Resorbable Small Diameter Vascular Grafts

描述（由申请人提供）：该申请题为“多功能抗血栓形成丝移植物的开发，表征和应用”，是对申请请求（RFA）号RFA- od - 09-009的回应：恢复法案有限竞争：加速创新研究的小型企业催化剂奖（R43）。在本提案中，我们寻求加速过渡到临床试验与新的小直径丝血管移植物。我们将重点关注血丝生物材料相互作用的控制，通过使用多功能方法对材料特性、生化功能化和药物装载和释放进行空间调节。该建议解决了一个关键的临床突出需求，即对于晚期血管疾病且没有合适的血管可采集的患者进行冠状动脉或股动脉搭桥的小直径血管移植，这是临床常见的做法。如果血管可以被改造成具有天然血管的功能，同时也能慢慢地完全融入宿主血管系统，这将彻底改变小血管手术，减少第二部位的发病率，并改善患者的康复。为了应对这一挑战，我们建议开发一种“细胞指导性”生物材料移植物，使用经FDA批准的天然生物聚合物丝素蛋白，结合生物活性分子来控制血液蛋白和生物材料的相互作用，以及招募和引导宿主细胞原位形成血管。我们特别建议开发无细胞丝移植物，旨在：(a)通过生化功能化或装载抗血栓形成药物来控制移植物蛋白和细胞的相互作用，(b)通过招募宿主细胞来引导融合内皮的形成（提供长期的非血栓形成性），(c)介导形成血管壁的宿主平滑肌细胞的迁移和增殖，(d)随着时间的推移缓慢降解和重塑，以实现完全整合和血管功能。移植物将在体外（在细胞组织工程研究中）和体内（在小动物模型中进行动脉替代）进行研究，以便将蛋白质和细胞反应与移植物参数联系起来，并优化其设计。

DESCRIPTION (provided by applicant): This application entitled "Development, Characterization, and Application of Multifunctional Antithrombogenic Silk Grafts," is a response to the Request for Applications (RFA) number RFA-OD- 09-009: Recovery Act Limited Competition: Small Business Catalyst Awards for Accelerating Innovative Research (R43). In this proposal, we seek to accelerate transitions to clinical trials with a new small diameter silk graft for blood vessels. We will focus on control of blood-silk biomaterial interactions by using a multifunctional approach for spatial regulation of material properties, biochemical functionalization, and drug loading and release from the silk grafts. This proposal addresses a critical outstanding clinical need for small diameter vascular grafts for coronary or femoral artery bypass in patients with advanced vascular disease and no suitable blood vessels to harvest, the common clinical practice. If vessels can be engineered to serve the function of native vessels, while also slowly fully integrating into the host vasculature, this would revolutionize small blood vessel surgery, reduce second site morbidity, and improve patient recovery. To address this challenge, we propose the development of a "cell-instructive" biomaterial graft using a natural biopolymer that is FDA approved, silk fibroin, combined with bioactive molecules to control blood protein and biomaterial interactions as well as recruit and guide host cells towards the formation of a blood vessel in situ. We specifically propose to develop acellular silk grafts designed to: (a) control graft protein and cellular interactions by biochemically functionalizing or loading the grafts with antithrombogenic drugs, (b) guide the formation of confluent endothelium by recruiting host cells (to provide long-term non-thrombogenicity), (c) mediate the migration and proliferation of host smooth muscle cells forming the vascular wall, and (d) degrade slowly and remodel over time for full integration and vascular function. The grafts will be studied in vitro (in tissue engineering studies with cells) and in vivo (artery replacement in a small animal model) in order to correlate protein and cellular responses to the graft parameters and optimize their design. PUBLIC HEALTH RELEVANCE: Improved options to repair and restore blood vessel function, particularly small diameter vessels, would have a significant positive impact human health. Cardiovascular disease remains a leading cause of death in the United States and coronary bypass surgery is common. The proposed approach in this program would overcome the limitations present with current coronary bypass surgeries and offer a new strategy for full regeneration of native blood vessels. The same technology has potential impact in a broader range of coatings for other medical devices, offering a range of benefits to human health and well being