The design of catheters for intraluminal sensing and imaging is confusing and complicated because of the desire to do so much in such a small space. Developing performance criteria, requires an understanding of the different types of objectives to be achieved, as well as how specific design parameters relate to these objectives.

This presentation addresses critical issues one faces in the design and fabrication of microsensors and associated 'on chip' circuitry. It focuses on the constraints which result from the merging of microelectronics and sensors to yield the integrated microsensor. Guidelines for successful microsensor design are given.

A brief review of recent advances in biosensor technologies which have contributed to the development of state-of-the-art biomedical microsensors is given. This is followed by a discussion of potential medical applications in the area of diagnosis and monitoring. The combination of IC fabrication technologies with membrane science has led to a new class of chemically sensitive devices. Those show promise of having important advantages over the conventional ion selective electrodes for biomedical applications. They are small, rugged, require only a very small sample of analyte, have a fast response, are inexpensive, and are compatible with microelectronic readouts. In the second part, some specific electrochemical microfabricated sensors will be given. The results of an - integrated multispecies sensor chip for the measurement of pH, Cl , K? and Na+in physiological fluids will be discussed.

Miniaturized sensors are required for invasive monitoring in research, diagnostic and control applications. Although miniaturized physical sensors can be reproduced rather well, miniaturized chemical sensors are still lacking reproducibility, stability and selectivity. A new chamber-type sensor design allows one, to a good extent, to overcome these problems and improve the performance of miniaturized electrochemical sensors: the thin-film electrodes are contained in a chamber formed by a carrier material and a thin insulation layer. The substance to be measured diffuses through a hole in the chamber, which is filled with an electrolyte and thus contains a complete electrochemical cell with working and reference electrodes. These devices can be made small enough in order to be added onto catheters in order to achieve measurements at various points along the catheters.

During the last 15 years we have developed and applied several types of catheter-mounted ultrasonic Doppler transducers for sensing coronary blood flow in man. Validation studies in the laboratory and in animals have shown that these catheters can accurately measure velocity from a small sample volume located ahead of the catheter tip. The Doppler transducers have been miniaturized enough to be mounted on the tip of a balloon angioplasty catheter without compromising any of the normal functions of the catheter. Good quality, high fidelity velocity signals have been recorded from many sites within the coronary circulation of patients during coronary arteriography and during balloon angioplasty.

An enzyme-based amperometric glucose sensor comprising a cylindrical hydrogen peroxide electrode with oxygen permeable walls and a glucose permeable tip is developed. The sensor has minimal oxygen dependency, low sensitivity to stirring and extended catalytic activity in vitro. The sensor monitored blood glucose levels reasonably well over two-day to three-day periods. However, long term blood exposures (two weeks) diminished the sensor sensitivity for glucose measurements.

Microsensors are increasing in importance in many fields, including medicine, analytical chemistry, and biology. Our recent efforts have focused on biosensors employing antibodies or receptors in conjunction with optical fibers for detecting chemical species of interest. In particular, we have attempted to integrate novel technologies in fluorescence spectroscopy, bioorganic chemistry, immunochemistry, and fiber optics to construct improved microsensors. Recent results of these efforts will be described.

Laser Doppler flowmetry is a method for the continuous and non-invasive recording of tissue blood flow. The method has already proved to be advantageous in a number of clinical as well as theoretical medical disciplines. In dermatology, plastic- and gastrointestinal surgery laser Doppler measurements have substantially contributed to increase knowledge of microvascular perfusion. In experimental medicine, the method has been used in the study of a great variety of microvascular problems. Spontaneous rhythmical variations, spatial and temporal fluctuations in human skin blood flow are mentioned as examples of problem areas in which new knowledge has been generated. The method has facilitated further investigations of the nature of spongeous bone blood flow, testis and kidney cortex blood flow. Recently we have showed that a variant of the laser Doppler method principle, using a single optical fiber, can be advantageous in deep tissue measurements. With this method laser light is transmitted bidirectionally in a single fiber. The tissue trauma which affects blood flow can be minimized by introducing small diameter fibers (0.1-0.5 mm). A special set-up utilizing the same basic principle has been used for the recording of blood flow in small vessels.

A non-invasive monitoring instrument of Cardiogreen (Indocyanine green) dye removal by a liver, which uses a new optical sensor and analytical method, was developed. The optical sensor utilizes 2 light emitting diodes operating at 810 and 940 nm wavelength, and 1 photodiode to sample the transmittance of light through the tip of the index finger. Since the transmittance of light is affected most by changes in both blood volume and the concentration of the dye in blood, adequate analysis must be taken to eliminate the change of blood volume in vivo. Fortunately, for a wavelength near the 805 nm isobestic wavelength, the transmittance of light does not vary with hemoglobin oxygen saturation, however it varies with hemoglobin content. In addition, at 805 nm wavelength, absorption by the dye is quite high, but it is quite low at 940 nm wavelength. Accordingly, the authors developed a new analytical. method by using the transmittance of light measured through the tip of the index finger before and after the dye injection. As a result, the change of blood volume in vivo was eliminated by using the newly developed analytical method. Therefore, the dye information was only measured. A quantitative estimation of plasma disappearance rate (PDR) in hepatic diseased patients which was obtained using this instrument showed that PDR values concurred fairly well with the PDR values from the blood sampling method.

