Thermography and thermometry in the assessment of diabetic neuropathic foot: a case for furthering the role of thermal techniques.

There are currently 3 established techniques employed routinely to determine the risk of foot ulceration in the patient with diabetes mellitus. These are the assessment of circulation, neuropathy, and foot pressure. These assessments are widely used clinically as well as in the research domain with an aim to prevent the onset of foot ulceration. Routine neuropathic evaluation includes the assessment of sensory loss in the plantar skin of the foot using both the Semmes Weinstein monofilament and the biothesiometer. Thermological measurements of the foot to assess responses to thermal stimuli and cutaneous thermal discrimination threshold are relatively uncommon. Indeed, there remains uncertainty regarding the importance of thermal changes in the development of foot ulcers. Applications of thermography and thermometry in lower extremity wounds, vascular complications, and neuropathic complications have progressed as a result of improved imaging software and transducer technology. However, the uncertainty associated with the specific thermal modality, the costs, and processing times render its adaptation to the clinic. Therefore, wider adoption of thermological measurements has been limited. This article reviews thermal measurement techniques specific to diabetic foot such as electrical contact thermometry, cutaneous thermal discrimination thresholds, infrared thermography, and liquid crystal thermography.

In-shoe measurement of plantar blood flow in diabetic subjects: results of a preliminary clinical evaluation.

The findings of clinical pilot study (n = 9 subjects) using a new laser Doppler sensor for assessing blood flux in plantar skin tissue are described. Cutaneous blood perfusion was recorded under the first metatarsal head (right foot) in standing and walking. The sensor was located in a measurement shoe custom made for each test subject. The test group comprised diabetic patients (type II) with vascular (n = 3) or neuropathic (n = 3) complications and three controls. All subjects were Caucasian males and in the age range considered particularly at risk of diabetic foot problems (mean 61 years, 51-72 years). Following static loading for 2, 3 and 4 min the blood.flux response increased rapidly in the control (mean = 10 s) and neuropathic (mean = 18 s) groups to a well-defined, peak blood flow. For the vascular group. the blood flux response was typically a slower rise (mean = 30 s) to a poorly defined peak blood flow value. Due to movement artifact a reliable signal could only be obtained for the swing phase of gait during which blood flux was observed to increase linearly. This was interpreted as reperfusion of the tissue following unloading. The rates of reperfusion expressed in arbitrary units (of blood flux) per millisecond (au ms(-1)) were 6.1-7.9 au ms(-1) for the control, 4-6.2 au ms- for the vascular and 2.3-4.5 au ms(-1) for the neuropathic groups. The feasibility of assessing the microcirculation of the plantar skin under conditions of static and dynamic loading, with the foot in-shoe, has been demonstrated for the first time. The results suggest that abnormal responses may be obtained from asymptomatic feet of diabetic patients with vascular and/or neuropathic complications. This method of assessment could be of use in predicting the occurrence of ulceration in the diabetic foot.

Progress towards automated diabetic ocular screening: a review of image analysis and intelligent systems for diabetic retinopathy.

Patients with diabetes require annual screening for effective timing of sight-saving treatment. However, the lack of screening and the shortage of ophthalmologists limit the ocular health care available. This is stimulating research into automated analysis of the reflectance images of the ocular fundus. Publications applicable to the automated screening of diabetic retinopathy are summarised. The review has been structured to mimic some of the processes that an ophthalmologist performs when examining the retina. Thus image processing tasks, such as vessel and lesion location, are reviewed before any intelligent or automated systems. Most research has been undertaken in identification of the retinal vasculature and analysis of early pathological changes. Progress has been made in the identification of the retinal vasculature and the more common pathological features, such as small aneurysms and exudates. Ancillary research into image preprocessing has also been identified. In summary, the advent of digital data sets has made image analysis more accessible, although questions regarding the assessment of individual algorithms and whole systems are only just being addressed.

Noninvasive measurement techniques for monitoring of microvascular function in the diabetic foot.

