SBIR-STTR Award

Lymphedema, accumulation of lymph fluid in the tissue, is a disabling condition most commonly caused by removal of lymphatic nodes during cancer surgery. There is no cure for lymphedema, and all available remedies are palliative and reduce fluid accumulation by massage and compressive garments. To address the lack of treatment for lymphedema patients we propose to guide lymphatic regeneration by the cell-seeded graft. The graft consists of multi-lumen thread made from aligned Nanoweave™ collagen fibrils by Fibralign patented process, seeded with human lymphatic endothelial cells (LECs). These collagen fibrils closely resemble the native structure of the inside wall of the lymphatic vessel, and provide for cell attachment and alignment. The collagen thread facilitates site-specific cell delivery, enhances the survival of implanted cells. Ultimately, the goal of the LEC-seeded graft is to bridge the gap in the lymphatics caused by surgery. Primary LECs have aligned on the collagen fibrils, and LECs seeded on the thread have demonstrated excellent survival rate after subcutaneous implantation in mice. We propose to standardize the physical properties of the collagen threads by crosslinking and to implant these constructs with and without LEC in mice to test whether the LEC will integrate into the existing lymphatics.

Keywords:
Cell-Seeded Guiding Graft, Multi-Lumen Collagen Thread, Lymphatic Endothelial Cells, Aligned Collagen Fibrils, Lymphatic Vessel Regeneration, Lymphedema, Interstitial Flow

To address the lack of treatment options for lymphedema patients we propose the use of nanopatterned collagen thread-like scaffolds (threads) designed to create new lymphatic channels. We have engineered these nanopatterned threads to closely mimic the native structure of vascular endothelial wall and we find that they provide a favorable environment for lymphatic endothelial cells. The nanopatterned thread aligns the endothelial cells, and regulates their migration along the direction of the nanofibrils. This morphological change is associated with beneficial functional effects, such as reduced expression of endothelial adhesion molecules, and reduced adhesiveness for inflammatory cells. The material enhances human endothelial cell survival after implantation in immunodeficient mice. Finally, the nanopatterned threads enhance perfusion in the murine model of limb ischemia, indicating that the threads may act to enhance the development of collateral channels, perhaps by serving as a favorable environment for endothelial cell proliferation and migration. The nanopatterned thread properties will be tested in rabbit and pig animal models. We plan to upgrade current manufacturing process to GMP grade, and to develop a novel minimally invasive catheter/trocar system for subcutaneous thread delivery, for example, across an area of surgical scar. The optimized nanopatterned thread may also be complexed with VEGF-C.

Keywords:
lymphedema, nanopatterned collagen scaffold, minimally invasive delivery, lymphatic endothelial cells, animal model, lymphatic vessel, catheter, MR imaging.