Novel Manufacturing Processes for Tissue Engineered Vascular Grafts

描述（由申请人提供）：此第二阶段SBIR申请是响应计划公告PA-09- 113，“医疗，牙科和生物技术的制造工艺”。该PA征集关于“制造植入装置和材料、假体器官和人工组织的技术”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良好的功能。移植物是通过在生物反应器中培养同种异体人平滑肌细胞来产生工程血管组织而制成的。然后将该工程化组织小心地脱细胞，以便去除免疫原性细胞组分，同时保留胶原性细胞外基质。这些移植物具有非活体的优点，因此可以在货架上储存长达9个月。直径为6 mm的血管透析移植物在狒狒动静脉移植模型中功能良好，并且对合成透析移植物的两种重要失效模式具有抗性：血栓形成和内膜增生。该SBIR应用旨在扩大这种令人兴奋的新型工程组织的制造。在我们的第一阶段提案中，我们的目标是构建和测试原型，一次性血管移植生物反应器。在本II期提案中，我们将在成功的I期工作的基础上，完善并建立一个规模扩大的制造系统，以实现具有成本效益的方式生产我们独特的、现成的透析用血管移植物。这种中试规模的系统也将适用于其他类型的工程组织的制造，因此将有利于整个再生医学领域。我们将完善一次性生物反应器系统，同时，我们将定义培养基的快速消耗组分，并制定补充这些限制因素的策略，从而减少总体培养基使用量。这些战略将使我们能够生产出规模化、经济的制造系统。在缩放系统中产生的透析移植物将使用移植物生物化学细胞外基质组成、细胞活力、机械完整性以及灵长类动物模型中移植物体内功能的标准测定进行评估。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.