女性盆底功能障碍的新型组织工程材料的优化设计及试验研究
摘要
女性盆腔脏器脱垂(POP)是一种常见病,国内发病率约为40%并且逐年增加,已成为严重影响中老年妇女健康和生活质量的一组妇科问题。
目前认为各种利用补片的术式是治疗POP的最佳手段,临床广泛使用的聚丙烯合成材料的补片虽然疗效确切的优点,但具有顺应性差、组织侵蚀性强、、感染率高等缺点并导致性交痛等相关并发症。而选择经过脱细胞处理的生物材料(ECM)是克服上述固有缺陷的方法之一。
ECM材料植入人体后最终会降解,通过致胶原组织增生、周围组织移行而形成支撑结构,从而达到支撑盆底的作用。相对于传统的聚丙烯补片,其优点是组织侵蚀率低,术后性交痛、盆腔慢性疼痛及小便困难的发生率少,其顺应性也相对较好。因此ECM补片有可能成为未来最有希望的盆底补片。
理想的ECM应具备如下特性:有良好的组织相容性;可降解及降解速度可控性;无抗原作用;诱导组织再生;有一定空隙率;有一定机械强度。目前几种常用的ECM材料都接近或具备以上部分特性:包括小肠粘膜下层(SIS)、脱细胞膀胱(UBM)、脱细胞真皮(ADM)、脱细胞心包(AP)以及脱细胞胆囊(CEM)等,作为盆底补片材料,ECM的选择非常重要,但目前却缺乏横向比较,导致ECM选择的随意性,我们研究的目的之一,就是依据盆底的特殊环境和要求,从常用的ECM材料中作各种特性的比较,选择其中一种最适合作为POP补片的ECM材料作为后续试验的研究对象。
但是ECM补片尚未在临床大量推广,存在的主要问题是:诱导周围组织再生的能力和ECM降解周期存在矛盾,目前尚无良好办法控制这一平衡,导致疗效特别是远期效果的不稳定。目前解决ECM以上不足的方法有两个,其一是在ECM材料上选择具有多项分化潜能的干细胞作为种子细胞,构建组织工程补片,将组织工程补片植入体内后,干细胞能在体内分化,增殖,理论上能丰富盆底细胞和组织结构,解决组织修复不足的矛盾,提高远期效果。其二是通过构建ECM-聚丙烯复合补片的方法,克服各种补片材料的不足,以期能提高ECM的远期效果,同时降低聚丙烯补片的相关并发症。
本研究通过制备五种最常研究的猪ECM材料,并根据盆底的特殊环境设计数项检测指标,选择其中一种最适合用作POP补片的ECM材料作为研究对象,并通过将骨髓间充质干细胞(BMSCs)作为种子细胞,和ECM材料构建组织工程补片,另外还将2层该ECM材料同一层聚丙烯材料一起构建三明治结构的POP复合补片,植入SD大鼠阴道粘膜下,检测组织相容性及免疫学指标的变化,从而为目前临床POP补片的开发或改进提供一条新的思路。主要实验方法及结果如下:
一、不同组织来源ECM支架材料的优化制备及种子细胞的选择
1.采用机械法和化学脱细胞法对bama小型猪的心包、真皮、小肠、膀胱、胆囊进行脱细胞处理后,并对各种材料进行冻干,γ射线消毒,塑料封装处理。构建不同来源的ECM材料。
2.成功对大鼠的BMSCs进行分离,培养和鉴定,将其作为POP组织工程补片的种子细胞。
二、不同组织来源ECM材料的体外特性检测以及支架材料的选择
1.从材料的抗菌性能、生物相容性、体外降解周期、吸水性、生物力学性能对5种常用ECM材料进行进行综合分析。观察5种材料交联前后上述检测指标的性能变化。
2.研究发现UBM具有最长的降解周期,最强的抗菌性、最高的吸水性、最好的生物力学性能、以及优秀的组织相容性,适合于盆底特殊环境。亦是最适合用作盆底组织工程补片的支架材料。
三、组织工程材料的构建及体内生物相容性试验
1.实验分为5组,每组12只大鼠,分别植入UBM,接种BMSCs的UBM,复合聚丙烯补片的UBM,单纯聚丙烯补片,假手术组。于术后第一、二、三、四周分别取材,做HE染色石蜡切片观察和免疫组化检测。
2.HE染色石蜡切片发现UBM组、UBM+BMSCs组和复合补片组第一周炎症反应明显,但第二周开始明显减轻,到第四周时仅有轻微反应;聚丙烯组强烈的炎症反应伴随整个实验观察阶段。炎症反应由低到高排序是:UBM+BMSCs组 3.免疫组化检测发现CD4的表达情况由低到高排序为:UBM+BMSCs组 总之,本研究依据盆底的特殊环境,通过对各种常用的ECM材料进行体外各项特性检测,发现UBM是最适合用于POP补片的ECM材料,并对UBM进行体内的生物学性能试验,发现接种BMSCs的UBM和UBM作为盆底修复补片具有引发的炎症和免疫反应较小,能诱导免疫反应向免疫适应转变,而且UBM还可修饰聚丙烯补片,起到炎症隔离和免疫调节的作用,但接种BMSCs的UBM和单纯UBM在体内降解速度较快,因此复合聚丙烯材料的UBM可能是未来盆底修复材料的理想候选者。
The femal pelvic organ prolapse (POP) is a common disease, with an incidence of 40% in china and increased year by years. The POP has been regarded as a considerable gynecologic problem that seriesly influenced the the health of middle-aged and old women.
It has been generally accepeted that various kinds of operation based on scaffolds were the best treatment method for POP, and the propolene scaffold widely used in clinic has the feature of certain curative effect with long-lasting period. However these prostheses carry an inherent risk of sepsis formation, erosion related to their biomechanical properties and low biocompatibility. Reversely, the bio-patch processed by decellular procedure treatment was a ideal scaffold for POP without these defects abovely mentioned.
