Lymphatic Tissue Engineering: A Further Step for Successful Lymphedema Treatment.

BACKGROUND: Secondary lymphedema, caused by oncologic surgery, radiation, and chemotherapy, is one of the most relevant, nononcological complications affecting cancer survivors. Severe functional deficits can result in impairing quality of life and a societal burden related to increased treatment costs. Often, conservative treatments are not sufficient to alleviate lymphedema or to prevent stage progression of the disease, as they do not address the underlying etiology that is the disruption of lymphatic pathways. In recent years, lymphatic surgery approaches were revolutionized by advances in microsurgical technique. Currently, lymphedema can effectively be treated by procedures such as lymphovenous anastomosis (LVA) and lymph node transfer (LNT). However, not all patients have suitable lymphatic vessels, and lymph node harvesting is associated with risks. In addition, some data have revealed nonresponders to the microsurgical techniques. METHODS: A literature review was performed to evaluate the value of lymphatic tissue engineering for plastic surgeons and to give an overview of the achievements, challenges, and goals of the field. RESULTS: While certain challenges exist, including cell harvesting, nutrient supply, biocompatibility, and hydrostatic properties, it is possible and desirable to engineer lymph nodes and lymphatic vessels. The path toward clinical translation is considered more complex for LNTs secondary to the complex microarchitecture and pending final mechanistic clarification, while LVA is more straight forward. CONCLUSION: Lymphatic tissue engineering has the potential to be the next step for microsurgical treatment of secondary lymphedema. Current and future researches are necessary to optimize this clinical paradigm shift for improved surgical treatment of lymphedema.

Characterization of Immune Cell Infiltration and Collagen Type III Disorganization in Human Secondary Lymphedema: A Case-control Study.

Background: Secondary lymphedema (SL) affects 120 million people globally, posing a lifelong burden for up to 37% of cancer survivors. Chronic inflammation and progressive fibrosis are key drivers of SL, yet detailed characterization of immune cell subpopulations across lymphedema stages is lacking. This study aimed to investigate the immunologic profile of lymphedematous skin and its association with extracellular matrix changes, which could serve as clinical biomarkers or therapeutic targets. Methods: This case-control study analyzed the skin from 36 patients with and without SL, using immunofluorescence to quantify T cells, B cells, macrophages, and their subpopulations. Collagen quantity and composition were examined using picrosirius red staining, and mast cell infiltration was assessed with toluidine blue staining. Early and late SL stages were compared to identify histomorphological and immunologic correlates of stage progression. Results: We found a predominance of CD4+ T cells and mast cells in SL skin (1.4/mm² versus 1.0/mm², P < 0.01; 1.2/mm² versus 0.2/mm², P < 0.0001) and a higher ratio of collagen III to collagen I fibers (51.6% versus 75.0%, P < 0.001). M2 macrophages were more abundant in late-stage than in early-stage lymphedema (1.7/mm² versus 1.0/mm², P = 0.02). Conclusions: This study demonstrated a shift toward CD4+ T cell and mast cell infiltration in SL skin, correlating with extracellular matrix disorganization and an altered collagen III/I ratio. These findings enhance our understanding of the cellular and morphological changes in SL, potentially guiding future diagnostic and therapeutic strategies.