Bone Scaffolds for Heat Shock Protein Induced Regeneration and Healing

用于热休克蛋白诱导再生和愈合的骨支架

• 批准号: 1505410
• 负责人: Marissa Rylander
• 金额: $ 18.93万
• 依托单位: University of Texas at Austin
• 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: 2014-08-10 至 2016-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1505410&HistoricalAwards=false
• 关键词: Bone; Scaffolds; Heat; Shock; Protein

PI: Rylander, NicoleProposal Number: 1067654Project Summary: Bone related disorders associated with cancer, injury, abnormal development, and degenerative conditions dramatically diminish the health and quality of life of millions of people. These disorders can cause significant disability through loss of bone or its functionality, creating a need for bone replacements (over 3 million orthopaedic procedures performed annually) or effective regenerative strategies. Conditioning using thermal and tensile stress can up-regulate ECM production, cell proliferation, and molecular chaperones called heat shock proteins (HSPs). A link has been shown between up-regulated HSPs and enhanced cell proliferation and collagen biosynthesis needed for ECM formation. The ultimate goal is to develop a transformative, superior bone scaffold through stress conditioning and HSP delivery with the capability to enhance wound healing and bone regeneration in vivo. Ideal stress conditioning strategies and exogenous HSP delivery protocols will be identified to create more functional bone scaffolds and the efficacy of these scaffolds to promote healing in a rodent craniofacial defect model will be tested. Study objectives are to 1) Construct a novel microbioreactor system to apply combinatorial (thermal+tensile) stress and create a scaffold capable of exogenous HSP delivery and wound healing, 2) Apply combinatorial thermal and tensile stress alone and in combination with HSP delivery to bone scaffolds using the microbioreactor system and determine ideal conditions for enhancing bone formation, and 3) Evaluate effectiveness of bone scaffolds preconditioned with thermal+tensile stress and HSP delivery to heal bone defects in a rat craniofacial defect model. Intellectual Merit: This will be the first study focused on harnessing the potential of HSP based bone regeneration through combinatorial stress conditioning and exogenous HSP delivery in development of functional bone scaffolds. Another novel aspect will be the combined use of thermal and tensile stress to enhance cell proliferation and bone ECM formation within bone scaffolds and in an in vivo craniofacial bone defect model. A first-of-its-kind microbioreactor system will be created and utilized to apply thermal and tensile stress in combination to allow determination of optimal stress conditioning protocols to promote bone formation. We seek to create a superior bone scaffold which is transformative due to the use of novel fabrication methods comprised of co-electrospinning polymers coupled with integrated HSP releasing microspheres, conditioning with thermal+tensile stress, and surface encapsulation of microspheres for HSP release from the scaffold to the surrounding tissue. Scaffolds capable of controlled HSP delivery spatially and temporally within the scaffold and to the surrounding wound site will provide a unique avenue to stimulate bone healing and promote successful integration of the scaffold within existing bone in patients with injured or diseased tissue. Broader Impacts: This research will establish a new methodology for enhancing bone growth and regeneration for development of more viable bone replacements and strategies for stimulating bone regeneration in patients. Knowledge gained from this study will directly translate to restoring functionality of bone tissue and eliminating the existing disabilities associated with bone-related impairments. Ultimately, stress conditioning strategies and HSP delivery methods can be utilized for development of a wide array of engineered tissue replacements such as ligaments, tendons, muscles, and nerves to permit stimulation of healing of any type of injured or diseased tissue in patients. This research will enable students to gain experience in tissue engineering, biotransport, imaging, and cell biology at the graduate, undergraduate, and high school level. Two underrepresented graduate students will be supported. Minority undergraduate students will be integrated into every aspect of the research to facilitate a mechanism for students to perceive the relevance of their education to research thereby inspiring them to excel in their studies and promote pursuance of graduate school. High school students with disabilities will experience first-hand research techniques related to this project such as fabrication of scaffolds and microspheres, testing of material properties using the Instron, conditioning scaffolds, and measuring scaffold response. This opportunity will create fascination with biomedical engineering and encourage students that despite their challenges a future in research is attainable.

PI：Rylander，Nicoloproposal编号：1067654Project摘要：与癌症，损伤，异常发育和退化状况相关的骨骼相关疾病大大降低了数百万人的健康和生活质量。这些疾病可能通过骨骼丧失或其功能而导致严重的残疾，从而产生骨骼置换的需求（每年执行300万个骨科手术）或有效的再生策略。使用热和拉伸应力的调节可以上调ECM的产生，细胞增殖和称为热休克蛋白（HSP）的分子伴侣。在上调的HSP与增强的细胞增殖与ECM形成所需的胶原蛋白生物合成之间已经显示了联系。最终的目标是通过应力调节和HSP递送来开发一种变革性的，上的骨支架，并在体内增强伤口愈合和骨再生能力。将确定理想的应力调节策略和外源性HSP输送方案，以创建更多功能性的骨支架，并将测试这些支架的功效，以促进在啮齿动物颅面缺陷模型中促进愈合。研究目标是1）构建一种新型的微生物反应器系统，以应用组合（热+拉伸）压力，并创建一个能够单独使用外源HSP递送和伤口愈合的脚手架，2）与HSP交付的骨骼系统，并确定骨骼的骨骼形式，并确定骨骼的骨骼形式，并与骨骼的骨骼相结合，并与骨形成骨骼的骨骼形式相结合，并与骨骼的骨骼相结合，并与骨骼的骨骼相结合，并与骨骼形成3）在大鼠颅面缺陷模型中，热+拉伸应力和HSP递送以治愈骨缺损。智力优点：这将是首次研究通过组合应力调节和外源性HSP递送在功能性骨支架的发展中利用基于HSP的骨骼再生的潜力。另一个新的方面将是热力和拉伸应力的综合使用，以增强骨支架内的细胞增殖和骨ECM形成以及体内颅面骨缺损模型。将创建和使用首个微生物反应器系统将热应力和拉伸应力组合起来，以确定最佳的应力调节方案以促进骨形成。我们试图创建一个优质的骨支架，由于使用新型制造方法，该方法由共同纺丝聚合物以及整合的HSP释放微球，与热+张力应力的调节以及从SPP释放到周围的HSP释放到周围组织组织的HSP释放。能够在脚手架内和周围伤口部位在空间和时间上控制HSP输送的脚手架将提供独特的途径，以刺激骨骼愈合并促进受伤或患病组织的患者在现有骨中的成功整合。更广泛的影响：这项研究将建立一种新方法，以增强骨骼生长和再生，以开发更可行的骨骼替代品和刺激患者骨骼再生的策略。从这项研究中获得的知识将直接转化为恢复骨组织的功能，并消除与骨有关的障碍相关的现有残疾。最终，可以将应力调节策略和HSP输送方法用于开发各种工程组织替代品，例如韧带，肌腱，肌肉和神经，以允许患者中任何类型的受伤或患病组织的治愈。 这项研究将使学生能够在研究生，本科和高中阶段获得组织工程，生物转移，成像和细胞生物学的经验。将支持两名代表性不足的研究生。少数群体的本科生将被整合到研究的各个方面，以促进学生感知教育与研究的相关性的机制，从而激发他们在学习中表现出色并促进促进研究生院。高中生的残疾学生将体验与该项目相关的第一手研究技术，例如脚手架和微球的制造，使用乐器测试材料特性，调节脚手架以及测量脚手架响应。这个机会将对生物医学工程的迷恋，并鼓励学生，尽管他们在研究中遇到的挑战还是可以实现的。