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Cervical Lymphatic Bypass Reduces Deep Cervical Lymph Node Resistance and Restores CSF Clearance: A Preclinical Model and Proof of Concept
Zach Papadopoulos, PhD
1, Stav Brown, MD
2, Felix Klimitz, MD
2, Bohdan Pomahac, MD
3 and Jonathan Kipnis, PhD
1
1Washington University, Saint Louis, WA, 2Yale School of Medicine, New Haven, CT, 3Yale University School of Medicine, New Haven, CT
Background:
Age-related impairment in cerebrospinal fluid (CSF) clearance has been linked to reduced drainage through the deep cervical lymphatic network. Structural remodeling of deep cervical lymph nodes (dcLNs), including fibrosis and stromal disorganization, increases hydraulic resistance and compromises CSF efflux. We hypothesized that microsurgical bypass of the dcLN could reduce lymphatic resistance and restore CSF clearance from the central nervous system (CNS).
Methods:
A collagen-based scaffolding fiber was implanted to promote lymphangiogenesis and redirect CSF outflow around the dcLN in a mouse model (Figure 1A). Four weeks post-implantation, bypass vascularization was assessed via fluorescent imaging. CSF-to-blood outflow was quantified using a small molecular tracer (DB53), with fluorescence measured at the femoral vein over 75 minutes.
Results:
Bypass surgery resulted in robust outgrowth of lymphatic vessels circumventing the dcLN, confirmed by tracer-imaging of the bypass vasculature (Figure 1B-C). At 75 minutes post-infusion, aged mice that received the bypass exhibited significantly greater femoral vein fluorescence intensity (Figure 2A), with an integrated mean fluorescence intensity (MFI) of CSF tracer in blood increased by approximately 2-fold compared to sham controls (p = 0.0018; Figure 2B-C). These findings confirm restoration of CSF lymphatic efflux through bypass-mediated diversion around the aged, fibrotic dcLN.
Conclusion:
Microsurgical bypass of dysfunctional deep cervical lymph nodes effectively reduces lymphatic resistance and restores CSF clearance in aged mice. This preclinical model offers translational potential for lymphatic-targeted strategies aimed at mitigating glymphatic dysfunction in age-related neurological diseases.
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