bmdo technologies for biomedical applications - MDA Technology

BMDO TECHNOLOGIESFOR BIOMEDICALAPPLICATIONSBALLISTIC MISSILE DEFENSE ORGANIZATION

INTRODUCTIONIn 1996, the Ballistic Missile Defense Organization (BMDO) and theNational Technology Transfer Center/Washington Operations (NTTC/WO)published a special report entitled BMDO Technology Applications inBiomedicine. With an emphasis on biomedical and biotechnical areas, thisreport detailed more than 60 technology stories that sprang from BMDOsupport through the Small Business Innovation Research (SBIR) program,the Small Business Technology Transfer(STTR) program, the Innovative Science andIn this report we highlightTechnology (IS&T) program, and theTechnology Applications (TA) program.advances in biomedicalThis year, we are again highlightingapplications of BMDO advances in biomedical applications ofBMDO technology, covering 32 stories intechnology.image processing, optical biopsy, laser treatments,information storage and networks,and biological analyses, among other topics.The SBIR and STTR programs are administered by BMDO and other governmentagencies to support and develop cutting-edge technologies andlead them to the American marketplace. SBIR concentrates on fundingproof-of-concept and prototype product development in small business settings,and STTR fosters cooperation between nonprofit research institutionsand businesses. The IS&T program is designed to quickly galvanize highrisktechnology through targeted research and development. In addition,IS&T seeks to shorten the interval between concept and application. TheTA program promotes commercialization of advanced technologies andcross-fertilization of ideas between government agencies. Through technologyreview meetings with small businesses, outreach publications, and aproactive stance in disseminating information about new commercializationefforts, the TA program nurtures the seedlings of technology transfer.4With decreasing government spending and continuous pressure to reducethe national deficit, all government agencies are aware of the need to makeevery dollar count. BMDO has operated from its inception with an eye todual use, and in 1994 it began to pursue a relationship with the Departmentof Health and Human Services to transfer BMDO-funded technologies tothe area of breast cancer detection and prevention. BMDO has also joinedthe Federal Multi-Agency Consortium on Imaging Technologies to ImproveWomen’s Health, a concerted government effort to develop advanced imagingtechnologies for improved screening, earlier diagnosis, and better treatmentof breast cancer. The consortium includes representatives from theCentral Intelligence Agency, the U.S. Army, the Defense Advanced ResearchProjects Agency, the National Aeronautics and Space and Administration,the National Cancer Institute, and the National Science Foundation, toIntroductionBMDO Technologies for Biomedical Applications

name just a sampling. This group is headed by the office of the AssistantSurgeon General and Deputy Assistant Secretary for Health (Women’sHealth). The consortium’s technology transfer subcommittee put out arequest to 297 Federal agencies and laboratories to submit potential technologiesthat could advance digital mammography, magnetic resonanceimaging, ultrasound, nuclear medicine, computer-aided diagnosis, 3-Dvisualization, and image storage and transmission. Of 82 technologyresponses, the subcommittee chose 14 for funding consideration; of these,6 were BMDO submissions. These technologies were large-format digitalsensors, avalanche photodiodes, acousto-optic tunable filters, active vibrationisolation systems, uncooled infrared cameras, and polarization imagingand fluorescent spectroscopy devices. BMDO continues its cooperationwith the consortium through meetings and technology development.5BMDO Technologies for Biomedical ApplicationsIntroduction

CHAPTER 1INFORMATION TECHNOLOGIESSome regard the information revolution as the most significantevent of the 20th century. Whether we are researchers, banktellers, insurance underwriters, supermarket cashiers, or stockbrokers,we deal with sometimes overwhelming quantities ofinformation. Those who study the education process have consistentlyfound that how information is presented is key to retainingfacts, organizing data, and consolidating important memories.Often, the combination of compelling visual display and pertinenttext, whether written or spoken, is highly successful in making along-term impression on the learner. Sometimes, visual display isthe only means of effectively conveying information. It takes farmore effort to outline in words the key sensory pathways in thebrain, or the distinguishing features of a malignant breast tumoron a mammogram, than to simply study the images and storethem as principally visual memories. Since these images do conveyso much information, it seems fitting that they would requirelarge amounts of memory for storage, and indeed they do. In addition,high-quality, high-resolution imaging requires very rapiddata transfer rates.THIS CHAPTER INCLUDES THE FOLLOWINGSECTIONS AND THEIR STORIES:Section A - Presentation3-D Picture in a CubeAstroTerra’s 3-D Volumetric DisplayAward-Winning High-Speed Optical ProcessorChip-Stacking Technology from Irvine Sensors & JPLSection B - Storage and TransmissionFiber-Optic Testbed at UCSD Under Way

SECTION APRESENTATIONThose involved in ballistic missile defense need to quicklyand efficiently identify objects and classify them as friend orfoe, gain a “big picture” view of the ever-changing battlefield,and track missiles in three dimensions. Similarly, doctorsneed to distinguish between benign and malignantgrowths and require high-resolution images with a sufficientlylarge format for optimal viewing. Surgeons especially canbenefit from the gradually evolving virtual-reality displaysthat employ 3-D imaging techniques. The military’s interest indisplay technology has yielded some promising cuttingedgeideas for displays in general, with applications in manyareas, including medicine.1. A novel 3-D display that uses a rare-earth-doped glasscube to create a truly three-dimensional, hologram-likeimage that can be viewed from any angle.2. A prototype 3-D display that intersects two laser beams inrubidium vapor, generating visible red fluorescence, withpromise for full-color applications.3. A high-speed optical processor that resulted from BMDOwork on an incoherent-to-coherent converter for opticalcomputing.4. A chip architecture that stacks integrated circuits andinterconnects them vertically, translating to faster data processingand downloading.

103-D PICTUREIN A CUBE• This prototype display offers true3-D without illusions.BMDO HISTORY3-D Technology Laboratories (Mountain View, CA) was founded byElizabeth Downing, Ph.D., in 1996. Her pioneering work in 3-D displaytechnology at Stanford University generated enormous interest and earnedwidespread publicity. Along with a number of agencies, BMDO is helpingto support her research in rare-earth-doped glass display technologythrough a Phase I SBIR contract. The applicationsare numerous, ranging from medicalimaging and air traffic control displaysSome neuroscientistsand battlefield management monitors totheorize that we storevideo games and virtual-reality entertainmentdevices.information in our brainsHOW IT WORKSholographically, with eachThe system uses two computer-controlledmemory stored in several infrared lasers to trace its 3-D picturesinside a cube of special laminated glass,places simultaneously. much as the electron beam from a cathoderay tube traces a 2-D image on a televisionWhen we remember screen. The energy generated at the pointwhere the invisible laser beams intersectsomething, all these areasmakes a single point of the glass glow withvisible light—a precise dot like a videoare alerted at the samescreen pixel seemingly suspended in space.time from one prompting “This allows you to address a pixel anywhereinside a three-dimensional volume,neuronal signal, much as and then by scanning rapidly, you can drawthree-dimensional images,” says Downing.a laser can tease out an The fluorescent glass display uses severalrare-earth compounds that emit differententire image from acolors of visible light when struck by thelaser beam. By varying the chemistry of thehologram with one beam.glass, the designers are able to generate red,Perhaps this is why we blue, and green light and mix them to createall the components necessary for a fullcolordisplay.relish 3-D reconstructions.The prototype display is about a cubic inchin volume, and the pictures it contains are simple three-color line drawings,which serve as test patterns. But its developers said they are confidentthat they can quickly make the viewing system larger while making its supportelectronics smaller. Standing between the developers and any immediatecommercial application are technical obstacles such as the cost of thehigh-purity materials needed to manufacture the special rare-earth glassChapter 1 - Information TechnologiesSection A - PresentationBMDO Technologies for Biomedical Applications

used in the display cube. In addition, the processing demands imposed bydata-intensive, high-resolution imaging are quite high.MEDICAL SIGNIFICANCEThe display draws real volumetric images. As a result, all the normal depthcues that are used for visualization can be applied, independent of theuser’s head position. No processing has to be done to update the viewwhen the user’s perspective changes. This is one of the primary differencesbetween true 3-D and virtual-reality or stereoscopic displays—no latencydue to rendering scenes from a new direction. The unique advantages ofthis system lend themselves exceptionally well to medical imaging.The display can offer models of anatomy that are not limited by the usualobscuring barriers. As an example, a surgeon could observe a transparentview of the human brain, seeing the skull and all the internal structures atonce, as if they were made of glass. This is an interesting way to look atphysical models. It takes virtual reality beyond what is possible in actualreality—to see any solid as a sort of 3-D line drawing. By referring to landmarksin the display, surgeons can be more confident that they are avoidingvital arteries and other areas as they move their instruments. A differentview can be obtained by simply looking at a different part of the display.As a teaching tool, current 3-D displays are already immensely popular.Animation and viewability from any angle are further advantages of thenew technology. The heart in motion, for instance, is a far more informativerepresentation than a static model.• Designs can range from whimsicallysimple to complex.VENTURES OR PRODUCT AVAILABILITYThis technology is in the research phase. Downing has obtained generoussupport from the National Science Foundation, the Air Force, the DefenseAdvanced Research Projects Agency, and the National Aeronautics andSpace Administration, and is submitting a Phase I SBIR proposal to theNational Institutes of Health. She has recently made a technical advance byincorporating praseodymium into a ceramic glass, which could reduce thecost of materials.CONTACT3D Technology LaboratoriesElizabeth Downing, Ph.D.P.O. Box 114200 Flower Blossom LaneMountain View, CA 94042-0114Telephone: (415) 964-4410Facsimile: (415) 964-2844Email: 3dlabs@pipeline.com11BMDO Technologies for Biomedical ApplicationsChapter 1 - Information TechnologiesSection A - Presentation

tion can certainly add to medical education. A far more likely and widespreaduse of this application would be in general biology. Students in secondaryschools and universities are turning away from performing traditionalfrog and rat dissections, frequently on ethical grounds, in favor ofstudying virtual animal models.VENTURES OR PRODUCT AVAILABILITYThus far, the technology has produced simple monochromatic (red)images of cubes and a rotating globe.CONTACTAstroTerra CorporationEric Korevaar, Ph.D.11526 Sorrento Valley Road, Suite VSan Diego, CA 92121Telephone: (619) 792-8501Facsimile: (619) 792-8503Email: korevaar@astro.comWWW: http://www.astroterra.com13BMDO Technologies for Biomedical ApplicationsChapter 1 - Information TechnologiesSection A - Presentation

