CAREER: Design Principles of Deformable and Adhesive Particles in Multiphase Flow through Microchannels

Massachusetts Institute Of Technology, Cambridge MA

Investigators

Abstract

Cells exhibit varying mechanical properties at healthy and diseased states, presenting enormous opportunities to harness physical principles in engineering applications such as biomedicine. Nanoparticles are commonly used to modify cell biology, but their influence on cell mechanics and movement in a physiological flow environment is poorly understood. This CAREER award aims to understand how nanoparticles adhered to leukocyte surfaces influence cell deformability and migration from blood microcirculation to inflamed tissues. A combination of biophysical models and microfluidic experiments will be used to generate both fundamental knowledge and design rules for engineering cellular drug carriers. The integrated education plan will disseminate research findings by providing enriching learning experiences at various levels: e.g., a nationwide outreach program for K-12 students, new interdisciplinary teaching examples for undergraduates and graduates, and science communications for the public. There exists a critical knowledge gap between multiscale mechanical and adhesive properties and particle transport in microscale flows, hindering the development of architected materials. This award aims to test the hypothesis that drug nanoparticles influence leukocyte mechanical and adhesive properties across multiple length scales, thus modulating the delivery of drug payload to the site of inflammation and therapeutic efficacy through three major transport steps: crossflow movement in small blood vessels; rolling and adhesion on the vascular surface under physiological shear; transendothelial migration through small pores. In contrast to in vivo techniques commonly used in biomedical research, this award explicitly models the physical interaction between nanoparticles and cell membranes to examine multiscale deformations; a microfluidic cell culture recapitulates the kinetics of vascular adhesion and transport in vitro. This in silico-in vitro approach will elucidate fundamental mechanisms of leukocyte transport and efficiently explore a multi-dimensional parameter space for nanoparticles (e.g., shape, size, rigidity, concentration, and adhesion strength). Phase diagrams and multiscale structure-property relationships generated over a broad parameter range will serve as a robust and high throughput platform technology to design drug carriers tailored for various species, diseases, and drug administration methods. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.