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）：可靠地调节或控制由植入生物材料引起的外国身体反应（FBR）在许多植入物和设备设计中很难。该反应的病理学是由标志性未解决的炎症标记，厚厚的纤维封装以及急性炎症性的厚实封装以及最终在软组织中免疫细胞的募集，降低了装置功能并预先撒上该部位以感染风险。最近的许多研究活动都试图使用仿生和天然材料以一些显着的成功来解决FBR问题。但是，仅这些材料策略就无法克服体内性能中设备的其他必要方面，包括组织特定特性：拉伸强度，孔隙率，孔隙率和微体系结构以及自定义缺陷特异性的设备形态（MacRostructure）。这些挑战和观察结果构成了我们的整体工作假设，即与微结构，天然材料化学整合的植入生物材料脚手架和天然软组织的机械性能在其细胞和组织愈合反应中具有优越性，与仅使用这些特征设计的经典生物材料相比，其细胞和组织愈合反应表现出降低的外务反应。围绕以下具体目的组织了直接解决该假设的任务：（1）证明，基于特定宏观和微观结构控制制造的基质蛋白化的多孔脚手架可减少基于细胞募集，细胞因子概况，细胞因子概况，纤维胶囊，纤维胶囊，血管厚度，血管范围，异常零件的临床模型/临床模型的反应。（1a）与类似的常规降解聚氨酯对照相比，使用这些生物指标来区分基质蛋白支架的体内性能；（1b）与类似的未修饰的聚氨酯对照相比，使用这些生物学指标的基质蛋白涂层的非降解聚氨酯支架区分体内性能；（2）评估改变蛋白/糖胺聚糖（GAG）比率，特异性蛋白电荷密度和基质交联该如何改变FBR，如细胞因子谱，纤维胶囊的厚度，血管厚度，血管性，降解，降解，降解和数量的常驻巨噬细胞/异物巨型细胞/异物巨型细胞中的Murine Subcutanes subcutanes subcutane Poctes; （3）区分脂肪衍生的干细胞（ASC）伤口部位前种子和装置ASC播种如何通过细胞群，细胞因子谱，纤维胶囊厚度，纤维状胶囊厚度，血管性，降解，降解和许多居民巨噬细胞/异物巨型细胞的数量来改变FBR。集成在一起，提出了这些基于设备的修改，以实质上改善与局部设备相关的愈合，并减轻围绕宿主FBR的不良事件。公共卫生相关性：生物相容性，建筑复杂，3D，医疗植入物将使数百万患者受益。但是，在文献中尚未充分理解外国体内的反应（FBR），这是成功进行设备整合的常见障碍。我们建议通过1）将新型蛋白质脚手架的FBR与常用的可降解生物材料进行比较，2）比较蛋白质涂层的FBR与非涂层的非涂层材料的FBR，3）将蛋白质的造型化学和交叉播种和杂物化的化学和4修改为蛋白质的化学和4个）。免疫调节性脂肪细胞干细胞（ASC）进一步减轻FBR植入材料。需要快速翻译拟议的细胞外基质衍生的支架和蛋白质涂层，可作为临床用作作为当前生物材料和组织工程脚手架阵列的替代品。