Engineering the Lymphatic Vasculature: Current Concepts and Challenges from Preclinical Strategies to Clinical Practice

Lymphedema is a chronic, debilitating condition characterized by impaired lymphatic drainage, tissue swelling, and fibrosis. Conventional treatments mainly focus on finding symptomatic solutions, rarely using tissue-engineered approaches of regenerative therapies. Tissue engineering approaches have emerged as promising strategies to restore lymphatic function by integrating molecular cues, cellular components, and biomaterial scaffolds. This review summarizes recent advances and challenges in lymphatic regeneration, focusing on (1) molecular regulation, including growth factors and chemical modulators; (2) cellular components with primary lymphatic endothelial cells (LECs), stem cells, fibroblasts, and macrophages; (3) biomaterials and engineering strategies, highlighting hydrogels, 3D scaffolds, and controlled delivery systems; and (4) preclinical and translational studies in different animal models. Finally, current and emerging strategies in clinical and plastic reconstructive surgery are discussed. Challenges such as cell survival, molecular specificity, and functional integration are highlighted, along with future directions for combinatorial approaches. This review provides a current framework for advancing tissue-engineered solutions and challenges for lymphedema and promoting translational success.