The ECM scaffold planted in body will degredated eventually. Meanwhile, the ECM could promote the proliferation of the collagen tissue and the migration of surrounding tissue, so the substitution tissues formed at the pelvic floor. Contrast to the propolene material, the ECM material show obvious predominances such as low tissue erosion, low incidence rate of algopareunia, chronic pelvic pain, and dysurination with good compliance. So the ECM material would become the perspective pelvic scaffold in the future.
The ideal ECM scaffold should have these properties: good biocompatibility, self degradation with a controllable rate; no antigene effect; could induce tissue regeneration; with cellule and and mechanical strength, etc. some kinds of commonly used ECM patial or fully possesed these properties as mentioned abovely. Such as small intestinal submucosa(SIS), urinary bladder matrix(UBM), acellular dermis matrix(ADM), acellular pericardium(AP), cholecyst-derived extracellular matrix(CEM), etc. it’s important to choose a suitable ECM scaffold for POP treatment as pelvic requirements. Unfortunely, the surgens choose the ECM scaffold for POP operation as their pleasure because lacking of a comparative study of these ECM materials for pelvic patch recently. One purpose of our study was to choose one kind of commonly used ECM materials for POP treatment base on the special enviroments and requirements of pelvic reconstruction surgery. The ECM scaffold have not been generalized in clinic for the main problem: the contradiction existed that the ability inducing surrounding tissue regeneration with the degradation period, and no sounded method presently to control this contradiction, therefore the curative effect especially the long-term curative effect are not stable. There are two meanses to tackle this problem: first, by means of tissue engineering method, the multiple-differentiation potent stem cells could be planted on the scaffold as seed cells. Then the stem cells could proliferated and differentiated when the tissue engineering scaffold was planted in vivo, and the pelvic tissue and cells could profusioned with a improved long-term curative effect theoretically. The other method is construction of the compound ECM-Propolene scaffold. With the expectation of overcoming the difects of the two kinds of materials, promoting the long-term curative rate and depressing the complications caused by single propolene material.
