经过近10年的研究和探索，在中国工程院院士王正国的带领下，第三军大学大坪医院、野战外科研究所副研究员张波等人研制出了具有组织相容性、无免疫源性和可降解，具备增强血液灌注和促血管化的骨组织工程支架材料——肝素/壳聚糖/脱细胞骨基质仿生支架材料，攻克了异种脱骨基质跨种属应用的大动物实验。该项研究成果的论文发表在美国《组织工程》杂志上，预计不久将有望应用于临床对人体骨缺损修复。
据了解，骨缺损修复一直是骨科医学的难题，而自然灾害、突发事故及战争等导致需植骨修复的人数呈上升趋势。应用组织工程技术构建的组织工程骨作为骨缺损修复的发展方向，虽临床初步应用效果确切，但因组织工程骨的血管化等问题成为世界关注的瓶颈，制约了临床大规模应用。研制新一代有特定结构和功能的仿生“智能”基质材料，成为当今组织工程学和生物材料学研究领域的前沿课题。
2002年，课题组开始异种骨基质的研究。他们采用牛骨经生化、理化处理去抗原、去细胞，经生物安全性检测达标后，将该骨基质材料应用于猪尺骨缺损修复，实验表明，3个月内骨基质全部降解，缺损修复效果良好。
2009年，团队受到水蛭抗血凝及负压吸血的启发，模拟其原理解决组织工程骨植入区血液循环障碍等难题。
实验结果显示，构建的肝素/壳聚糖/脱细胞骨基质仿生支架材料在超微结构上骨小梁结构无变化，而材料表面变平滑更利于种子细胞黏附；材料表面的分子结构检测证实肝素成功复合到材料表面，且体外肝素缓释检测表明一周内肝素可以有效释放，抗凝效果明显延长。动物实验结果证实肝素/壳聚糖/脱细胞骨基质仿生支架材料可以有效促进血液灌注。
课题组通过肝素/壳聚糖自组装表面改性后脱细胞骨基质材料，解决了植入材料被血凝块包围，以及移植物的氧和营养物质灌注障碍等瓶颈问题，为临床大块骨缺损修复提供了技术支持；同时也为进一步采用仿生学方法模拟水蛭疗法在断指再植、皮瓣移植及肢体循环障碍等领域促进微循环血液流动，改善组织血液循环提供了理论依据，经过临床试验后便可普遍推广应用。(生物谷 Bioon.com)
doi:10.1089/ten.tea.2011.0027
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Heparin-Chitosan-Coated Acellular Bone Matrix Enhances Perfusion of Blood and Vascularization in Bone Tissue Engineering Scaffolds
Xin-jun Sun,Wei Peng,Zai-liang Yang,Ming-liang Ren,Shi-chang Zhang,Wei-guo Zhang,Lian-yang Zhang,Kai Xiao,Zheng-guo Wang,Bo Zhang,andJin Wang
Currently, the main hurdle in the tissue engineering field is how to provide sufficient blood supply to grafted tissue substitutes in the early post-transplanted period. For three-dimensional, cell-dense, thick tissues to survive after transplantation, treatments are required for hypoxia, nutrient insufficiency, and the accumulation of waste products. In this study, a biomacromolecular layer-by-layer coating process of chitosan/heparin onto a decellularized extracellular bone matrix was designed to accelerate the blood perfusion and re-endothelialization process. The results of in vitro measurements of the activated partial thromboplastin time supported the theory that the combination of chitosan and heparin could bring both anticoagulation and hemocompatibility to the scaffold. A rabbit bone defect model was established for further evaluation of the application of this kind of surface-modified scaffold in vivo. The final results of computed tomography (CT) perfusion imaging and histological examination proved that this facile coating approach could significantly promote blood perfusion and re-endothelialization in the early post-transplanted period compared with an acellular bone matrix due to its much-improved anticoagulation property.
