Skip to main content
The AAPS Journal logoLink to The AAPS Journal
. 2005 Oct 26;7(3):E686–E692. doi: 10.1208/aapsj070369

Microdialysis of large molecules

Geraldine F Clough 1,
PMCID: PMC2751271  PMID: 16353945

Abstract

Microdialysis has been used in many tissues, including skin, brain, adipose tissue, muscle, kidney, and gastrointestinal tract, to recover low-molecular mass endogenous mediators, metabolites, and xenobiotics from the interstitial space. Recently, molecules of larger molecular mass, such as plasma proteins, cytokines, growth factors, and neuropeptides, have also been recovered successfully using largerpore membranes. Microdialysis recovery of large molecules offers the opportunity to identify patterns of protein expression in a variety of tissue spaces and to evaluate clinically useful biomarkers of disease. From this may develop a better understanding of the disease process and its diagnosis and more targeted approaches to therapy.

Keywords: microdialysis, proteins, cytokines

Full Text

The Full Text of this article is available as a PDF (191.0 KB).

References

  • 1.Bito L, Davson H, Levi EM, Murray M, Snider N. The concentration of free amino acids and other electrolytes in cerebrospinal fluid, in vivo dialysate of brain, and blood plasma of the dog. J Neurochem. 1966;13:1057–1067. doi: 10.1111/j.1471-4159.1966.tb04265.x. [DOI] [PubMed] [Google Scholar]
  • 2.Petersen LJ, Church MK, Skov PS. Histamine is released in the wheal but not the flare following challenge of human skin in vivo: a microdialysis study. Clin Exp Allergy. 1997;27:284–295. doi: 10.1046/j.1365-2222.1997.d01-502.x. [DOI] [PubMed] [Google Scholar]
  • 3.Andersson T, Wardell K, Anderson C. Human in vivo cutaneous microdialysis: estimation of histamine release in cold urticaria. Acta Derm Venereol. 1995;75:343–347. doi: 10.2340/0001555575343347. [DOI] [PubMed] [Google Scholar]
  • 4.Krogstad AL, Jansson PA, Gisslen P, Lonnroth P. Microdialysis methodology for the measurement of dermal interstitial fluid in hum ans. Br J Dermatol. 1996;134:1005–1012. doi: 10.1111/j.1365-2133.1996.tb07934.x. [DOI] [PubMed] [Google Scholar]
  • 5.Kellogg DL, Crandall CG, Liu Y, Charkoudian N, Johnson JM. Nitric oxide and cutaneous active vasodilation during heat stress in humans. J Appl Physiol. 1998;85:824–829. doi: 10.1152/jappl.1998.85.3.824. [DOI] [PubMed] [Google Scholar]
  • 6.Klede M, Clough G, Lischetzki G, Schmelz M. The effect of the nitric oxide synthase inhibitor N-nitro-L-arginine-methyl ester on neuropeptide-induced vasodilation and protein extravasation in human skin. J Vasc Res. 2003;40:105–114. doi: 10.1159/000070707. [DOI] [PubMed] [Google Scholar]
  • 7.Clough GF. Role of nitric oxide in the regulation of microvascular perfusion in human skin in vivo. J Physiol. 1999;516:549–557. doi: 10.1111/j.1469-7793.1999.0549v.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Rhodes LE, Belgi G, Parslew R, McLoughlin L, Clough GF, Friedmann PS. Ultraviolet-B-induced erythema is mediated by nitric oxide and prostaglandin E2 in combination. J Invest Dermatol. 2001;117:880–885. doi: 10.1046/j.0022-202x.2001.01514.x. [DOI] [PubMed] [Google Scholar]
  • 9.Sun L, Stenken JA. Improving microdialysis extraction efficiency of lipophilic eicosanoids. J Pharm Biomed Anal. 2003;33:1059–1071. doi: 10.1016/S0731-7085(03)00363-7. [DOI] [PubMed] [Google Scholar]
  • 10.Lindberger M, Tomson T, Wallstedt L, Stahle L. Distribution of valproate to subdural cerebrospinal fluid, subcutaneous extracellular fluid, and plasma in humans: a microdialysis study. Epilepsia. 2001;42:256–261. doi: 10.1046/j.1528-1157.2001.26600.x. [DOI] [PubMed] [Google Scholar]
  • 11.Newman JM, Di Maria CA, Rattigan S, Clark MG. Nutritive blood flow affects microdialysis O/I ratio for [(14)C]ethanol and (3)H(2)O in perfused rat hindlimb. Am J Physiol Heart Circ Physiol. 2001;281:H2731–H2737. doi: 10.1152/ajpheart.2001.281.6.H2731. [DOI] [PubMed] [Google Scholar]
