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Open flow microperfusion

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Open Flow Microperfusion (OFM) is a sampling method for clinical and preclinical drug development studies and biomarker research. OFM is designed for continuous sampling of analytes from the interstitial fluid (ISF) of various tissues. It provides direct access to the ISF by insertion of a small, minimally invasive, membrane-free probe with macroscopic openings.[1] Thus, the entire biochemical information of the ISF becomes accessible regardless of the analyte's molecular size, protein-binding property or lipophilicity.

OFM is capable of sampling lipophilic and hydrophilic compounds,[2] protein bound and unbound drugs,[3][4] neurotransmitters, peptides and proteins, antibodies,[5][6][7] nanoparticles and nanocarriers, enzymes and vesicles.

Method

The OFM probes are perfused with a physiological solution (the perfusate) which equilibrates with the ISF of the surrounding tissue. Operating flow rates range from 0.1 to 10 μL/min. OFM allows unrestricted exchange of compounds via an open structure across the open exchange area of the probe. This exchange of compounds between the probe’s perfusate and the surrounding ISF is driven by convection and diffusion, and occurs non-selectively in either direction (Figure 1).

The direct liquid pathway between the probe’s perfusate and the surrounding fluid results in collection of ISF samples. These samples can be collected frequently and are then subjected to bioanalytical analysis to enable monitoring of substance concentrations with temporal resolution during the whole sampling period.[8][9][10]

History

The first OFM sampling probe was described in an Austrian patent application filed by Falko Skrabal in 1987, where OFM was described as a device, which can be implanted into the tissue of living organisms.[11] In 1992, a US patent was filed claiming a device for determining at least one medical variable in the tissue of living organisms.[12] In a later patent by Helmut Masoner, Falko Skrabal and Helmut List a linear type of the sampling probe with macroscopic circular holes was also disclosed.[13] Alternative and current OFM versions for dermal and adipose tissue application were developed by Joanneum Research, and werewere patented by Manfred Bodenlenz et al.[14][15] Alternative materials featuring low absorption were used to enable manufacturing of probes with diameters of 0.55 mm and exchange areas of 15 mm in length. For cerebral application, special OFM probes were patented by Birngruber et al.[16] Additionally, a patent was filed to manage the fluid handling of the ISF by using a portable peristaltic pump with a flow range of 0.1 to 10 µL/min with delta push-pull modes that enables operation of up to three probes per pump.[17]

OFM System

Two types of OFM probes are currently available: Linear OFM probes for implantation into superficial tissues such as skin (dermal OFM, dOFM) and subcutaneous adipose tissue (adipose OFM, aOFM) as well as concentric probes for implantation into various regions of the brain (cerebral OFM, cOFM).

Areas of Application

OFM is routinely applied in pharmaceutical research in preclinical (e.g. mice, rats, pigs, primates) and in clinical studies in humans. OFM-related procedures such as probe insertions or prolonged sampling with numerous probes are well tolerated by the subjects.[18]

Dermal OFM (dOFM)

dOFM allows investigation of the transport and penetration effects of drugs in the dermis after local, topical or systemic application:

dOFM can be used to:

  • conduct tissue-specific PK and PD studies of drugs.[19][20]
  • perform head-to-head comparison of novel topical drug formulations
  • assess dermal bioavailability.[21][22]
  • investigate high molecular weight compounds, e.g. antibodies[23]

Head-to-head settings with OFM have proven particularly useful for the evaluation of topical generic products, which need to demonstrate bioequivalence[24] to the reference listed drug product to obtain market approval.

Applications of dOFM include ex-vivo studies with tissue explants and preclinical and clinical in-vivo studies.

Adipose OFM (aOFM)

aOFM allows continuous on-line monitoring of metabolic processes in the subcutaneous adipose tissue, e.g. glucose and lactate,[25][26][27] as well as larger analytes such as insulin (5.9 kDa).[28][29] The role of polypeptides for metabolic signaling (leptin, cytokine IL-6, TNFα) has also been studied with aOFM.[30] aOFM allows the quantification of proteins (e.g. albumin size: 68 kDa) in adipose tissue[31] and thus opens up the possibility to investigate protein-bound drugs directly in peripheral target tissues, such as highly protein-bound insulin analogues designed for a prolonged, retarded insulin action.[32] Most recently, aOFM has been used to sample agonists to study obesity, lipid metabolism and immune-inflammation. Applications of aOFM include ex-vivo studies with tissue explants and preclinical and clinical in-vivo studies.

Cerebral OFM (cOFM)

cOFM is used to conduct PK/PD preclinical studies in the animal brain. Access to the brain includes monitoring of the blood-brain barrier function and drug transport across the intact blood-brain barrier.[33] cOFM allows taking a look behind the blood-brain barrier and assesses concentrations and effects of neuroactive substances directly in the targeted brain tissue.[34]

The blood-brain barrier is a natural shield that protects the brain and limits the exchange of nutrients, metabolites and chemical messengers between blood and brain. The blood-brain barrier also prevents potential harmful substances from entering and damaging the brain. However, this highly effective barrier also prevents neuroactive substances from reaching appropriate targets. For researchers that develop neuroactive drugs, it is therefore of major interest to know whether and to what extent an active pharmaceutical component can pass the blood-brain barrier. Experiments have shown that the blood-brain barrier has fully reestablished 15 days after implantation of the cOFM probe in the brain of rats.[35] The cOFM probe has been specially designed to avoid a reopening of the blood-brain barrier or causing additional trauma to the brain after implantation. cOFM enables continuous sampling of cerebral ISF with intact blood-brain barrier cOFM and thus allows continuous PK monitoring in brain tissue.


