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. 2002 Sep;83(3):1650–1660. doi: 10.1016/S0006-3495(02)73933-7

Diffusion and convection in collagen gels: implications for transport in the tumor interstitium.

Saroja Ramanujan 1, Alain Pluen 1, Trevor D McKee 1, Edward B Brown 1, Yves Boucher 1, Rakesh K Jain 1
PMCID: PMC1302261  PMID: 12202388

Abstract

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.

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Selected References

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  1. Berk D. A., Yuan F., Leunig M., Jain R. K. Direct in vivo measurement of targeted binding in a human tumor xenograft. Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1785–1790. doi: 10.1073/pnas.94.5.1785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Berk D. A., Yuan F., Leunig M., Jain R. K. Fluorescence photobleaching with spatial Fourier analysis: measurement of diffusion in light-scattering media. Biophys J. 1993 Dec;65(6):2428–2436. doi: 10.1016/S0006-3495(93)81326-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Blum J. J., Lawler G., Reed M., Shin I. Effect of cytoskeletal geometry on intracellular diffusion. Biophys J. 1989 Nov;56(5):995–1005. doi: 10.1016/S0006-3495(89)82744-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Boucher Y., Brekken C., Netti P. A., Baxter L. T., Jain R. K. Intratumoral infusion of fluid: estimation of hydraulic conductivity and implications for the delivery of therapeutic agents. Br J Cancer. 1998 Dec;78(11):1442–1448. doi: 10.1038/bjc.1998.705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brightman A. O., Rajwa B. P., Sturgis J. E., McCallister M. E., Robinson J. P., Voytik-Harbin S. L. Time-lapse confocal reflection microscopy of collagen fibrillogenesis and extracellular matrix assembly in vitro. Biopolymers. 2000 Sep;54(3):222–234. doi: 10.1002/1097-0282(200009)54:3<222::AID-BIP80>3.0.CO;2-K. [DOI] [PubMed] [Google Scholar]
  6. Chang Y. S., Munn L. L., Hillsley M. V., Dull R. O., Yuan J., Lakshminarayanan S., Gardner T. W., Jain R. K., Tarbell J. M. Effect of vascular endothelial growth factor on cultured endothelial cell monolayer transport properties. Microvasc Res. 2000 Mar;59(2):265–277. doi: 10.1006/mvre.1999.2225. [DOI] [PubMed] [Google Scholar]
  7. Chen K. C., Nicholson C. Changes in brain cell shape create residual extracellular space volume and explain tortuosity behavior during osmotic challenge. Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8306–8311. doi: 10.1073/pnas.150338197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Costantini L. C., Bakowska J. C., Breakefield X. O., Isacson O. Gene therapy in the CNS. Gene Ther. 2000 Jan;7(2):93–109. doi: 10.1038/sj.gt.3301119. [DOI] [PubMed] [Google Scholar]
  9. Davies C. de L., Berk D. A., Pluen A., Jain R. K. Comparison of IgG diffusion and extracellular matrix composition in rhabdomyosarcomas grown in mice versus in vitro as spheroids reveals the role of host stromal cells. Br J Cancer. 2002 May 20;86(10):1639–1644. doi: 10.1038/sj.bjc.6600270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Friedl P., Maaser K., Klein C. E., Niggemann B., Krohne G., Zänker K. S. Migration of highly aggressive MV3 melanoma cells in 3-dimensional collagen lattices results in local matrix reorganization and shedding of alpha2 and beta1 integrins and CD44. Cancer Res. 1997 May 15;57(10):2061–2070. [PubMed] [Google Scholar]
  11. Gabizon A., Goren D., Cohen R., Barenholz Y. Development of liposomal anthracyclines: from basics to clinical applications. J Control Release. 1998 Apr 30;53(1-3):275–279. doi: 10.1016/s0168-3659(97)00261-7. [DOI] [PubMed] [Google Scholar]
  12. Griffon-Etienne G., Boucher Y., Brekken C., Suit H. D., Jain R. K. Taxane-induced apoptosis decompresses blood vessels and lowers interstitial fluid pressure in solid tumors: clinical implications. Cancer Res. 1999 Aug 1;59(15):3776–3782. [PubMed] [Google Scholar]
  13. Guidry C., Grinnell F. Heparin modulates the organization of hydrated collagen gels and inhibits gel contraction by fibroblasts. J Cell Biol. 1987 Apr;104(4):1097–1103. doi: 10.1083/jcb.104.4.1097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Huang-Lee L. L., Wu J. H., Nimni M. E. Effects of hyaluronan on collagen fibrillar matrix contraction by fibroblasts. J Biomed Mater Res. 1994 Jan;28(1):123–132. doi: 10.1002/jbm.820280116. [DOI] [PubMed] [Google Scholar]
