Near-Infrared Imaging of Glymphatic Clearance in a Pre-Clinical Model of Repetitive Closed Head Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major health disorder for which there are few treatments. The glymphatic system is the brain's inbuilt lymphatic-like system that is thought to be responsible for clearing waste products from the brain to the lymph nodes. Although there is evidence that glymphatic drainage is crucial for brain homeostasis, its role in TBI pathogenesis remains elusive.

Lymphatic vessel network injury reduces local tumor control despite preservation of the tumor-draining lymph node.

The lymphatic system plays complex, often contradictory, roles in many cancers, including melanoma; these roles include contributions to tumor cell metastasis and immunosuppression in the tumor microenvironment as well as generation of antitumor immunity. Advancing our understanding of lymphatic vessel involvement in regulating tumor growth and immune response may provide new therapeutic targets or treatment plans to enhance the efficacy of existing therapies. We utilized a syngeneic murine melanoma model in which we surgically disrupted the lymphatic vessel network draining from the tumor to the tumor-draining lymph node (TDLN) while leaving the TDLN intact.

Understanding the Lymphatic System: Tissue-on-Chip Modeling.

The lymphatic vasculature plays critical roles in maintaining fluid homeostasis, transporting lipid, and facilitating immune surveillance. A growing body of work has identified lymphatic dysfunction as contributing to the severity of myriad diseases and to systemic inflammation, as well as modulating drug responses. Here, we review efforts to reconstruct lymphatic vessels in vitro toward establishing humanized, functional models to advance understanding of lymphatic biology and pathophysiology.

Lymphatic endothelial cell-targeting lipid nanoparticles delivering VEGFC mRNA improve lymphatic function after injury.

Dysfunction of the lymphatic system following injury, disease, or cancer treatment can lead to lymphedema, a debilitating condition with no cure. Advances in targeted therapy have shown promise for treating diseases where conventional therapies have been ineffective and lymphatic vessels have recently emerged as a new therapeutic target. Lipid nanoparticles (LNPs) have emerged as a promising strategy for tissue specific delivery of nucleic acids.

A 1D model characterizing the role of spatiotemporal contraction distributions on lymph transport.

Lymphedema is a condition in which lymph transport is compromised. The factors that govern the timing of lymphatic contractions are largely unknown; however, these factors likely play a central role in lymphatic health. Computational models have proven useful in quantifying changes in lymph transport; nevertheless, there is still much unknown regarding the regulation of contractions.

Abnormal Lymphatic Sphingosine-1-Phosphate Signaling Aggravates Lymphatic Dysfunction and Tissue Inflammation.

Background: Lymphedema is a global health problem with no effective drug treatment. Enhanced T-cell immunity and abnormal lymphatic endothelial cell (LEC) signaling are promising therapeutic targets for this condition. Sphingosine-1-phosphate (S1P) mediates a key signaling pathway required for normal LEC function, and altered S1P signaling in LECs could lead to lymphatic disease and pathogenic T-cell activation.

Computational Exploration of Potential CFTR Binding Sites for Type I Corrector Drugs.

Cystic fibrosis (CF) is a recessive genetic disease that is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The recent development of a class of drugs called "correctors", which repair the structure and function of mutant CFTR, has greatly enhanced the life expectancy of CF patients. These correctors target the most common disease causing CFTR mutant F508del and are exemplified by the FDA-approved VX-809.

Abnormal lymphatic S1P signaling aggravates lymphatic dysfunction and tissue inflammation.

Background: Lymphedema is a global health problem with no effective drug treatment. Enhanced T cell immunity and abnormal lymphatic endothelial cell (LEC) signaling are promising therapeutic targets for this condition. Sphingosine-1-phosphate (S1P) mediates a key signaling pathway required for normal LEC function, and altered S1P signaling in LECs could lead to lymphatic disease and pathogenic T cell activation.

Lymphatic-draining nanoparticles deliver Bay K8644 payload to lymphatic vessels and enhance their pumping function.

Dysfunction of collecting lymphatic vessel pumping is associated with an array of pathologies. S-(-)-Bay K8644 (BayK), a small-molecule agonist of L-type calcium channels, improves vessel contractility ex vivo but has been left unexplored in vivo because of poor lymphatic access and risk of deleterious off-target effects. When formulated within lymph-draining nanoparticles (NPs), BayK acutely improved lymphatic vessel function, effects not seen from treatment with BayK in its free form.

Effect of valve spacing on peristaltic pumping.

Peristaltic fluid pumping due to a periodically propagating contraction wave in a vessel fitted with one-way elastic valves is investigated numerically. It is concluded that the valve spacing within the vessel relative to the contraction wavelength plays a critical role in providing efficient pumping. When the valve spacing does not match the wavelength, the valves open asynchronously and the volume of the vessel segments bounded by two consecutive valves changes periodically, thereby inducing volumetric fluid pumping.

Continuous, Nondestructive Detection of Microorganism Growth at Buried Interfaces with Vascularized Polymers.

Evaluating surface bacterial growth at buried interfaces can be problematic due to the difficulties associated with obtaining samples. In this work, we present a new method to detect signals from microorganisms at buried interfaces that is nondestructive and can be conducted continuously. Inspired by vascular systems in nature that permit chemical communication between the surface and underlying tissues of an organism, we created a system in which an inert carrier fluid could be introduced into an empty vascular network embedded in a polymer matrix.

Promoting Lymphangiogenesis and Lymphatic Growth and Remodeling to Treat Cardiovascular and Metabolic Diseases.