14AWARD-WINNING HIGH-SPEEDOPTICAL PROCESSOR• This optical processor can sharpenall types of medical displays.BMDO HISTORYSilicon Mountain Design, Inc. (SMD; Colorado Springs, CO), has designedan optical processor that can be used with visible and infrared light, as wellas for x-ray applications. This technology grew from a BMDO SBIR PhaseI project to develop an ultrahigh-speed incoherent-to-coherent converterfor optical computing, meant for automatic weapons targeting. The converterand processor have applications innight vision and image compression.Apoptosis, or cell suicide,HOW IT WORKSis thought to play a role SMD used a combination of micromachiningtechnology and ultrathin-wafer processingto put a charge-coupled device (CCD)in AIDS, autoimmuneand a spatial light modulator (SLM) on thediseases such as lupus,same chip. Because the SLM directs lightand cancer. The p53 tumor onto the CCD, the light conversion isdescribed as “incoherent to coherent.” Thissuppressor, mutations of parallel arrangement eliminates the databottleneck at the processor input, so imageswhich are found in about can be acquired much more rapidly thanwith a serial input arrangement. The resulthalf of all cancers, is ais a high-speed camera that has medical andindustrial applications. As an example, thegene that controls theSMD Mach-I digital camera can run atpathway to cell death. 1,000 frames per second with spatial resolutionsfrom 256 x 256 to 512 x 512 for 8-bit pixel depths. The camera’s parallel opticalinput features help to eliminate image smearing common to other highspeedcameras.MEDICAL SIGNIFICANCEThe high-speed processor can improve the image quality in x-rays, mammograms,and visible-light micrographs. High-speed image processing iscrucial for quickly downloading high-resolution medical images, screeningmicrographs such as those used in automated diagnostic systems, and capturingrapidly occurring events in living cells. For real-time fluoroscopicimaging, in which x-rays are used to image cardiac catheterization andangiography, the optical processor could improve image clarity. The imagercould also to be used in tandem with recently approved computer-aideddiagnostic systems for Pap smears. Another application is in evaluating calciumratios in cell samples to determine rates of cell death. Calcium releaseChapter 1 - Information TechnologiesSection A - PresentationBMDO Technologies for Biomedical Applications

can signal cell membrane rupture and subsequent cellular demise.Apoptosis, or programmed cell death, is an emerging field that continuesto increase our understanding of the mechanisms behind cancer developmentand aging.VENTURES OR PRODUCT AVAILABILITYSMD is currently performing demonstrations and negotiating with twolarge medical imaging companies and two major automotive manufacturers.The company continues to investigate applications in industrial areassuch as product inspection on assembly lines, and particulate matter inlubricants and hydraulic fluids.SMD is also working with the University of Colorado at Colorado Springsto develop a solid-state miniaturized imager with a disposable imaginghead for use in endoscopic procedures.SMD received the SBIR Technology of the Year Award for its optical processorat the October 1995 Technology 2005 conference, held in Chicago.The next year, SMD won the Grand Award for its SMD-1M60 camera atthe October 1996 Technology 2006 conference, also held in Chicago.CONTACTSilicon Mountain Design, Inc.Robert Thorp5055 Corporate Plaza Drive, Suite 100Colorado Springs, CO 80919Telephone: (719) 599-7700Facsimile: (719) 599-7775Email: rthorp@smd.com15BMDO Technologies for Biomedical ApplicationsChapter 1 - Information TechnologiesSection A - Presentation

CHIP-STACKING TECHNOLOGYFROM IRVINE SENSORS & JPLBMDO HISTORYTo fit ever more circuitry into computers, manufacturers and designers havedemanded narrow line widths and novel chip architectures. Chip stackingis one approach to both increase the speed and decrease the size of multichipmodules (MCMs). This 3-D architecture would shorten chip interconnections,thus producing smaller, faster MCMs. BMDO has funded researchinto this technology at Irvine SensorsCorporation (ISC; Costa Mesa, CA) and theVisual processing takes upJet Propulsion Laboratory (JPL; Pasadena,CA) for a number of programs, includinga little more than half theVIGILANTE, an Innovative Science andbrain’s workload. Humans Technology project that has as its goal thedevelopment of a neural-network moduleare so pictorially oriented that can perform image recognition.• 3-D neural networks can quicklyprocess and analyze images.that the blind can interprettouch as a visual signal.Neural activity in areas ofthe brain that subservevision can be stimulatedby tracing outlines ofsimple objects on theskin of a blind subject.HOW IT WORKSISC creates its MCMs by thinning eachwafer layer to less than 100 micrometers,patterning it, and dicing it to form separateintegrated circuits. After surface metallization,the chips are stacked together, aligned,and bonded with a thermally compatibleepoxy. Raised metallic leads on the surfaceof each chip provide electrical contactbetween adjacent chip elements. Thesethrough-thickness electrical connectionsreduce circuit path lengths and therebyincrease the module’s operating speed. Theshorter current paths also reduce overallpower consumption.16Using this technology, ISC and JPL are working on a 3-D neural-networkmicroprocessor. Artificial neural networks are designed to behave approximatelyas human brains are thought to function; they enable patternrecognition and learning behaviors that are difficult for conventional computersto handle. Thus, a neural-network processor involves large numbersof data and processing nodes that continuously interact with each other.The ISC chip-stacking techniques can achieve the high interconnectiondensities necessary to construct an efficient and fast neural network.JPL and ISC jointly developed and designed a 3-D neural-network microprocessingmodule called 3DANN, as well as a new device called theNeural Processing Module (NPM). The 3DANN module is three-quartersthe size of two stacked sugar cubes; 64 of them will be integrated into acube to form the NPM. Mounted on the cube will be a column loadingChapter 1 - Information TechnologiesSection A - PresentationBMDO Technologies for Biomedical Applications

input circuit chip to convert video data from digital to analog form for parallelprocessing. This image-processing device is expected to be able to performspecialized functions at up to a trillion operations per second.MEDICAL SIGNIFICANCEMedical imaging applications demand an enormous amount of datathroughput for downloading and reviewing x-rays, computed tomographyscans, MRIs, and ultrasound studies in a timely and clinically practicalmanner. Just one mammogram can contain 24 to 40 megabytes of pixeldata. Considering that a single radiological consult on a suspicious mammogramrequires eight separate images (four current views compared withfour historical views), one patient means 192 to 320 megabytes of data.Anyone who has twiddled thumbs while downloading mere kilobytes ofdata over a pretty good T1 line will immediately recognize the problem.ISC’s device can process more than 15,000 images that are 64 x 64 pixelseach, while the embedded neural network can supplement the throughputfunction with computer-aided diagnosis software. As filmless or digitalmammography comes into common use, the 3-D processor will be inherentlycompatible with such systems.• This compact processor will meet theneeds of shrinking device sizes.VENTURES OR PRODUCT AVAILABILITYA military demonstration of the chip is scheduled for late summer 1997.CONTACTIrvine Sensors CorporationLynn O’Mara3001 Redhill Avenue, Building 3Costa Mesa, CA 92626Telephone: (714) 444-8718Facsimile: (714) 557-1260Email: lomara@irvine-sensors.comWWW: http://www.irvine-sensors.com17BMDO Technologies for Biomedical ApplicationsChapter 1 - Information TechnologiesSection A - Presentation

SECTION BSTORAGE AND TRANSMISSIONWhile remarkably compact in conveying meaning to ourbrains, visual information takes up a lot of space in electronicform. And as many have discovered to their foot-tappingchagrin, it also takes an awfully long time to download. Warwearymilitary planners and HMO-frazzled doctors alike mustbe able to store and quickly recall information if it is to be ofvalue. A wider data-transfer conduit can be achieved in anumber of ways; fiber-optic technologies have already greatlyimproved and continue to increase the carrying capacity ofthe information pipeline. In addition, new optical media canbe manipulated to store data more compactly.1. A university-based network testbed that will employadvanced optical switching and multiplexer technologies toenable distributed image processing and shared access attransfer rates greater than 1 gigabit per second.

