Resorbable Small Diameter Vascular Grafts

描述(由申请人提供)：本申请名为“多功能抗血栓形成丝绸移植物的开发、表征和应用”，是对申请编号RFA-OD-09-009：Recovery Act Limited竞争：Small Business Catalyst Awards for Accelerating Innovation Research(R43)的回应。在这项提案中，我们寻求加快过渡到临床试验，使用一种新的小直径丝质血管移植物。我们将重点控制血-丝生物材料的相互作用，使用多功能方法来控制材料性质的空间调节、生化功能化以及从丝质移植物中装载和释放药物。这项建议解决了临床上对小直径血管移植物用于冠状动脉或股动脉搭桥的关键的突出临床需求，用于晚期血管疾病且没有合适的血管可供采集的患者，这是常见的临床实践。如果血管可以被设计成服务于本地血管的功能，同时也能缓慢地完全融入宿主血管系统，这将使小血管外科发生革命性的变化，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“细胞指导型”生物材料移植物，使用FDA批准的天然生物聚合物-丝素蛋白，与生物活性分子相结合，控制血液蛋白和生物材料的相互作用，并招募和引导宿主细胞形成原位血管。我们特别建议开发无细胞丝素移植物，旨在：(A)通过对移植物进行生物化学功能化或负载抗血栓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(以提供长期的非血栓形成)，(C)调节形成血管壁的宿主平滑肌细胞的迁移和增殖，以及(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(细胞组织工程学研究)和体内(小动物模型中的动脉置换)进行研究，以将蛋白质和细胞反应与移植物参数相关联，并优化它们的设计。 公共卫生相关性：改进修复和恢复血管功能的选择，特别是小直径血管，将对人类健康产生重大积极影响。在美国，心血管疾病仍然是主要的死亡原因，冠状动脉搭桥手术很常见。该计划中提出的方法将克服目前冠状动脉搭桥术的局限性，并为完全再生天然血管提供一种新的策略。同样的技术对其他医疗设备的更广泛的涂层具有潜在的影响，为人类的健康和福祉提供了一系列的好处

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