Foreign Body Response as a Performance Metric for Implanted Scaffolds

描述（由申请人提供）：已证明在许多植入部位和器械设计中难以可靠调节或控制植入生物材料引起的异物反应（FBR）。该反应的病理学特征为未解决的炎症标志物、厚纤维包裹和软组织中急性炎症细胞和最终免疫细胞的募集，降低了器械功能并使部位易于感染风险。最近的许多研究活动都试图使用仿生和天然材料来解决FBR问题，并取得了一些显着的成功。然而，这些材料策略本身无法克服器械体内性能的其他必要方面，包括组织特定特性：拉伸强度、孔隙率和微结构，以及定制缺陷特定器械形态（宏观结构）。这些挑战和观察结果构成了我们的总体工作假设，即与仅具有其中一种特征的经典生物材料相比，与天然软组织的微结构、天然材料化学和机械性能相结合的植入生物材料支架在其细胞和组织愈合反应方面具有上级优势，表现出减少的异物反应。直接解决这一假设的任务是围绕以下具体目标组织的：（1）基于小鼠皮下囊袋模型中的细胞募集、细胞因子谱、纤维囊厚度、血管分布、降解和驻留巨噬细胞/异物巨细胞的数量，证明用特定的宏观和微观结构控制制造的基质蛋白修饰的多孔支架减少了异物反应。(1A)（1B）与类似的未改性聚氨酯对照相比，使用这些生物学度量来区分基质蛋白质涂覆的多孔不可降解聚氨酯支架的体内性能;（2）评估改变蛋白质/糖胺聚糖（GAG）比率、特定蛋白质电荷密度和基质交联如何改变FBR，如通过细胞因子谱、纤维囊厚度、血管分布所证明的，（3）区分脂肪源性干细胞（ASC）伤口部位预接种和器械ASC接种如何改变FBR，如通过细胞群、细胞因子谱、纤维囊厚度、血管分布、降解和鼠皮下囊模型中驻留巨噬细胞/异物巨细胞的数量所评估的。将这些基于器械的修改整合在一起，可显著改善局部器械相关愈合并缓解宿主FBR周围的不良事件。 公共卫生相关性：生物相容性、结构复杂的3D医疗植入物将使数百万患者受益。然而，异物反应（FBR）是成功器械整合的常见障碍，在文献中尚未得到很好的理解。我们建议通过以下方式解决这个未解决的FBR问题：1）将我们的新型蛋白质支架的FBR与来自常用的可降解生物材料的FBR进行比较，2）将蛋白质涂覆的材料与未涂覆的不可降解材料的FBR进行比较，3）改变蛋白质支架的组成、表面电荷和交联化学，和4）用免疫调节脂肪细胞干细胞（ASC）接种这些支架以进一步减轻植入材料的FBR。所提出的细胞外基质衍生的支架和蛋白质涂层的快速翻译作为当前生物材料和组织工程支架阵列的替代物用于临床是期望的。

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.