FIBER-OPTIC TESTBEDAT UCSD UNDER WAY20• High-speed networks help doctorssee important information quickly.BMDO HISTORYThe University of California at San Diego (UCSD; San Diego, CA) is developinga regional network devoted to medical imaging as part of a consortiumon photonic computing networks. This effort is being funded byBMDO through a Focused Research Initiative on Photonics for Data FusionNetworks. The network will employ advanced optical switching and multiplexertechnologies to enable distributedimage processing and shared access at gigabit-per-secondtransfer rates. Defense agen-Fiber-optic systems willcies in general are interested in similar highspeednetworks that can link real-time sur-be crucial to implementveillance, simulations, and archived geographicdata for battle management.President Clinton’s callto connect the nation’s Confidentiality and security during informationtransfer are also major concerns for medicalpractitioners and hospital schools, libraries, hospi-administrators.tals, and clinics to the HOW IT WORKSThe testbed network links several UCSDNational Information medical departments, the School ofMedicine, a computer engineering department,a regional Veteran’s AdministrationInfrastructure, betterMedical Center, NASA’s Jet Propulsionknown as the Internet,Laboratory, and the San Diego SupercomputerCenter. The UCSD effort to date has concentratedon determining the imaging vol-by the year 2000.ume for computed tomography (CT), magneticresonance imaging (MRI), ultrasound, and x-ray diagnostic needs,from the standpoint of storage and retrieval requirements as well as trafficmanagement on the network. The researchers have also undertaken anextensive study of clinical needs, to include both the quality and presentationof the image data and the real service needs of the user. Real needswould include how fast a physician can pull up a patient history or a clinicalimage, access to monitors in the radiology department, large enoughscreens for comparative studies (such as comparing past mammogramswith present ones), search engines for finding records, and even allowancefor the radiologist’s traditional reliance on grease pencils and film images.MEDICAL SIGNIFICANCEInformation management and image presentation have become an area ofconcentration for clinicians and administrators alike. Systems must be userfriendly, quick to respond, and above all accurate. So far, the UCSD projecthas yielded a prototype system at the UCSD Hillcrest Center thatallows radiologists to use a touch screen to manipulate images and patientChapter 1 - Information TechnologiesSection B - Storage and TransmissionBMDO Technologies for Biomedical Applications

ecords on eight high-resolution monitors. All monitors are dual purpose,displaying either images or text. Doctors can view eight full-size x-rayimages at once. Smaller systems have been developed for an intensive careunit, allowing for seamless interaction between patient databases and thephysician. Currently, data transmission with a small sample database isperformed over an Ethernet connection at 100 megabits per second.In addition, the project is also planning a line-of-sight laser linkage betweenHillcrest Center in San Diego and another participating center in La Jolla.VENTURES OR PRODUCT AVAILABILITYThe technical objectives of the UCSD program are to explore and eventuallyimplement a scalable third-generation terabit-per-second photonicnetwork architecture and protocol for distributed imaging environments.In addition, the project will investigate spectral-domain processing usingultrashort pulses for terabit-per-second data rates and will address securityissues using classical and quantum cryptography. UCSD will also developnetwork interfaces between fiber-optic imaging networks and wirelessnetworks. There is a considerable R&D phase ahead before the photonictestbed is actually constructed. Conventional connections (such as theEthernet mentioned above and ATM) are now being used to develop thepractical framework of this initiative.Data fusion in real time, such as superimposing MRI images over CTimages, is another goal of this project. Work in this area is being performedat Brown University (Providence, RI).CONTACTUniversity of California at San Diego Medical CenterAlbert L. Kellner, Ph.D.Department of ECE, 04079500 Gilman DriveLa Jolla, CA 92093-0407Telephone: (619) 534-7919Facsimile: (619) 534-2486Email: akellner@ucsd.edu21BMDO Technologies for Biomedical ApplicationsChapter 1 - Information TechnologiesSection B - Storage and Transmission

CHAPTER 2OBSERVATION TECHNOLOGIESBiomedical researchers rely on many different methods to helpthem see beyond the facade that hides the workings of the organism.We have seen a revolution in our ability to decipher theprocesses that control growth and metabolism, and the diseasesthat result when these processes are disordered. The methods usedare diverse and represent intersections between disciplines thathave long operated on parallel tracks. Now the physics that producedlasers and radar meets the biology that brought us awarenessof the molecules of life. Materials science crosses paths with medicalinterventions such as laparoscopy and implant surgery andwith biotechnology tasks such as genetic analysis. Spectroscopy,once the domain of chemists and astronomers, now helps to identifyplaque in the lumen of arteries and even the presence of cancer.THIS CHAPTER INCLUDES THE FOLLOWINGSECTIONS AND THEIR STORIES:Section A - DetectionEssex Corporation’s Virtual Lens MicroscopeSimple Isotope SeparationSuperex Polymer TubingChip-Sized Radiation MonitorSection B - AnalysisVersatile Tunable Filter for Optical TasksHigh-Speed Molecular ModelingLiSAF Laser for CytometersSection C - DiagnosisAMT: Binocular 3-D Eye TrackerDeformable Mirrors to Uncover Eye DisordersNIH Infrared MicroscopeAdvanced Imaging SpectrometerMTC’s EndoscopeRaman-Based Gene Probe TechnologyNanophosphorsOptical BiopsySagebrush Gimbal for Needle Biopsy

SECTION ADETECTIONNondestructive testing allows us to study life with minimalalteration and disruption. Minimally invasive methods todiagnose disease are increasingly relied upon to reduce riskand discomfort to the patient. We monitor our surroundingsto detect harmful environmental influences and prevent theirdeleterious effects. Radioactive tracers can pinpoint tumors,detect stroke damage, and assist in metabolic studies. Allthese important enterprises have benefited from evolutionand innovation in technology.1. A synthetic aperture radar microscope that can producehigh-resolution 3-D images within seconds.2. An isotope separation method that economically producescarbon-13 for diagnostic tests.3. A high-strength, sterilizable polymer tubing that is bothversatile and economical.4. A low-cost, compact radiation monitor that can betterquantify radiotherapy regimes as well as protect workers innuclear medicine.

ESSEX CORPORATION’SVIRTUAL LENS MICROSCOPE• This microscope will support newstandards in nondestructive analysis.BMDO HISTORYEssex Corporation (Columbia, MD) has developed a Virtual LensMicroscope (VLM), based on the principles of synthetic aperture radar(SAR), that can produce high-resolution 3-D images in a few seconds. Themicroscope uses coherent light, in tandem with Essex’s patented ImSynimage processor, to produce holographic images with a resolution of onequarterthe incident wavelength used toilluminate the object. BMDO sponsored theAntony van Leeuwenhoekdevelopment of a wideband range-Dopplerimager for ground-based radar, from whichfirst observed “animal-both ImSyn and the VLM resulted.cules” in the 17th centurywith a magnifying lens, notthe compound microscopeof his British contemporary,Robert Hooke.However, Leeuwenhoek’slens-grinding skill andacute eyesight allowedhim better resolution withhis one-lens system thanwith the inferior two-lenssystem of the period.HOW IT WORKSThe VLM can operate in the ultraviolet, visible,infrared, and microwave regions of thespectrum. Thus if the operating wavelengthis in the ultraviolet sector, objects as smallas 70 nanometers, or one-hundredth thediameter of a human hair, can be resolved.The VLM’s resolution is also independent ofworking distance, so very small images canbe resolved from several inches away. TheImSyn optoelectronic processor uses a twodimensional,discrete Fourier transformalgorithm to produce a 256 x 256 pixel, 32-bit complex-valued transform (equivalentto 65,536 samples processed) in as little as50 milliseconds. Conventional methodssuch as data regridding followed by a fastFourier transform image reconstruction arenot rapid enough to provide the highthroughput and rapid data processingneeded for a variety of imaging modalities,including VLM, spiral magnetic resonanceimaging, and computed tomography.26MEDICAL SIGNIFICANCEA nondestructive microscope that can image features as small as 70nanometers would be ideal for viewing cell organelles, chromosomes, andorganic molecules. Unlike electron microscopes, which require considerablealteration of the sample, or two-photon confocal microscopes, whichhave problems with photobleaching (image washout), the VLM can providea three-dimensional view of living matter with minimal preparation.Researchers in molecular genetics, cellular and molecular biology, allChapter 2 - Observation TechnologiesSection A - DetectionBMDO Technologies for Biomedical Applications

aspects of medicine, and physiology would find the VLM a diverse tool forgathering accurate information about life processes.VENTURES OR PRODUCT AVAILABILITYEssex has a working relationship with the University of Maryland MedicalSchool for the study of video-rate MRI images produced by the ImSynprocessor and is also targeting the defense market for applications ofImSyn and SAR technologies, including VLM. The first SAR processor wasdelivered in late 1996, with several orders placed for delivery in the firstquarter of 1997. SAR can penetrate foliage, camouflage, and shallow soilto detect vehicles, buildings, mines, and other objects that cannot bedetected by conventional radar systems.CONTACTEssex CorporationDavid Parry9150 Guilford RoadColumbia, MD 21046-1891Telephone: (1-800) 533-7739Facsimile: (301) 953-7880Email: dap@essexcorp.comWWW: http://www.essexcorp.com27BMDO Technologies for Biomedical ApplicationsChapter 2 - Observation TechnologiesSection A - Detection

