Characterization and Optimization of a Nanofiber-Hydrogel Composite for Tissue Remodeling

用于组织重塑的纳米纤维-水凝胶复合材料的表征和优化

• 批准号: 10678462
• 负责人: Jessica Stelzel
• 金额: $ 4.85万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678462
• 关键词: Adipocytes; Autologous; Biocompatible Materials; Blood Vessels; Cell Therapy; Cells; Coupled; Data; Defect; Deposition; Engineering; Extracellular Matrix; Fibrosis; Foreign Bodies; Formulation; Goals; Growth Factor; Health Care Costs; Heterogeneity; Hydrogels; Immune; Immune response; In Vitro; Infection; Infiltration; Inflammation; Inflammatory; Injectable; Kinetics; Knock-out; Modeling; Morbidity - disease rate; Outcome; Pathway interactions; Patients; Property; Prosthesis; Regenerative Medicine; Research; Scientist; Signal Pathway; Site; Structure; Structure-Activity Relationship; System; Techniques; Testing; Time; Tissue Survival; Tissues; Variant; Vascularization; Work; angiogenesis; candidate identification; cell type; clinical translation; conditioning; design; immunoregulation; implantation; improved; in vivo; insight; interest; lipid biosynthesis; mechanical properties; migration; nanoengineering; nanofiber; next generation; novel; psychologic; reconstruction; recruit; regenerative cell; repaired; replacement tissue; response; restoration; single-cell RNA sequencing; soft tissue; theories; translational model; translational potential

Project Summary Restoration of soft tissue is a significant challenge facing clinicians. The available reparative options, whether prosthetic or autologous, present major drawbacks including donor site defects, unpredictable tissue survival, limited duration of restoration, prosthetic exposure, infection, and fibrosis. Therefore, a critical need exists for a solution which can replace missing tissue volume while encouraging natural remodeling of soft tissue over time. We have recently developed an injectable nanofiber-hydrogel composite (NHC) material which is capable of inducing remodeling of the injected volume into vascularized soft tissue with adipocytes without relying on exogenous growth factors and cells. However, the mechanisms by which it does so are not yet well understood. The goal of this proposed project is to characterize the immune and tissue remodeling kinetics of the injected NHC material, uncover the mechanism(s) by which it achieves soft tissue remodeling, and optimize its formulation to enhance this desired outcome. We will first investigate the local immune and tissue remodeling kinetics of the injected site caused by the NHC. This will include characterizing cell infiltration, healthy extracellular matrix (ECM) deposition vs. irregular fibrosis and foreign body response, inflammation, angiogenesis, and adipogenesis. In addition, we will uncover the NHC’s mechanism of instigating soft tissue remodeling by carrying out single-cell RNA sequencing to identify candidate cell subtypes and activated signaling pathways and then subsequently confirm them through immune knockout or targeted depletion models to establish a causal relationship. Gaining insight into how soft tissue remodeling can be accomplished with this biomaterial system will have wide-reaching implications for the regenerative medicine field as we work towards creating off-the-shelf biomaterials-based solutions for tissue replacement. Finally, through modulation of physical and structural properties as well as leveraging our mechanistic understanding, we will optimize the parameters of the NHC to maximize desired soft tissue remodeling. If successful, this proposal will produce an improved off- the-shelf biostimulatory NHC with enhanced capacity to achieve natural tissue restoration outcomes as well as a mechanistic understanding of how to achieve soft tissue remodeling, thereby expanding the ability to treat patients and allowing scientists to engineer the next generation of biomaterials for tissue replacement.

项目概要 软组织的修复是可用的修复方案面临的重大挑战。 无论是假体还是自体，都存在主要缺陷，包括供体部位缺陷、不可预测的组织 生存、修复时间有限、假体暴露、感染和纤维化因此是一个迫切的需求。 存在一种解决方案，可以替代缺失的组织体积，同时促进软组织的自然重塑 随着时间的推移，我们最近开发了一种可注射的纳米纤维-水凝胶复合材料（NHC）。 能够诱导注射体积重塑到带有脂肪细胞的血管化软组织中，而无需 依赖于外源生长因子和细胞然而，其作用机制尚不清楚。 明白了。 该项目的目标是表征免疫和组织重塑动力学 注射NHC材料，揭示其实现软组织重塑的机制，并优化其 我们将首先研究局部免疫和组织重塑。 由 NHC 引起的注射部位的动力学这将包括表征细胞浸润、健康。 细胞外基质（ECM）沉积与不规则纤维化和异物反应、炎症、 此外，我们还将揭示 NHC 促进软组织的机制。 通过进行单细胞 RNA 测序来识别候选细胞亚型和激活的信号传导来进行重塑 途径，然后通过免疫敲除或靶向耗竭模型来确认它们 建立因果关系，了解如何实现软组织重塑。 当我们努力实现这一目标时，生物材料系统将对再生医学领域产生广泛影响 最后，通过物理调节，创建现成的基于生物材料的组织替代解决方案。 和结构特性以及利用我们的机械理解，我们将优化参数 如果成功，该提案将产生改进的效果。 现成的生物刺激 NHC 具有增强实现自然组织恢复结果以及 对如何实现软组织重塑的机械理解，从而扩大治疗能力 患者并允许科学家设计下一代用于组织替代的生物材料。