  • 12.Tegeder I, Muth-Selbach U, Lotsch J, et al. Application of microdialysis for the determination of muscle and subcutaneous tissue concentrations after oral and topical ibuprofen administration. Clin Pharmacol Ther. 1999;65:357–368. doi: 10.1016/S0009-9236(99)70128-1. [DOI] [PubMed] [Google Scholar]
  • 13.Iversen HH, Celsing F, Leone AM, Gustafsson LE, Wiklund NP. Nerve-induced release of nitric oxide in the rabbit gastrointestinal tract as measured by in vivo microdialysis. Br J Pharmacol. 1997;120:702–706. doi: 10.1038/sj.bjp.0700967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Schmelz M, Luz O, Averbeck B, Bickel A. Plasma extravasation and neuropeptide release in human skin as measured by intradermal microdialysis. Neurosci Lett. 1997;230:117–120. doi: 10.1016/S0304-3940(97)00494-1. [DOI] [PubMed] [Google Scholar]
  • 15.Winter CD, Iannotti F, Pringle AK, Trikkas C, Clough GF, Church MK. A microdialysis method for the recovery of IL-1beta, IL-6 and nerve growth factor from human brain in vivo. J Neurosci Methods. 2002;119:45–50. doi: 10.1016/S0165-0270(02)00153-X. [DOI] [PubMed] [Google Scholar]
  • 16.Winter CD, Pringle AK, Clough GF, Church MK. Raised parenchymal interleukin-6 levels correlate with improved outcome after traumatic brain injury. Brain. 2004;127:315–320. doi: 10.1093/brain/awh039. [DOI] [PubMed] [Google Scholar]
  • 17.Dabrosin C. Variability of vascular endothelial growth factor in normal human breast tissue in vivo during the menstrual cycle. J Clin Endocrinol Metab. 2003;88:2695–2698. doi: 10.1210/jc.2002-021584. [DOI] [PubMed] [Google Scholar]
  • 18.Maurer MH, Berger C, Wolf M, et al. The proteome of human brain microdialysate. Proteome Sci. 2003;1:7–7. doi: 10.1186/1477-5956-1-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Ernberg MM, Alstergren PJ. Microdialysis of neuropeptide Y in human muscle tissue. J Neurosci Methods. 2004;132:185–190. doi: 10.1016/j.jneumeth.2003.09.009. [DOI] [PubMed] [Google Scholar]
  • 20.Haskins WE, Watson CJ, Cellar NA, Powell DH, Kennedy RT. Discovery and neurochemical screening of peptides in brain extracellular fluid by chemical analysis of in vivo microdialysis samples. Anal Chem. 2004;76:5523–5533. doi: 10.1021/ac049363y. [DOI] [PubMed] [Google Scholar]
  • 21.Woodroofe MN, Sarna GS, Wadhwa M, et al. Detection of interleukin-1 and interleukin-6 in adult rat brain, following mechanical injury, by in vivo microdialysis: evidence of a role for microglia in cytokine production. J Neuroimmunol. 1991;33:227–236. doi: 10.1016/0165-5728(91)90110-S. [DOI] [PubMed] [Google Scholar]
  • 22.Sjogren F, Svensson C, Anderson C. Technical prerequisites for in vivo microdialysis determination of interleukin-6 in human dermis. Br J Dermatol. 2002;146:375–382. doi: 10.1046/j.1365-2133.2002.04621.x. [DOI] [PubMed] [Google Scholar]
  • 23.Fellows PJ, Noble MR, Clough GF. Effect of perfusion rate on the recovery of albumin by microdialysis. J Vasc Res. 2003;40:304–304. [Google Scholar]
  • 24.Riese J, Boecker S, Hohenberger W, Klein P, Haupt W. Microdialysis: a new technique to monitor perioperative human peritoneal mediator production. Surg Infect (Larchmt) 2003;4:11–15. doi: 10.1089/109629603764655236. [DOI] [PubMed] [Google Scholar]
  • 25.Dabrosin C. Technical aspects of microdialysis of human breast. Scand J Clin Lab Invest. 2001;61:269–272. doi: 10.1080/00365510152378987. [DOI] [PubMed] [Google Scholar]
  • 26.Brown SA, Mayberry AJ, Mathy JA, Phillips TM, Klitzman B, Levin LS. The effect of muscle flap transposition to the fracture site on TNFalpha levels during fracture healing. Plast Reconstr Surg. 2000;105:991–998. doi: 10.1097/00006534-200004050-00009. [DOI] [PubMed] [Google Scholar]
