Biohybrid Strategies for Decellularized Tissues

当更换故障或病变组织时，心血管外科医生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，一种常用的处理方法是通过化学固定，如浸泡在戊二醛（GA）中。然而，GA治疗经常导致种植体有害的钙化。本提案的目标是通过在ECM上涂覆一种新型的可生物降解聚合物涂层（聚富马酸丙烯或PPF）来消除GA处理的需要，该涂层将提供具有许多理想性能的增强基板。机械性能和降解时间是可调的。通过在PPF中包埋生长洗脱微粒可以增强局部生物活性。因此，所得到的杂交材料将表现出减少钙化和来自宿主的免疫反应，并能抵抗快速降解，同时促进原生组织长入。这种新型材料的成功开发将显著改善可用材料的选择，并彻底改变许多心血管修复手术的期望。通过开发新的生物材料和生物制造（B&amp；B）车间，其目的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，从而提高教育影响。这个为期三年的项目的目标是开发新的混合材料，以制造出故障或病变组织的替代品。许多用于心血管手术的基于组织的假体采用戊二醛（GA）处理的心包。心包具有良好的力学性能，但GA治疗总是导致植入物有害的钙化。本研究验证了这样一种假设，即用合成聚合物聚富马酸丙烯（PPF）的物理涂层处理心包细胞外基质（ECM），所得到的杂交材料不仅在植入时表现出减少钙化和免疫反应，而且将为组织的受控再生和维护提供一个合适的平台。该研究还将验证一个假设，即通过添加生长因子洗脱聚乳酸-羟基乙酸（PLGA）微粒，可以增强平台的生物学和活性。将确定两种组分（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，并使用基于这些配方的3D打印树脂来研究对ECM随机组织的体外响应。ppf增强ECM和3DP ppf增强ECM的性能将在大鼠皮下模型中进行评估。将评估杂交材料的细胞长势、新产生的蛋白质和信号因子，以及可能的钙沉积。该项目的更广泛影响包括开发一类新的混合生物材料，阐明再生医学中的新策略和新技术。所提出的混合材料将提供促进原生细胞向内生长和新ECM沉积的基质。一种具有降低免疫活性和随后钙化率的新材料将显著改善可用材料的选择，并彻底改变许多心血管修复手术的期望。通过开发新的生物材料和生物制造（B&amp；B）车间，其目的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，从而提高教育影响。

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.