There are, currently, 3 established clinical techniques routinely employed to determine the risk of ulceration in the diabetic foot. These are assessment of the circulation, the nervous control of sensation, and foot sensitivity to loading. Macrovascular measurements are used to assess sufficiency of the arterial supply to the foot. Evaluation of somatic neuropathy provides an indication of loss of plantar sensation. Skin pressure measurements indicate abnormalities in plantar loading. This combined approach is effective in allowing preventative measures to be applied prior to the onset of ulceration. In contrast, clinical measurement of microvascular function in the diabetic foot is uncommon. Indeed, there remains uncertainty regarding the importance of micro-vascular complications in the development of foot ulcers. This is in part due to the difficulty of making in vivo measurements of microvascular function. This article evaluates 3 noninvasive measurement techniques for routine microvascular assessment of the diabetic foot: transcutaneous oxygen tension, laser Doppler flowmetry, and near-infrared spectroscopy. These techniques can be used to obtain useful parameters of microvascular function including surface oxygen,blood flow, intracellular oxygenation, and cellular respiration. In principle, such measurements can be related to underlying pathophysiology, for example, microangiopathy or autonomic neuropathy. This article considers how these general techniques can be adapted to support routine clinical measurement of microvascular function, particularly in the neuropathic diabetic foot.

An in-shoe laser Doppler sensor for assessing plantar blood flow in the diabetic foot.

Increased pressure due, to sensory neuropathy, is important in the development of plantar ulceration in type II diabetes. However, additional factors are thought to pre-dispose the skin tissue to ulceration. Autonomic neuropathy and microangiopathy are the basis for the capillary steal theory and the haemodynamic hypothesis, developed to explain the aetiology of this type of ulcer, in terms of microvascular complications. The aim of the present study was to develop a system to allow assessment of blood flow at prevalent sites of ulceration. Previous studies have been limited to assessment of the bare foot under rest conditions. The new system allows measurements to be made in-shoe, during static and dynamic loading. The system comprises a laser Doppler sensor, a load sensor, measurement shoe, instrumentation and analysis software. The measurement shoe was designed to minimise movement artefact and provide thermal insulation for the foot. A simple flow rig was used to characterise the sensor. The blood flux response was linear (<5% deviation from ideal) for particle concentrations up to 0.25% and for mean particle velocities up to 8mm s(-1). The worst case drift in the response over a six-month period was 3.7%. Device to device repeatability varied by 12.5% over five devices.

The application of engineering and technology in the management of diabetes.

Diabetes mellitus is a relatively common disorder in which many of the body's systems are affected, resulting in morbidity and mortality. Early diagnosis and good blood glucose control can delay or prevent the onset of these complications. This review illustrates how engineering and technology can help to achieve these goals.

Transducers for foot pressure measurement: survey of recent developments.

Recent advances in the development of transducers for the measurement of vertical and shear forces acting on the plantar surface of the foot are reviewed. Barefoot and in-shoe discrete and matrix transducers are reviewed in terms of structure, operation, performance and limitations. Examples of capacitive, piezo-electric, optical, conductive and resistive types of transducer are presented. Where available, the current clinical status is specified.

Responses and calibration of amperometric glucose sensors implanted in the subcutaneous tissue of man.

Glucose sensors based on immobilized glucose oxidase and hydrogen peroxide detection at a platinum base electrode were constructed and studied before, during and after implantation into the subcutaneous tissue of 11 non-diabetic subjects. A 75-g oral glucose load was given to elevate the blood glucose concentration. Seven of 14 sensors responded to the oral glucose administration with an increase in current and the output of the remainder was unchanged by the glucose load. Apparent subcutaneous glucose levels calculated from the pre-implantation calibration were a mean 58% of the plasma glucose values at baseline. A two-point in vivo calibration using paired current and glucose readings at baseline and at the maximum glucose and current after glucose ingestion showed a significantly reduced sensitivity in vivo compared with pre-implantation values (mean +/- SEM 52 +/- 21.5 vs 369 +/- 127 pA/mmol-1 per litre, P = 0.003). Recalibration of the subcutaneous glucose concentrations using the in vivo calibration sensitivity and extrapolated background current (I0) gave values similar to those in plasma. The sensitivity of five sensors recalibrated in vitro after explantation was also reduced compared with pre-implantation levels and not significantly different from the in vivo characteristics. Responding and non-responding sensors did not differ with respect to preimplantation I0, sensitivity or response time. However, provisional examination of some explanted sensors by scanning electron microscopy showed coating by cellular and other amorphous material in the non-functioning electrodes. We conclude that the sensitivity of glucose sensors of this design is markedly reduced, sometimes to zero, on implantation in the subcutaneous tissue of humans.(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro testing of a simply constructed, highly stable glucose sensor suitable for implantation in diabetic patients.