This research prepared 5 kinds of porcine ECM materials that commonly studied at present. Designed multiple detection index based on the special environment of pelvic floor, and choose one kind of ECM as the research object best for POP scaffold. The bone marrow stem cells(BMSCs) were taken as seed cells and seeded on the chosen ECM to construct the tissue engineering scaffold for POP. At the mean time, the compound scaffold sandwished by 2 layer of chosen ECM and one layer of propolene were constructed. Then these scaffolds were planted in the vaginal submucosa of SD rats, and the tissue compliance and immune index changes were decteted. Expect to provid a new idea for the development pelvic scaffold for treatment of POP. The main experiment methods and results were exploied as followed:
1, the preparation of each ECM and the choice of seeding cells
1), The pericardium, demis, small intestine, urinary bladder, and cholecyst of bama’s pig were decellularized by mechnical and chemical methods, then these materials were disinfected and rinsed, and terminally sterilized using CO60γradiation
2), The BMSCs of rats as the seeding cells of POP tissue engineering scaffold were detached, cultivated and indentificated successfully.
2, the characteristic evaluation of each ECM in vitro and the choice of the scaffold for POP
1), Each ECM materials were evaluated in terms of histological structure, water absorption ability, biodegradation ability, mechanical properties, antimicrobial activity and biocompatibility in vitro, and these ECM materials after cross-linked were evaluated also.
2), The UBM was indentificated that it possessed the most long-lasting degredation period, the best antimaicrobial activity, water absorption, mechanical properties, and biocompatibility. The UBM maybe the material most to fit the pelvic environment and the best choice for POP tissue patch or tissue engineering scaffold.
3, The construction of tissue scaffold and the biometical function and biocompatibility evaluation in vivo
1), The experiment tat were classified to 5 group, with 12 rats each, the UBM single, UBM+BMSCs(tissue-engineering scaffold), compound scaffold, or propelene single were planted into the vaginal submucosa of rats of each group respectively, the last group was false-surgery group. The scaffold and the tissue surrounded were harvested for HE staining and immunohistochemisry at the 1~(st), 2~(nd),3~(rd), and the forth week after operation.
2) Represented by HE staining, the inflame reaction were obvious at the first week after operation in UBM, UBM+BMSCs and compound scaffold group, but obviously relieved at the second week; the intensed inflame reaction viewed through the total experiment period in propolene group.
The sequence of the imflame reaction degree was: UBM+BMSCs group 3) The expressing level of CD4 was: UBM+BMSCs group On the whole, the study evaluated several ECM materials in vitro based on the special pelvic environment, founded that UBM is the best ECM material for POP scaffold, and the biocompatibility test of UBM were carried out later. The result was that UBM and UBM+BMSCs can led to decreased inflame reaction by induce immune reaction change to immune adaptation. Even more, the UBM can modify the propolene scaffold by modulate the immune reaction and isolate inflame reaction. The degredation period of BMSCs+UBM and UBM were relatively fast, it’s inferred that the compound scaffold composed of UBM and propolene maybe the future candidate for POP patch.
