Dual-modality probe intended for prostate cancer detection combining Raman spectroscopy and tactile resonance technology--discrimination of normal human prostate tissues ex vivo.

Prostate cancer is the most common cancer for men in the western world. For the first time, a dual-modality probe, combining Raman spectroscopy and tactile resonance technology, has been used for assessment of fresh human prostate tissue. The study investigates the potential of the dual-modality probe by testing its ability to differentiate prostate tissue types ex vivo. Measurements on four prostates show that the tactile resonance modality was able to discriminate soft epithelial tissue and stiff stroma (p < 0.05). The Raman spectra exhibited a strong fluorescent background at the current experimental settings. However, stroma could be discerned from epithelia by integrating the value of the spectral background. Combining both parameters by a stepwise analysis resulted in 100% sensitivity and 91% specificity. Although no cancer tissue was analysed, the results are promising for further development of the instrument and method for discriminating prostate tissues and cancer.

Combining scanning haptic microscopy and fibre optic Raman spectroscopy for tissue characterization.

The tactile resonance method (TRM) and Raman spectroscopy (RS) are promising for tissue characterization in vivo. Our goal is to combine these techniques into one instrument, to use TRM for swift scanning, and RS for increasing the diagnostic power. The aim of this study was to determine the classification accuracy, using support vector machines, for measurements on porcine tissue and also produce preliminary data on human prostate tissue. This was done by developing a new experimental set-up combining micro-scale TRM-scanning haptic microscopy (SHM)-for assessing stiffness on a micro-scale, with fibre optic RS measurements for assessing biochemical content. We compared the accuracy using SHM alone versus SHM combined with RS, for different degrees of tissue homogeneity. The cross-validation classification accuracy for healthy porcine tissue types using SHM alone was 65-81%, and when RS was added it increased to 81-87%. The accuracy for healthy and cancerous human tissue was 67-70% when only SHM was used, and increased to 72-77% for the combined measurements. This shows that the potential for swift and accurate classification of healthy and cancerous prostate tissue is high. This is promising for developing a tool for probing the surgical margins during prostate cancer surgery.

Technologies for localization and diagnosis of prostate cancer.

The gold standard for detecting prostate cancer (PCa), systematic biopsy, lacks sensitivity as well as grading accuracy. PSA screening leads to over-treatment of many men, and it is unclear whether screening reduces PCa mortality. This review provides an understanding of the difficulties of localizing and diagnosing PCa. It summarizes recent developments of ultrasound (including elastography) and MRI, and discusses some alternative experimental techniques, such as resonance sensor technology and vibrational spectroscopy. A comparison between the different methods is presented. It is concluded that new ultrasound techniques are promising for targeted biopsy procedures, in order to detect more clinically significant cancers while reducing the number of cores. MRI advances are very promising, but MRI remains expensive and MR-guided biopsy is complex. Resonance sensor technology and vibrational spectroscopy have shown promising results in vitro. There is a need for large prospective multicentre trials that unambiguously prove the clinical benefits of these new techniques.

Tactile resonance sensors in medicine.

Tactile sensors in general are used for measuring the physical parameters associated with contact between sensor and object. Tactile resonance sensors in particular are based on the principle of measuring the frequency shift, Deltaf, defined as the difference between a freely vibrating sensor resonance frequency and the resonance frequency measured when the sensor makes contact to an object. Deltaf is therefore related to the acoustic impedance of the object and can be used to characterize its material properties. In medicine, tactile resonance sensor systems have been developed for the detection of cancer, human ovum fertility, eye pressure and oedema. In 1992 a Japanese research group published a paper presenting a unique phase shift circuit to facilitate resonance measurements. In this review we summarize the current state-of-the-art of tactile resonance sensors in medicine based on the phase shift circuit and discuss the relevance of the measured parameters for clinical diagnosis. Future trends and applications enabled by this technology are also predicted.

An image analysis method for prostate tissue classification: preliminary validation with resonance sensor data.

