BBI Contributing Editor

PASADENA, California The National Aeronautics and Space Administration (NASA; Washington) has historically been an important source of new technologies that are spun off from the space program for commercial applications. NASA has partnered with hundreds of companies in a variety of industries, including the medical device industry, to develop new products. Recently, the agency has established an aggressive new initiative targeted at companies in the medical device sector, with the goal of introducing promising new technologies having medical applications to potential corporate partners. As part of that initiative, the agency sponsored the first NASA Medical Technology Summit here in mid-February aimed at increasing the involvement of medical device companies in NASA's development efforts.

Examples of NASA-developed technologies that are already commercialized for medical or biotechnology applications include the DeBakey Ventricular Assist Device, now being sold in Europe by MicroMed Technology (Houston, Texas), the Cell Fluorescence Analysis System from Ciencia (East Hartford, Connecticut), the Microvolt T-Wave Alternans Test commercialized by Cambridge Heart (Bedford, Massachusetts) and the accuDEXA Bone Mineral Density Assessment System manufactured by Schick Technologies (Long Island City, New York). The DeBakey VAD, for example, which is undergoing clinical trials in the U.S., is derived from technology used in the fuel pump in the space shuttle.

NASA operates 10 research centers spread across the U.S. on a $1.7 billion annual budget, pursuing more than 1,200 research projects. The agency is involved in more than 4,000 active partnerships with industry, mostly with small and mid-sized firms. NASA has had its greatest number of successes in spinning off technologies in the medical device industry and plans to continue to target that sector for future technology commercialization programs. NASA's mission, the exploration of space, requires it to adopt a unique perspective on life science research, aimed at enabling survival of living organisms in space. Research on the effects of radiation is one focus that can have important applications in earth-based medicine. Robotics that can provide self-sufficient treatment capabilities on long space missions are another example of a technology that also can prove useful in medical applications on earth. The need for smart, autonomous equipment in space has resulted in the development of technologies that may prove valuable in automation of medical procedures, including technologies for addressing problems with medical errors in today's healthcare system. Another important research focus within NASA is miniaturization of sensors and analytical instruments, leading to spin-off of technologies useful in the development of implantable sensors, low-cost and compact imaging devices, telemetry monitors and devices for rapid detection of pathogens.

A wide variety of technologies were presented at the NASA summit, including miniaturized lab-on-a-chip devices, technologies for cancer detection and diagnosis (including technologies under development at the National Cancer Institute), diagnostic imaging technologies, infectious disease detection devices, patient monitoring technologies for use in alternate sites including the home, and non-invasive monitoring technologies. New therapeutic devices also were described, including a unique design for obstetric forceps that can automatically maintain an optimal force level, orthopedic and other types of implant materials with improved biocompatibility, an artificial vision device, and drug delivery devices. Under the Bush administration, there is increased emphasis on the delivery of technology from government to the private sector for public and commercial applications.

Emerging technologies for diagnostics

A number of NASA technologies have potential applications in medical diagnostics, including both in vitro diagnostics as well as areas such as noninvasive monitoring and less-invasive methods for biopsy. Applications in cancer diagnosis are one area of potential opportunity for commercial partners. For example, Daniel Crichton of the Jet Propulsion Laboratory (JPL; Pasadena, California), one of the primary NASA research centers, has adapted its Object Oriented Data Technology, an informatics technology initially developed to provide a data management infrastructure for NASA's Planetary Data System and the Deep Space Network, to applications in early cancer detection. In collaboration with the National Cancer Institute (NCI; Bethesda, Maryland), the technology is now being applied to establish an Early Detection Research Network for identification of new cancer biomarkers. The goal is to develop an integrated on-line database containing information on new cancer markers, including results of clinical evaluations of new markers collected by the centers participating in the network. The network will also allow researchers to locate blood samples archived at other institutions participating in the program that meet specific requirements for evaluation of a new marker. For example, a researcher will be able to identify the location and mode of storage of archived blood specimens from cancer patients in a certain age group, and to evaluate the medical history of the patient who provided the sample. Eighteen labs around the country have agreed to participate in the program, and 10 sites have been integrated into the network so far.

