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Cell survival in engineered skeletal muscle: The role of complement

工程骨骼肌中的细胞存活：补体的作用

基本信息

批准号：
10449327
负责人：
Stephen Tomlinson
金额：
$ 40.58万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-16 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449327
关键词：
Adipose tissue Adopted Affect Anastomosis - action Atrophic Autologous Blood Blood Vessels Cell Death Cell Survival Cells Cicatrix Clinic Clinical Complement Complement 3a Complement 5a Complement Activation Complement Inactivators Complement Membrane Attack Complex Congenital Abnormality Contracts Defect Deformity Emotional Engineering Engraftment Event Excision Eye Family Fibroblasts Food Foreign Bodies Genetically Engineered Mouse Goals Hemostatic function Human Human body Immune Immunologics Implant Indigenous Infiltration Inflammation Inflammatory Inflammatory Response Injury Innate Immune Response Investigation Link Mediating Microcirculatory Bed Modality Modeling Modernization Mus Muscle Muscular Atrophy Natural Immunity Operative Surgical Procedures Opsonin Organ Outcome Pathway interactions Patients Peptides Perfusion Pharmaceutical Preparations Play Positioning Attribute Process Production Proteins Publishing Regenerative capacity Resolution Role Route Site Skeletal Muscle Skin Smiling Surgical Flaps Survival Rate Techniques Technology Testing Therapeutic Tissue Engineering Tissue Grafts Tissue Survival Tissues Translating Transplantation Trauma Treatment Protocols Vascular Endothelium Vascularization Walking activation product angiogenesis cell injury clinically relevant complement pathway complement system design healing implantation improved inhibitor injury and repair innate immune mechanisms innovative technologies ischemic injury loved ones neovascular new therapeutic target novel novel strategies novel therapeutic intervention pre-clinical prototype regenerative repaired satellite cell scaffold stem cells stressor tissue regeneration tool treatment planning tumor vascular tissue engineering

项目摘要

Abstract Muscle loss due to trauma, tumor resection or congenital malformation is devastating to the patient and their family. Current treatment regimens involve creative rearrangement of skin and muscle flaps to mitigate the deformity. However, these approaches are often sub-optimal as a percentage of mobilized flap tissues contract, atrophy and/or die and do not function like the original tissues. The field has long envisioned a treatment modality where using the patient's own cells to create tissue grafts, that can then be transplanted into a patient to restore form and function. However, unfortunately, there are numerous hurdles yet to be overcome for this new treatment plan to be broadly adopted in the clinic. One urgent and underappreciated hurdle is the poor survival rate of implanted cells which we hypothesize are killed by the innate immune response to the implanted graft. A major effector mechanism of innate immunity is the complement (Cp) system. The extent that early Cp inflammatory events kill a substantial number of cells within the TECs remains an important unanswered question in the tissue- engineering field. Even if cell death due to early inflammation can be avoided, there is insufficient vascular support. Techniques to generate pre-vascularized TECs which have rapid anastomotic potential would substantially improve cell survival and engraftment. These two highlighted events are intimately linked. Reduction of early inflammation without early vascular support or early vascular support in the presence of a substantial inflammatory response will still result in cell death and failed repair. Therefore, our central hypothesis is that; modulation of Cp effector pathways will promote survival of TEC by reducing inflammation, direct cell injury, and by promoting neovascularity. In this proposal we articulate a line of investigation that will lead to an enabling technology to improve the engraftment of cellularized implants by modulating the early inflammatory process and promoting nascent microvascular beds. Our lab has invented novel strategies and therapeutics that target the early inflammatory response. Additionally, we have recently developed a novel scaffold-free technology to generate Self-organizing Pre-vascularized Endothelial-fibroblast Constructs (SPECs). These engineered constructs can become perfused with blood very quickly once implanted. Using known mechanisms of inflammation, angiogenesis and anastomosis as our guide, we will systematically test these innovative technologies using specific inhibitors and genetically engineered mice in a sub-muscular implant model. The expected outcomes would significantly move the field forward by providing a workable solution to the principal hurdles facing tissue engineering - rapid vascularization and survival of implanted cells and tissues.

摘要