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/大型缺损性骨折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。组织工程学方法显示出作为骨替代品的前景，并且在生物反应器环境中的体外实验中特别成功。组织工程化再生的主要挑战是维持体内细胞的活性，并重建能够输送氧气和营养物质的血管网络，同时清除植入后的废物。最近，一种新的细胞归巢方法在招募内源性细胞然后在不进行细胞移植的情况下再生方面显示出有希望的结果。在体内，为了加速细胞归巢和维持细胞活性，机械负荷诱导的功能性骨流是启动和介导骨表面和骨适应的关键调节因子。流体在多孔结构中的动态流动将施加更大的流体剪应力，以促进体内细胞的分化和矿化。使用振荡加压骨髓液流和肌肉-骨界面刺激，发现频率相对较高、每日持续时间较短(10min)的小幅度液体压力(10-60 mm Hg)可以启动新骨形成，并缓解因废用性骨量减少而导致的皮质内孔洞增加。在体内多孔骨大块缺损区内建立功能良好的动态流体流动环境，并保持活跃的流体流动对骨再生至关重要。因此，我们将检验一个普遍的假设，即动态骨流调节的功能机械转导，以优化的强度和速度，是关键的缺损区愈合中体内组织再生、细胞分化和成骨矿化的关键和负责。最终的目标是在关键的缺损处和支架上产生振荡的流体压力梯度，作为体内生物反应器，促进功能性流体流动、血管循环和成骨。这些结果将加深我们对优化的流体流动环境如何提高细胞活性和矿化的理解，以及机械转导在组织修复和再生中的重要性，特别是在活体条件下。该项目有望提供一种通过体内液体流动刺激来调节骨形成的新方法，提高我们对加速组织再生中骨形成和矿化的动态力学转导关键信号的认识，最终将用于临床组织修复。