A fiber optic velocity sensor was developed based on optical heating of a fluoropticTm temperature sensor. Infrared radiation is pumped into the temperature sensor, thereby raising its equilibrium temperature. When the heated sensor is placed in thermal contact with a flowing fluid, heat is carried away by the fluid, lowering the sensor temperature. This energy loss is correlated to local flow rate or velocity. This approach to flow measurement is the optical analogy of the hot wire/hot film anemometer. The velocity probe consists of a single multimode optical fiber with temperature sensitive phosphor and heat absorber material attached to the tip. A short pulse of blue excitation light pumped into the fiber causes the phosphor to fluoresce. After the exitation has terminated, the exponential decay time of the fluorescent radiation intensity is measured and correlated with temperature. The optical heating energy is provided by a continuous wave (CW) infrared laser diode. The infrared light pumped into the fiber impinges on the absorber material, heating the phosphor sensor. The temperature measurement is utilized in a feedback control loop to modulate the CW laser diode. The sensor temperature is maintained constant utilizing pulse width modulation of laser diode drive current. The resulting duty cycle (laser input energy) is correlated to fluid flow velocity. Data are presented for volumetric flow rates in the range of 0 to 10 liters/minute in a 1.9 cm diameter tube showing very promising results.

A perfusion sensor was constructed by integrating a diode laser, two photodiodes and two current-voltage convertors in a small (diameter 17 mm and height 13 mm) and light (6 grams) probe. The perfusion is determined from intensity fluctuations on the detectors. These are induced by interference of light scattered in tissue which is partly frequency shifted by scattering at moving blood cells. This causes via heterodyne detection intensity fluctuations with frequencies equal to the frequency shift due to the Doppler effect. In a signal processor, which is connected with flexible electrical leads to the probe, the first moment and the weighted first moment of the spectral density of the intensity on the photodiodes are calculated. These signals are proportional to respectively the perfusion and the mean velocity of blood cells. In order to determine the measurement volume of the probe a Monte Carlo simulation program for the measurements was developed. The simulations show that the depth and the width of the probe volume is proportional with the distance between the diode laser and the photodiodes. Absorption of tissue decreases the depth of the probe volume. With these calculations we have demonstrated to be able to distinguish between blood flow at different depths in tissue, which is important for skin perfusion measurements in order to distinguish capillary blood flow from flow in the plexus beneath.

Evanescent fiber optic sensors are being developed for remote in situ immunoassay. The evanescently excited fluorescence can be collected from either the proximal or distal end of the sensing fiber. The tradeoffs between the two directions of collection are investigated to determine the efficiency of fluorescence detection. Tetramethylrhodamine was used as the fluorescent standard with excitation by the 514.5nm line of an argon laser. A comparison of the two collection geometries demonstrated that although the distal end collection had a higher background, similar fluorescence concentrations were detected. The immunoassay technique was demonstrated with the specific binding of tetramethylrhodamine-conjugated goat anti-human immunoglobulin G (aH-IgG) to preadsorbed H-IgG on the sensor surface. A detection limit of 14nmole/L was measured. Future improvements and disadvantages of the current optical system are discussed, as well as the importance of quantifying the protein concentration in terms of the fluorescence.

An optoelectronic system for measuring vibrational amplitudes below one micron has been developed. It was used to determine the microvibrational characteristics of the ossicles elicited by a prototype stimulator of an implantable middle ear hearing aid and the vibrational amplitude of a piezo-minifilm or silicon minidiaphragm of an implantable microphone design. Using a laser as light source a resolution of .005 micron was reached. Practical design using commercially available devices are surveyed.

A new type of pressure sensor, using fiber optic measurement techniques, has been designed and tested for biomedical applications. It has the advantage of being able to avoid kinetic errors when measuring static pressure under flow conditions. The sensor consists of two parts, a diaphragm which converts the pressure into mechanical displacement, and a fiber optic displacement sensor which converts the mechanical displacement into a light intensity change. The fiber optic displacement sensor is composed of two fibers which are polished at their endfaces, aligned and attached to the diaphragm. A theoretical analysis shows that a small displacement generated by the diaphragm is linearly related to the transmitting light intensity loss, and this relationship has been experimentally obtained with a linearity of ±1.796, and a slope of 2.36mV/um. Regression analysis yielded a 0.9983 correlation coefficient. The complete fiber optic pressure sensor has a sensitivity of 2.03mV/mmHg with a linearity of ±1.3%, and the correlation coefficient of 0.9991. The results suggest that this kind of sensor may have very promising applications for catheter based in vivo static pressure measurements.