References

  1. ^ Bodenlenz M, Aigner B, Dragatin C, Liebenberger L, Zahiragic S, Höfferer C, et al. Clinical applicability of dOFM devices for dermal sampling. Ski Res Technol Technol. 2013 Nov;19(4):474–83.
  2. ^ Altendorfer-Kroath, T.; Schimek, D.; Eberl, A.; Rauter, G.; Ratzer, M.; Raml, R.; Sinner, F. M.; Birngruber, T., 2019: Comparison of cerebral Open Flow Microperfusion and Microdialysis when sampling small lipophilic and small hydrophilic substances. Journal of Neuroscience Methods., 311, 394–401.
  3. ^ Schaupp L, Ellmerer M, Brunner GA, Wutte A, Sendlhofer G, Trajanoski Z, et al. Direct access to interstitial fluid in adipose tissue in humans by use of open-flow microperfusion. Am J Physiol. 1999;276(2):401–8.
  4. ^ Ellmerer M, Schaupp L, Brunner GA, Sendlhofer G, Wutte A, Wach P, et al. Measurement of interstitial albumin in human skeletal muscle and adipose tissue by open-flow microperfusion. Am J Physiol - Endocrinol Metab. 2000 Feb;278(2):352–6.
  5. ^ Dragatin C, Polus F, Bodenlenz M, Calonder C, Aigner B, Tiffner KI, et al. Secukinumab distributes into dermal interstitial fluid of psoriasis patients as demonstrated by open flow microperfusion. Exp Dermatol. 2016 Feb;25(2):157–9
  6. ^ Kolbinger F, Loesche C, Valentin M-A, Jiang X, Cheng Y, Jarvis P, et al. β-Defensin 2 is a responsive biomarker of IL-17A-driven skin pathology in patients with psoriasis. J Allergy Clin Immunol. 2017 Mar 5;139(3):923–32
  7. ^ Kleinert, M.; Kotzbeck, P.; Altendorfer-Kroath, T.; Birngruber, T.; Tschöp, M. H.; Clemmensen, C., 2018: Time-resolved hypothalamic open flow micro-perfusion reveals normal leptin transport across the blood–brain barrier in leptin resistant mice. Molecular Metabolism., 13, 77–82.
  8. ^ Bodenlenz M, Dragatin C, Liebenberger L, Tschapeller B, Boulgaropoulos B, Augustin T, et al. Kinetics of Clobetasol-17-Propionate in Psoriatic Lesional and Non-Lesional Skin Assessed by Dermal Open Flow Microperfusion with Time and Space Resolution. Pharm Res 2016;33:2229–38.
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  14. ^ M. Bodenlenz, L. Schaupp, Catheter having an oblong slit, WO 2007/131780 A1, 2007.
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  16. ^ WO2012156478A1
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  19. ^ M. Bodenlenz, C. Höfferer, C. Magnes, R. Schaller-Ammann, L. Schaupp, F. Feichtner, M. Ratzer, K. Pickl, F. Sinner, A. Wutte, S. Korsatko, G. Köhler, F. J. Legat, E. M. Benfeldt, A. M. Wright, D. Neddermann, T. Jung, and T. R. Pieber, “Dermal PK/PD of a lipophilic topical drug in psoriatic patients by continuous intradermal membrane-free sampling.,” Eur. J. Pharm. Biopharm., vol. 81, no. 3, pp. 635–41, Aug. 2012. [10]
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  21. ^ Bodenlenz M, Tiffner KI, Raml R, Augustin T, Dragatin C, Birngruber T, et al. Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence. Clin Pharmacokinet. 2017 Jan;56(1):91–8.
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  23. ^ Dragatin C, Polus F, Bodenlenz M, Calonder C, Aigner B, Tiffner KI, et al. Secukinumab distributes into dermal interstitial fluid of psoriasis patients as demonstrated by open flow microperfusion. Exp Dermatol. 2016 Feb;25(2):157–9.
  24. ^ Bodenlenz M, Tiffner KI, Raml R, Augustin T, Dragatin C, Birngruber T, et al. Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence. Clin Pharmacokinet. 2017 Jan;56(1):91–8.
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  33. ^ Birngruber T, Sinner FM. Cerebral open flow microperfusion (cOFM) an innovative interface to brain tissue. Drug Discov Today Technol 2016;20:19–25. doi:10.1016/j.ddtec.2016.07.003.
  34. ^ Birngruber T, Raml R, Gladdines W, Gatschelhofer C, Gander E, Ghosh A, et al. Enhanced Doxorubicin Delivery to the Brain Administered Through Glutathione PEGylated Liposomal Doxorubicin (2B3-101) as Compared with Generic Caelyx,(®) /Doxil(®) -A Cerebral Open Flow Microperfusion Pilot Study. J Pharm Sci 2014;103:1945–8. doi:10.1002/jps.23994.
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