28SIMPLE ISOTOPE SEPARATION• A faster, cheaper method of separatingisotopes can help visualize brain function.BMDO HISTORYNanoDynamics, Inc. (New York, NY), developed a method for separatingcarbon isotopes through a BMDO Phase I SBIR contract for synthetic diamondfilm growth. BMDO has had a long-term interest in diamond substratesbecause of their superior thermal and conductive properties inmicroelectronic devices. Through this research, NanoDynamics found aneconomical method of separating carbon-12 and carbon-13 from natural carbonFor decades, gastricsources. The method can reduce the cost ofenriched carbon-12 from $100 to less thanulcers were considered a$10 per gram.result of excessive stomachacid production orHOW IT WORKSNanoDynamics’ separation process takesadvantage of the difference between thestress, until a determined masses of the two isotopes, in a methodcalled time-of-flight separation. The methaneresearcher deliberately gas from which the carbon isotopes are isolatedis accelerated to supersonic speeds, anddrank a solution containingHelicobacter pylori. Itthe two isotopes are collected from two separaterotating nozzles. This “garden hose”separation method is much more cost-effectivethan conventional distillation methods.took just a few moreMEDICAL SIGNIFICANCEyears to confirm that theCarbon-13 is a nonradioactive isotope thathas at least two medical applications in diagnosticmedicine. The first is as a constituentbacterium causes theof urea, which is administered orally as partgreat majority of ulcersof a simple test for the ulcer-causingin the stomach.pathogen Helicobacter pylori. The bacteriumingests the urea and excretes it as carbondioxide (CO2) as part of its metabolic waste.With a breath analyzer, the expired CO2 is analyzed for isotopic content,indicating the presence or absence of the bacterium. The breath test is amajor improvement over the two alternative procedures for detection,blood tests for antibodies to the organism and endoscopic stomach biopsy.A similar breath test can be used for nutritional studies, but with aminoacids tagged with the isotope. This information can be used to study ratesof protein turnover (how fast one uses proteins), energy expenditure(metabolic rate), and nutritional availability of certain foodstuffs.Chapter 2 - Observation TechnologiesSection A - DetectionBMDO Technologies for Biomedical Applications

Because it has properties that make it easy to detect in an MRI examination,carbon-13 can also be used as a constituent of glucose for functional MRIstudies. For instance, glucose utilization in the brain is routinely studied asa window into brain function. Neurologists ask patients to perform tasksand observe which areas of the brain “light up” because of increased glucoseutilization. In this way, researchers can deduce the basic functions of brainareas, and clinicians can assess patients for loss or gain of function duringthe course of a disease.VENTURES OR PRODUCT AVAILABILITYNanoDynamics is seeking partnerships to develop products.CONTACTNanoDynamics, Inc.Chia-Gee Wang, Ph.D.510 East 73rd StreetNew York, NY 10021Telephone: (212) 249-2232Facsimile: (212) 249-402129BMDO Technologies for Biomedical ApplicationsChapter 2 - Observation TechnologiesSection A - Detection

SUPEREX POLYMER TUBINGBMDO HISTORYSuperex Polymer, Inc. (Waltham, MA), a subsidiary of Foster-Miller, Inc.,has adapted an ordered polymer technology developed originally for AirForce and BMDO cryogenic containers. In the quest for an inherently strongplastic with militarily interesting features such as radiation hardness, thecompany found other applications for the material. Superex uses an extrusionprocess that yields polymer tubing withmany characteristics useful for medical,“Keyhole” surgery haselectronic, and structural applications.• Reusable and rugged tubing forendoscopic procedures—an unexpectedresult of defense research.recently made kidneydonation a less painfulexperience. Instead of thewide incision formerlyused to remove the donorkidney, the operation cannow take place with foursmall punctures for instrumentsand a small incisionfor extrusion of the kidney.The new method hasHOW IT WORKSOrdered polymers are a subset of plasticsthat form a self-reinforcing microstructureof fine fibers. These polymer fibers are 100to 1,000 times finer than those used in continuousfiber reinforcement and 100 timesless permeable to oxygen and water vaporthan commonly used polymers. Used as apackaging material, they can provide asmuch protection with a single layer as otherpolymers provide with multiple layers.They are microwavable, sterilizable understandard autoclave conditions, and recyclable.When they are extruded as tubing,their properties of low thermal expansion,resistance to cracking, low electrical andthermal conductivity, and high tensilestrength make them very desirable componentsfor medical use.30greatly reduced donor MEDICAL SIGNIFICANCEEndoscopic examinations and surgeries,recovery time, blood loss, catheterization procedures, and the new“keyhole” surgical techniques requireand scarring.strong, reliable fibers that can be sterilizedor cheaply disposed of. In addition, someprocedures have unique problems that can be addressed by small changesin the basic materials. In cystoscopy, for example, a fiber optic is placedinside a tube that is then inserted through the urethra into the bladder. Aurologist can also insert the tubing beyond the bladder and into the uretersthat lead to the kidneys, but the tube must be properly guided, both toavoid injury to the patient and to shorten the time spent in this semi-invasiveexamination. Because catheters tend to flop over once they haveentered the bladder, they are difficult to control. The improved strengthand stiffness of ordered polymers can make catheters easier to guide.Chapter 2 - Observation TechnologiesSection A - DetectionBMDO Technologies for Biomedical Applications

VENTURES OR PRODUCT AVAILABILITYFoster-Miller has received eight patents for its ordered polymer technology.ACT Medical, Inc., is one of three companies that have licensed processingtechnology from Superex; at least three other companies are negotiatinglicenses.CONTACTSuperex Polymer, Inc.Richard W. Lusignea350 Second AvenueWaltham, MA 02154Telephone: (617) 890-3200Facsimile: (617) 890-4084Email: kkelley@foster-miller.comWWW: http://www.foster-miller.com31BMDO Technologies for Biomedical ApplicationsChapter 2 - Observation TechnologiesSection A - Detection

CHIP-SIZED RADIATIONMONITORBMDO HISTORYThe Jet Propulsion Laboratory (JPL; Pasadena, CA) has developed aBMDO-funded, chip-sized radiation monitor that combines a total dosemonitor, a particle spectrometer, and readout electronics on a single integratedcircuit package. Advantages of this scheme include small size (thechip area is 1 square centimeter), low cost, and low power consumption.The monitor flew on the Clementine andSpace Technology Research Vehicle (STRV-Ionizing radiation was1b) space missions. In these space flights,the chip provided total radiation data fromonce considered athe Earth’s radiation belt and tracked thesalubrious force. In the radiation from a solar flare that occurred onFebruary 21, 1994. BMDO is also sponsoringchip development for the STRV-2, inearly part of this century,which 14 total dose monitors will fly on theradon was sold in special Space Active Modular Materials Experiment.inhalers as a tonic. Now,millions of dollars arespent annually to pumpradon gas out of dwellings.HOW IT WORKSThe total dose monitor in this chip consistsof two p-type field-effect transistors (p-FETs). The p-FETs operate by monitoringshifts in the threshold voltage (the gate voltageat which the chip turns from off to on)that occur when exposed to radiation.32• This multi-faceted chip can fly spacemissions and protect earthbound workers.The particle spectrometer consists of a 4-kilobit static random-access memory (SRAM) chip that is designed toenhance the “single-event-upset effect,” a radiation-induced disruption ofSRAMs used as memory devices. Space satellite components can beknocked out by events such as these, leading to failure of costly experimentsand disruption of military and commercial satellite functions. Byenhancing this effect, the SRAM can detect exposure to protons, alpharadiation, and high-energy ions. In a test aboard the Clementine spacecraft,the SRAM particle spectrometer displayed a very wide detection range,showed that it is not affected by electronics, and detected a series of solarmicroflares over a span of 26.5 days.MEDICAL SIGNIFICANCEJPL’s chip has been used to calibrate proton beam delivery at the LomaLinda Proton Therapy Facility. Proton beams penetrate deeper into tissuesthan the x-rays used in conventional radiotherapy. For deep-seated tumorsthat are inoperable, proton radiation can better target the lesion withoutexposing the normal tissue in the path of the beam to excessive radiation.X-rays tend to deliver most of their energy at the surface, and thereafterChapter 2 - Observation TechnologiesSection A - DetectionBMDO Technologies for Biomedical Applications

dissipate their energy diffusely through tissue. JPL’s results show that the p-FET calibration was better than the standard ion chamber calibration, andthe p-FET chip was more convenient to use. The p-FET monitors could beused during radiation treatments to ensure that neither too much nor toolittle radiation exposure occurred so that treatment could be safer andmore efficient.For laboratory and industry workers, this chip could also be used as amonitor for those who frequently work around radiation, including techniciansin hospitals, veterinary clinics, and life science and physical sciencelaboratories. It could be worn by power plant operators and nuclear wastecleanup crews, as well as used to separately monitor any escaping radiation.The solid-state monitors could also be checked daily, rather thanmonthly or quarterly, like the film badges used now.VENTURES OR PRODUCT AVAILABILITYJPL is developing two commercial applications for Lockheed Martin—oneuses the chip as a spacecraft charge monitor, and the other will fly on theIntelsat communication satellite. JPL is also seeking commercial partnersfor development of radiation dosimeters for personnel, as well as for radiotherapycalibration.CONTACTJet Propulsion LaboratoryMartin Buehler, Ph.D.California Institute of Technology4800 Oak Grove DrivePasadena, CA 91109Telephone: (818) 354-4368Facsimile: (818) 393-4820Email: Martin.G.Buehler@ccmail.jpl.nasa.govWWW: http://www.jpl.nasa.gov33BMDO Technologies for Biomedical ApplicationsChapter 2 - Observation TechnologiesSection A - Detection

SECTION BANALYSISSpectroscopic methods are unlocking the chemical secrets ofheart disease and cancer, enabling doctors to make diagnosesat an earlier stage of disease. Advanced computeralgorithms predict critical structures that pave the way for lifesavingpharmaceuticals and new antibiotics. Solid-state laserdiodes light up the surfaces of lymphocytes and the interiorsof nuclei, advancing research in innumerable directions.1. An acousto-optic tunable filter that aids in the spectroscopicexamination of unstable plaque in cardiac arteries.2. A computer algorithm that increases computational speedfor predicting molecular structures useful to pharmaceuticaland other industries.3. Compact, solid-state laser diodes for cytometry (cell sortingand identification).

