Foreign Body Response as a Performance Metric for Implanted Scaffolds

描述(申请人提供)：在许多植入部位和装置设计中，可靠地调节或控制由植入的生物材料引起的异物反应(FBR)已被证明是困难的。这种反应的病理特征是未溶解的炎症标志物，厚厚的纤维包裹，以及软组织中急性炎症细胞和最终免疫细胞的招募，降低了设备的功能，并使部位预先暴露于感染风险。最近的研究活动试图利用仿生和天然材料来解决快堆问题，并取得了一些显着的成功。然而，这些材料策略本身并不能克服体内设备性能的其他必要方面，包括组织特定的属性：拉伸强度、孔隙率和微结构，以及定制的缺陷特定的设备形态(宏观结构)。这些挑战和观察为我们的整体工作假说奠定了基础，即植入的生物材料支架结合了自然软组织的微结构、天然材料化学和机械性能，在细胞和组织愈合反应方面更优越，表现出较少的异物反应，与仅具有这些特征之一的传统生物材料相比。直接解决这一假说的任务围绕下列具体目标进行组织：(1)展示采用特定宏观和微观结构控制制备的基质蛋白修饰的多孔支架可降低异物反应，该反应基于细胞募集、细胞因子谱、纤维被膜厚度、血管密度、降解和常驻巨噬细胞/异物巨细胞的数量。(1A)使用这些生物指标区分基质蛋白支架的体内性能与类似的常规可降解聚氨酯对照；(1B)使用这些生物指标区分基质蛋白涂层的多孔不可降解聚氨酯支架的体内性能与类似的未改性聚氨酯对照相比；(2)评估改变蛋白质/糖胺聚糖(GAG)比率、比蛋白质电荷密度和基质交联度如何改变FBR，如在小鼠皮下口袋模型中的细胞因子分布、纤维被膜厚度、血管、降解和驻留巨噬细胞/异物巨细胞的数量；(3)在小鼠皮下口袋模型中，区分脂肪来源干细胞(ASC)伤口部位预种植和装置ASC种植如何改变FBR，以评估细胞数量、细胞因子谱、纤维被膜厚度、血管、降解和常驻巨噬细胞/异物巨细胞的数量。这些基于设备的修改集成在一起，旨在显著改善本地设备相关的愈合并减少围绕主机FBR的不良事件。 公共卫生相关性：生物兼容、建筑复杂、3D、医用植入物将使数百万患者受益。然而，异物反应(FBR)是设备成功集成的常见障碍，在文献中并未得到很好的理解。我们建议通过1)比较我们的新型蛋白质支架和常用可降解生物材料的FBR，2)比较蛋白质涂层和非涂层不可降解材料的FBR，3)修改蛋白质支架的组成、表面电荷和交联化学，以及4)用免疫调节脂肪干细胞(ASCs)种植这些支架，以进一步缓解植入材料的FBR，以解决这一悬而未决的FBR问题。建议的细胞外基质衍生支架和蛋白质涂层的快速翻译用于临床，作为当前的生物材料和组织工程支架阵列的替代是必要的。

DESCRIPTION (provided by applicant): Reliably modulating or controlling the foreign body response (FBR) elicited by implanted biomaterials has proven difficult in many implant sites and device designs. The pathology of this reaction, noted by hallmark unresolved inflammatory markers, thick fibrous encapsulation and recruitment of acute inflammatory and eventually immune cells in soft tissues, reduces device functionality and pre-disposes the site to infection risk. Much recent research activity has sought to address the FBR problem using biomimetic and natural materials with some notable successes. However, these materials strategies alone are incapable of overcoming other requisite aspects of device in vivo performance, including tissue specific properties: tensile strength, porosity and micro-architecture, and custom defect-specific device morphologies (macrostructure). These challenges and observations frame our overall working hypothesis that implanted biomaterial scaffolds integrated with microstructure, natural materials chemistry, and mechanical properties of natural soft tissue are superior in their cell and tissue healing responses, exhibiting a reduced foreign body response, when compared to classic biomaterials designed with only one of these features. Tasks to directly address this hypothesis are organized around the following specific aims: (1) Demonstrate that matrix protein-modified porous scaffolds fabricated with specific macro- and micro-structural control reduce the foreign body response based on cell recruitment, cytokine profiles, fibrous capsule thickness, vascularity, degradation, and numbers of resident macrophages/foreign body giant cells in a murine subcutaneous pocket model. (1A) Distinguish in vivo performance of matrix protein scaffolds using these biological metrics compared to analogous conventional degradable polyurethane controls; (1B) Distinguish in vivo performance of matrix protein-coated porous non-degradable polyurethane scaffolds using these biological metrics compared to analogous unmodified polyurethane controls; (2) Assess how altering protein/glycosaminoglycan (GAG) ratios, specific protein charge density, and matrix crosslinking alter the FBR as demonstrated by cytokine profiles, fibrous capsule thickness, vascularity, degradation, and numbers of resident macrophages/foreign body giant cells in a murine subcutaneous pocket model; (3) Distinguish how adipose-derived stem cell (ASC) wound site pre-seeding and device ASC seeding alter the FBR as assessed by cell populations, cytokine profiles, fibrous capsule thickness, vascularity, degradation, and numbers of resident macrophages/foreign body giant cells in a murine subcutaneous pocket model. Integrated together, these device-based modifications are proposed to substantially improve local device-associated healing and mitigate adverse events surrounding the host FBR. PUBLIC HEALTH RELEVANCE: Biocompatible, architecturally complex, 3D, medical implants will benefit millions of patients. However, the foreign body response (FBR), a common barrier to successful device integration, is not well understood in the literature. We propose to address this unresolved FBR issue by 1) comparing the FBR of our novel proteinaceous scaffolds to that from commonly employed degradable biomaterials, 2) comparing the FBR of protein-coated versus non-coated non-degradable materials, 3) modifying the proteinaceous scaffold composition, surface charge, and crosslinking chemistry, and 4) seeding these scaffolds with immunomodulatory adipocyte stem cells (ASCs) to further mitigate the FBR to implanted materials. Rapid translation of the proposed extracellular matrix-derived scaffolds and protein coatings for clinical use as an alternative to the current array of biomaterials and tissue engineering scaffolds is desired.