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.
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.
|Hu, Minyi; Cheng, Jiqi; Bethel, Neville et al. (2014) Interrelation between external oscillatory muscle coupling amplitude and in vivo intramedullary pressure related bone adaptation. Bone 66:178-81|
|Hu, Minyi; Qin, Yi-Xian (2014) Dynamic fluid flow stimulation on cortical bone and alterations of the gene expressions of osteogenic growth factors and transcription factors in a rat functional disuse model. Arch Biochem Biophys 545:154-61|
|Wu, Junyi; Liu, Gaojun; Qin, Yi-Xian et al. (2014) Effect of low-intensity pulsed ultrasound on biocompatibility and cellular uptake of chitosan-tripolyphosphate nanoparticles. Biointerphases 9:031016|
|Lin, Liangjun; Oon, Han Yuen; Lin, Wei et al. (2014) Principal trabecular structural orientation predicted by quantitative ultrasound is strongly correlated with ?FEA determined anisotropic apparent stiffness. Biomech Model Mechanobiol 13:961-71|
|Hu, Minyi; Serra-Hsu, Frederick; Bethel, Neville et al. (2013) Dynamic hydraulic fluid stimulation regulated intramedullary pressure. Bone 57:137-41|
|Uddin, Sardar M Z; Hadjiargyrou, Michael; Cheng, Jiqi et al. (2013) Reversal of the detrimental effects of simulated microgravity on human osteoblasts by modified low intensity pulsed ultrasound. Ultrasound Med Biol 39:804-12|
|Qin, Yi-Xian; Lin, Wei; Mittra, Erik et al. (2013) Prediction of trabecular bone qualitative properties using scanning quantitative ultrasound. Acta Astronaut 92:79-88|
|Uddin, Sardar M Z; Qin, Yi-Xian (2013) Enhancement of osteogenic differentiation and proliferation in human mesenchymal stem cells by a modified low intensity ultrasound stimulation under simulated microgravity. PLoS One 8:e73914|