Biodegradable polymetric scaffolds and tissue engineeri*

描述(由申请人提供)： 组织工程化血管可能会为经常无法获得的自体移植物提供可行的替代方案，从而潜在地为血管替代手术带来革命性的变化。使用天然成分进行组织工程的血管结构提供了模仿天然动脉反应性质的可能性。然而，尽管在该领域取得了很大进展，但到目前为止开发的那些材料还不够强大，或者需要极长的体外生长时间才能实现。从我们最近努力优化开发使用血管平滑肌细胞(SMC)种植的胶原构建的组织工程血管移植物，我们了解到这种结构的力学性能的丧失与SMC释放的称为基质金属蛋白酶(MMPs)的酶导致支架过早降解有关。然而，事实证明，阻断MMP也会阻止SMC组装基质的能力，这是正确构建组织和功能所必需的过程。我们建议探索一种潜在的结构设计改进，通过添加可生物降解的支架在体外组装过程中提供额外的机械支持，从而保留有利的基质金属蛋白酶重塑功能，同时防止过早失败。这一想法的创新之处在于，我们寻求一种支架，除了提供机械支持外，还将优化自然成分的特征，这些特征与组织工程构建物增强的机械性能相关：细胞活性和自然基质成分的适当翻转和组织。为此，我们将使用一种新的有理组合方法，该方法允许测试可生物降解支架的大量潜在的化学和物理特性。我们还将评估合成支架是否容易被MMPs降解，MMPs会改变其性能，并可能与体内构建物植入后的身体反应有关。在这些实验中，我们将使用从基因工程的MMP基因敲除或转基因小鼠的动脉中分离出来的SMC，这将允许对这些酶的作用进行特定的测试。我们的研究应该有助于改进使用天然成分进行组织工程的血管移植物。我们计划利用所获得的信息来优化包含人血管平滑肌和内皮细胞的混合移植物的未来设计。

DESCRIPTION (provided by applicant): Tissue engineered blood vessels may potentially revolutionize vascular replacement surgery by providing viable alternatives for often unavailable autologous grafts. Vascular constructs tissue engineered using natural components offer the potential to mimic the responsive nature of native arteries. However in spite of much progress in the field those developed so far have insufficient strength or require an extremely long time of growth in vitro to achieve it. From our own recent efforts to optimize development of vascular grafts tissue engineered using vascular smooth muscle cells (SMC) seeded collagen, we learned that loss of mechanical properties of such constructs is associated with premature scaffold degradation by enzymes released by SMC, called matrix metalloproteinases (MMPs). Blocking MMPs however, proved to also prevent SMC capacity to assemble matrix, process essential for proper construct organization and function. We are proposing to explore a potential construct design improvement, which would preserve the advantageous MMP remodeling functions while preventing premature failure, by providing additional mechanical support during the in vitro assembly through the addition of a biodegradable scaffold. The innovative aspect of this idea is that we seek to identify a scaffold that, in addition to providing mechanical support, will also optimize the characteristics of natural components that have been associated with enhanced mechanical properties of tissue engineered constructs: cell viability and appropriate turn-over and organization of the natural matrix components. For this purpose we will use a novel rational combinatorial approach, which allows testing of a large number of potential chemical and physical characteristics of the biodegradable scaffold. We will also assess whether the synthetic scaffold is susceptible to degradation by MMPs, which would modify its properties and may be related to the body reaction following construct implantation in vivo. For these experiments we will use SMC that we isolate from the arteries of genetically engineered MMP knock-out or transgenic mice, which will allow the specific testing of the role of these enzymes. Our studies should contribute to the improvement of vascular grafts tissue engineered using natural components. We plan to use the gained information to optimize the future design of hybrid grafts containing human vascular smooth muscle and endothelial cells.