Muscle-based Tissue Engineering to Improve Bone Healing

基于肌肉的组织工程改善骨愈合

基本信息

批准号：
7234129
负责人：
JOHNNY HUARD
金额：
$ 33.88万
依托单位：
CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7234129
关键词：
Adipocytes Adipose tissue Adult Affect Age Alkaline Phosphatase Animals Anterior Appendix Attention Autologous BMP2 gene BMP4 Behavior Biological Assay Biology Biomechanics Biopsy Blood Circulation Bone Marrow Bone Regeneration Bone Tissue Bos taurus CD34 gene Calvaria Cattle Cell Count Cell Differentiation process Cell Proliferation Cells Clinical Treatment Collaborations Collagen Commit Constitution Data Defect Desmin Development Dose Doxycycline Endothelial Cells Engineering Ensure Environment Estrogens Exhibits Exposure to Fast-Twitch Muscle Fibers Female Fiber Fibrin Tissue Adhesive Fluorescence-Activated Cell Sorting Fostering Funding Future Gastrocnemius Muscle Gel Gelatin Gene Chips Gene Transfer Genes Goals Gold Gonadal Steroid Hormones Green Fluorescent Proteins Growth Factor Half-Life Healed Histologic Hormonal Hour Human Image Implant In Vitro Injectable Injection of therapeutic agent International Investigation Kinetics Knowledge Laboratories Lead Location Mechanical Stimulation Mechanics Mediating Methods Microscopic Molecular Mus Muscle Muscle Cells Muscle satellite cell Myocardium NCAM1 gene Natural regeneration Numbers Operative Surgical Procedures Osteogenesis Paper Patients Polymers Population Population Heterogeneity Porifera Principal Investigator Production Progesterone Property Proteins Rate Rattus Reporting Research Research Personnel Retroviral Vector Retroviridae Reverse Transcriptase Polymerase Chain Reaction Seeds Site Skeletal Muscle Skeletal system Skeleton Slow-Twitch Muscle Fibers Sorting - Cell Movement Source Staining method Stains Standards of Weights and Measures Stem cells Stromal Cells System Techniques Technology Testing Testosterone Tetanus Helper Peptide Time Tissue Engineering Transplantation Treatment Protocols Vascular Endothelial Growth Factors Week Work X-Ray Computed Tomography abstracting base bone bone healing bone morphogenetic protein 2 cell type cellular transduction clinical application craniofacial cranium design drinking water extracellular gene therapy genetic manipulation genetically modified cells healing human female human male implantation improved in vivo interest long bone male member muscle engineering novel strategies osteogenic protein peroxisome progenitor programs protein expression receptor repaired research study response scaffold sex size subcutaneous

项目摘要

DESCRIPTION (provided by applicant): Incomplete healing of bone defects in the craniofacial skeleton is common. Osteogenic proteins, including bone morphogenetic protein 2 and 4 (BMP2, -4), promote healing in bone defects, but the proteins' short half-lives and rapid clearance by the bloodstream limit their utility. The main goal of our initial R01 project was the development of tissue engineering approaches, based on muscle-derived stem cells (MDSCs), to efficiently deliver osteogenic proteins and improve craniofacial bone healing. We would like to thank NIDCR for their support during the initial funding period. We met and exceeded all the key objectives in the original R01 application, and our results formed the basis for 24 papers and 52 abstracts. We demonstrated that MDSCs genetically engineered to express BMP2 and BMP4 differentiate toward an osteogenic lineage and can improve bone healing in calvarial and long bone defects. We also found that concomitant expression of vascular endothelial growth factor (VEGF) improves the bone healing observed after implantation of BMP2-and BMP4-expressing MDSCs. This DE013420 competitive renewal application outlines experiments designed to extend our initial findings and facilitate the development of clinical applications of MDSCs to improve bone healing. First, we will examine the effect of the sex and age of donor mice on the number and the osteogenic potential of MDSCs. We will then determine if muscle biopsy size and source, time of culturing, hormonal stimulation, or ex vivo cyclic mechanical strain influence the number or osteogenic potential of MDSCs and might enable us to counterbalance sex-related differences exhibited by MDSCs. This research is integral to the clinical applicability of MDSCs for autologous bone tissue engineering applications, which will necessitate the isolation of highly osteogenic cells from patients of different sexes and ages. Next/we will investigate ways to optimize bone formation and healing by using MDSC-based tissue engineering techniques, including genetic manipulation and injectable scaffolds. Finally, we will use the results from the first 2 aims to isolate and characterize the human equivalents of the mouse MDSCs with the highest osteogenic potential and optimize their use for bone regeneration and repair. The proposed study will provide important information regarding the basic biology of MDSCs and their use for bone healing and should foster the development of clinical treatments for osseous deficiencies.

描述（由申请人提供）：颅面骨骼中骨骼缺陷的不完全治愈是常见的。成骨蛋白，包括骨形态发生蛋白2和4（BMP2，-4），可促进骨缺损的愈合，但是蛋白质的短半衰期和血液的快速清除限制了其效用。我们最初的R01项目的主要目标是基于肌肉衍生的干细胞（MDSC）的组织工程方法的开发，以有效地递送成骨蛋白并改善颅面骨骼愈合。我们要感谢NIDCR在最初的资金期间的支持。我们实现了原始R01应用程序中的所有关键目标，我们的结果构成了24篇论文和52个摘要的基础。我们证明了MDSC经过基因工程，以表达BMP2和BMP4朝着成骨谱系区分开，并可以改善颅骨和长骨缺损中的骨骼愈合。我们还发现，血管内皮生长因子（VEGF）的同时表达可改善植入BMP2和表达BMP4的MDSC后观察到的骨骼愈合。该DE013420竞争性更新应用程序概述了旨在扩展我们的初始发现并促进MDSC的临床应用以改善骨骼愈合的临床应用的实验。首先，我们将研究供体小鼠的性别和年龄对MDSC的数量和成骨潜力的影响。然后，我们将确定肌肉活检的大小和来源，培养时间，激素刺激或离体周期性机械应变会影响MDSC的数量或成骨潜力，并可能使我们能够由MDSCs表现出与平衡性别相关的差异。这项研究是MDSC在自体骨组织工程应用中的临床适用性的重要性，这将需要从不同性别和年龄的患者中分离高成骨细胞。 Next/我们将通过使用基于MDSC的组织工程技术（包括遗传操纵和可注射的支架）来调查优化骨形成和愈合的方法。最后，我们将使用前两个旨在隔离和表征具有最高成骨潜力的小鼠MDSC的人类等效物的结果，并优化其用于骨再生和修复的用途。拟议的研究将提供有关MDSC基本生物学及其用于骨骼愈合的重要信息，并应促进骨缺陷的临床治疗。