Modelling uptake and transport of therapeutic agents through the lymphatic system

Abstract

The ability of the lymphatic network to absorb large molecules and bypass the first-pass liver metabolism makes it appealing as a delivery system for therapeutic substances. In most cases, the drug is injected into the subcutaneous tissue and must negotiate the tissue space, before being drained via the lymphatics. Tracking the transport of drug molecules through this route is challenging, and computational models of lymphatic drainage can play an important role in assessing the efficacy of a proposed delivery strategy. The three-dimensional computational model we present here of the peripheral lymphatic network and surrounding interstitium is informed by anatomical data, and quantifies the degree to which uptake and transit times are affected by drug particle size, physiological flow rates, and specifics of drug injection.

Computational fluid dynamic modeling of the lymphatic system: a review of existing models and future directions

“…Han et al ( 2023a ) showed that lymphatic uptake following subcutaneous administration significantly affects macroscopic drug absorption. They also found that the injection depth does not affect lymphatic uptake, which contrasts with the findings of Jayathungage Don et al ( 2021 ). Following this, Han et al ( 2023b ) later improved their transport model to investigate the effects of the drug radius.…”

“…Some models spanned multiple components of the lymphatic system, while many focused on a single component, such as the collecting vessels. For example, Bertram et al ( 2011 ) focused on the larger collecting vessels to understand the pumping mechanism of lymphangions, while Ikhimwin et al ( 2020 ) and Jayathungage Don et al ( 2021 ) considered multiple parts of the lymphatic system to understand the drainage through the lymphatic vessel network hierarchy. Some studies reviewed key aspects of lymphatic physiology to consider in computational modeling approaches, such as Munn ( 2015 ), who summarised mechanobiological control mechanisms in the lymphatic vessels.…”

“…However, viscous effects can be present in the interstitium under normal conditions (Moore and Bertram 2018 ). Other studies have considered viscous terms when modeling the interstitial fluid flow (Jayathungage Don et al 2021 ; Roose and Swartz 2012 ), which has resulted in higher flow velocities in the interstitium immediately adjacent to the initial lymphatic vessel walls and lower velocities further away.…”

“…Jayathungage Don et al ( 2021 ) developed a 3D lymphatic drainage model based on rat tail lymphatic anatomy with surrounding interstitium to model the initial lymphatics, pre-collectors, and collecting vessels (Fig. 2 ).…”

“…They solved Navier–Stokes and mass transfer equations to estimate/simulate NO transport in the vessel, showing that NO concentration adjacent to the valve leaflets primarily resulted from a flow-mediated process rather than a sheer activated response of lymphatic endothelial cells. Meanwhile Jayathungage Don et al ( 2021 ) focused on understanding the local mechanics and efficacy of fluid uptake into the lymphatic network. They developed a comprehensive 3D computational platform considering initial lymphatics, pre-collectors, collecting vessels, and the interstitium to better understand the lymphatic system as a drug delivery route.…”