Programs to discover new cancer markers have been transformed by the emergence of genomics and proteomics technologies, including microarray technologies, which are allowing a wide array of potential markers to be evaluated on a single chip. At present, as shown in Table 1, the market for cancer markers is dominated by immunoassay products that measure a specific analyte, such as prostate specific antigen or carcinoembryonic antigen, in serum or whole blood samples. Molecular cancer tests have now emerged in the market, and represent the fastest-growing segment. In the future, the molecular testing segment is expected to become increasingly important, and will expand to include tests employing proteomics technology, making databases such as the NASA/NCI Early Detection Research Network a critical element of cancer research.

Another example of a technology derived fromNASAresearch with applications in cancer detection and diagnosis is a smart biopsy probe under development byBioLuminate(San Jose, California). The BioLuminate Smart Probe originated fromNASAtechnology designed to detect life on Mars during the Mars Lander Experiment. The probe measures six indicators, including oxygen partial pressure, electrical impedance, temperature and light scattering and absorption properties including deoxygenated hemoglobin, vascularization and tissue density. The panel of indicators is then analyzed to determine if cancer is present in a lesion previously identified via a screening exam. The initial application for the BioLuminate device is breast cancer diagnosis, where it is believed that it can help avoid part of the more than 1 million breast biopsy procedures performed annually in the U.S. that are negative for cancer. Because of the use of a combination of six parameters in real time for the measurement,BioLuminatebelieves its smart needle may have an accuracy approaching that of open surgical biopsy, surpassing that of core biopsy, currently the most commonly performed less invasive biopsy technique. Open surgical biopsy is used to perform about 75% of breast biopsies, and core needle biopsy is used to perform the remaining 25%. TheBioLuminatetechnology uses a 20 gauge to 21 gauge disposable needle connected to a computer, vs. the 14-gauge device typically employed for core biopsy today. Since theBioLuminateneedle is about the same size as a blood-sampling needle, the company said it believes it can be used to analyze all of the 8 million suspicious breast lesions uncovered by routine screening (mammography or physical palpation). TheBioLuminateprocedure will cost approximately $525 vs. an average cost of $2,620 for existing breast biopsy procedures.BioLuminateis partnering with bothNASAandLawrence Livermore National Laboratory(Livermore, California) in the development of the device.

The measurement of cancer markers in biopsy samples is another area of research at NASA. As discussed by Dennis Morrison, PhD, of the NASA Johnson Space Center (Houston, Texas) at the summit, a new method for evaluating the metastatic potential of tumor cells has been developed and patented (U.S. patent No. 5,869,238, granted in 1999). The method involves quantitation of urokinase plasminogen activator (uPA) and DNA in cancer cells in a biopsy specimen, and using the patient's own normal cells as a reference. Fluorescent antibodies have been developed against different molecular forms of urokinase and digital image analysis of the cells stained with the antibodies is used to correlate the level of urokinase expression with abnormal DNA content, DNA synthesis rate and selected hormone receptor density as determined by flow cytometric analysis of the same biopsy specimen. The goal is to identify specimens containing cells with metastatic potential, and ultimately to develop targeted therapies that can selectively eliminate those cells. Recent research by other groups has shown that only a small percentage of the cells in a tumor typically have the potential to metastasize, perhaps increasing the value of methods allowing those cells to be identified at an early stage.

