001] The present invention belongs to the technical field of tissue engineering medical biomaterials, particularly, to a method for preparing anti-adhesion and biofilm.

背景技术 Background technique

[0002] 术后粘连是一种常见的手术并发症,在外科肌腱手术后通常90%以上的患者均会发生粘连现象,在腹盆腔手术后几乎有70%以上的患者发生不同程度的粘连并发症,粘连可能导致术后正常生理功能的丧失,引发肠梗阻、慢性腹痛、慢性盆腔痛及不孕等严重不良症状,甚至危及生命。 [0002] Postoperative adhesions are a common complication after surgical tendon surgery is usually more than 90% of patients were blocking phenomenon will occur after abdominal and pelvic surgery almost more than 70% of patients with varying degrees of adhesions disease, adhesions can lead to loss of normal physiological function after surgery, causing intestinal obstruction, chronic abdominal pain, chronic pelvic pain and infertility and other serious adverse symptoms, even life-threatening.

[0003]目前应用于防粘连研究的材料有许多,如聚乳酸、透明质酸、纤维素、壳聚糖、硅胶、树脂和肌腱提取的胶原等,期望它们能够为组织的愈合提供暂时性的物理屏障。 [0003] Currently used anti-adhesion material has many studies, such as polylactic acid, hyaluronic acid, cellulose, chitosan, silica, resins, and extracted tendon collagen, which is desirable to provide for the temporary callus physical barrier. 上述材料采用高压静电纺丝技术、冷冻干燥技术或交联聚合的方法制备成膜状或凝胶状后应用,采用聚乳酸、硅胶和树脂等原料时,通常是在溶液中添加增塑剂、防腐剂和抗氧化剂等进行聚合反应,这些成分可能对人体带来潜在的危害;以透明质酸、纤维素、壳聚糖和肌腱提取的胶原为原料制备的防粘连生物膜,其防粘连效果尚未达到临床认可。 The above materials using electrospinning, after freeze-drying technology applied or crosslinked polymeric film or a method to prepare a gel, while using a raw material of polylactic acid, silicone resins and the like, a plasticizer is typically added in solution, preservatives and antioxidants polymerization reaction, these components may be potentially damaging to the human body; hyaluronic acid, cellulose, chitosan and extracted tendon collagen preparation of starting materials antiblocking biofilm, anti-blocking effect which not yet reached the clinical recognition. 据报道,国内外广泛使用的美国健赞公司(Genzyme Biosurgery)生产的Sepraf ilm透明质酸膜,用以防止术后粘连,其结果显示有效率仅为47% (Qiqiang Zeng, et, al.World J Surg (2007)31:2125 - 2131 ),该产品是由单一的天然多糖高分子材料制备而成,只能起到初步的物理屏障作用,无法达到抑制炎症,抑制纤维化,促进愈合的效果。 According to reports, Sepraf ilm hyaluronic acid films American Genzyme (Genzyme Biosurgery) are widely used in domestic and foreign production, to prevent postoperative adhesions, the results showed an efficiency of only 47% (Qiqiang Zeng, et, al.World J Surg (2007) 31: 2125 - 2131), the product is prepared from a polymer material from a single natural polysaccharides, can only play the initial physical barrier effect, unable to inhibit inflammation, inhibit fibrosis, healing promoting effect .

发明内容 SUMMARY

[0004] 针对现有技术的缺陷,本发明的目的是提供一种防粘连生物膜及其制备方法,该生物膜能够暂时性替代受损组织膜,抑制术后炎症及纤维化,防止手术部位的术后粘连,具有良好的生物相容性,无排异反应,操作使用方便。 [0004] for the disadvantages of the prior art, an object of the present invention is to provide a method for preparing anti-blocking and biofilm, the biofilm can be temporarily replace damaged tissue membrane, suppressing inflammation and fibrosis after surgery to prevent surgical site postoperative adhesions, have good biocompatibility, no rejection, and easy to operate.

[0005] 本发明所提出的防粘连生物膜,其特征在于,是以脱细胞去抗原的猪小肠粘膜下层基质(small intestinal submucosa,简称SIS)为支架材料,复合透明质酸、功能性蛋白和抗炎症药物而构成的干燥薄膜,干燥薄膜呈浅白色至淡黄色半透明状,厚度为0.01〜0.5mmο [0005] The anti-blocking biofilm by the present invention, wherein the antigen is to decellularized porcine small intestinal submucosa matrix (small intestinal submucosa, abbreviated SIS) as a scaffold, combined with hyaluronic acid, proteins and functional drying the film to form anti-inflammatory drug, dry film as a pale white to pale yellow translucent, thickness 0.01~0.5mmο

[0006] 本发明提出的防粘连生物膜的制备方法,是以SIS为支架材料,采用消毒、脱细胞去抗原、复合透明质酸、灭菌和改性处理;具体步骤包括: [0006] The method of preparing an anti-blocking biofilm proposed by the invention, as SIS scaffold is used disinfection, to acellular antigen, combined with hyaluronic acid, sterilization and modification; specific steps comprising:

步骤一、消毒处理:将片状SIS用纯化水清洗至无污物,置于浓度为0.5〜5 mol/L的碱溶液中浸泡0.5〜2.5小时,然后用纯化水清洗至pH中性;所述的碱溶液为氢氧化钠溶液、或氢氧化钾溶液、或氢氧化钙溶液的任一种; A step, disinfection: The SIS sheet-washed with purified water until free of dirt, placed in a concentration of 0.5~5 mol / L alkaline solution soak 0.5~2.5 hours, and then washed to neutral pH with purified water; the said alkaline solution is sodium hydroxide solution or potassium hydroxide solution, calcium hydroxide or any solution;

