Purpose Emerging evidence emphasizes the pivotal contribution of cardiac lymphatic activation following ischemic heart injury, with induced lymphangiogenesis driving edema resolution and inflammatory cell clearance. The aim of this study was to identify a bioactive small molecule with pro-lymphangiogenic activity and to develop a tissue engineering polymeric formulation for sustained local delivery in myocardial repair. Methods Through a high-throughput screen, we identified the bioactive molecule β-(3,4-dihydroxyphenyl) lactic acid (3,4-DHPLA) as a potent stimulator of lymphatic endothelial cells (LECs). To leverage this finding, we engineered a tissue engineering polymeric formulation (TEPF) to promote lymphangiogenesis during myocardial repair. The TEPF was fabricated via an integrated strategy combining 3D printing and near-field electrospinning to incorporate 3,4-DHPLA into a biodegradable polyurethane scaffold. The resulting structure mimics the microstructure of the cardiac extracellular matrix while supporting the microenvironment-responsive release of 3,4-DHPLA. Results We evaluated the therapeutic efficacy of TEPF in rat and porcine ischemia/reperfusion injury models, which markedly improved cardiac function and significantly attenuated adverse ventricular remodeling. Single-cell RNA sequencing and in vitro data further revealed the dual mechanisms of TEPF, not only promoting lymphangiogenesis but also orchestrating a pro-regenerative niche via expansion of Tregs, M2 macrophages, and pro-regenerative fibroblasts (COL12A1 + , COL11A1 + , NRG1 + ). Conclusions Thus, the tissue engineering polymeric formulations may enable sustained drug release during myocardial tissue repair, thereby alleviating the pain of injection administration for patients with cardiovascular diseases and potentially facilitating patient-friendly use of other functional molecules-based therapeutic tissue engineering formulations through durable delivery.
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Liu et al. (2026) studied this question.