Foreign Body Response as a Performance Metric for Implanted Scaffolds

异物反应作为植入支架的性能指标

基本信息

批准号：
8279213
负责人：
DAVID W GRAINGER
金额：
$ 25.79万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8279213
关键词：
Acute Address Adipocytes Adipose tissue Adverse event Architecture Attention Autologous Binding Proteins Biocompatible Biocompatible Materials Biological Biomechanics Biomimetics Capsid Proteins Catheters Cells Characteristics Charge Chemistry Chronic Clinical Comorbidity Complex Custom Defect Development Device Designs Devices Electrodes Excision Exhibits Extracellular Matrix Extracellular Matrix Proteins Foreign Bodies Foreign-Body Giant Cells Foreign-Body Reaction Glycosaminoglycans Healed Human Immune Immune response Implant Infection Inflammatory Literature Measures Mechanics Medical Device Methods Metric Modeling Modification Morphology Mus Operative Surgical Procedures Pathology Patients Performance Phase Polymers Polyurethanes Population Porosity Production Property Protein Biochemistry Proteins Reaction Reporting Research Activity Risk Scaffolding Protein Seed Implantation Severities Shapes Site Solid Stem cells Structure Surface Techniques Tensile Strength Thick Tissue Engineering Tissues Translations Work Wound Healing base capsule chemical property conditioning crosslink cytokine density design glucose sensor healing implant material implantable device improved in vivo inflammatory marker innovation macrophage medical implant novel novel strategies programs prototype public health relevance response scaffold soft tissue subcutaneous success wound

项目摘要

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.

描述（由申请人提供）：事实证明，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）是困难的。这种反应的病理学特点是未解决的炎症标记物、厚纤维包裹以及软组织中急性炎症细胞和最终免疫细胞的募集，降低了装置的功能并使该部位预先面临感染风险。最近的许多研究活动都试图利用仿生材料和天然材料来解决 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装置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，以及定制的缺陷特定装置形态（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，即与传统生物材料相比，与天然软组织的微观结构、天然材料化学和机械性能相结合的植入生物材料支架在细胞和组织愈合反应方面表现出优越性，表现出减少的异物反应仅设计有这些功能之一。直接解决这一假设的任务围绕以下具体目标进行组织：（1）证明通过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可减少基于细胞募集、细胞因子谱、纤维囊的异物反应小鼠皮下袋模型中驻留巨噬细胞/异物巨细胞的厚度、血管分布、降解和数量。 (1A) 使用这些生物指标与类似的传统可降解聚氨酯对照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区分基质蛋白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，如细胞因子谱、纤维囊厚度、血管分布、降解和常驻巨噬细胞/异物巨细胞数量所示小鼠皮下口袋模型； (3) 通过细胞群、细胞因子谱、纤维囊厚度、血管分布、降解和驻留巨噬细胞/异物数量评估，区分脂肪干细胞 (ASC) 伤口部位预接种和设备 ASC 接种如何改变 FBR小鼠皮下口袋模型中的巨细胞。这些基于设备的修改集成在一起，旨在显着改善与设备相关的本地愈合并减轻主机 FBR 周围的不良事件。公共健康相关性：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）是成功设备集成的常见障碍，在文献中并没有得到很好的理解。我们建议通过以下方式解决这一未解决的 FBR 问题：1) 将我们的新型蛋白质支架的 FBR 与常用的可降解生物材料的 FBR 进行比较，2) 比较蛋白质涂层与未涂层的不可降解材料的 FBR，3) 修饰蛋白质支架组成、表面电荷和交联化学，4) 在这些支架上接种免疫调节脂肪细胞干细胞 (ASC)，以进一步减轻 FBR植入材料。希望将所提出的细胞外基质衍生支架和蛋白质涂层快速转化为临床用途，作为当前生物材料和组织工程支架系列的替代品。