VERSATILE TUNABLE FILTERFOR OPTICAL TASKS• Radiofrequency-based technologyfrom Ciencia helped improve a commonbiotech task.BMDO HISTORYCiencia, Inc. (East Hartford, CT), developed acousto-optic tunable filters(AOTFs) for use in target identification and surveillance systems. In 1992,Ciencia was awarded a BMDO SBIR Phase I contract to develop a dynamicallyadjustable amorphous-material-based AOTF to replace birefringentcrystals. Phase II funding was later awarded to pursue further developmentof the polymer AOTF for use in sensors. TheAOTF, originally meant to capture ultravioletMucosal dysplasia is aradiation, has proven to be a versatile toolwith a considerable impact in biomedicalprecancerous conditionand biotechnology areas. For example,that occurs in theCiencia is developing a prototype AOTFbasedoptical probe that may help to pinpointcertain types of heart disease by detect-gastrointestinal tract,ing unstable plaque in the coronary arteries.mouth, pharynx, bladder,In addition, radiofrequency generationcervix, and lung. Cancers technology developed under a BMDO SBIRfor implementation of AOTFs is at the heartthat originate in these of the least expensive and most rapid fluorescencelifetime sensing system on theareas account for a market. The system, called LifeSense, ismanufactured and distributed by Orielquarter million deaths perInstruments (Stratford, CT).year in the United States. HOW IT WORKSAcousto-optic devices use ultrasound toalter the refractive index of an optical medium,typically a crystal. Ciencia developed an AOTF based on an organicamorphous material rather than crystals. Amorphous materials are easierand cheaper to make than crystals, allow for uniformity and quality controlduring manufacturing, and permit independent control of bandpassand bandwidth.36By the application of mechanical stress or electric fields, Ciencia’s amorphousmedium can be induced to exhibit birefringence, a type of refractionin which the speed of light through the material depends on directionas well as the light’s frequency. Birefringence allows the AOTF to separatelight into different colors. Unlike an ordinary monochromator, the AOTFcan be tuned electronically, so it has no moving parts. In addition to beingtunable, the polymeric device can produce spectrally resolved images.MEDICAL SIGNIFICANCEOptical Signatures. Recent studies suggest that the chemical compositionof arterial plaque can indicate whether a person is likely to develop a bloodclot. Ciencia’s Raman-spectroscopy-based optical probe, coupled with theChapter 2 - Observation TechnologiesSection B - AnalysisBMDO Technologies for Biomedical Applications

AOTF, can reveal whether a plaque contains destabilizing compounds, suchas collagen or oxidized low-density lipoprotein (LDL, or “bad” cholesterol),that might raise the risk of clot formation. The filters help decipher thechemical signatures picked up by the probe, which would be insertedthrough an ultrasound-guided catheter into the arteries of the heart.When developed, the optical probe can help to detect patients who arepoor candidates for balloon angioplasty, which carries the risk of postprocedureclot development. An even more promising application of this technologyis in optical biopsy, where a fiber-optic probe can replace the scalpelto detect cancer. For sites such as the lung and gastrointestinal tract, anoptical probe can be used in tandem with established endoscopic techniquesto identify abnormal cells without excising them.Fluorescence Lifetime Analyses. Oriel Instruments is using Ciencia’s technologyas part of LifeSense, a device that detects the fluorescence lifetimesignatures of organic compounds. For less than $20,000, Oriel’s LifeSensesystem can be used for biological and environmental research.In molecular biology, fluorescence lifetime sensing can unlock the secretsof the human genome, as well as observe molecular diffusion in cells, antibody-mediatedreactions, and a host of intra- and extracellular functions.Researchers bind special fluorescent dyes to cell structures of interest,excite the sample with an appropriate wavelength, and observe the movementand distribution of critical macromolecules. LifeSense can also pickup the signatures of nontreated cells and tissue via native fluorescence.VENTURES OR PRODUCT AVAILABILITYThe cardiovascular applications of Ciencia’s technology are under assessment.Oriel’s LifeSense performs real-time analysis with Windows-based softwareon a 486 or Pentium PC and provides measurements in 1 second. Thehigh-sensitivity, high-resolution instrument has interchangeable LED orlaser light source modules and is suitable for commonly used dyes such asfluorescein, rhodamine, and phycocyanin. In addition, its compact sizeand light weight make it a convenient benchtop system.CONTACTCiencia, Inc.Salvador M. Fernandez, Ph.D.111 Roberts Street, Suite KEast Hartford, CT 06108Telephone: (860) 528-9737Facsimile: (860) 528-5658Email: fernandez@ciencia.com37BMDO Technologies for Biomedical ApplicationsChapter 2 - Observation TechnologiesSection B - Analysis

HIGH-SPEEDMOLECULAR MODELING• Molecular modeling can greatlyspeed up decision making in drugselection strategy.BMDO HISTORYWith the help of BMDO contracts to simulate the mechanical behavior oflarge space-based structures, Photon Research Associates (PRA; San Diego,CA) has developed a computer algorithm that reduces the time needed tomodel the dynamics of large molecular systems. In the early to mid-1980s,PRA developed multibody modeling technology to simulate the dynamics oflarge space-based structures. The originalsponsors of this research included theIn the immune system,Defense Advanced Research Projects Agencyand NASA. Tests of the algorithm, calledthe shape of an invadingMBO(N)D, have shown that it can simulatepathogen and thethe dynamics of large molecules (10,000atoms) up to 50 times faster than conventionalall-atom modeling techniques, while“memory” of the immunemaintaining accuracy in the essential dynamics.Applications to larger molecules (10,000system for this shapeto 100,000 atoms) and further refinementshelp dictate whether ato the algorithm should make it about 100 to1,000 times faster than all-atom approaches.person acquires anHOW IT WORKSinfection, fights off theMBO(N)D accelerates computational speedwhile maintaining a great deal of chemicalinfection, or developsand physical realism. This achievement isan autoimmune disease. possible through a technique known as “substructuring,”which combines atoms intointeracting groups of rigid and flexible bodies.The algorithm also filters out high-frequency motions that do not affectthe overall behavior of the molecule. These two innovations reduce the numberof system variables and allow the simulation to be computed over asmaller number of time steps.38MEDICAL SIGNIFICANCEDrug discovery has changed over the past 15 years to include the study ofsignificant structural components in and around the cell. Molecular structuresof proteins and receptor-ligand complexes play an important role inthe discovery of novel agents. A ligand is a biological compound that fits areceptor within or on the cell surface in a “lock and key” arrangement.Drugs that mimic the shape of the natural ligand can be used to up- ordown-regulate a signal that is transduced by the cell receptor. Some receptorstructures are found by x-ray crystallography, some by nuclear magneticresonance, and some by homologous comparisons to similar structures.All of these techniques rely on molecular dynamics to find the correctpositions of all the atoms in the drug and the receptor and how theymove to interact with each other. While highly parallel supercomputersChapter 2 - Observation TechnologiesSection B - AnalysisBMDO Technologies for Biomedical Applications

(like those of Cray and IBM) have increased the number of structuresresolved and modeled the molecular dynamics motion of drug and receptorin the nanosecond range, this brute-force method has not broughtthese capabilities to the drug discovery desk.By increasing computational speed, MBO(N)D can improve on the allatomtechnique and can make predictive modeling, the discovery of newdrugs, and the development of new materials through computational techniquesmore practical. Drug development is a major risk for pharmaceuticalcompanies, often requiring at least a decade of development and manymillions of research dollars. Molecular modeling stands to considerablyimprove the risky environment in which this type of research takes place.VENTURES OR PRODUCT AVAILABILITYIn 1991, PRA formed a subsidiary called Moldyn, Inc. (Cambridge, MA),to further develop and market the MBO(N)D technology for the moleculardynamics applications mentioned above.In 1994 Moldyn received an Advanced Technology Program award fromthe National Institute of Standards and Technology to help bring the technologyto the pharmaceutical industry. In this project, Moldyn and its partnershave been refining the MBO(N)D algorithm for commercial use.Moldyn’s partners in this project include leading pharmaceutical companies(Bristol-Myers Squibb, Vertex Pharmaceuticals), a commercial computationalchemistry software firm (Molecular Simulations, Inc.), and leadingacademics in computational chemistry.Moldyn has received one patent covering a molecular dynamics simulationmethod and apparatus based on the MBO(N)D algorithm and has copyrightedthe MBO(N)D code.The MBO(N)D software will be marketed and distributed by MolecularSimulations, Inc., which has partnered with Moldyn to incorporateMBO(N)D within one of Molecular Simulations’ most popular graphic userinterfaces, Insight. The code can also run in stand-alone mode. Academicrelease of MBO(N)D is expected in 1998. Moldyn also plans to market servicesusing MBO(N)D directly to pharmaceutical companies.CONTACTMoldyn, Inc.Frank P. Billingsley, Ph.D.c/o PRA Washington Division1911 North Fort Myer Drive, Suite 408Arlington, VA 22209Telephone: (703) 243-6613Facsimile: (703) 243-661939BMDO Technologies for Biomedical ApplicationsChapter 2 - Observation TechnologiesSection B - Analysis

