Foreign Body Response as a Performance Metric for Implanted Scaffolds

描述（由申请人提供）：在许多植入部位和设备设计中，可靠地调节或控制植入生物材料引起的异物反应（FBR）已被证明是困难的。这种反应的病理表现为标志性的未解决的炎症标志物、厚纤维包封和软组织中急性炎症细胞和最终免疫细胞的募集，降低了设备的功能，并使该部位易受感染风险。最近的许多研究活动都试图利用仿生和天然材料来解决快堆问题，并取得了一些显著的成功。然而，这些材料策略本身无法克服设备在体内性能的其他必要方面，包括组织特异性性能：拉伸强度、孔隙率和微观结构，以及定制缺陷特定的设备形态（宏观结构）。这些挑战和观察构成了我们的总体工作假设，即与仅具有这些特征之一的经典生物材料相比，植入生物材料支架具有微观结构，天然材料化学和天然软组织的机械性能，在细胞和组织愈合反应方面具有优势，表现出较少的异物反应。直接解决这一假设的任务是围绕以下具体目标组织的：(1)在小鼠皮下袋模型中，基于细胞募集、细胞因子分布、纤维囊厚度、血管密度、降解和常驻巨噬细胞/异物巨细胞数量，证明具有特定宏观和微观结构控制的基质蛋白修饰多孔支架可以减少异物反应。（1A）与类似的常规可降解聚氨酯对照物相比，使用这些生物指标区分基质蛋白支架的体内性能；（1B）使用这些生物指标与类似的未改性聚氨酯对照相比，区分基质蛋白包被的多孔不可降解聚氨酯支架的体内性能；(2)在小鼠皮下袋模型中，通过细胞因子谱、纤维囊厚度、血管密度、降解和巨噬细胞/异物巨细胞的数量，评估改变蛋白质/糖胺聚糖（GAG）比例、特定蛋白质电荷密度和基质交联如何改变FBR；(3)在小鼠皮下袋模型中，通过细胞群、细胞因子分布、纤维囊厚度、血管分布、降解和常驻巨噬细胞/异物巨细胞数量来评估脂肪源性干细胞（ASC）伤口部位预播种和装置ASC播种如何改变FBR。综上所述，这些基于器械的修改可以显著改善局部器械相关的愈合，并减轻宿主FBR周围的不良事件。

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.