Purpose of Review
This review aims to summarize the current knowledge regarding the pharmacological interventions studied in both experimental and clinical trials for secondary lymphedema.
Recent Findings
Lymphedema is a progressive disease that results in tissue swelling, pain, and functional disability. The most common cause of secondary lymphedema in developed countries is an iatrogenic injury to the lymphatic system during cancer treatment. Despite its high incidence and severe sequelae, lymphedema is usually treated with palliative options such as compression and physical therapy. However, recent studies on the pathophysiology of lymphedema have explored pharmacological treatments in preclinical and early phase clinical trials.
Summary
Many potential treatment options for lymphedema have been explored throughout the past two decades including systemic agents and topical approaches to decrease the potential toxicity of systemic treatment. Treatment strategies including lymphangiogenic factors, anti-inflammatory agents, and anti-fibrotic therapies may be used independently or in conjunction with surgical approaches.
Lymphatic structure and function play a critical role in fluid transport, antigen delivery, and immune homeostasis. A dysfunctional lymphatic system is associated with chronic low-grade inflammation of peripheral tissues, poor immune responses, and recurrent infections, which are also hallmarks of aging pathology. Previous studies have shown that aging impairs lymphatic structure and function in a variety of organ systems, including the intestines and central nervous system. However, previous studies are mostly limited to qualitative analysis of lymphatic structural changes and quantification of intestinal collecting vessel contractile function. It is not clear whether decreased lymphatic function contributes to pathological conditions related to aging, nor how it affects the skin immune microenvironment. Further, the effects of aging on skin initial and collecting lymphatic vessels, dendritic cell (DC) migration, cutaneous lymphatic pumping, and VEGFR-3 signaling in lymphatic endothelial cells (LECs) have not been quantitatively analyzed. Here, using fluorescent immunohistochemistry and flow cytometry, we confirm that aging decreases skin initial and collecting lymphatic vessel density. Indocyanine green (ICG) lymphangiography and DC migration assays confirm that aging decreases both fluid pumping and cell migration via lymphatic vessels. At the cellular level, aging causes decreased VEGFR-3 signaling, leading to increased LEC apoptosis and senescence. Finally, we determined that aging causes decreased lymphatic production of chemokines and alters LEC expression of junctional and adhesion molecules. This in turn leads to increased peri-lymphatic inflammation and nitrosative stress that might contribute to aging pathology in a feed-forward manner. Taken together, our study, in addition to quantitatively corroborating previous findings, suggests diverse mechanisms that contribute to lymphatic dysfunction in aging that in turn exacerbate the pathology of aging in a feed-forward manner.
ensure that cells were not dislodged from the vessel surface, perfusion was started at 2.92 dyne/cm 2 and increased daily by 0.66 dyne/cm 2 .
RESULTS:We designed sacrificial loops with a 750um diameter. Some sacrificial materials previously published quickly dissolve following contact with liquid and cannot be sterilized with ethanol. The PVA properties allowed its submersion in 70% ethanol for 15 minutes without appreciable material degradation or structure loss. ECs incubated with an 8% PVA mixture over 72h did not experience significant cytotoxicity. Immunofluorescence demonstrated an elaborate blood vessel shape in the 3D printed structure robustly lined with complete SMC and EC layers. As early as 2 days after perfusion, ECs aligned and elongated matching perfusion direction comparable to physiologic flow changes.
CONCLUSIONS:To engineer larger tissue flaps with better nutrient perfusion, we explored the role of a perfused lab-fabricated vessel utilizing PVA as a sacrificial material in complex 3D shapes microns in diameter. PVA is beneficial over other loop materials, like Pluronic F127 or needles, because it can be sterilized, has good biocompatibility, high 3D-printability, and flexible mechanical properties.
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