碱溶液具有良好的病毒灭活及杀灭细菌的能力,保证SIS原料中病毒及细菌等微生物负载降低至可接受水平,有利于后续的操作;同时能够溶解SIS中水溶性蛋白,保留SIS胶原的三维支架结构。 Alkali solution has a good ability to kill bacteria and virus inactivating ensure SIS raw material of viruses and bacteria and other microbial load is reduced to an acceptable level, it facilitates the subsequent operations; while SIS is capable of dissolving the water-soluble protein, collagen retained SIS three-dimensional support structure. [0007] 步骤二、脱细胞去抗原处理:将消毒处理后的SIS置于浓度为I〜5 mg/mL的胰蛋白酶溶液中浸泡0.5〜4小时,再用纯化水清洗后,置于含10〜25 U/mL浓度DNA水解酶和30〜40 U/mL浓度α -半乳糖苷酶的酶液中浸泡0.5〜4小时,最后用纯化水清洗; [0007] Step two, acellular antigens to Treatment: After sterilization treatment the SIS concentration of trypsin solution was placed I~5 mg / mL immersed 0.5~4 hours, washed with water and then purified, was placed with 10 ~25 U / mL and the concentration of DNA hydrolase 30~40 U / mL concentration of α - galactosidase enzyme liquid immersed 0.5~4 hours and finally washed with purified water;

采用胰蛋白酶处理可对SIS中的异种细胞进行消化,并能够对SIS胶原支架结构进行适度消化,使其更有利于在体内的快速降解;同时,采用酶液处理最大限度地降低了SIS中DNA残留及α -半乳糖苷的含量,从而保证所得到的SIS具有良好的生物相容性和极低的免疫原性。 Trypsin treatment of the SIS may be digested xenogeneic cells, and can be appropriately digested to SIS collagen scaffold structure, make it more conducive to rapid degradation in vivo; simultaneously, by enzyme treatment minimizes the solution of DNA SIS the residue and α - galactosidase content, to ensure the resulting SIS has good biocompatibility and low immunogenicity.

[0008] 步骤三、复合透明质酸:将步骤二处理后的SIS按需要裁剪,置于浓度为5〜20mg/mL的透明质酸溶液中浸泡0.5〜2小时,取出后真空冻干得到复合有透明质酸的SIS膜片; [0008] Step three, combined with hyaluronic acid: SIS after the second processing step by the need to cut, placed in a concentration of hyaluronic acid solution 5~20mg / mL immersed 0.5~2 hours, after removing the vacuum freeze-dried to give compound there hyaluronic acid SIS diaphragm;

在SIS复合透明质酸制备成膜片,可有效提高SIS膜片的吸水能力,在应用于临床手术时透明质酸可迅速贴附至湿润的手术部位,避免防粘连生物膜的脱落移位,能长时间有效覆盖创面,发挥防粘连生物膜的作用。 Preparation of hyaluronic acid into the SIS composite membrane, can effectively improve the water absorption capacity of the membrane SIS, hyaluronic acid may be quickly attached to a surgical site moist, antiblocking avoid biofilm detachment displaced when used in clinical surgery, covering the wound for a long time can effectively play the role of anti-blocking biofilm.

[0009] 步骤四、灭菌处理:将复合有透明质酸的SIS膜片包装后采用辐照灭菌,辐照剂量为15〜40kGy的伽马射线; [0009] Step 4 sterilization: SIS composite membrane of hyaluronic acid using radiation sterilization after packaging, exposure dose of gamma 15~40kGy;

采用伽马射线辐照灭菌,既保证了SIS膜片产品达到无菌水平,也能对SIS膜片内部结构的支架造成适度破坏,以控制其在体内的降解速率,使其在降解前发挥良好的物理屏障作用,避免因降解过快而无法有效发挥防粘连作用,或是由于降解过慢而导致多种并发症发生。 Using gamma irradiation sterilization, both to ensure product sterility SIS membrane level, it can also cause damage to the stent SIS moderate internal configuration of the diaphragm, to control its rate of degradation in vivo, so as to play before degradation good physical barrier to avoid excessive degradation and can not effectively play the role of anti-adhesion, or too slow due to degradation caused by a variety of complications.

[0010] 步骤五、改性处理:将得到的无菌SIS膜片于室温下浸泡于无菌改性溶液中10〜60秒后,取出在无菌环境下晾干,无菌包装,得到防粘连生物膜;所述的无菌改性溶液是在生理盐水溶液中含有:0.05〜0.2 μ g/mL的TGF-β拮抗剂(如核心蛋白聚糖),5000〜25000AXaI⑶/mL (相当于每毫升肝素溶液中有5000〜25000IU抗凝血因子Xa的活性)的低分子量肝素,0.1〜0.5 mg/mL的纤维蛋白溶酶原激活剂和0.1〜I mg/mL的非甾体类抗炎症药物(如阿司匹林、对乙酰氨基酚、吲哚美辛、萘普生、萘普酮、双氯芬酸、布洛芬、尼美舒利、罗非昔布或是塞来昔布的任一种)。 [0010] Step V. modification treatment: The resulting membrane was immersed in sterile SIS sterile modified solution at room temperature after 10 to 60 seconds, taken out to dry in a sterile environment, sterile packaging, resulting in an anti biofilm adhesion; the modified solution is sterile physiological saline solution containing: 0.05~0.2 μ g / mL of TGF-β antagonists (e.g. decorin), 5000~25000AXaI⑶ / mL (equivalent to every ml heparin solution has 5000~25000IU anti-factor Xa activity) is low molecular weight heparin, 0.1~0.5 mg / mL of plasminogen activator and 0.1~I mg / mL of non-steroidal anti-inflammatory drugs (such as aspirin, acetaminophen, indomethacin, naproxen, nabumetone, diclofenac, ibuprofen, nimesulide, rofecoxib or celecoxib any one).

