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Engineering Lymphatic Vessels For Secondary Lymphedema Treatment
Qixu Zhang, Yewen Wu, Mark V. Schaverien, Summer E. Hanson, Edward I. Chang, Charles E. Butler.
MD Anderson Cancer Center, Houston, TX, USA.

PURPOSE: Lymphedema has been shown to be one of the most significant survivorship issues following the treatment of many solid tumor cancers, most publicized in breast cancer but also impacting patients with melanoma, gynecologic and urologic cancer. Recent advances in microsurgery, specifically lymphovenous bypass and vascularized lymph node transfers, have provided the closest chance at a cure for lymph flow disorders. However, the availability of qualitative autologous flaps and donor site morbidity significantly limit its application. Engineered lymphatic vessel tissues may offer a clinically alternative to autologous flaps. This study aimed to engineer lymphatic vessels with decellularized adipose tissue matrix (DAM) to improve the lymphedema symptom after transplantation.
METHODS: Human adipose tissues were treated with hypotonic solutions, Trypsin, TritonX-100, and isopropanol to remove cells and lipids, which was proved by immunohistochemistry and DNA quantification. DAM was characterized by proteomic analysis (LC-MS/MS) and scanning electron microscope (SEM). Human adipose derived stem cells (hASC) and Human dermal lymphatic endothelial cellsí (HDLEC) viability and adhesion on DAM were tested by immunostaining. DAM was implanted subcutaneously in Fisher rats to evaluate foreign body response and remodeling. Re-cellularized and pre-vascularized DAM with hASCs and HDLECs were then analyzed by two-photon imaging system at different time point in vitro and in vivo.
RESULTS: H&E, DAPI staining and DNA quantification confirmed cell removal in DAM. DAM maintained natural extracellular matrix structure with 3D nanofibrous features (SEM imagining), strong mechanical properties, biochemical compositions (collagen+, laminin+, MHC1- e.g.) (IHC staining and Mass Spectrometry). DAM provides a niche for hASCs and HDLECs proliferation. Extraction of DAM induced hASCs differentiation. DAM caused little foreign body response in vivo (few CD4+ / CD8+; M1-/M2+). Co-culture of hASCs and HDLECs on DAM successfully formed LYVE-1 positive lymphatic vessels-like structures, its density significantly increased along time course. Re-cellularized constructs were successfully subcutaneously transplanted in nude rats, which was survived and remodeled as indicated by lymphatic soft tissue formation at 1-3 months.
CONCLUSION: Pre-vascularized DAM-cell constructs showed great promise for lymphatic vessels tissue engineering. This platform may provide a novel strategy for secondary lymphedema treatment after transplantation.


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