An Outside-In Biophysical Paradigm for Cardiac Regeneration via Epicardial Delivery of a Bio-Regenerative Complex

The adult mammalian heart exhibits limited regenerative capacity following injury, contributing to heart failure as a major global health burden. Conventional regenerative strategies, while promising, are constrained by invasive delivery methods, poor therapeutic retention, and immune responses. This perspective proposes a biophysical framework for cardiac regeneration through epicardial delivery of an autologous Bio-Regenerative Complex (BRC), comprising patient-derived cells, tailored molecular cues, and a programmable hydrogel matrix. We hypothesize that minimally invasive epicardial application establishes a controlled trans-myocardial transport gradient, fostering sustained regeneration. This work delineates the biophysical principles of this "outside-in" approach, integrates advanced computational simulations including detailed one-dimensional and three-dimensional diffusion modeling across the heart wall, Bayesian inference, sensitivity analyses with Sobol indices, addresses mechanobiological and translational challenges, and outlines a multidisciplinary translational roadmap. Limitations, such as model assumptions and the need for empirical validation, are explicitly discussed.