Resonance sensor systems have been shown to be able to distinguish between cancerous and normal prostate tissue, in vitro. The aim of this study was to improve the accuracy of the tissue determination, to simplify the tissue classification process with computerized morphometrical analysis, to decrease the risk of human errors, and to reduce the processing time. In this article we present our newly developed computerized classification method based on image analysis. In relation to earlier resonance sensor studies we increased the number of normal prostate tissue classes into stroma, epithelial tissue, lumen and stones. The linearity between the impression depth and tissue classes was calculated using multiple linear regression (R(2) = 0.68, n = 109, p < 0.001) and partial least squares (R(2) = 0.55, n = 109, p < 0.001). Thus it can be concluded that there existed a linear relationship between the impression depth and the tissue classes. The new image analysis method was easy to handle and decreased the classification time by 80%.

Comparison of Goldmann applanation and applanation resonance tonometry in a biomicroscope-based in vitro porcine eye model.

We have developed an in vitro porcine eye model based on a biomicroscope, to simulate a clinical situation for IOP measurement on enucleated eyes. The aims of this study were to evaluate the model and to apply and compare Goldmann applanation tonometry (GAT) and applanation resonance tonometry (ART) measurements in porcine eyes. The GAT measurement (IOPGAT) showed a lower pressure, mean - 14.0 mm Hg (SD = 1.7 mm Hg) as compared with the reference pressure. For in vitro measurement with GAT on porcine eyes the linear calibration was IOP = 1.14 IOPGAT + 12.5 mm Hg (R2 = 0.99, p < 0.001, n = 280, four eyes). ART measurements correlated significantly to reference IOP, R = 0.86 (p < 0.001, n = 252, six eyes), with a mean difference of 5.4 mm Hg (SD = 6.7 mm Hg). GAT could only be used on porcine eyes if the IOP exceeded 13 mm Hg. Evaluation of the ART in this in vitro model showed position dependence for the sensor. To facilitate centre positioning a guiding tool is suggested. Porcine eyes are a possible substitute for human eyes in in vitro models for pre-clinical evaluation of new tonometry methods.

Evaluation of applanation resonator sensors for intra-ocular pressure measurement: results from clinical and in vitro studies.

Glaucoma is an eye disease that, in its most common form, is characterised by high intra-ocular pressure (IOP), reduced visual field and optic nerve damage. For diagnostic purposes and for follow-up after treatment, it is important to have simple and reliable methods for measuring IOP. Recently, an applanation resonator sensor (ARS) for measuring IOP was introduced and evaluated using an in vitro pig-eye model. In the present study, the first clinical evaluation of the same probe has been carried out, with experiments in vivo on human eyes. There was a low but significant correlation between IOP(ARS) and the IOP measured with a Goldmann applanation tonometer (r = 0.40, p = 0.001, n = 72). However, off-centre positioning of the sensor against the cornea caused a non-negligible source of error. The sensor probe was redesigned to have a spherical, instead of flat, contact surface against the eye and was evaluated in the in vitro model. The new probe showed reduced sensitivity to off-centre positioning, with a decrease in relative deviation from 89% to 11% (1 mm radius). For normalised data, linear regression between IOP(ARS) and direct IOP measurement in the vitreous chamber showed a correlation of r = 0.97 (p < 0.001, n = 108) and a standard deviation for the residuals of SD < or = 2.18 mm Hg (n = 108). It was concluded that a spherical contact surface should be preferred and that further development towards a clinical instrument should focus on probe design and signal analysis.

Intestinal pHi studied with continuous saline tonometry during ischaemia and reperfusion in the pig.

OBJECTIVE: To evaluate continuous saline tonometry for detection of progressive intestinal ischaemia and reperfusion in a porcine model. DESIGN: In eight anaesthetised pigs, small bowel mucosal pCO2 was recorded by means of two identical equipments for continuous saline tonometry and a standard tonometry balloon during ischaemia and reperfusion. RESULTS: Both systems of saline tonometry functioned stably during the four hour protocol ischaemia, although not significant until after 45 min for one of the tonometers. CONCLUSION: The equipment for continuous saline tonometry has a good reactivity, an accuracy comparable with standard tonometry.