We have constructed and tested in vitro a potentially implantable, needle-type amperometric enzyme electrode which is suitable for continuous monitoring of glucose concentrations in diabetic patients. The major requirements of stability during operation and ease of manufacture have been met with a sensor design which involves a simple dip-coating procedure for applying to a platinum base electrode an inner membrane of glucose oxidase immobilised in polyhydroxyethyl methacrylate (pHEMA), and an outer membrane composed of a pHEMA/polyurethane mixture. Sensors were operated at 700 mV for detection of hydrogen peroxide. Calibration curves for the sensor were linear to at least 20 mM glucose and were unaffected by a reduction in PO2 from 20 to 5 kPa. During continuous operation in 5 mM buffered glucose solutions in vitro, sensors suffered no significant loss of response over periods of up to 60 h. Such electrodes are, therefore, useful for development as in vivo glucose sensors.

In vivo molecular sensing in diabetes mellitus: an implantable glucose sensor with direct electron transfer.

Miniature, amperometric glucose sensors were constructed for implantation in the subcutaneous tissue of normal and insulin-dependent diabetic subjects. To minimise dependence on fluctuating tissue oxygen tension, we employed the technology of mediated electron transfer, with 1,1'-dimethylferrocene acting as the redox shuttle between immobilized glucose oxidase and a platinum base electrode. In 6 normal subjects, the subcutaneous sensor responses mirrored the simultaneously-measured changes in blood glucose concentration after a 75 g oral glucose load and after intravenous injection of 0.15 U/kg short-acting insulin, though increases and decreases in the sensor output were slower than the glycaemic changes. The mean peak delay in sensor response after the oral glucose was 40 min (range 0-45 min) and the delay in the hypoglycaemic nadir was 4 min (range 0-15 min). In 5 insulin-dependent diabetic subjects, spontaneous and induced hypoglycaemia was detectable by the implanted sensor. In addition, marked and frequent oscillations in the sensor current occurred in several normal and diabetic individuals as the blood glucose fell below about 1.9 mmol/l. These oscillations were present in a diabetic subject who had lost adrenergic warning symptoms to hypoglycaemia. Continuous metabolic monitoring in diabetes, particularly the detection of hypoglycaemia, may be possible with implanted sensors based on this technology.

Potentially-implantable, amperometric glucose sensors with mediated electron transfer: improving the operating stability.

The major problems with existing amperometric enzyme electrodes for glucose sensing are oxygen sensitivity and output drift. The recently described miniature glucose sensors using immobilised ferrocene (dicyclopentadienyl iron) to mediate electron transfer from glucose oxidase to a base electrode are oxygen-independent but are often unstable. In this study, we test the hypothesis that the stability of ferrocene-based sensors can be markedly improved by better retention of the enzyme at the electrode. Sensors with graphite foil as the base electrode, dimethylferrocene as the mediator and carbodiimide/glutaraldehyde for enzyme immobilisation lost most of their activity when calibration curves were compared before and after 18 h operation in vitro at 37 degrees C (mean current decrease at 20 mmol/litre glucose was 91%). This sensor type with a covering cellulose membrane also lost activity (mean current decrease of 40% after 18 h). Electrodes in which the base sensor was platinum and the enzyme was covalently attached to agarose lost no activity when operated either at 700 mV without mediator (as a hydrogen peroxide detector) or at 160 mV with mediator. We conclude that both ferrocene-mediated and hydrogen peroxide-detecting amperometric glucose sensors with a high density of covalently-linked enzyme have an operating stability in vitro which may render them suitable for clinical use as, for example, an overnight hypoglycaemia alarm.

Progress towards in vivo glucose sensing with a ferrocene-mediated amperometric enzyme electrode.

A range of miniature, amperometric enzyme electrodes have been constructed using the principle of mediated transfer of electrons. Ferrocene, or one of its derivatives, can be used in conjunction with immobilised glucose oxidase to produce sensors which are linear to at least 20 mmol/l glucose, have fast response times, are relatively oxygen insensitive and are suitable for implantation studies. In preliminary experiments in non-diabetic pigs, electrode responses followed blood responses, although mean tissue levels were about one fifth of those in blood. The ferrocene technology thus appears to be suitable for adaptation to the construction of implantable glucose electrodes for use in diabetic man.

Biosensors: clinical requirements and scientific promise.

Biosensors are currently very fashionable, even though they are not new! - an enzyme electrode being described almost 20 years ago by Updike and Hicks in 1967. The aim of this review is to put into perspective why biosensors are needed in clinical medicine and to describe some of the research that is being performed to develop such devices for, in particular, 'in vivo' applications.

Implantable glucose sensors: choosing the appropriate sensing strategy.