[0011] 本步骤对SIS膜片进行改性处理,添加可以抑制纤维化形成的功能性蛋白如TGF-β拮抗剂和纤维蛋白溶酶原激活剂等,并添加能够抑制炎症、减少出血的防粘连药物(如低分子量肝素、非留体类抗炎症药物等),使复合了透明质酸的SIS膜片可以作为生理屏障尽可能降低受损组织在愈合再生过程中受到的创口感染影响和干扰,从而起到促进受损组织愈合的作用。 [0011] In this step, the membrane of the modified SIS process, adding a functional protein can inhibit fibrosis such as TGF-β antagonist and plasminogen activators, etc., and adds the ability to inhibit inflammation, reduce anti-bleeding blocking drugs (e.g., low molecular weight heparin, a non-steroidal anti-inflammatory class of drugs, etc.), the composite membrane of hyaluronic acid SIS as a physiological barrier can reduce wound infection during the healing of damaged tissue by regeneration possible influence and interference , which play a role in promoting healing of damaged tissue. 本步骤最终采用晾干方式制备防粘连生物膜,可有效避免真空干燥造成的膜片结构疏松、产生大量孔隙结构而影响生物膜防粘连的效果。 This final step were prepared antiblocking dry biofilm embodiment, the diaphragm structure can effectively prevent osteoporosis caused by drying in vacuo, a large amount of pore structure affect biofilm effect on adhesion prevention.

[0012] 本发明制备的防粘连生物膜,为厚度0.01〜0.5mm的薄膜,主要成分为SIS、透明质酸、功能性蛋白以及抗炎症药物,其中SIS可有效作为三维支架复合其他成分,维持膜状的物理形态,保持防粘连生物膜体内物理屏障的基本构架;透明质酸可有效吸收手术部位的组织渗液及出血,使防粘连生物膜贴敷至手术创面时可迅速呈半固态半凝胶态薄膜,不易脱落;防粘连生物膜中的功能性蛋白及抗炎症药物能有效起到抑制炎症、促进纤维降解的作用。 [0012] Preparation of the anti-blocking biofilm present invention, a film thickness 0.01~0.5mm, the main component of SIS, hyaluronic acid, proteins and functional anti-inflammatory drug, wherein the SIS effective as a three-dimensional scaffolds other ingredients to maintain can quickly form a semi-solid semi tissue effectively absorb exudate hyaluronic bleeding surgical site and the anti-blocking biofilm sticking to the surgical wound; physical form of a film, remains substantially the biofilm architecture antiblocking physical barrier in vivo gel state film, not falling; antiblocking biofilm functional protein and anti-inflammatory drugs can effectively reduce inflammatory, promote fiber degradation effect. 本发明制备的防粘连生物膜,适用于腹腔、盆腔、神经、骨科、耳鼻喉等各类手术后预防手术部位术后粘连,具有极好的防粘连效果。 Antiblocking biofilm present invention is prepared, applied to the abdominal, pelvic, neurological, orthopedic, ENT surgical site and other surgical prophylaxis of postoperative adhesion, excellent anti-blocking effect. [0013] 与现有技术相比,本发明防粘连生物膜的生物相容性极好,既具有目前已有防粘连生物膜的良好物理屏障防粘连作用,又具有含抗炎症因子类防粘连生物膜(如生物羊膜)的抗炎症作用,还具有已有技术所没有的止血、促进纤维降解的作用,其效果明显优于已有的各类防粘连生物膜产品。 [0013] Compared with the prior art, the present invention biofilm antiblocking excellent biocompatibility, having both good physical barrier preventing adhesion formation biofilm present, anti-blocking, but also has anti-inflammatory factor containing antiblocking class antiinflammatory biofilm (e.g., amniotic membrane), further having no prior art hemostasis promoting effect of fiber degradation, which is better than existing types of antiblock biofilm products. 将本发明采用大鼠腹腔防粘连动物实验证明,所制备的防粘连生物膜预防腹腔术后粘连发生的有效率达90%以上,预防盆腔术后粘连发生的有效率达80%以上,预防肌腱手术术后粘连发生的有效率达70%以上。 The present invention is demonstrated using the animal experiment rat peritoneal anti-blocking, anti-blocking effective rate produced biofilm prevention of postoperative peritoneal adhesions than 90%, more than 80% effective prevention of postoperative pelvic adhesions, prevention tendons effective rate of 70% or more after surgery adhesions occur.

[0014] 以下通过机理分析,说明本发明技术方案的有益效果。 [0014] By the following mechanism analysis, the technical solutions described advantageous effects of the present invention.