40LiSAF LASER FORCYTOMETERS• Compact laser technology can helpimprove flow cytometry.BMDO HISTORYA new diode-pumped solid-state lithium strontium aluminum fluoride(LiSAF) laser is being developed by Science and Engineering Services,Inc. (SESI; Burtonsville, MD). It will provide simultaneous output wavelengthsof 490 and 980 nanometers. The Q-switched laser is based on aLiSAF crystal, doped with chromium. The short laser pulse durationsand solid-state nature of the laser contributeto the system’s low power consumption,compactness, and reliabilityCell sorters or cytometersunder severe vibrational stress and widehave become very sophisticatedin a short time in ed Phase II funding for this effort, withtemperature variation. BMDO has provid-matching funds provided by the Army andpart because of the Recon Exploration (Dallas, TX). BMDOhas also funded the development of frequency-agilelasers for spaceborne spec-enormous demand thattroscopic platforms, LIDAR, tracking,creative biologists havedetection of atmospheric constituents, anddetection of wind shear. SESI has performedresearch with NASA, the Army, thebrought to bear on theindustry. Advances in Navy, and the National Science Foundationin the areas of atmospheric sensing, LIDAR,lasers, coupled with general laser development, and novel medicalinstrumentation.newly available dyes andHOW IT WORKSever-increasing antigenantibodycombinations, a high repetition rate (1 to 2 kilohertz) andThe laser is tunable within a fundamentalrange of 780 to 1,000 nanometers and hasmicrojoule pulse capability (50 to 80 microjoules).SESI plans to couple the LiSAF laserhave played a large part insystem to a flow cytometer to make it morewidening the range of cellreliable than cytometers operated with nonsolid-state,continuous-wave laser outputs.types that can be identifiedA flow cytometer is a device that uses a laserwith cytometers.to detect the fluorescence intensity of cellsthat flow past a detector in a thin stream. Iffluorescence is detected, the cell is given anelectrical charge and deflected into a collection bin. The simultaneous outputof two different wavelengths can expand a cytometer’s ability to sortmultiple cell types during one sorting run. By frequency doubling, the secondharmonic of the laser can provide blue-green activity, tunable from390 to 500 nanometers, that would be valuable in the communicationsChapter 2 - Observation TechnologiesSection B - AnalysisBMDO Technologies for Biomedical Applications

field. A third harmonic bandwidth of 260 to 330 nanometers is possiblewith further development and would be applicable in ultraviolet flowcytometry. The ultraviolet wavelengths might prove especially useful inlighting up DNA and determining stages in the cell cycle, for example.MEDICAL SIGNIFICANCEThere is a very large market in biotechnology and medicine for flowcytometers. Among their uses are cell sorting by chromosome content,infective status, antigen presence (as in determination of tissue transplantcompatibility), and cell-receptor-ligand combinations. They are used inboth research and clinical institutions to analyze a large variety of cell typesand can identify cell characteristics through native fluorescence or dyebasedillumination strategies.VENTURES OR PRODUCT AVAILABILITYSESI is working to commercialize its LiSAF laser and is currently retrofittinga cell sorter manufactured by a well-known flow cytometer supplier.CONTACTScience and Engineering Services, Inc.Coorg Prasad, Ph.D.4014 Blackburn LaneBurtonsville, MD 20866-1166Telephone: (301) 989-1896Facsimile: (301) 421-413741BMDO Technologies for Biomedical ApplicationsChapter 2 - Observation TechnologiesSection B - Analysis

SECTION CDIAGNOSISAncient Chinese medicine held that the gallop of the pulsereflected the state of the body, and practitioners used theintricate patterns of the heartbeat to confirm many diagnoses.In the age of technology, patterns also hold clues tothe status of the organism. Two techniques used in adaptiveoptics technology, originally developed to discern wavelengthpatterns in the scattering atmosphere, can remotelydiagnose eye disorders. Vibrational spectroscopy can bothvisualize and quantify biochemical species in unstained cellsamples. Applications in both spectroscopy and luminescentmaterials have led to devices that can detect airborne contaminants,cancerous cells, bioluminescent signatures of bacteria,and specific gene sequences. Even ultraprecise gimbaltechnology derived from laser communications research hasfound a place in a needle biopsy system.1. A wavefront sensor that can process data on astigmatism,interpupil distance, and ocular accommodation andcan do so over telemedical routes.2. A deformable mirror that improves retinal imaging for thestudy of photoreceptors in the eye.3. An infrared array that is the heart of a microscope that canvisualize and quantify silicone leakage in breast tissue.4. A multispectral sensor that analyzes biological material inthree dimensions.5. A combination spectrometer-endoscope that helps doctorsdiagnose oropharyngeal cancer.6. A nonradioactive, nonfluorescent gene probe that distinguishesdouble-stranded DNA from single-stranded DNA.7. Nanocrystals that emit visible light when excited byinfrared wavelengths and have potential as molecular tags.8. A spectroscopic method that reveals true-color images ofcancerous versus normal tissue.9. A robust, extremely accurate driver for guided needlebiopsy of the breast.

AMT: BINOCULAR3-D EYE TRACKER• A novel wavefront sensor can helpdoctors remotely diagnose eye disorders.BMDO HISTORYApplied Modern Technologies Corporation (AMT; Huntington Beach, CA)has developed an eye-tracking device based on wavefront sensor technologyborrowed from adaptive optics. In the 1980s, BMDO focused muchattention on how light, particularly high-energy laser light, was propagatedthrough the atmosphere. This interest generated a host of techniques tocorrect the scatter of light in turbulent air,improving both transmission and detectionWhile our view of theof light. The astronomy field has benefitedgreatly from advances in adaptive optics—world may seem smoothfor example, using it to remove the “twinkle”from galactic objects—but other areasand uninterrupted to us,of science are also reaping the rewards ofthe continual, jerky this technology. AMT’s Ocular Vergence andAccommodation Sensor (OVAS) is a newmovements of the eye are product for the vision sciences and medicalresearch that can trace its lineage to BMDOessential to maintainingadaptive optics technology.this clear image.HOW IT WORKSOVAS uses two low-power (1.25 milliwattsParadoxically, if these eyeper square centimeter; eye-safe) infraredlaser beams that are reflected from eachmovements are artificiallyeye’s retina. The reflection provides informationabout the movement of the eyes andstilled, the world becomesother biometric data that can be processeda defocused blur.and used for a variety of applications. AMT’sdesign includes a 12-component optics systemand a Pentium processor with algorithmsfor processing data on the accommodative state, movements, andvergence of the eyes, as well as 10 other ocular functions.44MEDICAL SIGNIFICANCETelemedicine. OVAS could provide diagnostic data from a patient to a doctormany miles away. The application to soldiers in the field includes earlydetection of exposure to chemical warfare agents. The AMT system isrugged enough for battlefield conditions and can be miniaturized for integrationinto a portable, head-mounted system. OVAS is proposed as partof a testbed project for remote ophthalmic instruments for the TriplerArmy Medical Center. The center’s responsibilities include health care forthe U.S. South Pacific Protectorate. Doctors are scarce on these smallislands, and often the citizenry and military personnel must make do withlimited immediate medical care. With OVAS, an ophthalmologist at aremote location may be able to evaluate a Tripler patient’s eyes for correctiveeyewear and for such conditions as cataracts and diabetic retinopathy.Chapter 2 - Observation TechnologiesSection C - DiagnosisBMDO Technologies for Biomedical Applications

