New Functionally-Graded Biohybrid Vascular Graft

描述（由申请人提供）：在这个I期STTR提案中，我们的研发目标是开发和评估一种用于小直径（< 6mm）冠状动脉搭桥应用的新型功能分级生物杂交血管移植物。到目前为止，组织工程血管构建主要使用人工合成和动物来源的生物材料，并且在植入前需要预先播种宿主细胞以克服人工血管移植的并发症。然而，这些移植物系统表现出许多局限性，包括细胞粘附性差，生物力学和功能特性不足。PI最近在含有生物活性蛋白的功能层状聚合物支架上展示了体外再生的人类内皮。此外，VBI还开发了一种独特的人体生物基质（HuBiogel），可以通过培养单一或多种细胞类型来构建有活力的组织。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物策略与这种生理HuBiogel技术相结合，以制造先进的3D血管结构，展示增强的管腔内皮化、生物相容性和结构完整性。第一阶段的具体目标是：1)使用我们的顺序共纺hubigel /聚合物纳米基质配方方案，制造和优化具有生物力学性能的功能层状hubigel -生物杂化支架（4mm ID）；2)利用已建立的生物反应器培养方法，评估新型hubioggel -人类血管内皮细胞和骨骼肌细胞杂交移植物的体外抗血栓形成性、生物相容性和功能。此外，还将进行一项动物实验，通过植入兔主动脉-髂模型来验证新血管移植物的体内生物力学完整性。我们期望新的生物混合装置具有生物活性HuBiogel（功能性内皮）和聚合物梯度（强大的生物力学），将为小直径移植提供改进的准备植入物，而无需预先播种原代细胞。因此，生物杂交血管移植原型的成功开发将为未来II期详细的质量控制分析和体内动物验证研究（狗或猪冠状动脉搭桥模型）奠定重要基础。为了这项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术的新型小直径人类血管移植物。技术创新和商业应用潜力：目前市场上还没有采用人类生物基质支架设计的生物杂交血管移植物。我们期望一个现成的植入或移植装置将

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.