A Poroelasticity Theory Approach to Study the Mechanisms Leading to Elevated Interstitial Fluid Pressure in Solid Tumours

Abstract

Although the mechanisms responsible for elevated interstitial fluid pressure (IFP) in tumours remain obscure, it seems clear that high IFP represents a barrier to drug delivery (since the resulting adverse pressure gradient implies a reduction in the driving force for transvascular exchange of both fluid and macromolecules). R. Jain and co-workers studied this problem, and although the conclusions drawn from their idealized mathematical models offered useful insights into the causes of elevated IFP, they by no means gave a definitive explanation for this phenomenon. In this paper, we use poroelasticity theory to also develop a macroscopic mathematical model to describe the time evolution of a solid tumour, but focus our attention on the mechanisms responsible for the rise of the IFP, from that for a healthy interstitium to that measured in malignant tumours. In particular, we discuss a number of possible time scales suggested by our mathematical model and propose a tumour-dependent time scale that leads to results in agreement with experimental observations. We apply our mathematical model to simulate the effect of "vascular normalization" (as proposed by Jain in Nat Med 7:987-989, 2001) on the IFP profile and discuss and contrast our conclusions with those of previous work in the literature.

Non-invasive imaging of interstitial fluid transport parameters in solid tumors in vivo

“…Both solid and fluid phases are assumed to be incompressible. These assumptions are consistent to prior studies pertaining to cancer mechanics, medical imaging and drug delivery 1 , 25 , 26 . However, this assumption may be valid in the sense that IF primarily consists of water.…”

“…Likewise, poroelastic material properties such as interstitial hydraulic conductivity (IHC), vascular permeability (VP), extracellular volume fraction (EVF), interstitial space fraction (IVF), etc. are important markers of tumor progression and may be used to assess the efficacy of treatments 5 , 25 , 52 , 60 , 61 . These poroelastic properties can have substantial impact on drug delivery to the tumor.…”

“…In the context of biomechanics, to evaluate tissue interstitial phenomena, two continuum theories are commonly employed: poroelasticity theory and/or mixture theory. The former assumes soft tissue to be a fluid-saturated poroelastic solid (a spongelike material) containing a uniform distribution of fluid source/sink points representing the transvascular flow to or from the interstitial compartment 1 , 25 – 28 . The latter models soft tissue as an intimate mixture of cellular phase and extracellular phases (a concentrated macromolecular solution) 29 .…”

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“…Unlike A549 tumor tissue, the watery appearance and fast-growing behavior were found in B16F10. The elevated interstitial fluid pressure (IFP) in B16F10 tumor keep drugs out of vascular wall probably accounted for that 41–43. We further administrated Endostar to promote tumor vessel normalization following procedure addressed before,44,45 expected to normalize the tumor microenvironment (improving vascular integrity, reducing IFP, and so on).…”

Mathematical modeling reveals how the density of initial tumor and its distance to parent vessels alter the growth trend of vascular tumors

“…This solid stress leads in decrement of blood flow indirectly by contraction of vessel walls and as a consequence, decrement of oxygen concentration in the domain and results in tumor cell hypoxia accompanied by drug delivery obstruction and resistance to different therapeutics. Also, solid stress leads to less proliferation and more apoptosis directly by contraction of tumor cells and decrement of enough space for proliferation . In most of the work on simulation of tumor microenvironment, tumor pressure is absent especially in discrete models.…”