The South Pacific population experiences a very high rate of diabetes-relatedblindness.Ophthalmology and Optometry. OVAS is an automated system that candetermine prescription lens strength, astigmatism, interpupil distance, andaccommodation. Because OVAS is binocular, both eyes are measuredsimultaneously. AMT feels this is superior to the current practice, whichmeasures each eye separately. Potentially, lens prescriptions could be balancedto reduce the dominant-eye effect now common for correctedvision. Future units can be used to precisely measure the minute aberrationsof the cornea, helping to fit contact lenses or to determine the depthof abrasions. In surgery, OVAS could identify astigmatism introduced bythe surgery and allow immediate correction. The benefits extend to schoolchildren for a quick, accurate eye-screening device and to faster, more indeptheye exams requiring no feedback from the patient.Other Medical ApplicationsFor those who are paralyzed or seriously restricted in their ability to move,eye movement sensors have been in use for some time. With an “ocularmouse,” the user can look at an icon or array of letters on a monitor to initiatea program function or spell out words. These assistive computer interfacesadd immensely to the quality of life of such individuals, and sensorsthat can accurately track eye movement are crucial to the technology.Medical students, residents, and interns are taking increasing advantage ofvirtual reality (VR) for educational purposes. Surgical trainees can nowpractice such procedures as laparoscopies on a VR simulator before movingon to real patients. VR also needs eye movement and focusing informationfor its next-generation products.VENTURES OR PRODUCT AVAILABILITYAMT has applied for 89 patents related to OVAS and is marketing aresearch version of OVAS aimed at the medical market. This includes studieswhere OVAS’ data points are used for statistical analysis and includevision research, neuro-ophthalmology, display research, VR research, andscene generation. OVAS is suitable for office, laboratory, or mobile use.CONTACTApplied Modern Technologies CorporationLarry Horwitz, Ph.D.12062 Valley View Street, Suite 101Garden Grove, CA 92845-1738Telephone: (714) 379-2870Facsimile: (714) 379-2873Email: larry@amtvis.comWWW: http://rworld.compuserve.com/homepage/ovas45BMDO Technologies for Biomedical ApplicationsChapter 2 - Observation TechnologiesSection C - Diagnosis

DEFORMABLE MIRRORS TOUNCOVER EYE DISORDERSBMDO HISTORYXinetics, Inc. (Littleton, MA), is using adaptive optics technology developedfor BMDO to bring optical correction and precision to a medical imagingapplication. BMDO funded the original research primarily for the groundbasedfree electron laser, whose beams were subject to atmospheric distortion.With research and development funded by BMDO, the U.S. Navy’sOffice of Naval Research, and the U.S. AirForce’s Phillips Laboratory, Xinetics’ coreApproximately 80 percentteam developed lead magnesium niobate(PMN) actuators and deformable mirrorof premature infantstechnology at Itek Corporation and Unitedweighing less than Technologies Optical Systems.• Deformable mirrors help researcherstake a closer look at diseased retinas.1 kilogram at birth willdevelop retinopathy ofprematurity (ROP).Children with ROP arediagnosed with retinalscarring, nearsightedness,and crossed or “wandering”eyes at a much higherincidence than normalweightinfants.HOW IT WORKSAdaptive optics is an aggregate technologythat analyzes the characteristics of lightwaves and minimizes their distortion. Thetwo principal corrections are for the “tilt” ofthe light entering the optical system and forthe light scatter caused by collisions withmolecules in the atmosphere or in the vitreousfluid of the eye, for example. An adaptiveoptics system uses a wavefront sensorto measure the optical distortion and supplya control computer with an error map.The computer then sends commands to adeformable mirror that changes shape tocorrect the distortion. Deformable mirrorsuse small piston-like devices called actuatorsto bend a thin sheet of polishedultralow-expansion fused-silica glass.46The key elements in the Xinetics deformablemirror technology are piezoelectric or electrostatic actuators based on PMNcrystals. These actuators expand and contract when an electric field isapplied, pushing and pulling the mirror sections into different shapes. PMNactuators are well suited to deformable mirrors because of their high stiffness,negligible hysteresis, and excellent stability. To produce PMN actuatorsin high volumes, Xinetics uses a layered ceramic process developed in themicroelectronics and multilayer capacitor industries. The process eliminatesconventional glue bonding to provide high stiffness. It also reduces operatingvoltage from 3,000 to 100 volts.Chapter 2 - Observation TechnologiesSection C - DiagnosisBMDO Technologies for Biomedical Applications

MEDICAL SIGNIFICANCEA Xinetics deformable mirror is now part of a retinal camera being developedby David R. Williams, Ph.D., the director of the University ofRochester’s Center for Visual Science. The camera already provides atwofold improvement in resolution over present ophthalmic imagingdevices such as the fundoscope. The resolution of the retinal camera is currently2 to 10 micrometers and is expected to eventually reach 0.3 micrometers.The camera can provide detailed images of photoreceptors in the retinaand can detect early changes in disorders like diabetic retinopathy andretinitis pigmentosa. It can also be used to more precisely measure refractiveerror (the degree of nearsightedness or farsightedness) in the eye.Microaneurysms, or small balloon-like lesions of capillaries, can also bediagnosed. Microaneurysms can reflect the presence of more serious bloodvessel disorders in the brain. Developmental progress of neonatal eyes canalso be tracked with this device. Retinopathy due to oxygenation of immatureretinal cells is an increasing problem in premature infants, particularlyas gestational age at birth decreases.VENTURES OR PRODUCT AVAILABILITYXinetics, a 15-person company founded in 1993, makes custom and standardadaptive optics technologies for military and commercial customers.The company is engaged in a number of agreements to manufacturedeformable mirrors and actuators for medical applications, astronomicaltelescopes, optical scanners, and micropositioners.CONTACTXinetics, Inc.Mark Ealey37 MacArthur AvenueDevens, MA 01432-4443Telephone: (978) 772-0352Facsimile: (978) 772-2814Email: xinetics@xinetics.com47BMDO Technologies for Biomedical ApplicationsChapter 2 - Observation TechnologiesSection C - Diagnosis

NIH INFRARED MICROSCOPE• This novel microscope dramaticallyand specifically highlights cellconstituents.BMDO HISTORYE. Neil Lewis, Ph.D., and a group of researchers at the National Institutesof Health (NIH) have developed an infrared microscope that uses a focalplane array (FPA) to obtain both spectral images and signatures of biologicaland other materials. The group used an indium antimonide (InSb) FPAfor their initial work, in which they imaged silicone inclusions in paraffinembeddedbreast tissue sections. Throughan alliance with Ted Heilweil, Ph.D., aThe furor over siliconeresearcher at the National Institute ofStandards and Technology (NIST), the NIHbreast implants is far fromteam was able to access a mercury cadmiumresolved. Epidemiologists telluride (HgCdTe) FPA from BMDO’sExoatmospheric Kill Vehicle program runare pitted againstby the U.S. Army Space and StrategicDefense Command at Huntsville, AL. Thecytopathologists, many array is manufactured by Hughes and inthis case did not meet military specifications.The researchers say that the few deadof whom read differentpixels on the array do not in any way affectpatterns in the availablethe quality of their data. The HgCdTe arrayevidence. It is clear, however,that silicone leakagewill enable the group to expand the microscope’swavelength range.HOW IT WORKSinto living tissues is a The NIH group collaborated with colleaguesat NIST to extend the microscope’shighly undesirable event. spectral range to 11 micrometers by using aBMDO-funded 256 x 256 HgCdTe FPA.The InSb FPA limits the microscope to the2- to 5-micrometer range. Therefore, with the use of the HgCdTe FPA, it ispossible to expand the number of spectral signatures that the microscopecan detect, thereby greatly extending its chemical imaging capabilities.Both the InSb and the HgCdTe FPAs are nitrogen cooled.48Lewis developed the software that enables the acquisition and processingof the enormous amount of data that this microscope acquires. The microscopeuses an interferometer to record spectra, and therefore the softwareuses Fourier transform techniques to convert the data to chemical imagesand spectra. Typically, each image data set contains 16 to 20 megabytes ofdata, although standard PCs are used to manipulate and store the data.Chapter 2 - Observation TechnologiesSection C - DiagnosisBMDO Technologies for Biomedical Applications

MEDICAL SIGNIFICANCEMost components of living matter have a unique infrared signature thatcan be detected spectrographically. Molecular biology contributes new dataalmost every day about the molecular makeup of human beings and thesignificance of these molecules in health and disease. From cancerresearch, for instance, we know that abnormal proteins result from mutationsin critical genes that govern cell growth. Proteins such as prostatespecificantigen; the breast-cancer-associated genes BRCA1, BRCA2, andHER2; and many others may one day be detectable in minute quantitiesby their infrared signatures. The ability to image molecular informationfrom histological sections makes this instrument an especially qualifiedcandidate for use in the pathology laboratory. In general research, themicroscope’s uses can be as varied as the researcher’s interests.Lewis and his group clearly demonstrated the presence of silicone inclusionsin breast tissue samples and published their results in NatureMedicine (February 1997). Virtually all silicone gel breast implants haveshown a tendency to rupture and bleed their contents into surrounding tissues.These leaks have also been known to migrate into distant organs. Asa diagnostic tool in this controversial area, the microscope will enable cliniciansto identify leakage from silicone breast implants visually and bychemical signature.Many other industries are also interested in this technology. Polymers,pharmaceuticals, cosmetics, and semiconductors are just some of the itemsthat can be analyzed with this microscope.VENTURES OR PRODUCT AVAILABILITYLewis has generated interest from a number of Fortune 500 companies,including Procter & Gamble, Miles Laboratories, ICI, and Estee Lauder.Procter & Gamble has installed such an imaging system in collaborationwith NIH, which owns the patent on the technology.CONTACTNational Institutes of HealthE. Neil Lewis, Ph.D.Building 5, Room B1-38Bethesda, MD 20892-0510Telephone: (301) 496-6847Facsimile: (301) 496-0825Email: neil@spy.niddk.nih.govWWW: http://www.nih.gov49BMDO Technologies for Biomedical ApplicationsChapter 2 - Observation TechnologiesSection C - Diagnosis