The special requirements for implantable glucose sensors which differ from laboratory analysers and in vitro probes include continuous operation without drift, compatibility with in vivo body conditions, electrical and toxicological safety and patient acceptability. We have studied the effect of oxygen tension, operating temperature and pH, and the stability of various potentially implantable amperometric glucose sensors so as to aid the choice of the technologies most suitable for in vivo application.

Subcutaneous implantation of a ferrocene-mediated glucose sensor in pigs.

Miniature, amperometric glucose sensors were constructed using entrapped 1,1'-dimethylferrocene to mediate electron transfer between immobilised glucose oxidase and a carbon base electrode. Electrodes were calibrated in buffered glucose solutions and then implanted in the subcutaneous tissue of anaesthetised, non-diabetic pigs. Subcutaneous tissue glucose concentrations, as measured by the sensor, were about 20% of blood glucose values, measured by a conventional glucose oxidase assay. After an intravenous 0.07 mol bolus glucose injection, electrode responses increased with almost no time lag, but the subsequent rates of rise and fall of electrode-measured tissue glucose concentrations were slower than that of the blood values. After an intravenous 0.2 U/Kg bolus short-acting insulin injection the electrode response was also rapid, but decreased at a slower rate than the blood glucose concentrations. We conclude that this is a feasible technology for future development as an implantable glucose sensor for use in diabetic man.

Potentially-implantable, ferrocene-mediated glucose sensor.

We describe the construction and in vitro testing of a new potentially-implantable amperometric glucose sensor which is based on mediated electron transfer between immobilized glucose oxidase and a graphite base electrode. Under potentiostatic control, entrapped 1,1'-dimethylferrocene acts as an alternative electron acceptor to oxygen and provides a sensing strategy which is relatively unaffected by possible fluctuations in in vivo oxygen tension. Simple 1 mm wide electrodes with a polyurethane membrane gave linear current responses to at least 20 mmol/l glucose with a mean response time of 68 s. An acceptable proportion (17%) of electrodes had low or zero drift over 17 h at 37 degrees C. With plasma samples from diabetic and non-diabetic subjects, glucose concentrations measured by the sensor were significantly correlated with values obtained by a reference laboratory glucose analyser but were proportionally lower. Extension of this study to in vivo testing and further miniaturization of electrodes is justified.

Evaluation of a new re-usable electrode for continuous monitoring of blood PO2 during open-heart surgery.

In 46 patients undergoing cardiac surgery blood PO2 was continuously monitored with an in-line oxygen electrode during cardiopulmonary bypass and readings were compared with intermittent measurements of samples on a blood gas analyser. In 35 patients in whom arterial PO2 was monitored, there were rapid changes in PO2 and the mean difference between the in-line electrode and the blood gas analyser was 6.63 kPa (p less than 0.001). Venous PO2 was monitored in 11 patients and, in contrast to the arterial readings, the venous PO2 was relatively stable. The mean difference between the in-line electrode readings and the blood gas analyser was 0.21 kPa (p less than 0.05). The advantages of continuous monitoring of blood PO2 are described and the relative merits of mixed venous PO2 and mixed venous oxygen saturation measurements are discussed.

Continuous monitoring of blood PO2 in extracorporeal systems. An in vitro evaluation of a re-usable oxygen electrode.

The technique of intermittent sampling of blood during extracorporeal circulation and in vitro analysis to establish that the blood-gas status of the patient is within acceptable limits has drawbacks which may be overcome by continuous monitoring. An evaluation of an oxygen monitoring system and a comparison with a blood gas analyser have been performed. Blood of known PO2 was circulated at 15 degrees, 25 degrees and 37 degrees C in an extracorporeal system and the monitor readings and results from samples analysed on a blood gas analyser were compared with calculated partial pressures. There was no significant difference between the calculated value and the monitor readings but the blood gas analyser results were significantly lower (p less than 0.01) than the calculated values of the tonometered blood. The reasons for this difference and the potential clinical advantages of continuous monitoring are discussed.

Metabolic indices of pulmonary damage. Changes in angiotensin converting enzyme and alpha 1 anti-trypsin activity after cardiopulmonary bypass.

The activity of angiotensin-converting enzyme was measured in patients undergoing cardiopulmonary bypass and in a control group requiring thoracotomy for pulmonary surgery. The activity of the enzyme was higher in patients with cardiac disease, fell during operations involving cardiopulmonary bypass, but did not change during thoracotomy for pulmonary surgery. Possible reasons for these differences are discussed. The activity of another enzyme, alpha 1 anti-trypsin, did not change during cardiopulmonary bypass and no arteriovenous difference could be detected during or after operation.