Infectious agent detection is another major focus of diagnostics-related research within NASA. The primary impetus for such research within the agency is to develop methods for the detection of spores to insure that spacecraft sent to other planets such as Mars do not carry any life forms that could be mistakenly interpreted as originating from the planet. As described by Adrian Ponce of JPL, one earth-based application of the technology is detection of bacterial spores such as anthrax in the environment to guard against bioterrorist attacks, or to detect contamination in food preparation facilities and hospitals. Current methods of bacterial spore detection involving culture and colony counting or PCR/molecular analysis require trained personnel and are slow. The NASA technology, in contrast, resembles a smoke detector in function, and can provide an early warning of the presence of a lethal spore in seconds. The basis of the technique is the use of microwave energy to burst any spores present in an aerosol sample, followed by dipicolinic acid detection via fluorescence. The prototype device uses a fiber optic luminometer plus an air sampling cartridge and pump. The system sounds an alarm within 15 minutes if more than 100 spores per liter of air are collected. The system also has been shown to be capable of detecting bacillus or clostridium. NASA is partnering with Universal Detection Technology (Beverly Hills, California) to develop a commercial version of the device. Universal Detection is developing a bioterrorism detection system, and NASA has developed the fiber optic luminometer using time-delayed measurement of terbium luminescence used for spore detection.

Another technology for infectious agent detection, described at the summit by Harry Shaw of the NASA Goddard Space Flight Center (Greenbelt, Maryland), uses a sol-gel-filled fiber-optic probe to allow sensing in remote environments. The key advance is use of a hollow-fiber probe, which allows the gel to be fully illuminated by the optics and entraps the molecules to be measured. The probe is designed to be disposable, but not for use as a long-term implant for in vivo monitoring. A second technology for environmental monitoring, which also may have applications in testing of blood or other physiological fluids, uses a miniaturized gas chromatograph/mass spectrograph. The device, which functions as an electronic nose, provides quantitative results and can be applied to breath analysis, body fluid analysis and remote monitoring. A related development is a portable biosensor array for detection of Salmonella and other organisms in water supplies, developed jointly with the Office of Naval Research.

Perhaps one of the most important NASA technologies for diagnostic testing, at least in terms of the size of the target market, is one for noninvasive monitoring of glucose and other small molecule analytes. One approach under development at Jet Propulsion Laboratory and the California Institute of Technology (Pasadena, California) uses Raman spectroscopic analysis of the aqueous humor of the eye to measure the concentration of specific analytes including glucose, ethanol, lactate and urea. The technology also has been used to measure levels of large molecules (drugs) used to treat diseases of the central nervous system, since it has been found that concentrations of large molecules in the aqueous humor are correlated with levels in cerebrospinal fluid. The prototype instrument, which is based on technology covered by a U.S. patent, uses 785 nm light with an incident power on the corneal surface of 15 mW or less, conforming to established guidelines for safe exposure of the eye to incident radiation. The instrument employs a cooled CCD array detector and confocal optical techniques to focus the light source on the aqueous humor. Data from clinical studies with human subjects has demonstrated accuracy that is equivalent to that obtained with fingerstick glucose measurements, but without the pain associated with fingerstick sampling. Since the ocular technique measures glucose in the aqueous humor and not blood, there is about a three-minute lag time between changes in blood glucose and changes in the ocular glucose reading. According to James Lambert, PhD, of JPL, who is collaborating with Mark Borchert, MD, of the University of Southern California's (Los Angeles, California) Keck School of Medicine/Children's Hospital Los Angeles, in the research program, the next step is to proceed with performing the studies required to obtain FDA approval. However, it also will be necessary to develop a version of the instrument that meets the requirements for daily use by diabetics in terms of size, ease of use, and cost.