A resonator sensor for measurement of intraocular pressure--evaluation in an in vitro pig-eye model.

Intraocular pressure (IOP) measurement is performed routinely at every eye clinic. High IOP, which can be a sign of glaucoma, can lead to degeneration of the retina and can cause blindness. In this study we developed a resonator sensor for IOP measurement based on an oscillator consisting of a piezoelectric element made of lead zirconate titanate, a flat contact piece of nylon and a feedback circuit. The aim of this study was to evaluate the new sensor's ability to determine lOP in an in vitro pig-eye model. Six eyes from four pigs were removed and fixed in agar. They were then pressurized by a saline column (10-35 cm H2O) through a cannula inserted into the vitreous chamber. The IOP was measured with the resonator sensor applied to cornea. An Alcon applanation pneumatonometer and a standard Viggo-Spectramed pressure sensor connected to the saline column were used as references. The IOP as measured with the resonator sensor correlated well with the pressure elicited by the saline column for individual eyes (r = 0.96-0.99, n = 60) and for all eyes (r = 0.92, n = 360). The correlation between the resonance sensor and the pneumatonometer was r = 0.92 (n = 360). The pneumatonometer also showed a good correlation with the saline column (r = 0.98, n = 360). We conclude that our in vitro pig-eye model made it possible to induce reproducible variation in IOP, and measurement of that pressure with the newly developed resonator sensor gave very promising results for development of a clinically applicable IOP tonometer with unique properties.

Non-invasive assessment of fluid volume status in the interstitium after haemodialysis.

During dialysis excess fluid is removed from uraemic patients. The excess fluid is mainly located in the skin and subcutaneous tissues. In this study we wished, with two noninvasive techniques, the IM (impression method) and BIA (bioimpedance analysis), to study what mechanical (IM) and electrical cellular membrane (BIA) effects the fluid withdrawal has on these tissues. The IM measures the resistive force of the tissues when mechanically compressed. From the force curve two parameters are calculated, the F(0), indicative of interstitial tissue pressure and the FT corresponding to the translocation of tissue fluid (interstitial movable water). The BIA phase angle shift (phi), i.e. geometrical angular transformation of the ratio between reactance and resistance, which has been associated with cellular membrane function, was used as a measurement of electrical cellular membrane effects. Twenty patients were studied before and after haemodialysis measuring the F(0), FT and phi. Theresults showed that the patients lost a median of 3.7 kg during the haemodialysis. F(0) increased until after dialysis, but did not reach significant values, whereas FT increased significantly after dialysis, p < 0.001, as compared with before. After a peak at one hour postdialysis the FT value returned to predialysis values at four hours after termination of dialysis. Also phi increased from before to after dialysis, p < 0.001, but already after one hour it returned to predialysis values. It is common knowledge that dialysis alters the dynamics of fluid in the interstitium of the skin and subcutis. We conclude that the impression method is sensitive enough to detect and chronicle these changes. Furthermore, with the BIA, (phase angle) signs of changes in the electrical properties of the tissues, possibly reflecting cellular membrane function, could be detected.

A new method for continuous tonometric pCO2 measurement--in vitro studies.

The available methods for tonometric pCO2 measurement only provide the possibility of performing intermittent registrations. A new method allowing continuous tonometric pCO2 measurement has been developed and tested in an in vitro model. A standard tonometer for intestinal pCO2 measurement was modified to allow continuous perfusion of the balloon with physiological saline solution in a closed system. The pCO2 in the system was determined in a specially constructed measurement chamber with a TCM20 percutaneous pCO2 monitor. In this in vitro model the tonometer balloon was placed in a saline bath with a constant pCO2 concentration and the measurements from the closed circulating system were compared with those obtained from a standard tonometer placed in the same bath. In 8 and 24 h experiments the circulating system measured the pCO2 value as accurately and reliably as traditional tonometry. This study indicates that the new method makes continuous monitoring of pCO2 possible.

