Our CE-marked COMET measurement system non-invasively measures oxygen availability [mmHg] in human skin cells with a high concentration of protoporphyrin IX.
We expect that measuring in the cells rather than in the blood reflects the balance of supply (the entire transport chain) and demand and will allow the assessment whether oxygen supply is sufficient and how effective interventions are. Skin is an early warning sensor, so physicians should get time to act. The measurement in the cells should prove useful for patient management, to direct therapy for resuscitation, to assess the effects of and necessity for interventions, to detect alterations of cellular metabolism and to help develop treatments for metabolic dysfunction.
Editors of Anesthesiology summarized a publication of research results with a prototype of the COMET and wrote that directly measuring tissue oxygenation “would be a major advance for perioperative medicine.” O’Brien and Schmidt wrote in a separate editorial for Anesthesiology (July 2016): “A reliable measure of oxygen tension at the level of the mitochondria might significantly refine transfusion practice… Indeed, any clinical scenario where cellular oxygenation might be compromised could potentially benefit… If mitochondrial PO2 can be measured reliably in humans, the potential value of this technique is hard to overestimate.”
Several clinical trials are ongoing.
COMET measurement system
The science of cellular monitoring
Anesthesiologist Dr. Egbert Mik developed a way to measure oxygen availability and consumption where oxygen is needed: in the tissue cells (rather than in the blood). This first in-vivo measurement of mitochondrial oxygen availability is possible by determining the oxygen dependent duration of the afterglow of protoporphyrin IX, a heme-precursor metabolized in epidermal mitochondria after local priming with aminolevulinic acid used in photodynamic therapy or diagnosis. The signal therefore originates only in active mitochondria and reflects the balance between oxygen supply and demand. The COMET’s standard skin sensor collects a signal from several square millimeters of epidermis. This includes cells located at different positions along capillaries and different distances from them and results in a range of cellular oxygen availabilities (for a theoretical discussion refer to the Krogh model and its refinements e.g., here or here). Intense perfusion can result in average epidermal mitoPO2 values only slightly below the arterial oxygen tension. Temporary local pressure stops microvascular blood flow in the measurement region. Repeated measurements during and after pressure allow determination of cellular oxygen utilization and analysis of re-perfusion. Dr. Mik called his method the protoporphyrin IX-triplet state lifetime technique (PpIX-TSLT) and initiated the steps to make it clinically available. The technology and its application has been published in:
- Ubbink R et al. A monitor for Cellular Oxygen METabolism (COMET): monitoring tissue oxygenation at the mitochondrial level. J Clin Monit Comput (2016) DOI 10.1007/s10877-016-9966-x
- Zwaag J, Wefers Bettink MA, Kox M, Mik EG. Change of mitochondrial function in vivo during human endotoxemia: preliminary data. Nederlands tijdschrift voor anesthesiologie 27:100 (2016)
- Harms FA et al. Cutaneous Respirometry as Novel Technique to Monitor Mitochondrial Function: A Feasibility Study in Healthy Volunteers. PLoS One. 2016 Jul 25;11(7):e0159544 (2016)
- O’Brien EO, Schmidt U. Cellular Hypoxia in a Brand New Light (Editorial). Anesthesiology 2016 Jul; 125(1): 20-1 (2016)
- Romers LH et al. Cutaneous Mitochondrial PO2, but not Tissue Oxygen Saturation, Is an Early Indicator of the Physiologic Limit of Hemodilution in the Pig. Anesthesiology 2016 Jul;125(1):124-32 (2016)
- Ince C et al. Microcirculatory and mitochondrial hypoxia in sepsis, shock, and resuscitation. J Appl Physiol 120(2):226-35 (2016)
- Freebody M. Delivering optical devices to the medical market. Photonics Spectra 40(4):50-54 (2016)
- Harms FA et al. Non-invasive monitoring of mitochondrial oxygenation and respiration in critical illness using a novel technique. Crit Care.19(1):343 (2015)
- Harms FA et al. In vivo assessment of mitochondrial oxygen consumption. In: Weissig, Edeas (eds.). Mitochondrial Medicine: Vol. 1, Probing Mitochondrial Function. Methods Mol Biol. 2015;1264:219-29.
- Harms FA et al. Cutaneous mitochondrial respirometry: non-invasive monitoring of mitochondrial function. J Clin Monit Comput. 2015 Aug;29(4):509-19 (2014)
- Harms FA. Towards non‐invasive monitoring of mitochondrial function. PhD Thesis ErasmusMC University Medical Center Rotterdam (2014)
- Mik EG et.al. Towards real-time measurement of intracellular oxygen tension Photonic International/2013 pp.52-53 (2013)
- Mik EG Measuring Mitochondrial Oxygen Tension: From Basic Principles to Application in Humans. Anesthesia & Analgesia 117(4) p 834-845 (2013)
- Harms FA et al. Cutaneous respirometry by dynamic measurement of mitochondrial oxygen tension for monitoring mitochondrial function in vivo. Mitochondrion S1567-7249(12)00226-7 (2012)
- Piffaretti F et al. Real-time, in vivo measurement of tissular pO2 through the delayed fluorescence of endogenous protoporphyrin IX during photodynamic therapy. J. Biomed. Opt. 17(11) 115007 (2012)
- Harms FA et al. Validation of the protoporphyrin IX-triplet state lifetime technique for mitochondrial oxygen measurements in the skin. Optics Letters 37: 2625-2627 (2012)
- Bodmer SI et al.. Microvascular and mitochondrial PO2 simultaneously measured by oxygen-dependent delayed luminescence. J.Biophotonics 5(2):140-151 (2012)
- Harms FA et al. Oxygen-dependent delayed fluorescence measured in skin after topical application of 5-aminolevulinic acid. J.Biophotonics 4(10): 731-9 (2011)
- Piffaretti et al. Optical fiber-based setup for in vivo measurement of the delayed fluorescence lifetime of oxygen sensors. J. Biomed. Opt. 16:037005 (2011)
- Mik EG Measuring Microvascular and Mitochondrial Oxygen Tension – Novel Techniques for Studying Tissue Oxygenation, PhD Thesis, University of Amsterdam (2011)
- Mik EG et al. Mitochondrial oxygen tension within the heart. J. Moll. Cell. Cardiol. 46: 943-951 (2009)
- Mik EG et al.. In vivo mitochondrial oxygen tension measured by a delayed fluorescence lifetime technique. Biophys. J. 95: 3977-3990 (2008)
- Mik EG et al. Mitochondrial PO2 measured by delayed fluorescence of endogenous protoporphyrin IX. Nature Methods 3: 939-945 (2006)
Eurostars supported the development and testing of the COMET measurement system (project E!7294). Photonics Healthcare collaborates with AMC, Erasmus Medical Center, Leiden University, Sanquin Blood Supply and Unitron.