[0015] (I)由于本发明制备方法,有效保留了SIS的三维胶原支架结构,并通过适度消化和适度辐照处理来控制SIS的降解速率,使防粘连生物膜在体内降解前发挥有效的物理屏障作用;其能够在体内完全降解吸收,避免了不可降解材料在体内导致的异物反应、长期慢性炎症等并发症。 [0015] (I) due to the production method of the present invention, an effective three-dimensional collagen scaffold retained SIS and SIS is controlled by degradation rate of digestion and moderate moderate irradiation treatment, the anti-blocking biofilms play before the effective in vivo degradation physical barrier; which can be completely degraded and absorbed in the body, to avoid foreign body reaction of the non-degradable materials in the body cause long-term complications of chronic inflammation.

[0016] (2)由于本发明方法在SIS膜片复合透明质酸,利用了透明质酸吸收水分能力强的特性,使防粘连生物膜在手术应用时,能迅速有效贴附于各种手术创面,起到物理贴敷止血的作用,使用方便,操作简单,避免了因脱落引起的防粘连效果不佳的问题。 [0016] (2) Since the process of the present invention is a composite membrane SIS hyaluronic acid, hyaluronic acid using a strong ability to absorb moisture characteristics of the biofilm during antiblocking surgical applications, it can quickly and effectively attached to various surgical wounds, physical play sticking hemostasis, easy to use, simple operation, avoiding the poor anti-adhesion effect due to loss caused problems.

[0017] (3)本发明的防粘连生物膜在降解时,可以释出多种功能性蛋白及抗炎症药物,为受损组织再生提供良好的抑制纤维化、抑制炎症、降低出血的生理环境,从而具有促进愈合的作用,在受损部位再生前可以作为良好的组织膜替代物,有效防止粘连发生。 [0017] (3) of the present invention, anti-blocking biofilm upon degradation, can release a variety of anti-inflammatory drug and a functional protein, regeneration of damaged tissue to provide good inhibition of fibrosis, inhibition of inflammation, reduction in bleeding physiological environment to promote the healing of the damaged area before tissue regeneration membrane may serve as a good alternative to effectively prevent adhesions.

[0018] (4)由于本发明采用碱溶液进行脱细胞处理,易于清洗去除,而且未采用任何添加齐U、交联剂、固定剂等有机化学试剂,不会造成有害试剂的残留,避免了可能导致的毒性或免疫反应。 [0018] (4) Since the present invention employs an alkali solution decellularized easily removed by washing, and did not use any added together U, crosslinking agents, organic chemicals and the like is fixed, does not cause harmful residual reagent, avoiding It may lead to toxicity or immune response.

[0019] ( 5 )由于本发明采用无菌改性液处理,可避免灭菌时对各类活性蛋白、抗炎症药物活性的影响,最大程度发挥防粘连生物膜的抑制纤维化、抑制炎症的作用效果,确保防粘连生物膜的防粘连、促进愈合的能力。 [0019] (5) Since the present invention uses a modified sterile liquid processing, can avoid the influence of various types of activity of the protein, the activity of anti-inflammatory drugs sterilization, maximize the inhibition of fibrosis antiblocking biofilm suppression of inflammation effect, to ensure that the anti-blocking biofilm adhesion prevention ability to promote healing.

[0020] (6)由于本发明采用晾干处理,避免了真空冷冻干燥对膜片造成的结构疏松、产生孔隙结构的缺点,可有效保持防粘连生物膜的无孔径结构特点,以保持良好的物理屏障功倉泛。 [0020] (6) Since the present invention employs the drying process, to avoid the loose structure caused by vacuum freeze-drying of the membrane, resulting in disadvantages pore structure, pore-free structure can effectively maintain the anti-blocking characteristic of the biofilm, to maintain good physical barriers work cartridge pan.

附图说明 BRIEF DESCRIPTION

[0021] 附图1为本发明制备的SIS膜片的组织学切片染色结果照片,可以看出,SIS的主要成分为胶原,而且SIS膜片保持有良好的三维支架结构,有利于后续的改性处理。 [0021] FIG. 1 SIS membrane of the present invention is prepared histological sections staining photographs, it can be seen, the main component of the SIS collagen, and maintaining a good film SIS three-dimensional scaffold structure is conducive to the subsequent change treatment.

[0022] 附图2为本发明制备的防粘连生物膜应用于创面5秒后的效果照片,可以明显看至|J,防粘连生物膜迅速吸收水分并有效贴附于创面,30〜60秒内即可被组织渗液完全浸透,不易与组织分离脱落。 [0022] 2 antiblocking biofilm present invention prepared in figures 5 seconds after the effect is applied to the wound photographs, it is clear to see | J, antiblocking biofilm rapidly and effectively absorb moisture attached to the wound, 30~60 seconds the exudate can be organized completely soaked, easily separated from the tissue loss.

[0023] 附图3为采用本发明制备的防粘连生物膜进行动物有效性实验结果照片;其中A为将防粘连生物膜包裹大鼠肝脏损伤后2周的结果照片,可以明显看出,肝脏包裹处与腹腔内肠道和脏器未发生粘连,肝脏自由度良好,包裹处有部分材料剩余出为将防粘连生物膜包裹家兔小肠后4周的结果照片,小肠与周围肠道和脏器未发生粘连;C为将防粘连生物膜包裹家兔跟腱缝合部位8周后的结果照片,肌腱与周围组织未发生粘连,肌腱愈合情况良好;D为采用防粘连生物膜包裹大鼠坐骨神经8周后的结果照片,神经愈合部位与周围肌肉组织未发生粘连,神经愈合情况良好。 [0023] Figure 3 is a biofilm produced using an antiblocking present invention the effectiveness of animal experiments photographs; wherein A is a liver after antiblocking biofilm wrapped rats 2 weeks pictures result, it is clear that the liver parenterally intraperitoneally at a wrapping organ adhesion did not occur and good liver freedom wrapping material remaining at a part of the small intestine of rabbits 4 weeks antiblocking biofilm results photo package, small intestine and surrounding bowel and dirty is No adhesions; C for the anti-blocking biofilm rabbit Achilles wrap suture site 8 weeks after photographs, tendon and not the surrounding tissue adhesions, tendon healing in good condition; D is wrapped biofilm using rat sciatic antiblock after 8 weeks, the results of photo, parts of nerve healing adhesions with the surrounding muscle tissue did not occur, nerves heal in good condition.

