Oxygen in Acute and Chronic Wound Healing

S. Schreml; R.M. Szeimies; L. Prantl; S. Karrer; M. Landthaler; P. Babilas


The British Journal of Dermatology. 2010;163(2):257-268. 

In This Article

Oxygen Monitoring in Wounds

Different methods allow the evaluation of wound tissue oxygenation. Direct and indirect as well as invasive and noninvasive methods must be distinguished, whereas the noninvasive methods are preferable in routine clinical settings. Indirect methods estimate tissue oxygenation only by calculating the relation of oxygenated to nonoxygenated haemoglobin. This calculation is possible as haemoglobin changes its spectroscopic as well as its magnetic properties with its degree of oxygenation. Respective methods (for instance, near-infrared spectroscopy, tissue reflectance photometry, magnetic resonance chemistry, magnetic resonance saturation, blood oxygen-dependent magnetic resonance imaging) are rather imprecise: first, they do not allow the measurement of absolute values; second, the exact penetration depth of light is unknown;[122–124] and third, they are falsified by certain disturbance variables such as other tissue chromophores or global perfusion (for further details see reviews [122,123]). Direct methods allow direct measurements of oxygen or pO2 values. Tissue oxygen-dependent magnetic resonance imaging is based on the paramagnetic properties of oxygen in tissue. However, this technique is not applicable at the skin surface as the skin–air interface evokes a severe artifact.[124] The polarographic electrode technique allows the measurement of pO2 and is still the gold standard for assessing tissue oxygenation. This technique is usually applied using a planar electrode for surface measurements or a needle electrode for measurements within the tissue.[124,125] An alternative application method for measurements in wound tissue is to place the polarographic electrode in a subcutaneously implanted tonometer or to implant the polarographic electrode directly into subcutaneous tissue.[80,90,126] However, placing an electrode into tissue (i) is invasive and painful, (ii) causes tissue injury that alters microcirculation and thus pO2 levels, and (iii) may lead to irritation at the electrode membrane. A further fundamental limitation of the polarographic technique is the oxygen consumption during measurement, which makes long-term measurements impossible and overestimates pO2 values as the electrode 'sucks' oxygen through the tissue.[127] Besides, this technique provides only scattered single measurements, making multiple measurements necessary. The required calibration before and after each measurement and the lacking spatial resolution further limit the application of the polarographic electrode technique.[124,128] Therefore, the available methods suffer from disadvantages when measuring pO2 levels in tissue. Because of these disadvantages, only a few studies exist on tissue oxygenation in acute wounds and hardly any study on tissue oxygenation in chronic wounds.

The use of luminescence lifetime imaging (LLI) overcomes these limitations.[127–130] This method for two-dimensional pO2 measurements is based on the oxygen-dependent quenching of phosphorescence of the indicator platinum(II)-octaethyl-porphyrin. Hereby, the indicator is immobilized in a polystyrene matrix as a transparent planar sensor. This method was validated in vitro and in vivo, as well as in clinical settings.[127–129,131] This body of work has characterized this method as particularly suitable for surface measurements. First, sensors are transparent, allowing a simultaneous visualization of the underlying wound tissue. Second, sensor sensitivity remains stable during measurement because alterations due to ageing, moisture, toxic cell products, local enzymes or photobleaching as a result of exposure to light could be excluded in calibration sequences over 8 days both in vivo and in vitro.[128,130] Third, pO2 levels can be visualized in two dimensions with a high resolution (approximately 25 μm) over large areas,[128,131] thus allowing the simultaneous visualization of pO2 gradients in different skin conditions. This fact is of fundamental relevance in heterogeneously oxygenated tissues such as chronic wounds as the heterogeneity can be registered simultaneously in a single measurement. Single point measurements as provided by the Clark electrode are unable to provide oxygen gradients. Fourth, in vitro experiments documented a high sensitivity over a broad pO2 range (±0·2 mmHg at 0 mmHg; ±1·5 mmHg at 160 mmHg pO2).[128] The Clark electrode provides a sensitivity of at least ±10%. Fifth, in clinical investigations, accurate and reproducible pO2 values were provided under changing microcirculatory conditions. The lack of oxygen consumption during measurement allowed both a more realistic estimation of pO2 values compared with the gold standard and the permanent use in regions with critical oxygen supply.[127] Sixth, this noninvasive and rapid technique is simple to perform and prevents patient discomfort. Zhang et al.[132] recently published a dual-emissive material for luminescence imaging of pO2 in tumours, which may also be modified for use in two-dimensional wound oximetry.

Because of the great interest in new technologies that advance research on the role of oxygen in wound healing, Hopf and Rollins listed attributes of an ideal wound oximeter: noninvasive; repeatable; simple to use; stable for at least 24 h in vivo; not disturbed by motion, pH and CO2; provides accurate, precise and easily interpretable results in the range from 0 to ≥300 mmHg. Furthermore, such an oximeter should enable continuous long-term measurements, require just a single point calibration at room conditions in vivo, and simultaneously measure oxygen and temperature at the same site.[5] All these requirements are fulfilled by LLI.