How Minimally Invasive is Microdialysis Sampling? A Cautionary Note for Cytokine Collection in Human Skin and other Clinical Studies


It is common to refer to microdialysis as a minimally invasive procedure, likening it to insertion of an artificial capillary. While a comparison of this type allows the process to be easily visualized by those outside the field, it tends to provide a false impression of the localized perturbation of the tissue space that is caused by catheter insertion. With the increased acceptance of microdialysis sampling as a viable in vivo sampling method, many researchers have begun to use the technique to explore inflammatory and immune-mediated diseases in the skin and other organs. Unfortunately, many of the molecules of interest, particularly chemokines and cytokines, are known to be generated during the inflammatory response to wounding and the subsequent cellular events leading to wound repair. With more than 11,000 reports citing the use of microdialysis sampling, only a few researchers have sought to assess the tissue damage that is incurred by probe insertion. For this reason, caution is warranted when collecting these molecules and inferring a role for them in clinical disease states. This commentary seeks to remind the research community of the confounding effects that signaling molecules related to the wounding response will have on clinical studies. Proper controls must be incorporated into all studies in order to assess whether or not particular molecules are truly related to the disease state under investigation or have been generated as part of the tissue response to the wound incurred by microdialysis catheter implantation.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5


  1. 1.

    The Stenken group experience with microdialysis sampling probes is that polycarbonate/polyether (PC) membranes were able to function up to 7 days and PES probes to 10 days. However, PC membranes are no longer available and have been replaced with a polyarylethersulfone membrane. We have not tested the long-term implantation viability of these membranes in animals.


  1. 1.

    Westerink BHC, Cremers TIFH, eds. Handbook of microdialysis sampling: methods, applications, and clinical aspects. Amsterdam: Academic; 2007.

  2. 2.

    Helmy A, Carpenter KLH, Skepper JN, Kirkpatrick PJ, Pickard JD, Hutchinson PJ. Microdialysis of cytokines: methodological considerations, scanning electron microscopy, and determination of relative recovery. J Neurotrauma. 2009;26:549–61.

    Article  PubMed  Google Scholar 

  3. 3.

    Waelgaard L, Thorgersen EB, Line P-D, Foss A, Mollnes TE, Tonnessen TI. Microdialysis monitoring of liver grafts by metabolic parameters, cytokine production, and complement activation. Transplantation. 2008;86:1096–103.

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Murdolo G, Herder C, Wang Z, Rose B, Schmelz M, Jansson P-A. In situ profiling of adipokines in subcutaneous microdialysates from lean and obese individuals. Am J Physiol. 2008;295:E1095–105.

    CAS  Google Scholar 

  5. 5.

    Mellergard P, Aneman O, Sjogren F, Pettersson P, Hillman J. Changes in extracellular concentrations of some cytokines, chemokines, and neurotrophic factors after insertion of intracerebral microdialysis catheters in neurosurgical patients. Neurosurgery. 2008;62:151–7. Discussion 157–8.

    Article  PubMed  Google Scholar 

  6. 6.

    Groth L, Jorgensen A, Serup J. Cutaneous microdialysis in the rat: insertion trauma and effect of anaesthesia studied by laser Doppler perfusion imaging and histamine release. Skin Pharmacol Appl Skin Physiol. 1998;11:125–32.

    CAS  PubMed  Google Scholar 

  7. 7.

    Mitala CM, Wang Y, Borland LM, Jung M, Shand S, Watkins S, et al. Impact of microdialysis probes on vasculature and dopamine in the rat striatum: a combined fluorescence and voltammetric study. J Neurosci Methods. 2008;174:177–85.

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Morgan ME, Singhal D, Anderson BD. Quantitative assessment of blood–brain barrier damage during microdialysis. J Pharmacol Exp Ther. 1996;277:1167–76.

    CAS  PubMed  Google Scholar 

  9. 9.

    Benveniste H, Diemer NH. Cellular reactions to implantation of a microdialysis tube in the rat hippocampus. Acta Neuropathol. 1987;74:234–8.

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Benveniste H, Hansen AJ, Ottosen NS. Determination of brain interstitial concentrations by microdialysis. J Neurochem. 1989;52:1741–50.

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Clapp-Lilly KL, Roberts RC, Duffy LK, Irons KP, Hu Y, Drew KL. An ultrastructural analysis of tissue surrounding a microdialysis probe. J Neurosci Methods. 1999;90:129–42.

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Zhou F, Zhu X, Castellani RJ, Stimmelmayr R, Perry G, Smith MA, et al. Hibernation, a model of neuroprotection. Am J Pathol. 2001;158:2145–51.

    CAS  PubMed  Google Scholar 

  13. 13.

    de Lange ECM, Danhof M, de Boer AG, Breimer DD. Critical factors of intracerebral microdialysis as a technique to determine the pharmacokinetics of drugs in rat brain. Brain Res. 1994;666:1–8.

    Article  PubMed  Google Scholar 

  14. 14.

    Peters JL, Miner LH, Michael AC, Sesack SR. Ultrastructure at carbon fiber microelectrode implantation sites after acute voltammetric measurements in the striatum of anesthetized rats. J Neurosci Methods. 2004;137:9–23.

    Article  PubMed  Google Scholar 

  15. 15.

    Petersen LJ, Poulsen LK, Sondergaard J, Skov PS. The use of cutaneous microdialysis to measure substance P-induced histamine release in intact human skin in vivo. J Allergy Clin Immunol. 1994;94:773–83.