A catheter tactile sensor for measuring hardness of soft tissue: measurement in a silicone model and in an in vitro human prostate model.

Tissue hardness is related to tissue composition, and this is often changed by disease. It is therefore of interest to measure the hardness in an objective and non-invasive way. A tactile sensor based on a vibrating piezoelectric ceramic element in a feedback loop is described. When the sensor touches an object it produces a frequency shift related to the hardness of the object. The aim of this study was to develop an in vitro hardness measurement method using a catheter type version of the sensor. The method was evaluated in an established silicone tissue model and on human prostate tissue in vitro. A linear relationship was found with a high degree of explanation (R2 = 0.98) between a cone penetration hardness standard (DIN ISO 2137) applied to the silicone model and the corresponding frequency shift. The results from measurements on a human prostate tissue sample, fixed with formalin, showed that the relative hardness measured with the tactile sensor correlated (R = -0.96, p < 0.001, N = 60) with the proposed hardness related to the histological composition of the prostate tissue. The results indicated that hardness of prostate tissue, and maybe hardness of human tissue in general, can be expressed according to the cone penetration standard and that the hardness can be measured with this tactile sensory system. These findings hold the promise of further development of a non-invasive tool for hardness measurement in a clinical situation.

A tactile sensor for detection of physical properties of human skin in vivo.

A spring loaded tactile sensor with displacement sensing has been evaluated for non-invasive assessment of physical properties, stiffness and elasticity, of human skin in vivo. The tactile sensor consists of a peizoelectric vibrator (61 kHz) with a vibration pickup, electronics and PC with software for measurement of the change in frequency when the sensor is attached to an object. Integrated with the tactile sensor is a displacement sensor that shows the compression of the spring that loads the sensor element against the object during measurement. Under certain conditions (e.g. fixed contact pressure) this change in frequency monitors the acoustic impedance of the object and is related to the stiffness of soft tissue. The experimental results on silicone gum and on healthy Japanese and Swedish women indicated that the instrument was able to detect changes in stiffness and elastic related properties of human skin, related to age, day-to-day variations and application of cosmetics. The instrument was concluded to be easy to handle and suitable for field work.

Non-invasive assessment of intercompartmental fluid shifts in burn victims.

Two non-invasive methods (the bioimpedance technique, BIA, and the impression method, IM) were studied, to find out whether they are sensitive enough to detect and chronicle the development of the oedema and fluid resuscitation effects (Parkland formula) that occur secondary to a major burn. Ten patients with a total burned body surface area (TBSA) of more than 10% were included in this prospective study. Total body water (TBW), as measured by the resistance (BIA) or F(0) variable (IM), reached a maximum on day 2. The tissue fluid translocation (INT) variable (IM) followed a different course, increasing slowly to reach a maximum on day 6, when it was 40% higher than the 12 h value. TBW and the interstitial translocatable fluid were still increased 1 week post-burn. The non-invasive measurements of TBW (resistance by BIA and F(0) by IM) reflected the anticipated changes in TBW. The phase angle (BIA) indicative of cellular membrane effects of burn and sepsis had its lowest values at day 1.5, and stayed significantly low until day 4. Interestingly, the phase angle was lowest in the two cases that died subsequently. The different time course of the INT value (IM), which reflected the translocatable interstitial fluid volume in skin, may be the result of resuscitation fluid remaining in this compartment, due to the excess sodium content together with a possible change in tissue compliance secondary to the early total water peak on day 2.

Monitoring of renal pelvic pressure in patients with hydronephrosis.

