Diffusion and convection in collagen gels: implications for transport in the tumor interstitium.
Diffusion coefficients of tracer molecules in collagen type I gels prepared from 0-4.5% w/v solutions were measured by fluorescence recovery after photobleaching. When adjusted to account for in vivo tortuosity, diffusion coefficients in gels matched previous measurements in four human tumor xenografts with equivalent collagen concentrations. In contrast, hyaluronan solutions hindered diffusion to a lesser extent when prepared at concentrations equivalent to those reported in these tumors. Collagen permeability, determined from flow through gels under hydrostatic pressure, was compared with predictions obtained from application of the Brinkman effective medium model to diffusion data. Permeability predictions matched experimental results at low concentrations, but underestimated measured values at high concentrations. Permeability measurements in gels did not match previous measurements in tumors. Visualization of gels by transmission electron microscopy and light microscopy revealed networks of long collagen fibers at lower concentrations along with shorter fibers at high concentrations. Negligible assembly was detected in collagen solutions pregelation. However, diffusion was similarly hindered in pre and postgelation samples. Comparison of diffusion and convection data in these gels and tumors suggests that collagen may obstruct diffusion more than convection in tumors. These findings have significant implications for drug delivery in tumors and for tissue engineering applications.
E. L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Saroja
S
Ramanujan
Alain
A
Pluen
Trevor D
TD
McKee
Edward B
EB
Brown
Yves
Y
Boucher
Rakesh K
RK
Jain
D001692:Biological Transport; D001703:Biophysics / Q000379:methods*; D003094:Collagen / Q000737:chemistry* / Q000378:metabolism; D004058:Diffusion; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry; D018613:Microscopy, Confocal / Q000379:methods*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D038761:Photobleaching; D014407:Tumor Cells, Cultured
D006820:Hyaluronic Acid; D003094:Collagen