目前认为各种利用补片的术式是治疗POP的最佳手段,临床广泛使用的聚丙烯合成材料的补片虽然疗效确切的优点,但具有顺应性差、组织侵蚀性强、、感染率高等缺点并导致性交痛等相关并发症。而选择经过脱细胞处理的生物材料(ECM)是克服上述固有缺陷的方法之一。
ECM材料植入人体后最终会降解,通过致胶原组织增生、周围组织移行而形成支撑结构,从而达到支撑盆底的作用。相对于传统的聚丙烯补片,其优点是组织侵蚀率低,术后性交痛、盆腔慢性疼痛及小便困难的发生率少,其顺应性也相对较好。因此ECM补片有可能成为未来最有希望的盆底补片。
理想的ECM应具备如下特性:有良好的组织相容性;可降解及降解速度可控性;无抗原作用;诱导组织再生;有一定空隙率;有一定机械强度。目前几种常用的ECM材料都接近或具备以上部分特性:包括小肠粘膜下层(SIS)、脱细胞膀胱(UBM)、脱细胞真皮(ADM)、脱细胞心包(AP)以及脱细胞胆囊(CEM)等,作为盆底补片材料,ECM的选择非常重要,但目前却缺乏横向比较,导致ECM选择的随意性,我们研究的目的之一,就是依据盆底的特殊环境和要求,从常用的ECM材料中作各种特性的比较,选择其中一种最适合作为POP补片的ECM材料作为后续试验的研究对象。
但是ECM补片尚未在临床大量推广,存在的主要问题是:诱导周围组织再生的能力和ECM降解周期存在矛盾,目前尚无良好办法控制这一平衡,导致疗效特别是远期效果的不稳定。目前解决ECM以上不足的方法有两个,其一是在ECM材料上选择具有多项分化潜能的干细胞作为种子细胞,构建组织工程补片,将组织工程补片植入体内后,干细胞能在体内分化,增殖,理论上能丰富盆底细胞和组织结构,解决组织修复不足的矛盾,提高远期效果。其二是通过构建ECM-聚丙烯复合补片的方法,克服各种补片材料的不足,以期能提高ECM的远期效果,同时降低聚丙烯补片的相关并发症。
本研究通过制备五种最常研究的猪ECM材料,并根据盆底的特殊环境设计数项检测指标,选择其中一种最适合用作POP补片的ECM材料作为研究对象,并通过将骨髓间充质干细胞(BMSCs)作为种子细胞,和ECM材料构建组织工程补片,另外还将2层该ECM材料同一层聚丙烯材料一起构建三明治结构的POP复合补片,植入SD大鼠阴道粘膜下,检测组织相容性及免疫学指标的变化,从而为目前临床POP补片的开发或改进提供一条新的思路。主要实验方法及结果如下:
一、不同组织来源ECM支架材料的优化制备及种子细胞的选择
1.采用机械法和化学脱细胞法对bama小型猪的心包、真皮、小肠、膀胱、胆囊进行脱细胞处理后,并对各种材料进行冻干,γ射线消毒,塑料封装处理。构建不同来源的ECM材料。
2.成功对大鼠的BMSCs进行分离,培养和鉴定,将其作为POP组织工程补片的种子细胞。
二、不同组织来源ECM材料的体外特性检测以及支架材料的选择
1.从材料的抗菌性能、生物相容性、体外降解周期、吸水性、生物力学性能对5种常用ECM材料进行进行综合分析。观察5种材料交联前后上述检测指标的性能变化。
2.研究发现UBM具有最长的降解周期,最强的抗菌性、最高的吸水性、最好的生物力学性能、以及优秀的组织相容性,适合于盆底特殊环境。亦是最适合用作盆底组织工程补片的支架材料。
三、组织工程材料的构建及体内生物相容性试验
1.实验分为5组,每组12只大鼠,分别植入UBM,接种BMSCs的UBM,复合聚丙烯补片的UBM,单纯聚丙烯补片,假手术组。于术后第一、二、三、四周分别取材,做HE染色石蜡切片观察和免疫组化检测。
2.HE染色石蜡切片发现UBM组、UBM+BMSCs组和复合补片组第一周炎症反应明显,但第二周开始明显减轻,到第四周时仅有轻微反应;聚丙烯组强烈的炎症反应伴随整个实验观察阶段。炎症反应由低到高排序是:UBM+BMSCs组
The femal pelvic organ prolapse (POP) is a common disease, with an incidence of 40% in china and increased year by years. The POP has been regarded as a considerable gynecologic problem that seriesly influenced the the health of middle-aged and old women.
It has been generally accepeted that various kinds of operation based on scaffolds were the best treatment method for POP, and the propolene scaffold widely used in clinic has the feature of certain curative effect with long-lasting period. However these prostheses carry an inherent risk of sepsis formation, erosion related to their biomechanical properties and low biocompatibility. Reversely, the bio-patch processed by decellular procedure treatment was a ideal scaffold for POP without these defects abovely mentioned.
The ECM scaffold planted in body will degredated eventually. Meanwhile, the ECM could promote the proliferation of the collagen tissue and the migration of surrounding tissue, so the substitution tissues formed at the pelvic floor. Contrast to the propolene material, the ECM material show obvious predominances such as low tissue erosion, low incidence rate of algopareunia, chronic pelvic pain, and dysurination with good compliance. So the ECM material would become the perspective pelvic scaffold in the future.