具体实施方式 Detailed ways

[0024] 以下结合实例说明本发明技术方案的具体实施方式和应用效果。 [0024] The following examples illustrate specific embodiments in conjunction with the application and technical solution of the present invention. 实例中猪小肠粘膜下层来源于Cook Medical公司生产的Surgisis产品;核心蛋白聚糖购自SinoBiological,产品货号10189-H08H;低分子量肝素购自齐鲁制药,国药准字H20000095 ;纤维蛋白溶酶原激活剂购至德国Boehringer Ingelheim Pharma GmbH & C0.KG,注册证号S20110051。 Example porcine small intestine submucosa from Cook Medical products produced Surgisis; available from decorin SinoBiological, Item No 10189-H08H; low molecular weight heparin was purchased from Qilu Pharmaceutical Zhunzi H20000095; plasminogen activator purchased from Germany Boehringer Ingelheim Pharma GmbH & C0.KG, registration No S20110051.

[0025] 实施例1、 [0025] Example 1,

步骤一、消毒处理:将除去粘膜层、淋巴结的片状SIS用纯化水清洗至无污物,置于浓度为0.5mol/L的氢氧化钠水溶液中浸泡半小时,然后用纯化水清洗至pH中性; A step, disinfection: The mucosal layer was removed, washed with lymph SIS sheet to purified water free of dirt, placed in a concentration of 0.5mol / L sodium hydroxide aqueous solution was immersed for half an hour, then washed with purified water until the pH neutral;

步骤二、脱细胞去抗原处理:将消毒处理后的SIS置于浓度为I mg/mL的胰蛋白酶溶液中浸泡半小时,再用纯化水清洗后,置于含25 U/mL的DNA水解酶和40 U/mL的α -半乳糖苷酶的酶液中浸泡4小时,最后用纯化水清洗10次; Step two, acellular antigens to Treatment: After sterilization treatment the SIS soaked in trypsin concentration was placed a solution of I mg / mL of half an hour, washed with water and then purified, disposed hydrolase DNA containing 25 U / mL of and 40 U mL of α / - galactosidase enzyme solution was immersed for 4 hours and finally washed 10 times with purified water;

步骤三、复合透明质酸:将步骤二处理后的SIS裁剪至3X4cm,置于浓度为20 mg/mL的透明质酸溶液中浸泡2小时,取出后真空冻干得到复合有透明质酸的SIS膜片; Step three, combined with hyaluronic acid: SIS after the second processing step to cut 3x4cm, placed in a concentration of 20 mg / mL of hyaluronic acid solution soak 2 hours, after removing the vacuum freeze-dried to give hyaluronic acid with a compound SIS diaphragm;

步骤四、灭菌处理:将复合有透明质酸的SIS膜片包装后采用15kGy的伽马射线辐照灭 Step 4 sterilization: hyaluronic acid composite packaging film of SIS With 15kGy gamma irradiation off

菌;· bacteria;·

步骤五、改性处理:将得到的无菌SIS膜片在室温下浸泡于无菌改性溶液中I分钟后,取出在无菌环境下晾干,无菌包装,得到防粘连生物膜;所述的无菌改性溶液是在生理盐水溶液中含有:0.05 μ g/mL的核心蛋白聚糖,5000AXaI⑶/mL的低分子量肝素,0.lmg/mL的纤维蛋白溶酶原激活剂和0.1 mg/mL的阿司匹林。 Step five, modification treatment: The film obtained sterile SIS soaked at room temperature in the sterile modified solution I minute, to dry out in a sterile environment, sterile packaging, to obtain anti-blocking biofilm; the said modified solution is sterile physiological saline solution containing: 0.05 μ g / mL of decorin, low molecular weight heparin 5000AXaI⑶ / mL of, 0.lmg / mL of plasminogen activator and 0.1 mg / mL aspirin.

[0026] 本实例所制备的防粘连生物膜采用较轻微的碱处理,透明质酸复合浓度较高,得到的膜片较厚(0.2〜0.5mm),且灭菌剂量较低,使该膜片降解较慢,适用于需要较长时间隔离的肌腱、神经等部位,能够起到预防术后粘连的效果。 [0026] The present anti-blocking biofilm Examples prepared using milder alkali treatment, the higher the concentration of hyaluronic acid complex, relatively thick membrane obtained (0.2~0.5mm), and low sterilization dose, so that the film slower degradation sheet for a long time is required isolation tendons, nerves and other parts, can be postoperative adhesion preventive effect. 参见附图3中C和D,该防粘连生物膜应用至肌腱、神经缝合部位,可起到良好的物理隔离作用,有效地抑制炎症,术后8周肌腱和神经愈合良好,未发生肌腱或神经坏死、再断裂,与周围组织无任何粘连发生。 See FIG. 3 C and D, to apply the anti-blocking biofilm tendon, nerve suture site, can play a good physical isolation effectively inhibit inflammation, nerve 8 weeks after surgery and good healing tendon, tendon or does not occur nervous necrosis, then broken, and the surrounding tissue without any adhesions.

