Engineering capillary networks

描述(由申请人提供)： 目前迫切需要新的治疗方法来治疗缺血性心血管疾病，而新生血管可能是这些治疗方法中的关键组成部分，而大多数临床前和临床上促进心血管疾病新生血管形成的努力主要集中在团注促血管生成生长因子上，这些方法可能受到潜在副作用和单一生长因子不能促进成熟和稳定的血管形成的限制。这一提议的假设是，通过使用可生物降解的聚合物载体局部输送适当的血管形成细胞和生长因子组合，可以快速促进缺血肢体成熟血管网络的形成。这一假说将由聚丙交酯-乙交酯(PLG)构建三维多孔支架来解决，该支架能够局部和持续地输送血管生成分子(血管内皮生长因子[VEGF]、血小板衍生生长因子[PDGF]和转化生长因子-β[TGF-β])的组合和序列。在小鼠皮下植入模型中，将分析持续注射每种因子所诱导的新生血管形成，与联合或连续注射这些因子形成对比。其次，在使用三维多孔支架进行预培养和植入后，将评估分化的内皮细胞和内皮细胞前体(包括小鼠和人类来源)形成新的血管网络并与宿主血管整合的能力。最后，这些细胞类型将被移植到小鼠的缺血后肢，使用支架释放生长因子的组合，发现导致最佳宿主血管细胞反应。在这些最后的研究中，将利用模拟人类严重肢体缺血的小鼠。这些研究的成功完成可能导致治疗性血管生成的新方法(例如，输送生长因子和血管形成细胞的组合)。此外，这些研究中开发的系统可能为研究依赖于多种生长因子信号的各种发育过程提供新的和重要的模型系统。

DESCRIPTION (provided by applicant): There exists a critical need for new therapeutic approaches to treat ischemic cardiovascular diseases, and neovascularization will likely be a critical component of these therapies While most pre-clinical and clinical efforts to promote neovascularization in cardiovascular diseases have focused on bolus delivery of proangiogenic growth factors, these approaches may be limited by potential side-effects and the inability of single growth factors to promote the formation of a mature and stable vasculature. The hypothesis underlying this proposal is that one may rapidly promote the formation of mature vascular network in an ischemic lower limb by the localized delivery of an appropriate combination of blood-vessel forming cells and growth factors using biodegradable polymer carriers. This hypothesis will be addressed by fabricating three-dimensional porous scaffolds from poly (lactide-co-glycolide) (PLG) that are capable of the localized and sustained delivery of combinations and sequences of angiogenic molecules (vascular endothelial growth factor [VEGF], platelet derived growth factor [PDGF], and transforming growth factor-beta [TGF-beta). Neovascularization induced from sustained delivery of each factor alone, as contrasted with combination or sequential delivery of the factors will be analyzed in a subcutaneous mouse implant model. Secondly, the ability of differentiated endothelial cells and endothelial cell precursors, both mouse and human-derived, to form new networks of blood vessels and integrate with host vasculature will be evaluated following pre-culture and implantation using the 3-D porous scaffolds. Finally, these cell types will be transplanted into ischemic hind limbs of mice using scaffolds releasing the combination of growth factors found to lead to optimal host vascular cell response. In these last studies, mice that mimic human critical limb ischemia will be utilized. Successful completion of these studies may lead to new approaches in therapeutic angiogenesis (e.g., delivery of combinations of growth factors and blood vessel forming cells). In addition, the systems developed in these studies may provide novel and important model systems to study a variety of developmental processes dependent on the signaling of multiple growth factors.