Hydrogel-based strategies for promoting lymphangiogenesis: mechanisms, design principles, and therapeutic...

The lymphatic system plays a crucial role in maintaining tissue fluid homeostasis, immune surveillance, and lipid transport. Dysfunction of the lymphatic system is associated with a variety of diseases, including lymphedema, cardiovascular disease, chronic inflammation, and metabolic disorders. Recent advances in biomaterials have highlighted hydrogels as promising platforms for promoting lymphatic regeneration, thanks to their unique biocompatibility and tunable physicochemical properties. This review provides a comprehensive overview of hydrogel-based approaches for lymphatic vessel regeneration (lymphangiogenesis). We first outline the anatomical and functional characteristics of lymphatic vessels and their involvement in disease pathogenesis. We then discuss the key biological mechanisms governing lymphangiogenesis, covering transcriptional control, growth factor signaling, extracellular matrix remodeling, mechanoregulation, immune cell interactions, and metabolic regulation. Based on these mechanistic insights, the discussion focuses on key hydrogel design principles, including biomimetic extracellular matrix engineering, optimization of mechanical properties, controllable degradation synchronized with tissue repair, and multifunctional platforms for delivery of growth factors, cells, and immunomodulatory agents. The preclinical evidence supporting these systems in treating lymphedema, repairing cardiac lymphatic injury, neurological disorders, skin wounds, and bone defects is also discussed. Finally, the review concludes by assessing the translational barriers that currently separate preclinical findings from clinical application, including the gap between acute injury models and chronic disease, manufacturing and regulatory challenges, and the need for more rigorous functional evaluation of therapeutic outcomes, providing valuable insights for the clinical translation of hydrogel-based lymphatic regeneration strategies.