Many inflammatory conditions such as inflammatory bowel disease, or IBD, and allergic airway inflammation are associated with epithelial damage and/or lymphangiogenesis. Lymphangiogenesis is thought to accommodate the increased need to drain fluid, antigens, and cells from the peripheral tissues to the draining lymph nodes. Indeed, it has been shown that inflammatory cues can modulate endothelial cell barrier function and transport of model proteins in vitro. We have used in vitro and in vivo models to study changes in drainage/transport of antiges and macromolecules through lymphatics in various disease conditions including lymphangioleiomyomatosis and allergic airway inflammation. Small nanocarriers have also been shown to drain into lymphatic vasculature once they enter the interstitial space in the tissue. We design and use nanocarriers and macromolecules as probes to determine disease effects on lymphatic function, specifically their drainage. Interestingly, our previous work has shown that in inflammatory bowel disease, nanoparticles, can also lead to penetration of nanocarriers into tissue from which they could be drained into lymphatics. Nanocarriers thus provide a unique tool to test epithelial barriers and lymphatic drainage. Using our engineering tools, we seek to understand how inflammation induced epithelial damage and inflammatory lymphangiogenesis modulate drainage and distribution of drugs and nanocarriers from peripheral tissues such as the lungs and GI tract remains poorly understood.
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Molecular targets and therapeutic design characteristics resulting from our projects probing tissues in health and disease will provide insights into the necessary design criteria and targets for developing nanotherapeutic approaches to enhance treatment of diseases at mucosal surfaces. Lymphatic vasculature drains molecules and nanocarriers from the periphery to the draining lymph nodes, where the immune response is shaped. Targeting lymphatic drainage using nanoparticles has been shown to enhance various immunotherapy approaches including anti-cancer vaccination and Th1 adjuvant treatments against respiratory allergies. Thus, approaches taking into consideration lymphatics and lymphangiogenesis may further enhance existing and drive novel treatment strategies. We design and formulate novel carriers that can target local tissues or lymphoid organs, assess pharmacokinetics and pharmacodynamics for optimal treatment, and combine imaging modalities with therapeutics to form novel theranostics that will enhance treatments while improving our understanding of therapeutic biodistribution.
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The complexity of cellular interactions in tissues, e.g. how secreted molecules vs. direct interactions modulate immune responses and matrix remodeling, presents a unique problem to enhancing our overall understanding of disease pathology. This is particularly true with respect to lymphatics, which play important roles in both physiological transport and immune modulation. We are thus faced with differentiating how drainage of fluid/antigens from the periphery, direct interactions with immune cells, and indirect interactions with immune cells through secretion of immune-modulatory molecules modulate immunity. When used in complementary ways to in vivo models, in vitro models are a useful tool in probing individual questions and can give novel insights into the molecular mechanisms governing disease progression. However, currently few models of disease models include the lymphatic compartment and are not designed to include multiple physiologically relevant parameters, such as transmural flow, while maintaining other important factors such as air-liquid interface or different cellular compartments. We develop new tools to probe model multi-cellular stromal cell compartments to achieve better understanding of lymphatic transport/drainage and the immune involvement of the stromal cell compartment.
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Fischell Department of Bioengineering
3121 A. James Clark Hall 8278 Paint Branch Drive University of Maryland College Park, MD 20742 |
For General Lab Inquiries:
[email protected] To reach Dr. Maisel: Email: [email protected] Phone: 301-405-9805 |