Functional Fluid Flow Regulated Bone Regeneration

功能性流体流量调节骨再生

• 批准号: 8444451
• 负责人: Yi-Xian Qin
• 金额: $ 32.87万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444451
• 关键词: 3-Dimensional; Affect; Animal Model; Biochemistry; Bioreactors; Birds; Blood Circulation; Blood Vessels; Bone Marrow Stem Cell; Bone Regeneration; Bone Substitutes; Bone Surface; Bone Tissue; Bone Transplantation; Cell Culture Techniques; Cell Differentiation process; Cell Proliferation; Cell Survival; Cell Transplantation; Cells; Clinical; Cultured Cells; Defect; Dose; Endosteum; Engineering; Environment; Equation; Finite Element Analysis; Fourier Transform; Frequencies; Goals; Growth; Healed; Health; Healthcare; Histology; Homing; Immature Bone; In Vitro; Knowledge; Liquid substance; Marrow; Measures; Mechanics; Mediating; Mediator of activation protein; Modality; Modeling; Muscle; Natural regeneration; Nutrient; Operative Surgical Procedures; Osteoblasts; Osteogenesis; Osteopenia; Outcome; Oxygen; Patients; Perfusion; Periosteum; Permeability; Phase; Physiologic calcification; Physiological; Porosity; Quality of life; Recruitment Activity; Regulation; Relative (related person); Role; Signal Transduction; Solid; Spatial Distribution; Stimulus; Synchrotrons; Techniques; Tissue Engineering; Tissue Grafts; Uncertainty; Vascularization; Waste Products; base; bone; bone cell; bone healing; calcification; design; fluid flow; healing; implantation; improved; in vivo; mineralization; novel; novel strategies; osteogenic; osteoporosis with pathological fracture; pressure; public health relevance; response; scaffold; shear stress; stem cell differentiation; tissue regeneration; tissue repair; ulna

DESCRIPTION (provided by applicant): Traumatic and osteoporotic fractures, critical/large defects and nonunion represent a significant burden in health care and affects quality of life for these patients. Tissue engineering approaches show promise as bone substitutes, and have been particularly successful in vitro in a bioreactor environment. The major challenge of tissue engineered regeneration is to maintain viability of cells in vivo and to rebuild vascular networks capable of delivering oxygen and nutrients while removing waste products after the implantation. Recently, a new cell homing approach has shown promising results in recruiting endogenous cells and then regeneration without cell transplantation. To accelerate cell homing and maintain cell viability in vivo, functional bone fluid flow induced by mechanical loading has been shown to be a critical regulator in initiating and mediating bone surface and osteonal adaptation. Dynamic fluid flow through porous constructs will exert increased fluid shear stress to promote in vivo cell differentiation and mineralization. Using oscillatory pressurized marrow fluid flow and muscle-bone interface stimuli, small magnitude fluid pressure (10-60 mmHg) with relative high frequency and short daily duration (10min) was found to initiate new bone formation and mitigate increased intracortical porosities caused by disuse osteopenia. It is essential to establish a functional dynamic fluid flow environment within the in vivo porous bone large defect and maintain an active fluid flow for bone regeneration. Thus, we will examine the general hypothesis that functional mechanotransduction regulated by dynamic bone fluid flow, with optimized intensity and rate, is essential and responsible for in vivo tissue regeneration, cellular differentiation, and osteogenic mineralization in critical defect healing. The ultimate gol is to generate an oscillatory fluid pressure gradient in the critical defect and the scaffold, servng as an in vivo bioreactor to promote functional fluid flow, vascular circulation, and osteogenesis. The outcomes will improve our understanding of how an optimized fluid flow environment enhances cellular viability and mineralization, and the importance of mechanotransduction in tissue repair and regeneration particularly under in vivo conditions. It is expected that this project will provide a novel approach to regulate bone formation via in vivo fluid flow stimuli, an improve our knowledge of critical signals for dynamic mechanotransduction in accelerating bone formation and mineralization in tissue regeneration, which will be ultimately used for clinical tissue repair.

描述（由申请人提供）：创伤性和骨质疏松性骨折、严重/大缺陷和骨不连是医疗保健的重大负担，并影响这些患者的生活质量。组织工程方法显示出作为骨替代物的前景，并且在体外生物反应器环境中特别成功。组织工程再生的主要挑战是维持体内细胞的活力，并重建能够输送氧气和营养物质的血管网络，同时在植入后清除废物。最近，一种新的细胞归巢方法在募集内源性细胞然后在没有细胞移植的情况下再生方面显示出有希望的结果。为了加速细胞归巢和维持细胞在体内的活力，由机械负荷诱导的功能性骨液流动已被证明是启动和介导骨表面和骨细胞适应的关键调节剂。通过多孔结构的动态流体流动将施加增加的流体剪切应力以促进体内细胞分化和矿化。使用振荡加压骨髓液流和肌肉-骨界面刺激，发现相对高频率和短的每日持续时间（10分钟）的小幅度流体压力（10-60 mmHg）可启动新骨形成并减轻废用性骨量减少引起的皮质内孔隙增加。在体内多孔性骨大面积缺损内建立一个功能性的动态流体流动环境，维持活跃的流体流动对骨再生至关重要。因此，我们将检验这样的一般假设：由动态骨液流动调节的功能性机械传导（具有优化的强度和速率）对于关键缺陷愈合中的体内组织再生、细胞分化和成骨矿化至关重要并负责。最终目标是在关键缺损和支架中产生振荡流体压力梯度，作为体内生物反应器，以促进功能性流体流动、血管循环和成骨。这些结果将提高我们对优化的流体流动环境如何增强细胞活力和矿化的理解，以及机械转导在组织修复和再生中的重要性，特别是在体内条件下。预计该项目将提供一种通过体内流体流动刺激来调节骨形成的新方法，提高我们对动态机械传导在加速骨形成和组织再生中矿化的关键信号的认识，这将最终用于临床组织修复。