Development of a Bioengineered Therapeutic Device for the Prevention of Lymphedema - ABSTRACT: Lymphedema affects approximately 200 million patients globally, and it is characterized by the accumulation of lymph fluid in soft tissues due to obstructions in the lymphatic system. In Western countries, it most commonly occurs as a direct outcome of the cancer treatment itself, most frequently in survivors of breast and gynecological cancers. Lymphedema is a chronic and progressive disease that has no cure. Current treatment approaches mainly address the symptoms of tissue swelling and discomfort by physiotherapy and compression. We recently developed an aligned-braided nanofibrillar collagen conduit that is implanted to bridge the region of lymphatic obstruction as a new surgical treatment strategy. Our preliminary preclinical and clinical studies demonstrate that implantation of the conduit reduces symptoms associated with lymphedema. We propose to advance translational research and application of this novel resorbable conduit to deliver a much- needed surgical preventative treatment for lymphedema. Based on technology developed by Fibralign Corp. and a previous version of the conduit that showed promising preclinical and clinical results in lymphedema treatment, the objective is to optimize the structural and mechanical properties of the conduit for targeting lymphedema prevention in well-established mouse and rat lymphedema models. Accordingly, in Specific Aim 1, we hypothesize that aligned nanofibrillar conduits with optimally engineered structural and mechanical properties will promote capillary flow and lymphatic endothelial cell (LEC) function. We will determine the optimal properties (stiffness, nanofibril diameter, degradation rate, and capillarity) of the conduit that maximize LEC phenotype and lymphatic sprouting. In Specific Aim 2, we will test the hypothesis that optimally engineered aligned nanofibrillar conduits will accelerate lymphatic regeneration and normalize lymphatic flow in a murine tail model of secondary lymphedema. We will first test the therapeutic efficacy in a mouse model of lymphedema, in which conduit formulations will be implanted into the mouse tail immediately after induction of lymphedema. Output measures will consist of tail volume and lymph drainage pattern, based on indocyanine green (ICG) imaging. ICG imaging will enable non-invasive tracking of perfusion over time to track for the ability of the conduits to promote lymphangiogenesis. The conduit whose properties maximize lymphatic regeneration and lymph drainage will undergo further analysis in a more clinically relevant rat model of lymphedema induced by lymph node resection and irradiation in Aim 3. Here, conduits will be implanted immediately after lymphedema induction surgery as a preventative intervention. Treatment groups will consist of optimally engineered conduit compared to the no treatment control group or to reference conduit formulations. Over 3 months, we will quantify edema accumulation by micro computed tomography, lymph drainage pattern by ICG imaging, and lymphatic regeneration will be confirmed by histological quantification of lymphatic density. Through this industry-academia partnership, we anticipate these studies will advance the surgical prevention of lymphedema.
