Programmable Paracrine-Mimetic Microneedle System for Temporal Regulation of Cardiac Repair

Dynamic paracrine signaling governs tissue repair, yet replicating this temporal complexity using acellular systems remains challenging. While recent advances include microcapped microneedle patches and the TIMED platform, these systems face limitations in customizability, release duration, and fabrication simplicity. Here, this study reports a programmable microneedle platform that mimics the temporal paracrine signaling logic of stem cell therapy by generating phase-biased, kinetically staggered, and partially overlapping availability of TGF-β, IGF-1, and VEGF through a tris(2,2'-bipyridyl)dichlororuthenium(II) hexahydrate/sodium persulfate (Ru/SPS)-modulated tyramine crosslinked hydrogel network. This system demonstrates enhanced advantages, including straightforward tunability of release kinetics via Ru/SPS concentration adjustment, extended release duration up to ∼60 days, and a simplified fabrication process. In myocardial infarction models, this stem cell-inspired temporal release promoted anti-inflammatory, anti-apoptotic, and pro-angiogenic responses, restoring ventricular function. Direct schedule-control experiments further showed that the tested TGF-β/IGF-1/VEGF program outperformed 7- and 28- day simultaneous-window delivery and two order-swapped 7/14/28-day programs across functional, structural, angiogenic, and cardiomyocyte-proliferation readouts. This strategy establishes a generalizable framework for engineering time-coded therapeutic materials that emulate biological signaling programs.