Particle adhesion to tissue (vascular endothelium) depends critically upon particle/cell property (size, receptors), scale/geometric features of vasculature (diameter, bifurcation, etc.) and local hemodynamic factors (stress, torque etc). Currently, this is investigated using in-vitro parallel-plate flow chambers which suffer from several serious limitations including (a) idealized, macrocirculatory scaling (b) lack of critical morphological features (junctions, network), healthy vs. diseased vasculature and (c) large volumes (several ml) and (d) contamination due to non-disposability. We propose to develop a novel microfluidics-based platform for cell/drug-particle adhesion which overcomes these limitations In Phase I, anatomically detailed microvascular network structures were obtained from in-vivo image data and patterned onto a plastic, disposable substrate (PDMS). Perfusion and particle adhesion studies were successfully carried-out and the data was analyzed using high-fidelity computational models. The presence of significant stagnant regions, non-intuitive particle and flow splits, spatially non-uniform adhesion as well as first evidence of dependence of particle adhesion on vessel branching angle were identified and documented. In addition, endothelial cells were cultured on the PDMS and success was demonstrated with the upregulation of adhesion molecule (P-selectin) and subsequent adhesion of anti-P-selectin coated particle to the cultured endothelial cells. Net usage of reagents was decreased by over two orders of magnitude. Phase I results clearly established the value of using the proposed microvascular environment to gain new insights and make quantitative predictions on particle adhesion in the microvasculature. The Phase II efforts will include (a) expansion of the in-vivo network databases (and idealizations) (b) adhesion studies using micro/nano particles and endothelial/cancer cells and (c) validation against intra-vital measurements and analysis with computational models. By enabling the study of particle/cell-tissue interactions under controlled conditions that truly mimic the microvascular environment, the final Phase II product will advance drug discovery and delivery research in a variety of therapeutic areas including inflammation, allergy/infectious disease, cardiovascular disease and cancer among others. A multidisciplinary team has been assembled with expertise in microcirculation and cell adhesion research, microfabrication/microfluidics, computational modeling and intra-vital microscopy. ? ? ?
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