[0027] 实施例2、 [0027] Example 2,

步骤一、消毒处理:将除去粘膜层、淋巴结的片状SIS用纯化水清洗至无污物,置于浓度为3 mo I/L的氢氧化钠水溶液中浸泡2.5小时,然后用纯化水清洗至pH中性; A step, disinfection: The mucosal layer was removed, washed with lymph SIS sheet to purified water free of dirt, placed in a concentration of 3 mo I / L sodium hydroxide aqueous solution was immersed for 2.5 hours and then washed with purified water to neutral pH;

步骤二、脱细胞去抗原处理:将消毒处理后的SIS置于浓度为lmg/mL胰蛋白酶溶液中浸泡半小时,再用纯化水清洗后置于含10U/mL的DNA水解酶和30U/mL的α -半乳糖苷酶的酶液中浸泡半小时,最后用纯化水清洗5次; Step two, acellular antigens to Treatment: After the sterilization process is placed after the SIS concentration of lmg / mL trypsin solution soak for half an hour, then placed in purified water wash containing 10U / mL of DNA hydrolase and 30U / mL the α - galactosidase enzyme solution soaked for half an hour, and finally washed 5 times with purified water;

步骤三、复合透明质酸:将步骤二处理后的SIS裁剪至4X6cm,置于浓度为5 mg/mL的透明质酸溶液中浸泡半小时,取出后经真空冻干得到复合有透明质酸的SIS膜片; Step three, combined with hyaluronic acid: SIS after the second processing step to cut 4X6cm, placed in a solution of hyaluronic acid at a concentration of 5 mg / mL soaked for half an hour, after removing the vacuum freeze-dried to give hyaluronic acid was compounded with SIS diaphragm;

步骤四、灭菌处理:将复合有透明质酸的SIS膜片包装后进行辐照灭菌,辐照剂量为25kGy的伽马射线; Step 4 sterilization: irradiating the composite with a sterilized membrane hyaluronic SIS packaging, gamma irradiation dose of 25kGy;

步骤五、改性处理:将得到的无菌SIS膜片在室温下浸泡于无菌改性溶液中10秒后,取出在无菌环境下晾干,无菌包装,得到防粘连生物膜;所述的无菌改性溶液是在生理盐水溶液中含有:0.2 μ g/mL的核心蛋白聚糖,25000AXaI⑶/mL的低分子量肝素,0.5 mg/mL的纤维蛋白溶酶原激活剂和I mg/mL的布洛芬。 Step five, modification treatment: The obtained membrane was immersed in sterile SIS sterile modified solution at room temperature in 10 seconds, taken out to dry in a sterile environment, aseptic packaging, give anti-blocking biofilm; the said modified solution is sterile physiological saline solution containing: low molecular weight heparin proteoglycan core 0.2 μ g / mL of, 25000AXaI⑶ / mL to, 0.5 mg / mL of plasminogen activator and I mg / ibuprofen mL.

[0028] 本实例制备的防粘连生物膜采用较强的碱处理,透明质酸复合浓度较低,得到的膜片较薄(0.02〜0.1mm),且灭菌剂量较高,从而使该膜片降解较快,适用于需要降解较快的腹腔、盆腔等部位,能够起到预防术后粘连的效果。 [0028] anti-adhesion biofilm present example prepared using strong base treatment, a lower concentration of hyaluronic acid complex, to give a thin diaphragm (0.02~0.1mm), and high doses of sterilization, such that the membrane sheet degradation speed applications requiring rapid degradation abdominal, pelvic and other parts, can be postoperative adhesion preventive effect. 参见附图3中A和B所示,该防粘连生物膜应用至腹腔肝脏、小肠手术部位后,可起到良好的物理隔离作用,有效地防止脏器、肠道粘连,术后2周肝脏自由度良好,术后4周小肠与周围肠道、脏器未发生粘连。 Referring to the drawings in FIG. 3 A and B, to apply the anti-blocking biofilm abdominal liver, small intestine surgical site, can play a good physical isolation effectively prevent organ, intestinal adhesions, liver after 2 weeks good freedom, small intestine and the surrounding gut 4 weeks postoperative organ adhesion did not occur.

[0029] 实施例3、 [0029] Example 3,

步骤一、消毒处理:将除去粘膜层、淋巴结的片状SIS用纯化水清洗至无污物,置于浓度为I mol/L的氢氧化钾水溶液中浸泡I小时,然后用纯化水清洗至pH中性; A step, disinfection: The mucosal layer was removed, washed with lymph SIS sheet to purified water free of dirt and placed immersion concentration of I mol / L aqueous potassium hydroxide solution in I h, then washed with purified water until the pH neutral;

步骤二、脱细胞去抗原处理:将消毒处理后的SIS置于浓度为3mg/mL胰蛋白酶溶液中浸泡2小时,再用纯化水清洗后置于含15U/mL的DNA水解酶和35U/mL的α -半乳糖苷酶的酶液中浸泡2小时,最后用纯化水清洗7次; Step two, acellular antigens to Treatment: After the sterilization process is placed after the SIS concentration of 3mg / mL trypsin solution soak 2 hours, then placed in purified water wash containing 15U / mL of DNA hydrolase and 35U / mL the α - galactosidase enzyme solution to soak 2 hours and finally washed 7 times with purified water;