  • 27.Licht P, Losch A, Dittrich R, Neuwinger J, Siebzehnrubl E, Wildt L. Novel insights into human endometrial paracrinology and embryo-maternal communication by intrauterine microdialysis. Hum Reprod Update. 1998;4:532–538. doi: 10.1093/humupd/4.5.532. [DOI] [PubMed] [Google Scholar]
  • 28.Trickler WJ, Miller DW. Use of osmotic agents in microdialysis studies to improve the recovery of macromolecules. J Pharm Sci. 2003;92:1419–1427. doi: 10.1002/jps.10410. [DOI] [PubMed] [Google Scholar]
  • 29.Ao X, Sellati TJ, Stenken JA. Enhanced microdialysis relative recovery of inflammatory cytokines using antibody-coated microspheres analyzed by flow cytometry. Anal Chem. 2004;76:3777–3784. doi: 10.1021/ac035536s. [DOI] [PubMed] [Google Scholar]
  • 30.Schutte RJ, Oshodi SA, Reichert WM. In vitro characterization of microdialysis sampling of macromolecules. Anal Chem. 2004;76:6058–6063. doi: 10.1021/ac0493626. [DOI] [PubMed] [Google Scholar]
  • 31.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. 2003;302:681–686. doi: 10.1124/jpet.102.035634. [DOI] [PubMed] [Google Scholar]
  • 32.Wiig H, Sibley L, DeCarlo M, Renkin EM. Sampling interstitial fluid from rat skeletal muscles by intermuscular wicks. Am J Physiol. 1991;261:H155–H165. doi: 10.1152/ajpheart.1991.261.1.H155. [DOI] [PubMed] [Google Scholar]
  • 33.Haaverstad R, Romslo I, Larsen S, Myhre HO. Protein concentration of subcutaneous interstitial fluid in the human leg: a comparison between the wick technique and the blister suction technique. Int J Microcirc Clin Exp. 1996;16:111–117. doi: 10.1159/000179159. [DOI] [PubMed] [Google Scholar]
  • 34.Rutili G, Arfors KE. Protein concentration in interstitial and lymphatic fluids from the subcutaneous tissue. Acta Physiol Scand. 1977;99:1–8. doi: 10.1111/j.1748-1716.1977.tb10345.x. [DOI] [PubMed] [Google Scholar]
  • 35.Hamrin K, Rosdahl H, Ungerstedt U, Henriksson J. Microdialysis in human skeletal muscle: effects of adding a colloid to the perfusate. J Appl Physiol. 2002;92:385–393. doi: 10.1063/1.1485111. [DOI] [PubMed] [Google Scholar]
  • 36.Sun H, Bungay PM, Elmquist WF. Effect of capillary efflux transport inhibition on the determination of probe recovery during in vivo microdialysis in the brain. J Pharmacol Exp Ther. 2001;297:991–1000. [PubMed] [Google Scholar]
  • 37.Church MK, Griffiths TJ, Jeffery S, et al. Are cysteinyl leukotrienes involved in allergic responses in human skin? Clin Exp Allergy. 2002;32:1013–1019. doi: 10.1046/j.1365-2222.2002.01436.x. [DOI] [PubMed] [Google Scholar]
  • 38.Winter CD, Iannotti F, Pringle AK, Trikkas C, Clough GF, Church MK. A microdialysis method for the recovery of IL-1beta, IL-6 and nerve growth factor from human brain in vivo. J Neurosci Methods. 2002;119:45–50. doi: 10.1016/S0165-0270(02)00153-X. [DOI] [PubMed] [Google Scholar]
  • 39.Ao X, Stenken JA. Water-soluble cyclodextrin polymers for enhanced relative recovery of hydrophobic analytes during microdialysis sampling. Analyst. 2003;128:1143–1149. doi: 10.1039/b308057a. [DOI] [PubMed] [Google Scholar]
  • 40.Kjellstrom S, Emneus J, Laurell T, Heintz L, Marko-Varga G. On-line coupling of microdialysis sampling with liquid chromatography for the determination of peptide and non-peptide leukotrienes. J Chromatogr A. 1998;823:489–496. doi: 10.1016/S0021-9673(98)00361-6. [DOI] [PubMed] [Google Scholar]
  • 41.Davies MI, Cooper JD, Desmond SS, Lunte CE, Lunte SM. Analytical considerations for microdialysis sampling. Adv Drug Deliv Rev. 2000;45:169–188. doi: 10.1016/S0169-409X(00)00114-9. [DOI] [PubMed] [Google Scholar]
  • 42.Lunte SM, Lunte CE. Microdialysis sampling for pharmacological studies: HPLC and CE analysis. Adv Chromatogr. 1996;36:383–432. [PubMed] [Google Scholar]