Voltage-sensitive dyes bind to the plasms membrane of excitable cells (ie., muscle or nerve cells) and exhibit fluorescence and/or absorption changes that vary linearly with changes in transmembrane electrical potential. These potentiometric optical probes can be used to measure local changes in transmembrane potential by monitoring optical signals from dye molecules bound to the surface membrane. Consequently, when excitable cells are stained with such a dye and are stimulated to fire an electrical impulse (ie., an action potential (AP)), the changes in dye fluorescence have the characteristic shape and time course of APs recorded with an intracellular micro-electrode. Potentiometric dyes in conjuction with imaging techniques can now be used to visualize complex patterns and propagation of electrical activity. With photodiode arrays on video imaging techniques, patterns of biological electrical activity can be obtained with high temporal and spatial resolution which could not be obtained by conventional micro-electrodes. These methods reveal new details and offer powerful approaches to study fundamental problem in cardiac electrophysiology, communication in nerve networks, and the organization of cortical neurons.

Measurement of systolic wall thickening by sonomicrometry is an accurate index of regional left ventricular (LV) function, but the trauma of crystal inserion precludes its clinical use. We have developed a 4-mm 10 MHz ultrasonic probe which can either be sutured or applied via suction to the epicar-diuui and can measure wall thickening at anv depth of the LV wall. In 18 dogs, the suction probe correlated well (r=0.97) with previously validated sutured probe. To assess clinical feasibility, the probe was applied to the epicardium of 45 patients undergoing coronary bypass surgery. Good wall thickening tracings were obtained with no trauma. Transmural LV thickening fraction prior to bypass surgery was 32 ± 6 % (X ± SEM) at the midventricular lateral wall, 29 ± 5 % at the anterior basal wall and 25 ± 5 % at the midventricular posterior wall. Right ventricular thickening fraction averaged 25 ± 4 %. In general, wall thickening during immediate postoperative period remained unchanged compared to preoperative thickening fraction. Exteriorization of a wire attached to the sutured probe allows in situ monitoring of wall thickening for 48-72 h after surgery and subsequent removal. Thus, this probe is an accurate, atraumatic method for measuring right and LV regional function. Transmural, endocardial and epicardial function can be mapped at various sites during surgery and post-operatively one can follow serial changes of regional function and assess the effects of cardioplegia and other therapeutic interventions.

Studies attempting to define the role of the respiratory tract in heating and humidifying inspired air point to the need for sensing many variables including airway wall and airstream temperatures, humidity, and surface fluid pH and osmolarity. In order to make such measurements in vivo in human volunteers, catheter based technologies must be exploited both to assure subject safety and subject comfort. Miniturization of the electrodes or sensors becomes a top priority. This paper describes the use of thin-film microelectronic technology to fabricate a miniature, flexible sensor which can be placed directly onto the surface of the airway to measure the electrical conductance of the fluids present. From this information the osmolarity of the surface fluid was calculated. Physiologic evaluation of the device and corroboration of the calculations was performed in mongrel dogs. We also describe the successful application of current thermistor technology for the thermal mapping of the airways in humans in order to characterize the dynamic intrathoracic events that occur during breathing. The thermal probe consisted of a flexible polyvinyl tube that contained fourteen small thermistors fixed into the catheter. Data have been obtained in dozens of people, both normal subjects and asthmatic patients, under a variety of interventions. These data have substantively advanced the study of asthma, a particularly troublesome chronic obstructive pulmonary disorder.

Significant progress in methods for the treatment of arterial disease has been made during the past several years. The trend towards least invasive therapies has led to an increasing need for instruments which quantify arterial disease status before, during, and after an intervention or treatment. Such instruments should provide safer and more effective disease treatment by providing the physician with a procedure guidance tool. The use of miniature ultrasound transducers, mounted at the distal end of a vascular catheter or probe, offers a promising method for producing images and quantitative measure-ment of arterial lumen and wall thickness. Several approaches have been suggested for placing the transducers in a probe configuration which is then mounted in a catheter and advanced to the vascular site of interest for image generation. The "best" probe configuration is defined by the specific questions of interest to the physician. It also depends upon transducer characteristics and how the sound beam "interacts" with the arterial wall. Imaging the small diameter coronary arteries, in particular, requires careful consideration of various transducer-tissue parameters. Transducer signal-to-noise ratio will likely be a critical parameter for systems designed to image healthy and diseased coronary arteries. The reported study shows how arterial wall echo amplitude changes as the angle between sound beam and wall varies. Changes are measured under carefully defined laboratory conditions.

