Biohybrid Strategies for Decellularized Tissues

PI：Fisher，John P Proposal number：1604742心血管外科医生在更换功能不全或患病的组织时，通常使用含有天然组织成分的生物材料，如脱细胞心包，作为植入物的细胞外基质(ECM)。为了保持机械性能，一种常见的组织处理方法是通过化学固定，如浸泡在戊二醛(GA)中。然而，GA治疗通常会导致种植体的有害钙化。这项提议的目标是通过在ECM上涂上一种新型的可生物降解的聚合物涂层(聚富马酸丙二酯或PPF)来消除对GA处理的需要，这种涂层将提供具有许多理想性能的增强基材。机械性能和降解时间是可调的。通过将生长洗脱微粒包埋在PPF中可以提高局部生物活性。因此，由此产生的杂化材料将表现出减少的钙化和来自宿主的免疫反应，并能抵抗快速降解，同时鼓励天然组织向内生长。这种新型材料的成功开发将显著改善可用的材料选择，并彻底改变人们对许多心血管修复手术的期望。通过开发一个新的生物材料和生物制造(B&amp；B)工作坊，提高了教育效果，该工作坊的目标是将具有工程和科学背景的本科生介绍到涉及生物材料和生物制造的多样化研究环境中。这个为期三年的项目的目标是开发新型混合材料，以创造出故障或疾病组织的替代品。心血管外科中使用的许多基于组织的假体使用戊二醛(GA)处理的心包。心包具有良好的力学性能，但GA处理总是会导致植入物的有害钙化。这项研究验证了这样的假设，即通过用合成的聚合物聚富马酸丙酯(PPF)的物理涂层处理心包细胞外基质(ECM)，所产生的杂化材料不仅在植入时表现出减少的钙化和免疫反应，而且将提供适合于组织可控再生和维护的平台。这项研究还将测试这一假设，即通过添加生长因子洗脱的聚(乳酸-乙醇酸)(PLGA)微粒可以增强平台的生物和活性。将确定两种成分(PPF和ECM)的理想组成，以获得贴片模型的适当机械性能和降解，并将基于这些配方的3D打印树脂用于研究ECM随机组织的体外响应。PPF增强的ECM和3DP PPF增强的ECM的性能将在大鼠皮下模型中进行评估。杂交材料将接受细胞生长、新产生的蛋白质和信号因子以及可能的钙沉积的评估。该项目的更广泛影响包括开发一类新的杂交生物材料，以及阐明再生医学领域的新战略和新技术。建议的混合材料将提供一种基质，鼓励天然细胞内生长和沉积新的细胞外基质。一种免疫活性降低和随后的钙化率降低的新型材料将显著改善可用的材料选择，并彻底改变许多心血管修复手术的预期。通过开发一个新的生物材料和生物制造(B&amp；B)研讨会来提高教育影响，该研讨会的目标是向具有工程和科学背景的本科生介绍涉及生物材料和生物制造的多样化研究环境。

PI: Fisher, John PProposal Number: 1604742When replacing malfunctioning or diseased tissues, cardiovascular surgeons often use biomaterials that contain a natural tissue component such as decellularized pericardium, which serves as an extracellular matrix (ECM) for the implant. To preserve mechanical properties, one common treatment of the tissue is through chemical fixation, such as soaking in glutaraldehyde (GA). However, GA treatment often leads to detrimental calcification of the implant. The goal of this proposal is to eliminate the need for GA treatment by coating the ECM with a novel biodegradable polymer coating (poly(propylene fumarate) or PPF) that will provide a reinforced substrate with many desirable properties. Mechanical properties and degradation times are tunable. Local bioactivity can be enhanced by embedding growth eluting microparticles in the PPF. Thus, the resulting hybrid material will exhibit diminished calcification and immune response from the host and be resistant to rapid degradation while at the same time encouraging native tissue ingrowth. Successful development of this novel material would significantly improve the material options available and revolutionize expectations for many cardiovascular repair operations. Educational Impact is advanced through the development of a new Biomaterials and Biofabrication (B&B) Workshop whose objective is to introduce undergraduates with engineering and science backgrounds to a diverse research environment involving biomaterials and biofabrication.The goal of this three year project is to develop novel hybrid materials to create a replacement for malfunctioning or diseased tissues. Many of the tissue based prosthetics used in cardiovascular surgery employ glutaraldehyde (GA)-treated pericardium. Pericardium possesses advantageous mechanical properties, but GA treatment invariably results in detrimental calcification of the implant. This study tests the hypothesis that by treating pericardium extracellular matrix (ECM) with a physical coating of the synthetic polymer poly(propylene fumarate) (PPF), the resulting hybrid materials will not only exhibit diminished calcification and immune response upon implantation, but will provide a platform suitable for controlled regrowth and maintenance of the tissue. The study will additionally test the hypothesis that the biologic and activity of the platform may be enhanced through the addition of growth factor eluting poly(lactic-co-glycolic acid) (PLGA) microparticles. The ideal composition of both components (PPF and ECM) to obtain appropriate mechanical properties and degradation for a patch model will be determined and a 3D printing resin based on these formulations will be used to investigate the in vitro response to a random organization of the ECM. The performance of PPF-reinforced ECM and 3DP PPF-reinforced ECM will be evaluated in a rat subcutaneous model. The hybrid materials will be assessed for cellular ingrowth, newly produced proteins and signaling factors, as well as possible calcium deposits. The Broader Impacts of the project include the development of a new class of hybrid biomaterials and the elucidation of new strategies and technologies within regenerative medicine. The proposed hybrid material will provide a substrate that encourages native cellular ingrowth and deposition of new ECM. A novel material with a decreased immune activity and subsequent calcification rate would significantly improve the material options available and revolutionize expectations for many cardiovascular repair operations. Educational Impact is advanced through the development of a new Biomaterials and Biofabrication (B&B) Workshop whose objective is to introduce undergraduates with engineering and science backgrounds to a diverse research environment involving biomaterials and biofabrication.