  • 43.Graham DR, Elliott ST, Van Eyk JE. Broad-based proteomic strategies: a practical guide to proteomics and functional screening. J Physiol. 2005;563:1–9. doi: 10.1113/jphysiol.2004.080341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Kellar KL, Douglass JP. Multiplexed microsphere-based flow cytometric immunoassays for human cytokines. J Immunol Methods. 2003;279:277–285. doi: 10.1016/S0022-1759(03)00248-5. [DOI] [PubMed] [Google Scholar]
  • 45.Anderson L. Candidate-based proteomics in the search for biomarkers of cardiovascular disease. J Physiol. 2005;563:23–60. doi: 10.1113/jphysiol.2004.080473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Rohlff C, Hollis K. Modern proteomic strategies in the study of complex neuropsychiatric disorders. Biol Psychiatry. 2003;53:847–853. doi: 10.1016/S0006-3223(03)00233-6. [DOI] [PubMed] [Google Scholar]
  • 47.O’Riordan E, Orlova TN, Mei JJ, et al. Bioinformatic analysis of the urine proteome of acute allograft rejection. J Am Soc Nephrol. 2004;15:3240–3248. doi: 10.1097/01.ASN.0000145241.83482.68. [DOI] [PubMed] [Google Scholar]
  • 48.Richter R, Schulz-Knappe P, Schrader M, et al. Composition of the peptide fraction in human blood plasma: database of circulating human peptides. J Chromatogr B Biomed Sci Appl. 1999;726:25–35. doi: 10.1016/S0378-4347(99)00012-2. [DOI] [PubMed] [Google Scholar]
  • 49.Tolson J, Bogumil R, Brunst E, et al. Serum protein profiling by SELDI mass spectrometry: detection of multiple variants of serum amyloid alpha in renal cancer patients. Lab Invest. 2004;84:845–856. doi: 10.1038/labinvest.3700097. [DOI] [PubMed] [Google Scholar]
  • 50.Schmid P. Quantitation of specific proteins in blister fluid. J Invest Dermatol. 1970;55:244–248. doi: 10.1111/1523-1747.ep12259948. [DOI] [PubMed] [Google Scholar]
  • 51.Nedrebo T, Reed RK, Jonsson R, Berg A, Wiig H. Differential cytokine response in interstitial fluid in skin and serum during experimental inflammation in rats. J Physiol. 2004;556:193–202. doi: 10.1113/jphysiol.2003.057216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Iversen VV, Bronstad A, Gjerde EA, Reed RK. Continuous measurements of plasma protein extravasation with microdialysis after various inflammatory challenges in rat and mouse skin. Am J Physiol Heart Circ Physiol. 2004;286:H108–H112. doi: 10.1152/ajpheart.00542.2003. [DOI] [PubMed] [Google Scholar]
  • 53.Schmelz M, Petersen LJ. Neurogenic inflammation in human and rodent skin. News Physiol Sci. 2001;16:33–37. doi: 10.1152/physiologyonline.2001.16.1.33. [DOI] [PubMed] [Google Scholar]
  • 54.Weidner C, Klede M, Rukwied R, et al. Acute effects of substance P and calcitonin gene-related peptide in human skin: a microdialysis study. J Invest Dermatol. 2000;115:1015–1020. doi: 10.1046/j.1523-1747.2000.00142.x. [DOI] [PubMed] [Google Scholar]
  • 55.Krogstad AL, Lonnroth P, Larson G, Wallin BG. Increased interstitial histamine concentration in the psoriatic plaque. J Invest Dermatol. 1997;109:632–635. doi: 10.1111/1523-1747.ep12337620. [DOI] [PubMed] [Google Scholar]
  • 56.Garvin S, Dabrosin C. Tamoxifen inhibits secretion of vascular endothelial growth factor in breast cancer in vivo. Cancer Res. 2003;63:8742–8748. [PubMed] [Google Scholar]
  • 57.Simonsen L, Holstein P, Larsen K, Bulow J. Glucose metabolism in chronic diabetic foot ulcers measured in vivo using microdialysis. Clin Physiol. 1998;18:355–359. doi: 10.1046/j.1365-2281.1998.00111.x. [DOI] [PubMed] [Google Scholar]
  • 58.Clough GF, Noble MR. Microdialysis: a model for studying chronic wounds. Int J Low Extrem Wounds. 2003;2:233–239. doi: 10.1177/1534734603261124. [DOI] [PubMed] [Google Scholar]
  • 59.Westerink BH, De Vries JB. A method to evaluate the diffusion rate of drugs from a microdialysis probe through brain tissue. J Neurosci Methods. 2001;109:53–58. doi: 10.1016/S0165-0270(01)00401-0. [DOI] [PubMed] [Google Scholar]

Articles from The AAPS Journal are provided here courtesy of American Association of Pharmaceutical Scientists

RESOURCES