Interstitial-lymphatic transport phenomena

The lymphatic system plays important roles in tissue fluid balance, protein transport, and the immune system, and has great potential for the delivery of certain drugs. Despite its importance, our quantitative understanding of interstitial-lymphatic transport is limited. The first goal of this work was to examine lymphatic function as an integral component of interstitial mechanics. A theoretical description of this mechanical equilibrium was developed in parallel with a novel experimental model. Tissue was modeled as a poroelastic continuum to describe the fluid pressure distribution following an interstitial injection, predicting that spatial gradients would be governed by the ratio of lymphatic to tissue resistances and temporal gradients governed additionally by elasticity. The mouse tail was a unique experimental model for examining both of these theoretical frameworks because of its geometry and anatomical features. Pressure measurements using micropipettes showed remarkable consistency with the theoretical assumptions and gave unique in vivo estimates of the effective parameter values (for tail skin, hydraulic conductivity was 1.5 x 10-6 cm2 sec' * mm Hg', lymphatic conductance was 4 x 10.5 sec' . mm Hg' 1, and the bulk elastic modulus was 110 20 mm Hg). The second part of the thesis built on this model of tissue fluid balance to describe convective transport of macromolecules. 1-D concentration gradients in the tail could be observed using fluorescence microscopy. These gradients were described in terms of a dispersivity and excluded volume fraction as well as fluid convection. The model could characterize differences in transport profiles of various molecules (differing in size, shape, and charge) and constituted an extremely useful model for in vivo studies of convective transport. Finally, the model was applied to studies in gene expression of the lymphatic system and to investigate the effects of edema, tissue grafting, and mechanical forces on overall lymphatic function. This is the first in vivo model of interstitial-lymphatic transport which accounts for the dynamics of the interstitium and allows for simple and accurate in situ measurements of tissue elasticity, hydraulic conductivity, and molecular transport parameters. Furthermore, it yields estimates for an effective or overall conductance of the lymphatics which is important for examining pathological changes in interstitial-lymphatic fluid. Thesis supervisors: Rakesh K. Jain Professor, Harvard Medical School Linda G. Griffith Associate Professor, Department of Chemical Engineering