Microphysiological endothelial models to characterize subcutaneous drug absorption

Area of Science:

• Biomedical Engineering
• Pharmacology
• Cell Biology

Background:

• Subcutaneous bioavailability of protein therapeutics exhibits high variability, hindering patient access to novel treatments.
• Existing preclinical models lack physiological relevance for studying human bioavailability.
• Understanding the hypodermal microenvironment is crucial for optimizing protein drug delivery.

Purpose of the Study:

• To develop a microphysiological model of the human hypodermal vasculature.
• To investigate the factors within the injection site microenvironment influencing protein therapeutic bioavailability.
• To provide a physiologically relevant platform for preclinical assessment of subcutaneous drug delivery.

Main Methods:

• Constructed a three-dimensional, perfusable microvessel model using human dermal endothelial cells, fibroblasts, and adipocytes.
• Incorporated relevant extracellular matrix components into the model.
• Measured biophysical parameters within the hypodermal microenvironment impacting protein kinetics and distribution.

Main Results:

• The model successfully replicated key features of the human hypodermal microenvironment.
• Demonstrated the ability to measure critical biophysical parameters affecting protein drug behavior.
• Validated the model's utility for studying protein-microenvironment interactions.

Conclusions:

• Microphysiological models of the subcutaneous space offer a promising approach for preclinical drug development.
• This model can aid in optimizing subcutaneous administration of protein therapeutics for improved bioavailability.
• Facilitates better prediction of in vivo drug performance, potentially reducing development timelines and costs.