A diagnostic method for the determination of obstructions in the pelvoureteral junction in patients with suspected idiopathic hydronephrosis is described and discussed. Two microtransducer catheters (MTCs) with infusion lumens are inserted under fluoroscopic control, one into the renal pelvis and the other in the perirenal space as a reference. The pressure values obtained are stored on a portable microcomputer system, carried by the ambulatory patients. Renal pelvic pressure, intra-abdominal pressure and differential pressure are calculated and displayed as time-pressure diagrams on a plotter. The pressures can be measured for long periods (3-24 h). Furthermore, steady state conditions can be evaluated during pelvic infusion of saline. The results from the pressure measurements are compared with clinical and radiological evaluations. Our results show that this method of long-term monitoring of intrapelvic pressure together with intra-abdominal pressure contributes to the evaluation of patients with suspected pelvoureteral obstructions and complements other methods in the preoperative investigation. However, this study reveals difficulties with measurements of intra-abdominal pressure. Carrying the equipment was not inconvenient for the patients.

The evaluation of a biexponential model for description of intercompartmental fluid shifts in compressed oedematous tissue.

A parametric model was fitted to force curve data gained by a non-invasive impression method that measures force and fluid translocation during mechanical compression of the skin. The ability of the model parameters to estimate high- and low-viscosity fluid flow in compressed areas were evaluated in a silicone rubber model and in six patients with chronic pitting oedema. Different softnesses of silicone rubber gave significantly different parameter values. The flow properties of the silicone model could be analysed in detail with the suggested model. Parameter analysis showed a higher fraction of low-viscosity fluid for oedema than for reference sites. The model parameters could be interpreted in softness value according to an international standard for consistency (ISO 2137). The suggested parametric model gave reliable and detailed information about high- and low-viscosity fluid flow and can be used to estimate intercompartmental fluid shifts in oedematous tissue.

Impression technique for the assessment of oedema: comparison with a new tactile sensor that measures physical properties of tissue.

To measure tissue oedema, the impression technique and a new tactile sensor technique are compared and evaluated in a silicone rubber model and in an in vivo rat testis model. The principles of the two techniques differ in that the impression technique evaluates interstitial fluid flow FT and peak force F(O) when tissue is compressed, whereas the tactile sensor evaluates the hardness/softness or change in resonance frequency delta f when a vibrating rod is attached to tissue. Both techniques can detect changes in silicone hardness/softness or in hormone-induced changes of testis interstitial fluid. Although both F(O) and FT are significantly correlated to delta f in the experiments, it is concluded that F(O) is the most promising impression parameter to give valuable information about the hardness of living tissue as compared with delta f. The comparison indicates that the impression technique is the most easy to interpret, non-invasive tool to assess tissue oedema so far developed.

Grip strength of the human hand--measurements on normal subjects with a new hand strength analysis system (Hastras).

This study describes a method of acquiring data from healthy and non-injured men that can be used as reference data when measuring the grip strength of the human hand using newly developed, PC-based hand strength analysis equipment--'Hastras'. Hastras can be used for continuous measurement and recording of force when the subject grips a sensor with maximum power. Computerized analysis of the force signal gives information about maximum force, fatigue, area and rise (force/s). The statistical analysis of the measurements on 81 subjects are consistent with earlier published data from other hand strength equipment. It is concluded that Hastras gives easy processing and storage of data, and also a detailed analysis of grip function.

Human postburn oedema measured with the impression method.

The course of tissue swelling in human non-injured skin after burn injury was investigated with a non-invasive impression method that measures force and tissue fluid translocation during mechanical compression of the skin. Time-dependent changes in the fluid translocation and the interstitial-pressure related to impression force were measured on 11 occasions, during 3 weeks, in seven patients postburn. A mathematical model was fitted to the impression force curves and the parameters of the model depicted the time-dependent compartmental fluid shift in the postburn generalized oedema. Tissue fluid translocation increased significantly (P < 0.05) up to a maximum value after 6 days postburn and declined thereafter. This indicated a continuous increase in the generalized postburn oedema for the first 6 days postburn. Impression force at 3 weeks postburn was significantly lower (P < 0.001) as compared with the half-day postburn value, indicating an increased tissue pressure during the first days postburn. Parameter analysis indicated a flux of water-like fluid from the vasculature to the interstitial space during the first 6 days postburn. The spread of the values registered between different measurement sites was, however, large.