Lymphatic vessels are low-pressure, blind-ended tubular structures that play a crucial role in the maintenance of tissue fluid homeostasis, immune cell trafficking, and dietary lipid uptake and transport. Emerging research has indicated that the promotion of lymphatic vascular growth, remodeling, and function can reduce inflammation and diminish disease severity in several pathophysiologic conditions. In particular, recent groundbreaking studies have shown that lymphangiogenesis, which describes the formation of new lymphatic vessels from the existing lymphatic vasculature, can be beneficial for the alleviation and resolution of metabolic and cardiovascular diseases.

Evaluation of Longitudinal Lymphatic Function Changes upon Injury in the Mouse Tail with Photodynamic Therapy.

Purpose: The lymphatic system is an essential but often understudied component of the circulatory system in comparison with its cardiovascular counterpart. Such disparity could often be explained by the difficulty in imaging lymphatics and the specialized microsurgical skills that are often required for lymphatic injury models. Recently, it has been shown that verteporfin, a photosensitive drug used for photodynamic therapy (PDT) to ablate the blood vessels, provides a similar effect on lymphatic vessels.

Lentiviral overexpression of VEGFC in transplanted MSCs leads to resolution of swelling in a mouse tail lymphedema model.

Background: Dysfunction of the lymphatic system following injury, disease, or cancer treatment can lead to lymphedema, a debilitating condition with no cure. Despite the various physical therapy and surgical options available, most treatments are palliative and fail to address the underlying lymphatic vascular insufficiency driving lymphedema progression. Stem cell therapy provides a promising alternative in the treatment of various chronic diseases with a wide range of therapeutic effects that reduce inflammation, fibrosis, and oxidative stress, while promoting lymphatic vessel (LV) regeneration.

Synthetic hydrogels engineered to promote collecting lymphatic vessel sprouting.

The lymphatic vasculature is an essential component of the body's circulation providing a network of vessels to return fluid and proteins from the tissue space to the blood, to facilitate immune ce-ll and antigen transport to lymph nodes, and to take up dietary lipid from the intestine. The development of biomaterial-based strategies to facilitate the growth of lymphatics either for regenerative purposes or as model system to study lymphatic biology is still in its nascent stages. In particular, platforms that encourage the sprouting and formation of lymphatic networks from collecting vessels are particularly underdeveloped.

Effect of Human Synovial Fluid From Osteoarthritis Patients and Healthy Individuals on Lymphatic Contractile Activity.

The lymphatic system has been proposed to play a crucial role in preventing the development and progression of osteoarthritis (OA). As OA develops and progresses, inflammatory cytokines and degradation by-products of joint tissues build up in the synovial fluid (SF) providing a feedback system to exacerbate disease. The lymphatic system plays a critical role in resolving inflammation and maintaining overall joint homeostasis; however, there is some evidence that the lymphatics can become dysfunctional during OA.

Multichromatic near-infrared imaging to assess interstitial lymphatic and venous uptake in vivo.

Significance: Changes in interstitial fluid clearance are implicated in many diseases. Using near-infrared (NIR) imaging with properly sized tracers could enhance our understanding of how venous and lymphatic drainage are involved in disease progression or enhance drug delivery strategies.

Aim: We investigated multichromatic NIR imaging with multiple tracers to assess in vivo microvascular clearance kinetics and pathways in different tissue spaces.

Review on Nonconventional Fibrillation Methods of Producing Cellulose Nanofibrils and Their Applications.

The production of cellulose nanofibrils (CNFs) continues to receive considerable attention because of their desirable material characteristics for a variety of consumer applications. There are, however, challenges that remain in transitioning CNFs from research to widespread adoption in the industrial sectors, including production cost and material performance. This Review covers CNFs produced from nonconventional fibrillation methods as a potential alternative solution.

Fluid pumping of peristaltic vessel fitted with elastic valves.

Using numerical simulations, we probe the fluid flow in an axisymmetric peristaltic vessel fitted with elastic bi-leaflet valves. In this biomimetic system that mimics the flow generated in lymphatic vessels, we investigate the effects of the valve and vessel properties on pumping performance of the valved peristaltic vessel. The results indicate that valves significantly increase pumping by reducing backflow.

Soluble and Microparticle-Based Delivery of TLR4 and TLR9 Agonists Differentially Modulate 3D Chemotaxis of Bone Marrow-Derived Dendritic Cells.

Vaccines are commonly administered subcutaneously or intramuscularly, and local immune cells, notably dendritic cells (DCs), play a significant role in transporting vaccine antigens and adjuvants to draining lymph nodes. Here, it is compared how soluble and biomaterial-mediated delivery of Toll-like receptor (TLR)-targeted adjuvants, monophosphoryl lipid A (MPLA, TLR4 ligand) and 5'-C-phosphate-G-3' DNA (CpG DNA, TLR9 ligand), modulate 3D chemotaxis of bone marrow-derived dendritic cells (BMDCs) toward lymphatic chemokine gradients. Within microfluidic devices containing 3D collagen-based matrices to mimic tissue conditions, soluble MPLA increases BMDC chemotaxis toward gradients of CCL19 and CCL21, while soluble CpG has no effect.

The Kinetics of Lymphatic Dysfunction and Leukocyte Expansion in the Draining Lymph Node during LTB Antagonism in a Mouse Model of Lymphedema.

The mechanisms of lymphedema development are not well understood, but emerging evidence highlights the crucial role the immune system plays in driving its progression. It is well known that lymphatic function deteriorates as lymphedema progresses; however, the connection between this progressive loss of function and the immune-driven changes that characterize the disease has not been well established. In this study, we assess changes in leukocyte populations in lymph nodes within the lymphatic drainage basin of the tissue injury site (draining lymph nodes, dLNs) using a mouse tail model of lymphedema in which a pair of draining collecting vessels are left intact.