One of the major unresolved problems in the development of laser angioplasty is in monitoring the process of plaque ablation in real-time to provide the necessary operator feedback. As part of a project to test the feasibility of intravascular imaging with ultrasound we have developed, constructed, and tested a 20 MHz transmitter/receiver which can detect echoes from transducers small enough to fit on a 3-F (1 mm diameter) catheter. Resolution with a small aperture (0.5 x 1.0 mm) focused transducer is about 0.25 mm in both axial and longitudinal directions at 1.5 to 6.0 mm from the transducer face. Images of arteries made in the laboratory with a simple rotational scanner have sufficient resolution to show lumen size and geometry, wall thickness, branches, and craters caused by laser ablation. From these initial studies intravascular ultrasonic imaging appears feasible.

Presently many recanalization methods are being developed to reopen obstructed arteries during catherization. Spark erosion is such a new obstruction removal technology. As reported by Slager et al (1), spark erosion can be used to evaporate atherosclerotic plaque and other arterial obstructions. The technique was studied in specimen of human aorta obtained at autopsy. It works well on fatty and fibrous tissue. The method is less suited for removal of purely calcified areas. The removal of obstructing tissue and the healing response are important parameters, but so is the steerability of the ablation process. one of the main problems is arterial curvature and the asymmetry of the obstruction in relation to the arterial wall. In many of the newly proposed recanalization methods, this asymmetry introduces the risk of arterial wall perforation. For optimal use knowledge of the localization and geometry of arterial obstruction is necessary. Catheter tip ultrasonic guidance seemed a good choice. In principle it can be combined with spark erosion, which in turn can be made steerable by the use of multiple electrodes.

This paper describes experimental results of tests performed on cadaver arteries using a pulsed ultrasonic imaging transducer. Computer generated three-dimensional hidden line images based on pulsed data show the artery thickness both in normal areas and in areas with complex plaque. Thin fatty deposits on the interior artery wall are also imaged. A series of ultrasonic echo images were taken on human aorta plaque deposits and the corresponding set of histological sections prepared. A side-by-side presentation is made in which specific plaque features and internal structures are identified ultrasonically and verified on the histological section. The performance of the ultrasonic transducer is consistent with an ability to perform ultrasonic signature arterial tissue typing. The transducer is sized to allow mounting within a 0.8 mm catheter that is equipped with a guide wire and a laser delivery system.

A prototype ultrasonic imaging system typical of the size necessary to be embedded in a catheter delivery system was developed to examine the feasibility of high resolution, intravascular ultrasonic imaging in vivo. Although the current system is too large to be useful in examination of proximal coronary arteries, the signal-to-noise ratio (SNR) and resolution obtained clearly indicate that catheter-borne, intravascular ultrasonic imaging is indeed feasible and could be very informative as an adjunct to angioplasty or vascular surgery.

A catheter based percutaneous transluminal ultrasound imaging system has been developed by Summit Technology which enables the vascular surgeon or radiologist to acquire real-time ultrasonic images of the cross-section of blood vessels from the unique vantage point of being inside of the vessel lumen. This system was developed for use in the human vascular system to assist in the diagnosis and treatment of vascular disease.

The musocal surface of the intestine may be inspected by physicians using flexible fiberoptic endoscopes. Ultrasound energy can be used with these endoscopes to interrogate beyond the surface of the intestine and acquire information about the wall and adjacent tissue. Combined ultrasonic and fiberoptic probes have been built for this purpose, but the combination of both modalities results in a complex endsocope. Alternatively, we have developed miniature ultrasonic probes that can be used as an accessory devices for standard endoscopes. Probes have been built to obtain either a cross sectional image of the wall or acquire blood flow information. Technical details of the probes, their fabrication, and representative results are given.

We report on a new imaging catheter using high frequency ultrasound to produce short range (8 mm), high resolution rotary scan images from within blood vessels. The objective of the system is to aid the interventional physician in performing angioplasty on stenoses. This system provides an adjunct, and potentially an alternative, to fluoroscopy and optical angioscopy in the diagnosis and visualization of stenotic lesions. We have constructed prototypes of a 6 F (2 mm) system and begun clinical evaluation in human peripheral vessels.

Medical science now dictates more precise and more physiological treatment of disorders in the circulation and myocardium. One of the major limitations of conventional catheters, laser catheters, angioscopes and other flexible micro-instrumentation is that their distal ends are not functionally maneuverable. Catheter Research, Inc. has developed an angulation mechanism using shape memory alloys to manipulate the distal tip of a catheter, fiber optic bundle, or other flexible micro-instrumentation. This technology features the following: 1. Controlled angulation of the tip 2. Precise tip placement 3. Miniature size 4. Advancement of a catheter, angioscope, or fiber optics bundle without a guide wire 5. Center lumen of catheters which are free of any obstructions and adaptable for use of fiber optics or micro-instrumentation