Functional Fluid Flow Regulated Bone Regeneration

功能性流体流量调节骨再生

基本信息

批准号：
8307695
负责人：
Yi-Xian Qin
金额：
$ 34.6万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
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/8307695
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 response scaffold shear stress stem cell differentiation tissue regeneration tissue repair ulna

项目摘要

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. PUBLIC HEALTH RELEVANCE: Bone critical defects resultant from traumatic and osteoporotic fractures are major health problems. These patients have limited options, such as early surgical interventions with bone grafts with uncertainties in calcification and nonunion. Tissue engineering represents promising potentials, but requires large scale in vitro cell proliferation and differentiation. This project is expected to generate a new paradigm in bone tissue engineering by promoting osteogenic response and vascularization via enhanced in vivo dynamic fluid flow perfusion in the constructs to regulate and accelerate regeneration. Such approaches may accelerate in vivo healing and ultimately enhance clinical tissue repair through further design of novel non-invasive stimulator from the outcome of this application.

描述（由申请人提供）：创伤性和骨质疏松性骨折，关键/大缺陷和不工会代表着医疗保健的重大负担，并影响了这些患者的生活质量。组织工程方法表现出有望作为骨骼替代品，并且在生物反应器环境中在体外特别成功。组织工程再生的主要挑战是维持体内细胞的生存能力，并重建能够输送氧气和养分的血管网络，同时植入后去除废物。最近，一种新的细胞归巢方法显示出有希望的结果在募集内源细胞，然后再生无细胞移植的情况下。为了加速细胞归巢并维持体内细胞活力，机械负荷诱导的功能性骨流体流已被证明是启动和介导骨表面和腾腾适应的关键调节剂。通过多孔构建体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。使用振荡性加压流体流动和肌肉骨界面刺激，发现相对高频率和短期持续时间（10分钟）的小幅度流体压力（10-60 mmHg）被发现启动新的骨形成并减轻骨内孔隙的增加，这会导致骨内孔隙率增加。在体内多孔骨大缺陷中建立功能动态流体流动环境至关重要，并保持活跃的液体流动以进行骨骼再生。因此，我们将研究以下一般假设：具有优化强度和速率的动态骨流动调节的功能机械传导是必不可少的，并且是体内组织再生，细胞分化和成骨矿化的临界缺陷愈合中的必不可少的。最终的GOL是在临界缺陷和支架中产生振荡的流体压力梯度，作为一种体内生物反应器，以促进功能流体流动，血管循环和成骨。结果将提高我们对优化流体流动环境如何增强细胞活力和矿化的理解，以及组织修复和再生中机械转导的重要性，尤其是在体内条件下。预计该项目将通过体内流体流动刺激提供一种新型的方法来调节骨形成，这提高了我们对组织再生中骨形成和矿物质的动态机械传导的关键信号的了解，最终将用于临床组织修复。公共卫生相关性：创伤性骨折和骨质疏松性骨折导致的骨骼危害缺陷是主要的健康问题。这些患者的选择有限，例如早期的手术干预措施与钙化和骨不确定性的骨移植物进行。组织工程代表有希望的潜力，但需要大规模的体外细胞增殖和分化。预计该项目将通过增强体内动态流体流动灌注以调节和加速再生，从而通过促进成骨的反应和血管形成来产生骨组织工程的新范式。这种方法可能会加速体内愈合，并通过从本应用的结果中进一步设计新型的非侵入性刺激剂来增强临床组织修复。