Noninvasive, wireless monitoring

Noninvasive monitoring, particularly remote monitoring of physiological parameters, has of course been a key focus for NASA since the agency was formed. NASA pioneered technologies for remote monitoring of ECG, body temperature, blood pressure, and other parameters to allow the condition of astronauts to be tracked during space flight. One of the early leaders in patient monitoring, Spacelabs Medical (Redmond, Washington), now a unit of Instrumentarium (Helsinki, Finland), was formed to collaborate with the U.S. Air Force and NASA to develop systems for monitoring the vital signs of astronauts in space. NASA has continued to develop new technologies for physiological monitoring, and to make them available for transfer to the private sector for medical applications. One opportunity discussed at the NASA summit may have important applications in neurological monitoring. As described by James Weiss of JPL, technologies are under development at NASA's Langley Research Center that allow noninvasive monitoring of intracranial pressure using skull expansion measurements based on optical coherence tomography. Intracranial pressure is an important parameter used to manage patients with hydrocephalus, and typically is monitored using an invasive probe with pressure-sensing capabilities. Techniques using a catheter and external pressure sensor also are used. The skull expansion method would potentially eliminate the need for invasive techniques. A noninvasive method for determining absolute intracranial pressure is also under development. Patents are pending on both techniques, and the technologies are available for licensing. As shown in Table 2, the market for intracranial pressure monitoring products is essentially stable at about $37 million in the U.S., with only marginal growth projected over the next five years. Noninvasive technology could help expand the market in the future, since intracranial pressure can be an important parameter for the management of a number of conditions (e.g., Alzheimer's disease) where invasive monitoring is problematic.

Another opportunity described at the summit involves technology for home monitoring of high-risk pregnancies. Allan Zuckerwar of the NASA Langley Research Center has developed a prototype sensor using a piezopolymer film to monitor fetal heart sounds during pregnancy. The system consists of a belt with the attached sensor, a speaker that can be connected to hear heart sounds, and a connection to a laptop computer. The measurement allows noninvasive tracking of fetal heart rate. Changes in heart rate (three accelerations over a 20-minute test period) indicate fetal hypoxia or other stress conditions. Testing to detect fetal distress is accepted and reimbursed by insurers. About 10% of the 4.1 million live births annually in the U.S. are associated with high-risk pregnancies, and it is estimated that fetal monitoring could prove beneficial in 5% to 10% of high-risk pregnancies, particularly those involving women in rural areas, career women, social services cases and situations where frequent monitoring is indicated.

Technology used in diagnosis and monitoring of eye disease is an important research area within NASA. A device for monitoring of intraocular pressure has been developed to a prototype stage that, in its final form, will be small enough to be implanted in the eye. Elevated intraocular pressure is the most common cause of glaucoma, a disease that in its most common form (open-angle glaucoma) affected about 2.2 million people over the age of 40 in the U.S. in 2000, according to statistics from the National Eye Institute, a unit of the National Institutes of Health. Existing methods for intraocular pressure measurement can only be performed in a doctor's office, limiting the practicality of frequent monitoring. Like blood pressure, intraocular pressure varies considerably throughout the day, making a single measurement unreliable, and existing pressure measurement methods rely on determining deformation of the cornea, which varies from patient to patient depending on tissue characteristics. The new NASA sensor, known as the Wireless Intraocular Pressure Sensor (WIPS), allows continuous monitoring of pressure, and can provide an alarm if harmful pressure levels are detected. The existing prototype is approximately the size of the eye, but the next stage of the program will involve development of a microminiaturized version with a total volume of about three to four cubic millimeters. NASA is collaborating with the Doheny Eye Institute at the University of Southern California for animal studies, as well as for development of biocompatible components of the device. The Doheny Institute also will conduct initial human feasibility trials as well as clinical studies needed for FDA approval.

Methods to test for eye diseases target a large population in the U.S., as shown in Table 3. The incidence of many vision disorders tends to increase with age, and is expected to double within the next three decades in the U.S. Consequently, the number of patients who are potential candidates for vision-related tests is continuing to increase rapidly. NASA also is developing a system for visual field testing, which will be particularly useful to test for glaucoma and macular degeneration, diseases that affect almost four million people in the U.S. The technology was developed initially to test astronauts for retinal burns resulting from direct exposure to the sun and to radiation in space, but has since been reconfigured for use in the clinical setting. The NASA technology offers an advantage over existing test methods because it combines checks of both peripheral and central vision in a single exam, and also allows contrast to be varied during the exam, enabling detection of subtle vision defects that are missed by current techniques. The technology reduces the time required for vision testing, from up to 40 minutes to about four minutes, and improves the quality of test results since it avoids the fatigue associated with existing complex methods. Clinical pilot studies are ongoing at the Doheny Eye Institute, with more than 200 patients examined so far. A future goal is to create a database of exams of large numbers of patients over time to develop correlations of patterns observed in the exams with the development of eye diseases.

