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; 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.

项目摘要 恢复软组织是临床医生面临的重大挑战。可用的修复选项， 无论是假肢还是自体，都存在主要缺点，包括供体部位缺陷，不可预测的组织 生存，恢复持续时间有限，人工暴露，感染和纤维化。因此，急需 存在可以替代缺失组织体积的溶液，同时鼓励软组织的自然重塑 随着时间的推移。我们最近开发了一种可注射的纳米纤维 - 凝胶凝胶复合材料（NHC）材料 能够诱导注射体积的重塑，并用脂肪细胞中的血管化软组织 依靠外源生长因子和细胞。但是，这样做的机制还不好 理解。 该提议的项目的目的是表征免疫和组织重塑的动力学 注入NHC材料，发现实现软组织重塑的机制，并优化其 增强这种预期结果的公式。我们将首先研究局部免疫和组织重塑 由NHC引起的注射位点的动力学。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， 血管生成和脂肪形成。此外，我们将发现NHC启动软组织的机制 通过进行单细胞RNA测序来重塑以识别候选细胞亚型和激活的信号传导 途径，然后通过免疫敲除或有针对性的部署模型确认它们 建立因果关系。了解如何实现软组织重塑 生物材料系统将对再生医学领域具有广泛的影响 创建基于现成的生物材料的解决方案，以替代组织。最后，通过调节身体 以及结构属性以及利用我们的机械理解，我们将优化参数 NHC最大化所需的软组织重塑。如果成功的话，该提案将产生改善的外部 具有增强能力实现天然组织恢复结果的能力增强的现成生物刺激性NHC以及 对如何实现软组织重塑的机械理解，从而扩大了治疗的能力 患者并允许科学家设计下一代生物材料以进行组织。