The ideal ECM scaffold should have these properties: good biocompatibility, self degradation with a controllable rate; no antigene effect; could induce tissue regeneration; with cellule and and mechanical strength, etc. some kinds of commonly used ECM patial or fully possesed these properties as mentioned abovely. Such as small intestinal submucosa(SIS), urinary bladder matrix(UBM), acellular dermis matrix(ADM), acellular pericardium(AP), cholecyst-derived extracellular matrix(CEM), etc. it’s important to choose a suitable ECM scaffold for POP treatment as pelvic requirements. Unfortunely, the surgens choose the ECM scaffold for POP operation as their pleasure because lacking of a comparative study of these ECM materials for pelvic patch recently. One purpose of our study was to choose one kind of commonly used ECM materials for POP treatment base on the special enviroments and requirements of pelvic reconstruction surgery. The ECM scaffold have not been generalized in clinic for the main problem: the contradiction existed that the ability inducing surrounding tissue regeneration with the degradation period, and no sounded method presently to control this contradiction, therefore the curative effect especially the long-term curative effect are not stable. There are two meanses to tackle this problem: first, by means of tissue engineering method, the multiple-differentiation potent stem cells could be planted on the scaffold as seed cells. Then the stem cells could proliferated and differentiated when the tissue engineering scaffold was planted in vivo, and the pelvic tissue and cells could profusioned with a improved long-term curative effect theoretically. The other method is construction of the compound ECM-Propolene scaffold. With the expectation of overcoming the difects of the two kinds of materials, promoting the long-term curative rate and depressing the complications caused by single propolene material.
This research prepared 5 kinds of porcine ECM materials that commonly studied at present. Designed multiple detection index based on the special environment of pelvic floor, and choose one kind of ECM as the research object best for POP scaffold. The bone marrow stem cells(BMSCs) were taken as seed cells and seeded on the chosen ECM to construct the tissue engineering scaffold for POP. At the mean time, the compound scaffold sandwished by 2 layer of chosen ECM and one layer of propolene were constructed. Then these scaffolds were planted in the vaginal submucosa of SD rats, and the tissue compliance and immune index changes were decteted. Expect to provid a new idea for the development pelvic scaffold for treatment of POP. The main experiment methods and results were exploied as followed:
1, the preparation of each ECM and the choice of seeding cells
1), The pericardium, demis, small intestine, urinary bladder, and cholecyst of bama’s pig were decellularized by mechnical and chemical methods, then these materials were disinfected and rinsed, and terminally sterilized using CO60γradiation
2), The BMSCs of rats as the seeding cells of POP tissue engineering scaffold were detached, cultivated and indentificated successfully.
2, the characteristic evaluation of each ECM in vitro and the choice of the scaffold for POP
1), Each ECM materials were evaluated in terms of histological structure, water absorption ability, biodegradation ability, mechanical properties, antimicrobial activity and biocompatibility in vitro, and these ECM materials after cross-linked were evaluated also.
2), The UBM was indentificated that it possessed the most long-lasting degredation period, the best antimaicrobial activity, water absorption, mechanical properties, and biocompatibility. The UBM maybe the material most to fit the pelvic environment and the best choice for POP tissue patch or tissue engineering scaffold.
3, The construction of tissue scaffold and the biometical function and biocompatibility evaluation in vivo
1), The experiment tat were classified to 5 group, with 12 rats each, the UBM single, UBM+BMSCs(tissue-engineering scaffold), compound scaffold, or propelene single were planted into the vaginal submucosa of rats of each group respectively, the last group was false-surgery group. The scaffold and the tissue surrounded were harvested for HE staining and immunohistochemisry at the 1~(st), 2~(nd),3~(rd), and the forth week after operation.
2) Represented by HE staining, the inflame reaction were obvious at the first week after operation in UBM, UBM+BMSCs and compound scaffold group, but obviously relieved at the second week; the intensed inflame reaction viewed through the total experiment period in propolene group.
The sequence of the imflame reaction degree was: UBM+BMSCs group
引文
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