Novel Manufacturing Processes for Tissue Engineered Vascular Grafts

描述（由申请人提供）：这项SBIR二期申请是对项目公告PA-09- 113“医疗、牙科和生物技术制造工艺”的回应。本PA征集关于“可植入装置和材料、假体器官和人工组织制造技术”的工作。Humacyte开发了一种新型血管移植物，在大型动物模型中显示出优异的功能。移植物是通过在生物反应器中培养异体人类平滑肌细胞来产生工程血管组织。然后仔细地将这种工程组织去细胞化，以去除免疫原性细胞成分，同时保留胶原细胞外基质。这些移植物的优点是没有生命，因此可以在架子上储存长达9个月。直径为6mm的血管透析移植物在狒狒动静脉移植模型中功能良好，并且能够抵抗合成透析移植物的两种重要失效模式：血栓形成和内膜增生。这项SBIR应用旨在扩大这种令人兴奋的新型工程组织的生产规模。在我们的第一阶段提案中，我们的目标是构建和测试一个原型，一次性血管移植物生物反应器。在这个II期项目中，我们将以我们成功的I期工作为基础，完善和建立一个规模化的制造系统，使我们独特的、现成的透析血管移植物的生产具有成本效益。这个试点规模的系统也将适用于制造其他类型的工程组织，因此将有利于再生医学领域作为一个整体。我们将完善一次性生物反应器系统，同时，我们将定义培养基中快速消耗的成分，并制定一项策略来补充这些限制因素，从而减少整体培养基的使用。总之，这些策略将使我们能够生产出一个规模化的、经济的制造系统。在该系统中生产的透析移植物将在灵长类动物模型中使用移植物生化细胞外基质组成、细胞活力、机械完整性以及移植物体内功能的标准分析进行评估。这些研究的结果将有助于向FDA提交IND申请。

DESCRIPTION (provided by applicant): This Phase II SBIR application is responsive to Program Announcement PA-09- 113, "Manufacturing Processes of Medical, Dental and Biological Technologies". This PA solicits work on "technology for the manufacture of implantable devices and materials, prosthetic organs, and artificial tissues". Humacyte has developed a novel vascular graft that has shown excellent function in large animal models. The graft is made by culturing allogeneic human smooth muscle cells in a bioreactor to produce an engineered vascular tissue. This engineered tissue is then carefully decellularized, so as to remove the immunogenic cellular components, while retaining the collagenous extracellular matrix. These grafts have the advantage of being non-living, and hence can be stored on the shelf for periods of up to 9 months. Vascular dialysis grafts that are 6 mm in diameter function well in a baboon model of arterio-venous grafting, and are resistant to two important failure modes of synthetic dialysis grafts: thrombosis and intimal hyperplasia. This SBIR application is directed at scaling the manufacture of this exciting and novel engineered tissue. In our Phase I proposal, our aim was the construction and testing of a prototype, disposable vascular graft bioreactor. In this Phase II proposal, we will build on our successful Phase I work, and we will refine and build a scaled-up manufacturing system that will enable cost-effective production of our unique, off-the-shelf vascular graft for dialysis access. This pilot scaled system will also be applicable to the manufacture of other types of engineered tissues, and hence will benefit the regenerative medicine field as a whole. We will hone the single-use bioreactor system and in parallel, we will define rapidly consumed components of culture medium and develop a strategy to supplement those limiting factors, thereby reducing overall culture medium usage. Together, these strategies will allow us to produce a scaled, economical manufacturing system. Dialysis grafts produced in the scaled system will be assessed using standard assays for graft biochemical extracellular matrix composition, cell viability, mechanical integrity, as well as graft in vivo function in a primate model. The results of these studies will contribute to the submission of an IND application to the FDA. PUBLIC HEALTH RELEVANCE: This Phase II SBIR application addresses a critical need in regenerative medicine: the development of scaled manufacturing systems that produce engineered tissues in a reproducible and economical fashion.