步骤三、复合透明质酸:将步骤二处理后的SIS裁剪至5X 5cm,置于浓度为10mg/mL的透明质酸溶液中浸泡I小时,取出后经真空冻干得到复合有透明质酸的SIS膜片; Step three, combined with hyaluronic acid: SIS after the second processing step to cut 5X 5cm, placed at a concentration of 10mg / mL hyaluronic acid solution soak I hour, the composite was taken out of the freeze-dried hyaluronic acid was vacuum SIS diaphragm;

步骤四、灭菌处理:将复合有透明质酸的SIS膜片包装后进行辐照灭菌,辐照剂量为20kGy的伽马射线; Step 4 sterilization: irradiating the composite with a sterilized membrane hyaluronic SIS packaging, gamma irradiation dose of 20kGy;

步骤五、改性处理:将得到的无菌SIS膜片浸泡于无菌改性溶液中30秒后,取出在无菌环境下晾干,无菌包装,得到防粘连生物膜;所述的无菌改性溶液是在生理盐水溶液中含有:0.1 μ g/mL的核心蛋白聚糖,IOOOOAXaI⑶/mL的低分子量肝素,0.3 mg/mL的纤维蛋白溶酶原激活剂和0.5 mg/mL的对乙酰氨基酚。 Step five, modification treatment: The obtained membrane was immersed in a sterile aseptic SIS modified solution after 30 seconds, taken out to dry in a sterile environment, aseptic packaging, give antiblocking biofilm; the free bacteria containing a modified solution in a physiological saline solution: low molecular weight heparin proteoglycan core 0.1 μ g / mL of, IOOOOAXaI⑶ / mL to, 0.3 mg / mL of plasminogen activator and 0.5 mg / mL of Acetaminophen.

[0030] 本实例制备的防粘连生物膜,以碱处理有效去除细胞成分,采用胰蛋白酶、DNA酶和α -半乳糖苷酶处理可有效去除SIS中的能引起免疫排斥的抗原成分,在动物实验中应用至神经、肌腱、腹腔、盆腔等手术部位预防粘连时,具有良好的生物相容性,极少出现排异反应,防粘连生物膜应用部位的周围组织愈合良好,无致瘤性、无毒性,体温无异常升高,动物各项生理活动正常。 [0030] Preparation of anti-adhesion biofilm present example, in order to effectively remove alkali treatment cell components, trypsin, and the DNA enzyme α - galactosidase treatment can effectively remove the SIS can cause immune rejection antigen component in the animal experiment applied to nerves, tendons, abdominal, pelvic surgical site when the prevention of adhesion, good biocompatibility, little to rejection, anti-blocking biofilm surrounding tissue application site healed without tumorigenic non-toxic, no abnormal elevation of body temperature, animal normal physiological activities.

[0031] 实施例4、 [0031] Example 4,

步骤一、消毒处理:将除去粘膜层,淋巴结的片状SIS用纯化水清洗至无污物,置于浓度为2 mol/L的氢氧化钙水溶液中浸泡2小时,然后用纯化水清洗至pH中性; A step, disinfection: The mucosal layer was removed, washed with lymph SIS sheet to purified water free of dirt, placed in a concentration of 2 mol / L aqueous calcium hydroxide soak 2 hours, then washed with purified water until the pH neutral;

步骤二、脱细胞去抗原处理:将消毒处理后的SIS置于浓度为2 mg/mL胰蛋白酶溶液中浸泡3小时,再用纯化水清洗后置于含20U/mL的DNA水解酶和32U/mL的α -半乳糖苷酶的酶液中浸泡3小时,最后用纯化水清洗8次; Step two, acellular antigens to Treatment: After sterilization treatment was placed SIS concentration 2 mg / mL trypsin solution soak for three hours, after washing with water and then placed in purified containing 20U / mL of DNA hydrolase and 32U / mL of α - galactosidase enzyme solution was immersed for 3 hours and finally washed 8 times with purified water;

步骤三、复合透明质酸:将步骤二处理后的SIS裁剪至4X4cm,置于浓度为15 mg/mL的透明质酸溶液中浸泡1.5小时,取出后经真空冻干得到复合有透明质酸的SIS膜片; Step three, combined with hyaluronic acid: SIS after the second processing step to cut 4x4 cm, was placed a solution of hyaluronic acid at a concentration of 15 mg / mL immersed for 1.5 hours after removing the composite obtained by vacuum freeze-dried hyaluronic acid SIS diaphragm;

步骤四、灭菌处理:将复合有透明质酸的SIS膜片包装后进行辐照灭菌,辐照剂量为40kGy的伽马射线; 步骤五、改性处理:将得到的无菌SIS膜片在室温下浸泡于无菌改性溶液中15秒后,取出在无菌环境下晾干,无菌包装,得到防粘连生物膜;所述的无菌改性溶液是在生理盐水溶液中含有=0.15 μ g/mL的核心蛋白聚糖,15000AXaI⑶/mL的低分子量肝素,0.2 mg/mL的纤维蛋白溶酶原激活剂和0.8 mg/mL的非甾体类抗炎症药物萘普生。 Step 4 sterilization: irradiating the composite with a sterilized membrane hyaluronic SIS packaging, gamma irradiation dose of 40kGy; Step 5 modification: a sterile membrane obtained SIS soaked at room temperature in sterile modified solution after 15 seconds, taken out to dry in a sterile environment, aseptic packaging, give antiblocking biofilm; the modified solution is sterile physiological saline solution containing = 0.15 μ g / mL of decorin, 15000AXaI⑶ / mL of low molecular weight heparin, 0.2 mg / mL of plasminogen activator and 0.8 mg / mL of non-steroidal anti-inflammatory drug naproxen.