  15. Jain R. K. The next frontier of molecular medicine: delivery of therapeutics. Nat Med. 1998 Jun;4(6):655–657. doi: 10.1038/nm0698-655. [DOI] [PubMed] [Google Scholar]
  16. Jain R. K. Transport of molecules in the tumor interstitium: a review. Cancer Res. 1987 Jun 15;47(12):3039–3051. [PubMed] [Google Scholar]
  17. Jain R. K. Transport of molecules, particles, and cells in solid tumors. Annu Rev Biomed Eng. 1999;1:241–263. doi: 10.1146/annurev.bioeng.1.1.241. [DOI] [PubMed] [Google Scholar]
  18. Kulkarni S. B., Betageri G. V., Singh M. Factors affecting microencapsulation of drugs in liposomes. J Microencapsul. 1995 May-Jun;12(3):229–246. doi: 10.3109/02652049509010292. [DOI] [PubMed] [Google Scholar]
  19. Levick J. R. Flow through interstitium and other fibrous matrices. Q J Exp Physiol. 1987 Oct;72(4):409–437. doi: 10.1113/expphysiol.1987.sp003085. [DOI] [PubMed] [Google Scholar]
  20. Netti P. A., Berk D. A., Swartz M. A., Grodzinsky A. J., Jain R. K. Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res. 2000 May 1;60(9):2497–2503. [PubMed] [Google Scholar]
  21. Netti P. A., Hamberg L. M., Babich J. W., Kierstead D., Graham W., Hunter G. J., Wolf G. L., Fischman A., Boucher Y., Jain R. K. Enhancement of fluid filtration across tumor vessels: implication for delivery of macromolecules. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3137–3142. doi: 10.1073/pnas.96.6.3137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Nicholson C., Phillips J. M. Ion diffusion modified by tortuosity and volume fraction in the extracellular microenvironment of the rat cerebellum. J Physiol. 1981 Dec;321:225–257. doi: 10.1113/jphysiol.1981.sp013981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Nicholson C., Syková E. Extracellular space structure revealed by diffusion analysis. Trends Neurosci. 1998 May;21(5):207–215. doi: 10.1016/s0166-2236(98)01261-2. [DOI] [PubMed] [Google Scholar]
  24. Phillips R. J. A hydrodynamic model for hindered diffusion of proteins and micelles in hydrogels. Biophys J. 2000 Dec;79(6):3350–3353. doi: 10.1016/S0006-3495(00)76566-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pins G. D., Christiansen D. L., Patel R., Silver F. H. Self-assembly of collagen fibers. Influence of fibrillar alignment and decorin on mechanical properties. Biophys J. 1997 Oct;73(4):2164–2172. doi: 10.1016/S0006-3495(97)78247-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pluen A., Boucher Y., Ramanujan S., McKee T. D., Gohongi T., di Tomaso E., Brown E. B., Izumi Y., Campbell R. B., Berk D. A. Role of tumor-host interactions in interstitial diffusion of macromolecules: cranial vs. subcutaneous tumors. Proc Natl Acad Sci U S A. 2001 Mar 27;98(8):4628–4633. doi: 10.1073/pnas.081626898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Pluen A., Netti P. A., Jain R. K., Berk D. A. Diffusion of macromolecules in agarose gels: comparison of linear and globular configurations. Biophys J. 1999 Jul;77(1):542–552. doi: 10.1016/S0006-3495(99)76911-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rusakov D. A., Kullmann D. M. Geometric and viscous components of the tortuosity of the extracellular space in the brain. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8975–8980. doi: 10.1073/pnas.95.15.8975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sano A, Hojo T, Maeda M, Fujioka K. Protein release from collagen matrices. Adv Drug Deliv Rev. 1998 May 4;31(3):247–266. doi: 10.1016/s0169-409x(97)00119-1. [DOI] [PubMed] [Google Scholar]
  30. Turley E. A., Erickson C. A., Tucker R. P. The retention and ultrastructural appearances of various extracellular matrix molecules incorporated into three-dimensional hydrated collagen lattices. Dev Biol. 1985 Jun;109(2):347–369. doi: 10.1016/0012-1606(85)90461-0. [DOI] [PubMed] [Google Scholar]
  31. Williams B. R., Gelman R. A., Poppke D. C., Piez K. A. Collagen fibril formation. Optimal in vitro conditions and preliminary kinetic results. J Biol Chem. 1978 Sep 25;253(18):6578–6585. [PubMed] [Google Scholar]
  32. Williams R. M., Zipfel W. R., Webb W. W. Multiphoton microscopy in biological research. Curr Opin Chem Biol. 2001 Oct;5(5):603–608. doi: 10.1016/s1367-5931(00)00241-6. [DOI] [PubMed] [Google Scholar]

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