New Functionally-Graded Biohybrid Vascular Graft

描述（由申请人提供）：在本I期STTR提案中，我们的研发目标是开发和评价一种用于小直径（<6 mm）冠状动脉搭桥术的新型功能分级生物混合血管移植物。迄今为止开发的组织工程化血管构建体主要利用合成的和动物来源的生物材料，并且需要在植入之前预接种宿主细胞以克服假体血管移植物的并发症。然而，这些移植系统表现出许多局限性，包括差的细胞粘附，不足的生物力学和功能特性。PI最近已经证明了在含有生物活性蛋白的功能性层状聚合物支架上的体外再生人内皮。此外，VBI还开发了一种独特的人类生物基质（HuBiogel），通过培养单一或多种细胞类型来构建可行的组织。HuBiogel环境也可以通过富集特定生长因子（VEGF）来控制。我们现在建议将我们的功能分层移植策略与这种生理HuBiogel技术结合联合收割机，用于制造先进的3D血管结构，证明增强的管腔内皮化和生物相容性以及结构完整性。第一阶段的具体目标是：1）使用我们的顺序共纺HuBiogel/聚合物纳米基质配制方案制造和优化具有有希望的生物力学性质的功能性分层HuBiogel-生物杂交支架（4 mm ID）;和2）使用已建立的生物反应器培养方法评估具有人血管内皮和骨骼肌细胞的新型HuBiogel-杂交移植物的体外抗血栓形成性、生物相容性和功能性。此外，还将进行一项初步动物研究，通过植入兔主动脉-髂动脉模型来证明新血管移植物的体内生物力学完整性。我们预计，用生物活性HuBiogel（功能性内皮）和聚合物梯度（稳健的生物力学）设计的新生物杂交装置将为小直径移植提供改进的即插即用型植入物，而无需预接种原代细胞。因此，原型生物混合血管移植物的成功开发将为未来II期的详细质量控制分析和体内动物验证研究（犬或猪冠状动脉旁路模型）奠定重要基础。对于这项STTR提案，一个由生物工程师、细胞生物学家和心脏病学家组成的专门团队聚集在一起，开发并商业化一种用于冠状动脉置换的新型小直径人体血管移植物。技术创新和商业应用的潜力：目前市场上没有采用人类生物基质支架设计的生物混合血管移植物。我们预计，准备植入或移植装置将 旁路治疗在全球范围内拥有市场，估计价值数百万美元。

DESCRIPTION (provided by applicant): In this Phase I STTR proposal, our R&D goal is the development and evaluation of a novel functionally-graded biohybrid vascular graft for small diameter (<6 mm) coronary bypass applications. Tissue engineered vascular constructs developed to date have mostly utilized synthetic and animal- derived biomaterials and require pre-seeding of host cells before implantation to overcome the complications of prosthetic vascular grafts. However, these graft systems exhibit many limitations including poor cellular adhesion, inadequate biomechanical and functional properties. The PI has recently demonstrated an in vitro regenerated human endothelium on functionally-layered polymeric scaffolds containing bioactive proteins. Moreover, VBI has developed a unique human biomatrix (HuBiogel) that allows viable tissue constructs by cultivating single or multiple cell types. HuBiogel milieu can also be controlled via enrichment with specific growth factors (VEGF). We now propose to combine our functionally-layered graft strategy with this physiological HuBiogel technology for fabricating an advanced 3D vascular construct demonstrating enhanced lumen endothelialization and biocompatibility and structural integrity. Phase I specific aims are: 1) Fabricate and optimize functionally layered HuBiogel-biohybrid scaffolds (4 mm ID) with promising biomechanical properties using our sequentially co-spun HuBiogel/polymer nanomatrix formulation protocol; and 2) Evaluate in vitro anti-thrombogenicity, biocompatibility and functionality of new HuBiogel-hybrid graft with human vascular endothelial and skeletal muscle cells using established bioreactor culture methods. In addition, a pilot animal study will be performed to demonstrate in vivo biomechanical integrity of new vascular graft by implanting in rabbit aorto-iliac model. We anticipate that new biohybrid device engineered with bioactive HuBiogel (functional endothelium) and polymeric gradient (robust biomechanics) will provide an improved ready-to-implant for small diameter grafting without requiring pre-seeding of primary cells. Thus, successful development of prototypic biohybrid vascular graft will form important basis for detailed quality control analyses and in vivo animal validation studies (dog or pig coronary bypass models) in future Phase II. For this STTR proposal, a dedicated team of bioengineers, cell biologist and cardiologists is gathered to develop and commercialize a novel small- diameter human vascular graft for coronary replacement. Potential for technological innovation and commercial application: No biohybrid vascular graft employing human biomatrix scaffold design is currently in market. We anticipate that a ready-to- implant or graft device will have worldwide market for the bypass treatments, estimated to be in millions of dollar.