[0032] 本实例制备的防粘连生物膜,通过与透明质酸复合,可有效利用透明质酸极强的吸收保持水分的能力,使防粘连生物膜有效吸收手术部位的组织渗液,贴附至创面不易脱落,手术操作方便,使用简单,如附图2所示。 [0032] Preparation of anti-adhesion biofilm present example, the hyaluronic acid compound, hyaluronic acid can be effectively utilized to maintain strong ability to absorb water, so that anti-blocking biofilm effectively absorb exudate tissue surgical site, attached to wounds not peel off easily surgical procedure, simple to use, as shown in Figure 2. 该防粘连生物膜通过改性处理,应用至动物手术部位时,具有抑制纤维化、抑制炎症、降低出血的作用,可有效防止粘连发生,应用防粘连生物膜的实验组与空白组相比,具有明`显的优效结果,防粘连有效率高于空白组30〜50%。 The anti-blocking biofilm by modification, when applied to an animal surgical site, inhibit fibrosis, inhibition of inflammation, reduction in bleeding effect, can effectively prevent the occurrence of adhesions, as compared to application of anti-adhesion biofilm experimental group and the control group, results have clear superiority `obvious, anti-blocking efficiency 30 ~ 50% higher than the control group.

Claims (2)

1.一种防粘连生物膜,其特征在于,是以Sis为支架材料,复合透明质酸、功能性蛋白和抗炎症药物而构成的干燥薄膜,干燥薄膜呈浅白色至淡黄色半透明状,厚度为0.0l〜0.5mmο An anti-blocking biofilm, wherein the scaffold is to Sis, dry film combined with hyaluronic acid, anti-inflammatory drugs and functional protein constituted, dry film as a pale white to pale yellow translucent, thickness 0.0l~0.5mmο
2.制备权利要求1所述的防粘连生物膜的方法,具体步骤包括: 步骤一、消毒处理:将片状SIS用纯化水清洗至无污物,置于浓度为0.5〜5 mol/L的碱溶液中浸泡0.5〜2.5小时,然后用纯化水清洗至pH中性; 步骤二、脱细胞去抗原处理:将消毒处理后的SIS置于浓度I〜5 mg/mL的胰蛋白酶溶液中浸泡0.5〜4小时,再用纯化水清洗后,置于含10〜25 U/mL浓度DNA水解酶和30〜.40 U/mL浓度α -半乳糖苷酶的酶液中浸泡0.5〜4小时,最后用纯化水清洗; 步骤三、复合透明质酸:将步骤二处理后的SIS按需要裁剪,置于浓度为5〜20 mg/mL的透明质酸溶液中浸泡0.5〜2小时,取出后经真空冻干得到复合有透明质酸的SIS膜片;步骤四、灭菌处理:将复合有透明质酸的SIS膜片包装后采用辐照灭菌,辐照剂量为.15〜40kGy的伽马射线; 步骤五、改性处理:将得到的无菌SIS膜片浸泡于无菌改性溶液中10〜60秒 The method of the anti-blocking biofilm 2. Preparation of claim 1, comprising specific steps: Step one, disinfection: the sheet to SIS washed with purified water free of dirt and placed at a concentration of 0.5~5 mol / L of alkali solution immersion 0.5~2.5 hours, and then washed to neutral pH with purified water; step two, acellular antigens to treatment: after the sterilization process is placed SIS concentration I~5 mg / mL trypsin solution was immersed 0.5 ~ 4 hours, washed with water and then purified, was placed containing 10~25 U / mL and the concentration of DNA hydrolase 30~.40 U / mL concentration of α - galactosidase enzyme liquid immersed 0.5~4 hours and finally washing with purified water; step three, combined with hyaluronic acid: SIS after the second processing step by the need to cut, placed in a solution of hyaluronic acid at a concentration of 5~20 mg / mL immersed 0.5~2 hours, taken out in vacuo lyophilized to give a composite membrane with a hyaluronic acid SIS; step 4 sterilization: SIS composite membrane of hyaluronic acid using radiation sterilization after packaging, exposure dose of gamma .15~40kGy ; step five, modification treatment: the obtained membrane was immersed in a sterile aseptic SIS modified solution in 10 to 60 seconds ,取出在无菌环境下晾干,无菌包装,得到防粘连生物膜;所述的无菌改性溶液是在生理盐水溶液中含有:0.05〜0.2 μ g/mL的TGF-β拮抗剂,5000〜25000AXaICU/mL的低分子量肝素,.0.1〜0.5 mg/mL的纤维蛋白溶酶原激活剂和0.1〜I mg/mL的非甾体类抗炎症药物。 , Taken in a sterile environment dry, aseptic packaging, give antiblocking biofilm; the modified solution is sterile physiological saline solution containing: 0.05~0.2 μ g / mL of TGF-β antagonists, 5000~25000AXaICU / mL of low molecular weight heparin, .0.1~0.5 mg / mL of plasminogen activator and 0.1~I mg / mL of non-steroidal anti-inflammatory drugs.
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