Bioengineered lymphatic regenerating platform for treatment of breast cancer related lymphedema

Project Summary Breast cancer remains a global affliction with more than 1.5 million people impacted each year worldwide and is expected to increase in incidence. Breast cancer related lymphedema (BCRL) is a common and feared result of breast cancer, with 40% of breast cancer survivors being tethered to the lifelong condition. Despite decades of research, there is no cure for BCRL, and the current standard of care remains life-long symptom management with compression devices that lead to infections, tissue damage, and increased hospitalizations. Recent advancements in microsurgery offer hope for improved lymphatic drainage. However, these procedures have their limitations such as mismatches in replacement vessel size, requiring two invasive surgeries that may lead to secondary lymphedema, and fibrosis. Tissue-engineered alternatives have yet to successfully resolve lymphedema and regenerate lymphatics on their own and often result in foreign body response, leading to graft morbidity. To address these key obstacles, we propose a unique alginate mechacrylate (AlMA) hydrogel platform that is coated with an anti-fibrotic small molecule and contains programmable cell therapies for lymphatic vessel recruitment and regeneration to correct lymphedema. We have demonstrated that AlMA hydrogels can encourage lymphatic vessel guidance within a pre-clinical lymphedema model. Additionally, a synthesized small molecule will be modified to AlMA that avoids foreign body response (FBR) from the host immune system that would normally lead to graft fibrosis and therefore maintains viability of loaded cell therapies. PI Veiseh has shown that such immunoprotective modified hydrogels limits FBR in rodent and primate models. Additionally, PI Veiseh has established a method to engineer non-tumorigenic and human-sourced cells to produce a local and targeted therapy that have advanced to clinical applications. Here, we have engineered cells to regulate vascular endothelial growth factor-c (VEGF-C) secretion and termination. VEGF-C is a factor responsible for regeneration of lymphatic vessels, that will be encapsulated within our guiding hydrogel. PI Zhang and Chang have experience in tissue engineered solutions for lymphedema clnicalal applications, along with pre-clinical lymphedema models to evaluate lymphatic regeneration, reduced swelling, and safety. PI Dondossola has demonstrated real-time foreign body response to implanted biomaterials utilizing intravital microscopy, such technique will be applied to investigate the mechanism behind foreign body response to our platform along with lymphatic regeneration. In this research project, we will fabricate 3D hydrogels and optimize VEGFC engineered cell dosage to elevate pro-lymphangiogenesis features such as vessel guidance and regeneration in vivo. The AlMA hydrogel will be modified to resist FBR in rodent models and will be fabricated and combined with optimized lymphangiogenic cells to encourage local regeneration. Upon regeneration of the hydrogel graft in vivo, the graft will be evaluated for reinstatement of flow and reduction of swelling within rodent and porcine hindlimb lymphedema models. Intravital imaging will provide insights on the fibrosis and regeneration process in real-time. We anticipate that upon completion of this project, we will have identified a therapeutic AlMA hydrogel that succeeds in pre-clinical rodent lymphedema models for clinical translation.