Therapeutic Lymphatic Collecting Vessel Regeneration by Directed Fluid Flow

通过定向流体流进行治疗性淋巴收集管再生

• 批准号: 8287227
• 负责人: Jeremy Goldman
• 金额: $ 45.96万
• 依托单位: MICHIGAN TECHNOLOGICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8287227
• 关键词: Adverse effects; Axilla; Axillary Lymph Node Dissection; Chronic; Dependence; Dissection; Goals; Growth; Growth Factor; Human; In Vitro; Injury; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic Capillaries; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic vessel; Lymphedema; Mediating; Natural regeneration; Nitric Oxide; Pharmaceutical Preparations; Rattus; Relative (related person); Swelling; Therapeutic; Vascular Endothelial Growth Factor C; arm; cell motility; compare effectiveness; fluid flow; in vivo; interstitial; lymph nodes; malignant breast neoplasm; non-drug; novel

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.

描述(申请人提供)：继发性淋巴水肿通常是腋窝清扫的结果，在努力治疗乳腺癌时进行。淋巴结节和相关的淋巴收集血管在解剖过程中被切断并从腋下移除，减少淋巴流量，并经常导致手臂的慢性肿胀。由于手臂的肿胀是在淋巴系统损伤之后发生的，因此有人假设，通过生长因子介导的毛细淋巴管生成来促进淋巴管的生长可能会减少肿胀。然而，我们发现功能性毛细淋巴管的生长可能依赖于先前存在的间质血流。此外，增加淋巴管的功能，而不是毛细淋巴管，对于治疗继发性淋巴水肿可能更重要。我们假设淋巴管的功能再生依赖于预先存在的液体流动，类似于我们对淋巴管的发现。我们打算通过使用新型的生物可降解管道来桥接淋巴管的断端，以保持淋巴管的流动，并通过管道实现收集血管的功能性淋巴管生成，从而研究淋巴管功能再生对预先存在的液体流动的依赖。由于过量的血管内皮生长因子-C输送给人类可能会产生有害的副作用，我们将研究从生物管道中释放一氧化氮(NO)作为治疗淋巴管生成的血管内皮生长因子-C的替代品。我们的目标是确定可生物降解的管道是否可以作为淋巴液运输的桥梁并促进淋巴管的生成，以及管道中释放的NO是否可以促进淋巴管内皮细胞(LEC)的迁移和增殖。我们计划通过植入一个大的淋巴管收集管来评估药物释放管道。 老鼠。 公共卫生相关性：继发性淋巴水肿通常是腋窝清扫的结果，这是为了治疗乳腺癌而进行的。我们假设淋巴收集血管的功能再生依赖于预先存在的液体流动。我们打算通过使用新型的生物可降解管道来桥接淋巴管的断端，以保持淋巴管的流动，并通过管道实现收集血管的功能性淋巴管生成，从而研究淋巴管功能再生对预先存在的液体流动的依赖。我们还将研究从生物管道释放一氧化氮(NO)作为治疗淋巴管生成的血管内皮生长因子-C的替代品。

项目成果

Synthesis and Characterization of the Novel Nitric Oxide (NO) Donating Compound, S-nitroso-N-acetyl-D-penicillamine Derivatized Cyclam (SNAP-Cyclam).

• DOI: 10.1021/acsami.5b12548
• 发表时间: 2016-02
• 期刊: ACS applied materials & interfaces
• 影响因子: 9.5
• 作者: Connor McCarthy;J. Goldman;M. Frost

Fabrication and Short-Term in Vivo Performance of a Natural Elastic Lamina-Polymeric Hybrid Vascular Graft.

• DOI: 10.1021/acsami.5b03892
• 发表时间: 2015-07
• 期刊: ACS applied materials & interfaces
• 影响因子: 9.5
• 作者: Connor McCarthy;Danielle C Ahrens;David Joda;Tyler E. Curtis;Patrick K Bowen;Roger J. Guillory;Shu Q. Liu;F. Zhao;M. Frost;J. Goldman