This Small Business Innovation Research (SBIR) Phase I project will develop a compact, widely-tunable, high-brightness laser diode spectrometer that will be the core of an automated point-of-care (POC) monitor capable of tracking key blood metabolites for patients in intensive care units. The tunable laser is based on a 2.4 micron wavelength laser diode that utilizes antimonide III-V semiconductor materials and is coupled to an external cavity. A high-brightness source will be a great aid for spectroscopy in turbid solutions with low optical throughput like whole blood. The tunable laser spectrometer will have significantly higher brightness than is available with conventional broad-band sources. The wide tunability required to differentiate the spectral signatures of the target analytes from those of other biomolecules will be achieved first by broadening the gain spectrum through a series of quantum wells with staggered emission wavelengths, and second, by fabricating laser devices using a curved-waveguide geometry to suppress optical feedback from the laser diode facets. An intracavity, temperature-controlled acousto-optic tunable filter will provide the necessary wavelength stability and tuning range, giving the instrument a rugged, compact, all-solid state design with no moving parts. The tunable laser diode will enable direct spectroscopic measurements in small volumes of whole blood.
The broader impact/commercial potential of this project is to significantly enhance patient care. The point-of-care monitor based on this tunable laser spectrometer will provide automated measurement of key blood metabolites at the bedside and semi-continuous monitoring of metabolic status. The monitor will periodically collect absorption spectra of a small blood sample, and reinfuse the blood into the patient through an arterial catheter, allowing regular monitoring of glucose, urea, creatinine and lactate. Regular monitoring of glucose enables the use of intensive insulin therapy, which has been shown to improve the outcome of intensive care unit patients. Tracking urea and creatinine concentrations provides a measure of renal function that can be used for early identification of acute kidney failure. Detection of elevated lactate concentrations can be used as an indicator of metabolic distress for unstable patients. The tunable laser-based point-of-care monitor can provide more information than is available now without increasing costs. Unlike standard blood chemistry assays, optical measurements do not require reagents, so there is no incremental cost to limit the frequency of monitoring. Since the measurement results in no blood loss, it is safe to use in patients who would be intolerant of frequent blood draws.
The objective of this Phase I Small Business Innovation Research project was to develop a semiconductor tunable laser diode (TLD) as a high brightness source for near-infrared whole-blood spectroscopy. Specifically, this device was intended to serve as the core of an instrument which would be employed for point-of-care testing (POC) to monitor key blood constituents, such as glucose, lactate, urea, and creatinine, in critically ill patients. The monitor, which would be connected to an arterial catheter, would periodically (e.g., at 5 minute intervals) pull a small blood volume into the catheter, collect absorption spectra of the blood sample necessary for quantifying the target constituents, and reinfuse the blood sample into the patient. As opposed to conventional off-line measurements where a blood sample is drawn and then analyzed in a laboratory, this POC monitor would enable semi-continuous measurements to be made at the bedside, providing real-time feedback to clinicians. Such a capability is expected to improve outcomes for both diabetic and non-diabetic ICU patients by enabling the use of intensive insulin therapy. By tracking urea and creatinine concentrations, a measure of renal function may be determined to help detect the onset of acute kidney failure. In addition, tracking of lactate concentration can provide feedback on metabolic distress, cardiac function, and sepsis, potentially allowing physicians to intervene before a patient’s condition worsens substantially. Tunable laser devices were grown by molecular beam epitaxy (MBE), a highly precise crystal growth technique whereby layers may be deposited with the accuracy of a single atomic layer. To accomplish this high precision growth, a substrate crystal and the materials for deposition are housed in an ultra-high vacuum reactor to ensure high purity of the growing crystal. Furnaces containing the materials are directed at the substrate, and deposition is controlled by furnace temperature and mechanical shutters. This allows very rapid transitions in material composition, a technological necessity as some of the layers in the devices are only 10 nanometers thick. Quantum well structures, where a thin "well" region is surrounded by a "barrier" region to specifically tune the optical properties of the material by quantum confinement of charge carriers, were employed to achieve laser emission in the desired wavelength range. The layers were composed of III-V compound semiconductors; the well regions were composed of InGaAsSb and the other layers in the structure were composed of AlGaAsSb. In total, four laser growth runs were executed with two 3" wafers grown per run. Wafers were fabricated into laser diodes by conventional microfabrication techniques. The laser geometry was defined by photolithography and wet chemical etching, and metal contacts were deposited by electron beam evaporation. An external cavity was constructed to allow tuning of the laser by adjustment of a ruled grating, and spectral measurements were performed with a Fourier transform infrared spectrometer. Laser emission was observed from all devices that were tested, with the wavelength varying from 2.0-2.3 µm. A key goal of this project was to obtain a very wide tuning range, which is critical for making accurate spectroscopic measurements in whole blood. The tuning range measured from one laser diode was 550 cm-1, a significant improvement over previous technology. The widest tuning range that has been reported previously for this type of device was 330 cm?1. Additional development of the material is needed to test alternative designs of the laser structure and optimize the emission properties; however these initial findings are a strong proof of concept for the instrument. In summary, ASL has developed a near-infrared laser diode with wide tunability that is a strong candidate for a high-brightness source for use in whole-blood spectroscopy. This Phase I SBIR project has allowed ASL to demonstrate a device with a much wider tuning range than was achievable with previous material. We anticipate that with further development, this high-brightness source will enable substantial advancement of POC monitoring technology.