Advances in bioprostheses, surgical devices

Treatment of vision disorders is also a subject of significant research activity within NASA. An artificial vision device for the treatment of blindness, which combines biotechnology and nanotechnology, is under development at the NASA Ames Research Center (Moffett Field, California). Blindness affects about one million people over the age of 40 in the U.S., and significant vision impairment affects an additional 3.4 million people over 40 years of age, as shown in Table 3 on page 62. David Loftus, MD, PhD, described the current status of the development program at the summit. The device uses carbon nanotubes, which are a new molecular form of carbon with very high strength, the ability to withstand considerable deformation, and high electrical conductivity. The nanotubes are also highly biocompatible.

Loftus has developed arrays of carbon nanotubes on a silicon chip that can be used to treat macular degeneration, the leading cause of blindness in the elderly. The nanotubes are used to acquire signals generated by a CCD image detection chip and transmit them to the ganglion cells in the optic nerve. Strategies have been developed to allow the signals from the CCD chip to be transmitted to the nanotubes via wireless technology. The researchers envision a system comprised of two CCD imaging chips mounted on the lenses of a pair of glasses, linked via a wireless interface to nanotube arrays implanted in the patient's eye to stimulate signals in the optic nerve and restore vision. While restoration of normal vision would require a large detector and nanotube array, the present prototype uses a nine-conductor array.

Another approach to curing vision loss associated with macular degeneration involves the use of carbon nanotubes, configured in an array known as Bucky paper, as a substrate for culture of retinal epithelial cells. The project, which is being conducted at NASA with collaboration by Visx (Santa Clara, California), has progressed to studies in animals, with promising results. The key feature of the nanotube-based material is its ability to support cell growth while providing the mechanical stability needed to perform the precision surgical implant required for vision restoration. At present, the researchers estimate that initial human implants are about five years away.

Medical imaging, data analysis technologies

Other NASA technologies address the areas of data analysis, including new approaches for processing of complex physiological data, as well as imaging technologies offering improved resolution as compared to today's computed tomography or magnetic resonance imaging systems. Dr. Norden Huang of the NASA Goddard Space Flight Center discussed the Hilbert-Huang Transform, a new computational method with a wide range of applications in medical data analysis, including analysis of physiological data coming from the heart, brain, lungs and nervous system. Specific applications have been studied for the analysis of sleep apnea and the prediction and detection of epileptic seizures, as well as analysis of Parkinson's disease. The Hilbert-Huang Transform is considered to be one of the most important scientific developments emerging from NASA research.

A new noninvasive imaging technology that promises to provide spatial resolution down to levels as low as 10 to 100 microns has been developed to a prototype stage by researchers at NASA's Marshall Space Flight Center (Huntsville, Alabama). The technology uses gamma rays, hard X-rays and neutrons, and offers several advantages due to the penetrating nature of such particles and photons. Until recently, technologies were not available to provide the control needed for high-resolution imaging using high-energy particles and photons.

Dr. Jonathan Campbell of the Marshall center has devised a system of rotating/translating grids that allows such particles or photons to be used in medical imaging. In collaboration with the Oak Ridge National Laboratory (Oak Ridge, Tennessee), methods have been developed allowing fabrication of the slits used for focusing down to dimensions as low as 70 microns, and the potential may exist to reach levels as low as 10 microns. The technology could allow new imaging systems to be developed that can, for example, detect tumors as small as 100 microns in diameter embedded deep within the body.