Microphysiological endothelial models to characterize subcutaneous drug absorption

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Giovanni S. Offeddu
Jean Carlos Serrano
Zhengpeng Wan
Mark A. Bryniarski
Sara C. Humphreys
Sophia W. Chen
Hamsini Dhoolypala
Kip Conner
Roger D. Kamm


The high variability in subcutaneous bioavailability of protein therapeutics is poorly understood, contributing to critical delays in patient access to new therapies. Preclinical animal and in vitro models fail to provide a physiologically relevant testbed to parse potential contributors to human bioavailability, therefore new strategies are necessary. Here, we present a microphysiological model of the human hypodermal vasculature at the injection site to study the interactions of administered protein therapeutics within the microenvironment that influence subcutaneous bioavailability. Our model combines human dermal endothelial cells, fibroblasts, and adipocytes, self-assembled into three-dimensional, perfusable microvessels that express relevant extra-cellular matrix. We demonstrate the utility of the model for measurement of biophysical parameters within the hypodermal microenvironment that putatively impact protein kinetics and distribution at the injection site. We propose that microphysiological models of the sub-cutaneous space have applications in preclinical development of protein therapeutics intended for sub-cutaneous administration with optimal bioavailability.

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Offeddu, G. S., Serrano, J. C., Wan, Z., Bryniarski, M. A., Humphreys, S. C., Chen, S. W., Dhoolypala, H., Conner, K. and Kamm, R. D. (2022) “Microphysiological endothelial models to characterize subcutaneous drug absorption”, ALTEX - Alternatives to animal experimentation. doi: 10.14573/altex.2207131.

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