Acellular composite hydrogel scaffolds for volumetric muscle regeneration

用于体积肌肉再生的脱细胞复合水凝胶支架

• 批准号: 10372733
• 负责人: Jonathan M. Grasman
• 金额: $ 16.57万
• 依托单位: NEW JERSEY INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372733
• 关键词: Ablation; Address; Anastomosis - action; Animal Model; Animals; Architecture; Autologous Transplantation; Benchmarking; Biocompatible Materials; Biological Assay; Biomimetics; Biopolymers; Blood Vessels; Cells; Cellular Infiltration; Cicatrix; Circular Dichroism Spectroscopy; Clinical; Collagen; Complement; Cosmetics; Defect; Development; Electron Microscopy; Endothelial Cells; Excision; Future; Generations; Goals; Gold; Growth; Health; Histologic; Histology; Human; Hydrogels; Implant; In Situ; In Vitro; Infiltration; Inflammation; Injury; Investigation; Isometric Exercise; Lead; Leucocytic infiltrate; Longitudinal Studies; Malignant Neoplasms; Measures; Mechanics; Mediating; Microfabrication; Mus; Muscle; Muscle Contraction; Muscle function; Myogenin; Myosin ATPase; Natural regeneration; Outcome; Output; PECAM1 gene; Patients; Peptides; Phenotype; Porifera; Procedures; Production; Quality of life; Recovery of Function; Recruitment Activity; Residual state; Signal Transduction; Site; Skeletal Muscle; Structure; Techniques; Testing; Tissue Engineering; Tissues; Traumatic injury; VWF gene; Vascular Endothelial Growth Factors; Vascular regeneration; Vascularization; Vehicle crash; Weight-Bearing state; Work; angiogenesis; base; combat injury; design; functional outcomes; graft function; hydrogel scaffold; in vivo; infrared spectroscopy; injured; innovation; macrophage; mimicry; mouse model; muscle regeneration; nanofiber; neovascularization; nerve supply; nestin protein; preclinical study; reconstruction; recruit; repaired; restoration; satellite cell; scaffold; self assembly; success; tibialis anterior muscle; tissue regeneration; tissue repair; traumatic event; vascular contributions; volumetric muscle loss; wound

Project Summary There are almost 5 million reconstructive procedures performed annually as a result of traumatic injury, cancer ablation, cosmetic procedures, or combat injuries. The destruction or removal of large amounts of skeletal muscle, termed volumetric muscle loss (VML), resulting from traumatic events such as car crashes or combat injuries, represents a significant health concern. Skeletal muscle is highly vascularized, and relies on adequate infiltration of blood vessels to repair and regenerate. The gold standard for VML repair is autologous grafting, and is limited by reduced functional outcomes and inadequate host-mediated graft revascularization. Current biomaterial-based tissue engineered approaches towards the repair of skeletal muscle tissue after VML rely on passive neovascularization from the host, as opposed to actively recruiting vascular networks to accompany satellite cell infiltration during repair. As such, there remains a significant need to develop materials that will actively stimulate the development of vasculature that will guide organized and aligned skeletal muscle tissue regeneration. We hypothesize that scaffolds that stimulate the rapid creation of a new vasculature and aligned muscle tissue will significantly enhance skeletal muscle repair in VML injuries. To test this hypothesis, we will create a class of biodegradable composite scaffolds that will be implanted into VML injuries to enable the recruitment of endothelial cells and satellite cells. As such, the objective is to create a composite material that promotes in situ regeneration of mature functional muscle tissue. To fabricate these scaffolds, collagen sponges with defined, anisotropic architectures will be fabricated and embedded with angiogenic self-assembling peptide hydrogels, termed SLan (Aim 1). Assessment of the mechanics of scaffolds will complement in vitro analyses of cellular infiltration and compatibility to define material parameters that will induce aligned vascularized skeletal muscle tissue. Scaffolds comprised of collagen, SLan, or composites will then be implanted into a murine model of VML to assess the contribution of each material to enhance VML repair (Aim 2). Particular emphasis will be placed on the ability of these scaffolds to support functional recovery as measured by muscular contraction in longitudinal studies. Histologic assessments will characterize i) the cellular infiltrate and the contribution of aligned scaffolds to guide organized skeletal muscle tissue growth, ii) the modulation of in situ neovascularization and supporting structures, and iii) changes in inflammation. Ultimately, we aim to address two major limitations within skeletal muscle tissue regeneration: i) inadequate vascularization of constructs in situ, and ii) the lack of organized alignment of nascent myofibers during repair of VML injuries; both factors known to inhibit functional recovery. These outcomes will result in the creation of a new class of composite materials to functionally drive cellular infiltration with hydrogels that are specifically designed to recruit specific supporting structures necessary for tissue regeneration and repair.

项目概要 There are almost 5 million reconstructive procedures performed annually as a result of traumatic injury, cancer 消融、整容手术或战斗受伤。 The destruction or removal of large amounts of skeletal 肌肉，称为体积肌肉损失（VML），由车祸或战斗等创伤事件引起 伤害，代表着重大的健康问题。 Skeletal muscle is highly vascularized, and relies on adequate 渗透血管以修复和再生。 The gold standard for VML repair is autologous grafting, and is limited by reduced functional outcomes and inadequate host-mediated graft revascularization.当前的 biomaterial-based tissue engineered approaches towards the repair of skeletal muscle tissue after VML rely on passive neovascularization from the host, as opposed to actively recruiting vascular networks to accompany 修复过程中卫星细胞浸润。因此，仍然迫切需要开发能够 actively stimulate the development of vasculature that will guide organized and aligned skeletal muscle tissue 再生。我们假设支架可以刺激新脉管系统的快速创建并对齐 muscle tissue will significantly enhance skeletal muscle repair in VML injuries.为了检验这个假设，我们将 create a class of biodegradable composite scaffolds that will be implanted into VML injuries to enable the recruitment of endothelial cells and satellite cells. As such, the objective is to create a composite material that promotes in situ regeneration of mature functional muscle tissue.为了制造这些支架，胶原蛋白海绵 with defined, anisotropic architectures will be fabricated and embedded with angiogenic self-assembling peptide hydrogels, termed SLan (Aim 1). Assessment of the mechanics of scaffolds will complement in vitro analyses of cellular infiltration and compatibility to define material parameters that will induce aligned vascularized skeletal 肌肉组织。 Scaffolds comprised of collagen, SLan, or composites will then be implanted into a murine model of VML to assess the contribution of each material to enhance VML repair (Aim 2).将特别强调的是 placed on the ability of these scaffolds to support functional recovery as measured by muscular contraction in 纵向研究。 Histologic assessments will characterize i) the cellular infiltrate and the contribution of aligned scaffolds to guide organized skeletal muscle tissue growth, ii) the modulation of in situ neovascularization and supporting structures, and iii) changes in inflammation. Ultimately, we aim to address two major limitations within skeletal muscle tissue regeneration: i) inadequate vascularization of constructs in situ, and ii) the lack of organized alignment of nascent myofibers during repair of VML injuries; both factors known to inhibit functional 恢复。 These outcomes will result in the creation of a new class of composite materials to functionally drive cellular infiltration with hydrogels that are specifically designed to recruit specific supporting structures necessary for tissue regeneration and repair.