COLLABORATIVE RESEARCH: Enhancing bone regeneration by mimicking the osteogenic niche

合作研究：通过模仿成骨生态位增强骨再生

• 批准号: 1264832
• 负责人: Carl Gregory
• 金额: $ 10.04万
• 依托单位: Texas A&M University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-15 至 2018-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1264832&HistoricalAwards=false
• 关键词: COLLABORATIVE; RESEARCH; Enhancing; bone; regeneration

1264848/1264832Kaunas/GregoryOf the 13 million yearly fractures that occur in the United States, about 10% fail to repair and in extreme cases result in immobility or amputation. While autologous bone grafts are the most effective method to heal complex defects, the available graft material is limited, and the procedure involves additional surgery known to cause chronic donor-site pain in many patients. Human mesenchymal stem cells (hMSCs) have been intensely investigated for their ability to promote bone healing, but results have been variable and disappointing. This is at least partly due insufficient retention of hMSCs at the site of injury for sufficient time to achieve engraftment and promote repair. In an attempt to solve these problems, hMSCs have been treated with the small molecule PPARã inhibitor GW9662 to produce osteogenically-enhanced hMSCs (OEhMSCs). These OEhMSCs produce extracellular matrix (hMatrix) that dramatically increases hMSC retention and osteorepair in calvarial defects. The central hypothesis for this project is that an injectable microsphere vehicle co-administering GW9662, hMatrix and hMSCs will promote osteo-repair through a mechanism that involves extended hMSC retention, trophic factor secretion and paracrine activation of the host stroma. To test this, composite microspheres will be constructed and assessed for GW9662 delivery and hMatrix presentation to hMSCs in culture, as well as for their ability to promote repair of critical-sized defects in a mouse calvarial model. Finally, soluble factors secreted by hMSCs responsible for promoting osteoregeneration will be identified. These studies will lay the groundwork for translating this novel hMSC-based method for osteo-repair to the clinic. Successful completion of this project could lead to a revolutionary new method for bone repair that could effectively dismiss the need for autologus bone graft in regenerative orthopedics. These studies are based on the concept that providing an in vivo-like microenvironment stimulates hMSCs to behave as they do during normal tissue generation. This concept applies to hMSC-mediated healing in general, thus the knowledge gained from the proposed studies may eventally be applied to the regeneration of other tissue targets. The methods and concepts used to construct and evaluate the microsphere composites will be broadly disseminated in journals and conferences and incorporated into courses taught at Texas A&M. The PI has a record of successfully mentoring undergraduate researchers from underrepresented populations in his lab; the proposed project will provide additional opportunities for undergraduate research in the laboratory. As part of the project, two graduate students will be supported for their doctoral studies. The PI and the graduate students will each participate in outreach to high schools in the greater Houston area and develop media for broad use in the Texas school system.

1264848/1264832Kaunas/Gregory 在美国每年发生 1300 万例骨折中，约 10% 无法修复，在极端情况下会导致无法活动或截肢。虽然自体骨移植是治愈复杂缺损的最有效方法，但可用的移植材料有限，并且该过程涉及额外的手术，已知会导致许多患者出现慢性供区疼痛。人们对人类间充质干细胞 (hMSC) 促进骨愈合的能力进行了深入研究，但结果各不相同且令人失望。这至少部分是由于 hMSC 在损伤部位的保留时间不足以实现植入和促进修复。为了解决这些问题，我们用小分子 PPARã 抑制剂 GW9662 处理 hMSC，以产生成骨增强的 hMSC (OEhMSC)。这些 OEhMSC 产生细胞外基质 (hMatrix)，可显着增加颅骨缺损中 hMSC 的保留和骨修复。该项目的中心假设是，共同施用 GW9662、hMatrix 和 hMSC 的可注射微球载体将通过涉及延长 hMSC 保留、营养因子分泌和宿主基质的旁分泌激活的机制促进骨修复。为了测试这一点，将构建复合微球并评估其向培养中的 hMSC 的 GW9662 递送和 hMatrix 呈递，以及它们促进小鼠颅骨模型中临界尺寸缺陷修复的能力。最后，将鉴定 hMSC 分泌的负责促进骨再生的可溶性因子。这些研究将为将这种基于 hMSC 的新型骨修复方法转化为临床奠定基础。该项目的成功完成可能会带来一种革命性的骨修复新方法，可以有效消除再生骨科中对自体骨移植的需求。这些研究基于这样的概念：提供类似体内的微环境可以刺激 hMSC 的行为与正常组织生成过程中的行为相同。这个概念一般适用于 hMSC 介导的愈合，因此从拟议研究中获得的知识最终可能应用于其他组织靶标的再生。用于构建和评估微球复合材料的方法和概念将在期刊和会议上广泛传播，并纳入德克萨斯农工大学教授的课程中。 PI 拥有成功指导其实验室中代表性不足人群的本科研究人员的记录；拟议的项目将为本科生在实验室进行研究提供更多机会。作为该项目的一部分，两名研究生将获得博士学位研究的支持。 PI 和研究生将各自参与大休斯顿地区高中的推广活动，并开发在德克萨斯州学校系统中广泛使用的媒体。