Short Communication
A simple method for measuring interstitial fluid pressure in cancer tissues

https://doi.org/10.1016/j.mvr.2005.07.003Get rights and content

Abstract

A novel procedure using a polyurethane transducer-tipped catheter (Millar) is described that allows reliable measurement of interstitial fluid pressure (IFP) in cancer tissues. Before and after each use, the transducer is calibrated at 37°C by a water column. After calibration, the transducer is passed through the lumen of a surgical needle. The sensor is kept in the lumen of the needle during penetration into the tumor. The sensor tip is then introduced into the center core of the tumor as the needle sleeve is withdrawn from the tumor surface. Our new technique is simple and provides IFPs equal to those provided by the well-established, wick-in-needle technique. Using our new technique, we compared IFP in skin melanoma grafts in NG2 knockout and wild-type mice. Knocking out NG2 proteoglycan on vasculogenic and angiogenic pericytes reduced interstitial fluid pressure in melanoma from +4.9 cm H2O to −0.4 cm H2O (P = 0.0054 Mann–Whitney U test).

Introduction

When a piece of bark is peeled off a transpiring tree and a cut is made in the xylem, no sap runs out; in fact, a drop of water placed on the cut is drawn in for the sap is under negative pressure. Similarly, when the subcutaneous tissue of an animal is exposed, fluid does not seep out since the interstitial fluid is under negative pressure. In normal subcutaneous tissue, the interstitial fluid pressure (IFP) is negative (Scholander et al., 1968). By contrast, IFP is often increased in tumor tissue (Young et al., 1950) and forms a barrier against efficient drug delivery into the tumor (Jain, 1987a, Jain, 1987b). There are several techniques described for IFP measurements, all of which require experience to use ramified instrumentation and surgical procedures. They include: wick catheter (Scholander et al., 1968, Hargens, 1981, Mubarak and Hargens, 1981), modified wick technique (wick-in-needle technique) (Fadnes et al., 1977, Wiig et al., 1987), servo-micropipette (Wiederhielm et al., 1964) for acute studies of IFP, and subcutaneous capsule implantation for 4–6 weeks (Guyton, 1963) allowing chronic tests of IFP.

Here, we describe a simplified procedure using a transducer-tipped catheter and a precision glide needle that allows reliable measurement of IFP in tumor tissues. We believe this technique will allow the researchers in the vascular biology field and clinicians in the oncology field to apply IFP measurement easily as a useful tool in research.

Section snippets

Materials and methods

In order to compare and validate the pressures obtained with the miniature pressure transducer with a well-established, conventional method (0.6 mm wick-in-needle) (Fadnes et al., 1977, Wiig et al., 1987), we simultaneously compared a needle-guided Millar SPC 320, 2F Mikro-Tip sensor (http://www.millarinstruments.com) and wick-in-needle probes side-by-side in a pilot study in two mice (C57BL/6) bearing B16F1 skin tumor grafts. For wick-in-needle technique, a 0.6 mm needle was provided with a

Results

Polyurethane ultraminiature pressure transducers, recognized for impeccable accuracy in the pressure range between −50 mm Hg to +300 mm Hg, provide a simple, accurate, and thromboresistant method of measuring the pressure at the source (Zimmer and Millar, 1998). Entire procedure of calibration of the sensor, introduction of the sensor into the tumor, and IFP reading does not take more than 10 min and can be performed with ease by anyone who can perform a subcutaneous injection. Our preliminary

Discussion

The interstitial fluid pressure within a tumor is actively regulated through interactions between cells and extracellular matrix molecules. Many anticancer drugs and antibodies used for treating patients with cancer are transported from the circulatory system through the interstitial space by convection (i.e. by streaming of a flowing fluid) rather than by diffusion. Increased tumor IFP causes inefficient uptake of therapeutic agents by decreasing convection. Cancer cells are therefore exposed

Critique of four IFP measurement techniques

The micropuncture (0.1 μm glass micropipette) technique does not allow for measurements in deep tissues; usually recordings can only be made down to about 1 mm from the surface (Wiederhielm, 1981, Adair et al., 1983). Furthermore, the glass micropipette breaks very easily during tissue penetration and from the slightest motion of the mouse. The wick catheter technique (Scholander et al., 1968) is vulnerable to clotting if there is extravasated blood within the tissue (Wiederhielm, 1981, Adair

Acknowledgments

This brief report is dedicated to P.F. Scholander, M.D., Ph.D. (1905–1980) who made pioneering contributions to the wealth of knowledge in the field of interstitial tissue fluid pressure. This work has been supported by grants from NIH (National Institute of Child Health and Human Development) RO3 HD044783, the U.S. Department of Defense Prostate Cancer Research Program New Investigator Award PC020822, and University of California, Tobacco-Related Disease Research Program Idea Award (TRDRP

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