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Clough GF, Jackson CL, Lee JJ, Jamal SC, Church MK. What can microdialysis tell us about the temporal and spatial generation of cytokines in allergen-induced responses in human skin in vivo? J Invest Dermatol. 2007;127:2799–806.

    CAS  PubMed  Google Scholar 

  17. 17.

    Zweiman B, Kaplan AP, Tong L, Moskovitz AR. Cytokine levels and inflammatory responses in developing late-phase allergic reactions in the skin. J Allergy Clin Immunol. 1997;100:104–9.

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Sjogren F, Svensson C, Anderson C. Technical prerequisites for in vivo microdialysis determination of interleukin-6 in human dermis. Br J Dermatol. 2002;146:375–82.

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Averbeck M, Beilharz S, Bauer M, Gebhardt C, Hartmann A, Hochleitner K, et al. In situ profiling and quantification of cytokines released during ultraviolet B-induced inflammation by combining dermal microdialysis and protein microarrays. Exp Dermatol. 2006;15:447–54.

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Angst MS, Clark JD, Carvalho B, Tingle M, Schmelz M, Yeomans DC. Cytokine profile in human skin in response to experimental inflammation, noxious stimulation, and administration of a COX-inhibitor: a microdialysis study. Pain. 2008;139:15–27.

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Anderson JM, Rodriguez A, Chang DT. Foreign body reaction to biomaterials. Semin Immunol. 2008;20:86–100.

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Grabb MC, Sciotti VM, Gidday JM, Cohen SA, Van Wylen DGL. Neurochemical and morphological responses to acutely and chronically implanted brain microdialysis probes. J Neurosci Methods. 1998;82:25–34.

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Wisniewski N, Rajamand N, Adamsson U, Lins PE, Reichert WM, Klitzman B, et al. Analyte flux through chronically implanted subcutaneous polyamide membranes differs in humans and rats. Am J Physiol. 2002;282:E1316–23.

    CAS  Google Scholar 

  24. 24.

    Wisniewski N, Klitzman B, Miller B, Reichert WM. Decreased analyte transport through implanted membranes: differentiation of biofouling from tissue effects. J Biomed Mater Res. 2001;57:513–21.

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Wientjes KJC, Grob U, Hattemer A, Hoogenberg K, Jungheim K, Kapitza C, et al. Effects of microdialysis catheter insertion into the subcutaneous adipose tissue assessed by the SCGM1 system. Diabetes Technol Ther. 2003;5:615–20.

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Wang X, Lennartz MR, Loegering DJ, Stenken JA. Interleukin-6 collection through long-term implanted microdialysis sampling probes in rat subcutaneous space. Anal Chem. 2007;79:1816–24.

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Anderson C, Andersson T, Wardell K. Changes in skin circulation after insertion of a microdialysis probe visualized by laser Doppler perfusion imaging. J Invest Dermatol. 1994;102:807–11.

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Clough GF, Boutsiouki P, Church MK, Michel CC. Effects of blood flow on the in vivo recovery of a small diffusible molecule by microdialysis in human skin. J Pharmacol Exp Ther. 2002;302:681–6.

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Benveniste H, Huttemeier PC. Microdialysis—theory and application. Prog Neurobiol. 1990;35:195–215.

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Kehr J. A survey on quantitative microdialysis: theoretical models and practical implications. J Neurosci Methods. 1993;48:251–61.

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Bungay PM, Morrison PF, Dedrick RL. Steady-state theory for quantitative microdialysis of solutes and water in vivo and in vitro. Life Sci. 1990;46:105–19.

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Bungay PM, Newton-Vinson P, Isele W, Garris PA, Justice JB Jr. Microdialysis of dopamine interpreted with quantitative model incorporating probe implantation trauma. J Neurochem. 2003;86:932–46.

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Petersen LJ. Quantitative measurement of extracellular histamine concentrations in intact human skin in vivo by the microdialysis technique: methodological aspects. Allergy. 1997;52:547–55.

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Sugawara T, Gallucci RM, Simeonova PP, Luster MI. Regulation and role of Interleukin 6 in wounded human epithelial keratinocytes. Cytokine. 2001;15:328–36.

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    Sehgal PB. Interleukin-6: molecular pathophysiology. J Invest Dermatol. 1990;94:2S–6.

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Mou X. Modulation of foreign body response towards implanted microdialysis probes; Ph.D. dissertation, Rensselaer Polytechnic Institute; 2007.

  37. 37.

    Stenken JA. Membrane-based separations applied to in vivo glucose sensing—microdialysis and ultrafiltration sampling. In: Cunningham DD, Stenken JA, editors. In vivo glucose sensing. Hoboken: Wiley; 2010. p. 157–90.

    Google Scholar 

Download references


JAS acknowledges NIH EB 001441 for funding. CAG acknowledges the Geraldine Kerkut Studentship for funding.

Author information



Corresponding author

Correspondence to Julie A. Stenken.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Stenken, J.A., Church, M.K., Gill, C.A. et al. How Minimally Invasive is Microdialysis Sampling? A Cautionary Note for Cytokine Collection in Human Skin and other Clinical Studies. AAPS J 12, 73–78 (2010).

Download citation

Key words

  • biocompatability
  • cytokines
  • microdialysis
  • wound healing and repair