Suturable bioprinted vascularized muscle constructs for treatment of skeletal muscle loss

用于治疗骨骼肌损失的可缝合生物打印血管化肌肉结构

基本信息

批准号：
10353393
负责人：
Su Ryon Shin
金额：
$ 53.65万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10353393
关键词：
3-Dimensional Address Affect Alginates Allografting Architecture Area Autologous Transplantation Biocompatible Materials Biomimetics Blood Vessels Cell Survival Cells Characteristics Cicatrix Clinical Collagen Complex Elderly Electrophysiology (science)Electrospinning Endothelial Cells Endothelium Engineering Extracellular Matrix Fibrosis Functional Regeneration Gelatin Growth Growth Factor Hematopoietic Hydrogels Image Immune response Impairment Implant Infection Injury Insulin-Like Growth Factor I Kinetics Lasers Methods Modeling Morbidity - disease rate Muscle Muscle Fibers Muscle function Muscular Atrophy Musculoskeletal Diseases Myoblasts Nerve Regeneration Neuromuscular Junction Nude Mice Operative Surgical Procedures Pain Patients Persons Physiological Population Positioning Attribute Printing Production Protocols documentation Quality of life Recovery Regenerative Medicine Regenerative capacity Reproducibility Scheme Site Skeletal Muscle Soldier Surgical sutures System Techniques Testing Therapeutic Thick Tissue Grafts Tissue constructs Tissues Traumatic injury Vascular Endothelial Cell Vascular blood supply Vascular regeneration Vascularization angiogenesis base bioink biomaterial compatibility bioprinting cell assembly clinically relevant directed differentiation disability functional disability functional restoration healing human pluripotent stem cell implantation improved in vivo induced pluripotent stem cell injured mechanical properties migration mouse model muscle engineering muscle form muscle regeneration nanofiber nerve injury neuromuscular personalized medicine physical property poly(glycerol-sebacate)precursor cell quadriceps muscle regeneration function repaired restoration satellite cell scaffold self assembly skeletal muscle wasting stem cell delivery stem cell differentiation subcutaneous technology development traumatic event treadmill vehicular accident volumetric muscle loss

项目摘要

Project Summary Volumetric muscle loss (VML) usually occurs following traumatic injury and results in a composite loss of muscle mass. These injuries manifest in decreased strength and functional impairments. Clinically, these injuries often heal with fibrosis, as opposed to skeletal muscle regeneration. Current existing therapeutic options are also insufficient for VML treatment, and complications are often associated with surgical repair including nerve injury, excessive immune response, infection, scarring, and limitations of tissue graft supply. Indeed, natural healing and surgical procedures are inefficient in restoring the functionality of injured muscles, resulting in a poor quality of life. Therefore, developing clinically relevant three-dimensional (3D) tissue using patient-specific genetically identical cells has emerged as a potential solution to address the above issues. To achieve this aim, there are two existing main challenges. The first challenge is obtaining large amounts of patient-specific genetically identical cells. The use of human pluripotent stem cells (hiPSCs) differentiated to the muscle lineage represents a promising candidate to build upon personalized therapy. However, directing the differentiation of hiPSCs to the muscle fate along with reproducible differentiation schemes has proven to be challenging. The second challenge is developing a highly organized and vascularized 3D skeletal muscle tissue to maintain the viability of cells inside thick tissue constructs via engineered vessel networks. Furthermore, the fabricated tissues have to strongly integrate into injured site via surgical methods. To address these challenges, we plan to develop a suturable 3D vascularized muscle tissue from hiPSC-derived myogenic precursor cells (hiPSC-MPCs) embedded in biomaterials using bioprinting techniques. We will optimize the recently developed protocols allowing efficient production of functional myofibers from hiPSCs in hydrogels with tunable mechanical properties and degradable profiles, which mimic the extracellular matrix (ECM) of native skeletal muscle tissue. To create biomimetic vascularized muscle constructs, a multi-material embedded bioprinting technique will be used to precisely control the positions of the vascular network and aligned muscle fibers with biologically relevant architectures. With the conventional bioprinting system, it is difficult to precisely control the materials’ position in Z directions to create freestanding hydrogel architectures. Also, to achieve prolonged retention of implants into the injured site and to improve muscle regeneration, a muscle growth factor (IGF-1) laden suturable graft will be developed. hiPSC-MPCs-laden constructs will be printed on the suturable graft consisting of IGF-1-laden PGS/GelMA substrates using electrospinning.

项目概要体积肌肉损失（VML）通常发生在外伤后，并导致复合损失这些损伤在临床上表现为力量下降和功能障碍。与目前现有的治疗方法不同，损伤通常会随着纤维化而愈合。 VML 治疗的选择也不足，并且并发症通常与手术修复相关包括神经损伤、过度免疫反应、感染、疤痕和组织移植供应的限制。事实上，自然愈合和外科手术对于恢复受伤肌肉的功能效率低下，因此，使用开发临床相关的三维（3D）组织。患者特异性基因相同的细胞已成为解决上述问题的潜在解决方案。要实现这一目标，目前存在两个主要挑战，第一个挑战是获取大量的资源。使用人类多能干细胞（hiPSC）分化为患者特异性基因相同的细胞。然而，肌肉谱系是基于个性化治疗的有希望的候选者。 hiPSC 向肌肉命运的分化以及可重复的分化方案已被证明第二个挑战是开发高度组织化和血管化的 3D 骨骼肌。通过工程血管网络维持厚组织结构内细胞的活力。此外，制造的组织必须通过手术方法牢固地融入受伤部位。针对这些挑战，我们计划从 hiPSC 衍生的肌原性中开发可缝合的 3D 血管化肌肉组织我们将使用生物打印技术将前体细胞 (hiPSC-MPC) 嵌入生物材料中。最近开发的协议允许从水凝胶中的 hiPSC 高效生产功能性肌纤维具有可调节的机械性能和可降解的特性，模仿细胞外基质（ECM）天然骨骼肌组织，用于创建仿生血管化肌肉结构，一种嵌入的多种材料。生物打印技术将用于精确控制血管网络和对齐肌肉的位置使用传统的生物打印系统很难精确地制备具有生物相关结构的纤维。控制材料在 Z 方向的位置以创建独立的水凝胶结构。延长植入物在受伤部位的保留时间并改善肌肉再生（肌肉生长）载有因子 (IGF-1) 的可缝合移植物将被打印在载有 hiPSC-MPC 的结构上。使用静电纺丝技术，由负载 IGF-1 的 PGS/GelMA 基质组成的可缝合移植物。