Subcutaneous drug delivery: from simple release testing to biomimetic systems

INTRODUCTION: Subcutaneous (SC) administration is increasingly used for biologics and long-acting therapeutics, yet formulation performance and human bioavailability remain difficult to predict. This is because the injection site is a heterogenous environment comprising extracellular matrix, interstitial fluid, tissue-resident cells, and distinct vascular and lymphatic vessels. AREAS COVERED: This review evaluates 17-year SC drug-delivery growth, market trends, and in vitro tools spanning shake-flask, dialysis, USP apparatus 4, and biomimetic acellular platforms including SCISSOR, BioJect, ESCAR, and hydrogel-based membrane-inserts. Cellular and microphysiological systems, including 3D adipose models, SubCuTIS, and lymphatics-on-chip, are assessed alongside in silico approaches. Peer-reviewed studies and industry and regulatory reports are evaluated for physiological relevance, accessibility, validation, and translational utility. EXPERT OPINION: Progress has been substantial, but no current model independently reproduces the mechanisms governing human SC absorption. Cellular components remain underutilized despite extensive foundational work in related fields. Priorities include physiologically characterized matrices, realistic interstitial fluids, quantitative mass-balance endpoints, and multicenter validation against human pharmacokinetic data. A modular, fit-for-purpose qualification strategy offers the most practical route toward predictive and animal-sparing SC drug development.