Therapeutic Lymphatic Collecting Vessel Regeneration by Directed Fluid Flow

描述（由申请人提供）：继发性淋巴水肿通常是在治疗乳腺癌时进行腋窝清扫的结果。在此过程中，淋巴结和相关的淋巴收集血管被切断并从腋窝移除，减少淋巴流量，并经常引起手臂的慢性肿胀。由于淋巴系统损伤会导致手臂肿胀，因此有假说认为，通过生长因子介导的淋巴毛细血管的淋巴管生成而增加的淋巴生长可能会减轻肿胀。然而，我们发现功能性淋巴毛细血管生长可能依赖于预先存在的间质流动。此外，增加淋巴收集血管的功能，而不是淋巴毛细血管的功能，可能对治疗继发性淋巴水肿更重要。我们假设淋巴收集血管的功能再生依赖于先前存在的液体流动，类似于我们在淋巴毛细血管中发现的情况。我们打算通过使用新型可生物降解导管来桥接淋巴收集血管的断端，以维持淋巴流动，并使收集血管通过导管进行功能性淋巴管生成，来研究淋巴收集血管功能再生对原有液体流动的依赖。由于过量的血管内皮生长因子(VEGF)- C输送到人体可能会产生有害的副作用，我们将研究从生物管道释放一氧化氮（NO）作为VEGF-C治疗性淋巴管生成的替代方法。我们的目的是确定可生物降解的导管是否可以作为淋巴液运输的桥梁，促进淋巴管的淋巴管生成，以及从导管中释放no是否可以增加淋巴内皮细胞（LEC）的迁移和增殖。我们计划将药物释放导管插入到一个大的淋巴收集血管中

DESCRIPTION (provided by applicant): Secondary lymphedema is often acquired as a consequence of axillary dissection, performed in an effort to treat breast cancer. Lymph nodes and associated lymphatic collecting vessels are severed and removed from the axilla during this dissection, reducing lymphatic flow and often causing chronic swelling of the arm. Because swelling of the arm follows injury to the lymphatic system, it has been hypothesized that increased lymphatic growth via growth factor mediated lymphangiogenesis of the lymphatic capillaries may reduce the swelling. However, we have found that functional lymphatic capillary growth may be dependent upon pre-existing interstitial flow. Furthermore, increasing function of lymphatic collecting vessels, as opposed to lymphatic capillaries, may be more important for treating secondary lymphedema. We hypothesize that functional regeneration of the lymphatic collecting vessels is dependent upon pre-existing fluid flow, similar to what we have found with the lymphatic capillaries. We intend to investigate the dependence of functional regeneration of lymphatic collecting vessels on pre-existing fluid flow by employing novel biodegradable conduits to bridge the severed ends of a lymphatic collecting vessel to maintain lymphatic flow and enable functional lymphangiogenesis of collecting vessels through the conduit. Because delivery of excess vascular endothelial growth factor (VEGF)- C to the human may produce harmful side effects, we will investigate Nitric Oxide (NO) release from the bioconduit as an alternative to VEGF-C for therapeutic lymphangiogenesis. Our goal is to determine whether a biodegradable conduit may serve as a bridge for lymphatic fluid transport and promote lymphangiogenesis of lymphatic vessels and whether NO-release from the conduit may increase lymphatic endothelial cell (LEC) migration and proliferation. We plan to evaluate the drug releasing conduits by interpositional grafting into a large lymphatic collecting vessel in the rat. PUBLIC HEALTH RELEVANCE: Secondary lymphedema is often acquired as a consequence of axillary dissection, performed in an effort to treat breast cancer. We hypothesize that functional regeneration of the lymphatic collecting vessels is dependent upon pre-existing fluid flow. We intend to investigate the dependence of functional regeneration of lymphatic collecting vessels on pre-existing fluid flow by employing novel biodegradable conduits to bridge the severed ends of a lymphatic collecting vessel to maintain lymphatic flow and enable functional lymphangiogenesis of collecting vessels through the conduit. We will also investigate Nitric Oxide (NO) release from the bioconduit as an alternative to VEGF-C for therapeutic lymphangiogenesis.