From molecule to absorption: a multiscale framework for subcutaneous biologic delivery

Subcutaneous (SC) injection has become the preferred route for self-administered monoclonal antibodies (mAbs), yet achieving consistent bioavailability remains challenging because molecular-scale interactions (protein self-association) propagate through device mechanics (cavitation, sloshing) into tissue response (depot geometry, lymphatic uptake) as a coupled system where optimizing any single component in isolation yields diminishing returns. This review introduces the Drug-Device-Container-Tissue (DDCT) framework-a unified, multiscale approach that traces the monoclonal antibody (mAb) journey from storage through injection to lymphatic absorption. We synthesize findings from molecular dynamics simulations, rheological measurements, high-speed imaging, and poromechanical modeling to establish four key principles. First, concentration-dependent viscosity and diffusion arise from antibody self-association, directly impacting injectability and tissue transport. Second, device actuation induces sloshing, cavitation, and hydrodynamic shear, which can compromise protein stability; design strategies to mitigate these phenomena are now well-characterized. Third, device actuation parameters such as spring force and injection time critically influence delivery reliability and the risk of intramuscular injection. Fourth, tissue heterogeneity-including adipocyte geometry, collagen septa, and lymphatic distribution-governs depot formation and absorption kinetics in ways that patient-specific factors such as body mass index significantly modulate. By mapping these coupled phenomena across scales, the DDCT framework identifies cross-interface interactions as the critical bottleneck for optimizing SC delivery, providing a foundation for the rational design of next-generation autoinjectors, high-concentration formulations, and predictive computational tools.