Altering fibrotic and rejection responses using biomaterial systems

使用生物材料系统改变纤维化和排斥反应

• 批准号: 298472-2011
• 负责人: Jones, Kim
• 金额: $ 1.53万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=571498
• 关键词: Altering; fibrotic; rejection; responses; using

From the established (e.g. stitches) to the futuristic (e.g. tissue-engineered constructs), polymers have found diverse applications as implanted biomaterials. Yet, their utility is limited by the accumulation of fibrous tissue that inevitably occurs and accompanying immune responses. The long-term objective of the proposed research program is to design biomaterial systems that minimise fibrosis and allogeneic rejection. In order to accomplish these goals, we have two major aims within the five year duration of the grant. 1) Using a model biomaterial, we will deliver candidate anti-fibrotic drugs to decrease local scarring responses. 2) By delivering key compounds from the biomaterial, we will induce tolerogenic cells that reduce allogeneic rejection. Creation of biologically active "combination" devices is relatively recent and has been driven primarily by tissue engineering. However (and despite more complex regulatory issues), the field of implanted devices will also benefit greatly from biomaterials that actively direct responses away from fibrosis and rejection. The macrophage has been identified as the key cell activated by biomaterials. Recent research has shown that macrophages can differentiate into a spectrum of phenotypes that control subsequent wound-healing, scarring and immune responses. We hypothesize that controlled release of drugs from a biomaterial construct will direct these macrophages to regenerative, tolerogenic phenotypes. Thus, subsequent responses to a biomaterial scaffold would abrogate scarring and induce tolerance to allogeneic cells introduced as part of the tissue engineered construct. This engineering challenge is both scientifically and clinically significant. By moving beyond chemistry, we have the opportunity to rationally design biomaterial systems that actively interact with the recipient's inflammatory, fibrotic and immune responses. Moving to biologically active "combination products" will improve outcomes for traditional medical devices and for newer regenerative medicine applications.

从已建立的（例如缝合）到未来的（例如组织工程构建），聚合物已经发现了作为植入生物材料的各种应用。然而，它们的效用受到不可避免地发生的纤维组织积累和伴随的免疫反应的限制。拟议研究计划的长期目标是设计生物材料系统，以尽量减少纤维化和同种异体排斥反应。为了实现这些目标，我们在五年的赠款期限内有两个主要目标。1)使用模型生物材料，我们将提供候选抗纤维化药物，以减少局部瘢痕反应。2)通过从生物材料中递送关键化合物，我们将诱导耐受原性细胞，减少同种异体排斥反应。 生物活性“组合”装置的创建是相对较新的，并且主要由组织工程驱动。然而（尽管存在更复杂的监管问题），植入设备领域也将从积极引导反应远离纤维化和排斥的生物材料中受益匪浅。 巨噬细胞是生物材料激活的关键细胞。最近的研究表明，巨噬细胞可以分化成一系列表型，这些表型控制随后的伤口愈合、瘢痕形成和免疫反应。我们假设，从生物材料结构中控制释放药物将引导这些巨噬细胞再生，耐受性表型。因此，随后对生物材料支架的反应将消除瘢痕形成并诱导对作为组织工程构建体的一部分引入的同种异体细胞的耐受性。 这一工程挑战在科学和临床上都具有重要意义。通过超越化学，我们有机会合理设计生物材料系统，积极与受体的炎症，纤维化和免疫反应相互作用。转向具有生物活性的“组合产品”将改善传统医疗器械和更新的再生医学应用的结果。