ADVANCED IMAGINGSPECTROMETERBMDO HISTORYPacific Advanced Technology, Inc. (PAT; Solvang, CA), has developed animaging spectroradiometer that can be used to detect and identify chemicalsand biological matter for military, environmental, law enforcement, andmedical applications. Called the image multispectral sensor (IMSS), thistechnology is based on advances in diffractive optics and image and signalprocessing. It images a scene in three dimensions,two spatial and one spectral, to build aBioluminescence, a traitmultispectral spatial imaging cube of data.• The IMSS imaging device can helpdetect bioluminescence in dangerousbacteria.found in the familiar firefly,is a natural phenomenonthat has enabled biologiststo develop clever ways totrack gene expression inanimals. For instance, aglowing protein found injellyfish has been successfullyincorporated as areporter gene in transgeniclaboratory mice.BMDO funded PAT’s multispectral sensingtechnology in 1995 through the SBIR programin a joint project with Amber, aRaytheon company (Goleta, CA). Amberand BMDO provided $150,000 each for theproject. With IMSS technology, BMDOcould detect theater missiles in clutter,identify friend or foe, and detect and identifychemical agents. PAT previouslyobtained a BMDO SBIR Phase I contractoutside this teaming arrangement.HOW IT WORKSWhile other spectral imaging devices havevery complex optics and require exact alignment,PAT’s instrument uses a simple opticaldesign that allows for relaxed tolerances onoptical alignment. Rugged and portable, itcan operate in harsh environments such asairborne and space-based platforms.50PAT has commercialized this instrumentwith joint funding from the BMDO SBIR program and Amber. Amber sellsthe commercial IMSS as an attachment to its RADIANCE 1 and Galileocameras to make a midwave infrared multispectral radiometric imager, usefulfor spectroscopy and radiometry. PAT supplies Amber with the multispectrallens system as well as the image- and signal-processing softwarecalled HYPAT. This system uses an f/2.5 nominal 102-millimeter focallength lens and covers the full 3- to 5-micrometer spectral band with a spectralresolution of less than 0.01 micrometers. Using the Galileo camera inthe highest data acquisition mode, spectral images over the 3- to 5-micrometerband with 400 spectral bins can be collected in less than 1 second.Chapter 2 - Observation TechnologiesSection C - DiagnosisBMDO Technologies for Biomedical Applications

MEDICAL SIGNIFICANCEPAT’s multispectral imaging device is an ideal instrument for collectingoptical signatures from biological matter, whether the task is to identifybacteria or a cancerous lesion. Bioluminescence systems are already in usefor rapidly detecting the presence of E. coli, for example, in foodstuffs. Foridentifying cancers without surgical sampling of the suspicious area, opticalbiopsy is very close to clinical adaptation in a number of institutions.The IMSS can also be used for reading the optical signatures of tumors andfor localizing them in a 3-D image. The device has an adaptive spectral filterthat can separate excitation light from emission light; this is critical forthe fiber-optic system that both delivers and collects light in the opticalbiopsy system.If the capability of the IMSS is extended to longer wavelengths, the technologycan be used to detect and identify chemical agents, such as sarinand other nerve gases. Through an Air Force SBIR Phase II contract, PATis designing a system that will detect signatures at longer wavelengths forchemical warfare applications.VENTURES OR PRODUCT AVAILABILITYPAT is a woman-owned small business focused on electro-optic researchand development. The company has one patent on the IMSS technology.PAT supplies its lens product to Amber, which has sold two RADIANCE 1systems with the lens for military use. Another order is pending. Systemsincluding the Amber camera cost roughly $70,000.With the IMSS technology, Amber and PAT are focusing on applications toremotely monitor smokestack emissions and, in 1995, demonstratedpromising results in the field. From 1 kilometer away, PAT’s system detectedcarbon monoxide, carbon dioxide, and hydrocarbons from two smokestacksat an oil refinery. PAT is interested in demonstrating its technologyto detect sulfur dioxide for environmental applications.CONTACTPacific Advanced Technology, Inc.Michele HinnrichsP.O. Box 3591000 Edison StreetSanta Ynez, CA 93460-0359Telephone: (805) 688-2088Facsimile: (805) 686-2723Email: micheleh@syv.com51BMDO Technologies for Biomedical ApplicationsChapter 2 - Observation TechnologiesSection C - Diagnosis

Courtesy of Beckman Laser Institute.MTC’s ENDOSCOPE• MTC’s endoscope will be used incancer drug trials in 1998.BMDO HISTORYAnother beneficiary of the BMDO-funded Medical Free Electron Laser(MFEL) program was Robert Alfano, Ph.D., at the City College of NewYork (New York, NY). Alfano is a physicist who has studied the opticalproperties of living tissue for a number of years. His recent work in visiblelight transmission through breast tissue has attracted considerable attention.Early in the MFEL program, however,Alfano experimented with the native fluorescenceof tumor cells as compared withCancers of the mouth andtheir normal counterparts. Fluorescenceesophagus are largelyspectroscopy is an up-and-coming technologythat is widely expected to become anpreventable throughintegral part of cancer diagnosis within thelifestyle changes such as next few years. Along with MediscienceTechnology Corporation (MTC; Cherrysmoking cessation and Hill, NJ), Alfano devised an endoscopic toolthat could be inserted into the mouth andlimited alcohol use. It isesophagus to look for signs of cancer asdetermined by the fluorescence signature ofimperative to catch thethe mucosal lining. This tool, the CD-Scandisease early to prevent and CD-Ratiometer, will be evaluated in amajor clinical trial at the Memorial Sloandevelopmentof potentially Kettering Cancer Center in New York City.52disfiguring and life-threateninglesions.illuminate tissue with a laser or other lightHOW IT WORKSMTC’s devices use a fiber-optic probe tosource and a spectrometer to analyze thefluorescence that results from the illumination.Increasing numbers of investigators in oncology are finding that thereare discernible and very useful differences between malignant and normaltissue fluorescence signatures. Trials such as those described below arenecessary to correlate these signatures with conventional microscopicmeans of cancer diagnosis to create a useful clinical database. Consistentresults that match fluorescence signals with cancer evidence mean thatsome future biopsies will be performed with light rather than scalpels.This database is growing significantly.MEDICAL SIGNIFICANCEIn a previous report, we noted that MTC was planning an investigationaldevice exemption (IDE) application for its device, which it obtained inearly 1997. Stimson P. Schantz, M.D., an otolaryngologist at Sloan-Kettering who specializes in cancers of the head and neck, is using the CD-Chapter 2 - Observation TechnologiesSection C - DiagnosisBMDO Technologies for Biomedical Applications

Scan and CD-Ratiometer as part of his patients’ clinical evaluations in aPhase II drug trial. A new and promising vitamin A derivative, 13-cisretinoicacid, is being tested as a treatment for oral leukoplakia, a whitishlesion of the mouth that can progress to cancer. The CD-Scan will be usedto corroborate excisional biopsy findings with the unique fluorescence signalof the precancerous lesion. The device will also be used in a Phase IIItrial that will follow the completion of the Phase II trial.In addition, the U.S. Army Medical Research, Development, Acquisition,and Logistics Command will be using a fiber-optic needle and the CD-Ratiometer to diagnose breast cancer via needle biopsy techniques. As inSchantz’s trial, the device will be used along with conventional histopathologymethods to determine the fluorescence signals associated with breastmalignancies. This trial will be conducted at Massachusetts GeneralHospital (Boston, MA). The principal investigator is radiologist Daniel B.Kopans, M.D.MTC is also planning to file an IDE for detecting gastrointestinal premalignancywith the CD-Scan device.VENTURES OR PRODUCT AVAILABILITYMTC has 15 patents in the area of biomedical optics. The CD-Scan and CD-Ratiometer are based on its patented tissue fluorescence technology. MTC isalso working with the City University of New York and General Electric todevelop a non-ionizing optical mammography system, although opticaltechniques for this application are in the very earliest stages of development.MTC has received private equity financing from Allen and Company, aninvestment banking company, to carry out its research activities.CONTACTMediscience Technology CorporationRonald Krumm49 Willow PlaceAlbertson, NY 11507Telephone: (516) 484-9141Facsimile: (516) 484-479553BMDO Technologies for Biomedical ApplicationsChapter 2 - Observation TechnologiesSection C - Diagnosis

RAMAN-BASED GENEPROBE TECHNOLOGY• Dr. Vo-Dinh’s nonradioactive, nonfluorescentgene probe is safe and sensitive.BMDO HISTORYWith the help of funding through BMDO’s Innovative Science andTechnology Directorate and the Department of Energy, an advanced opticaltechnology called surface-enhanced Raman optical data storage(SERODS) was born. Developed to greatly expand data storage capabilitiesbeyond those achievable with conventional silicon technology, SERODSalso spawned a novel gene probe technology,SERGen. SERGen requires no radioactivetags or special fluorescing dyes and cutsSince the race togene identification time drastically, from assequence the humanmany as 16 hours to a matter of minutes. Itgenome began, about 20 can also be used with conventional molecularbiology techniques such as polymerasepercent of human genes chain reaction.have been at least partiallyHOW IT WORKSSurface-enhanced Raman spectroscopysequenced. However, (SERS) is the basis for SERGen’s ability todistinguish between single-stranded andscientists have identified double-stranded DNA. Adsorbing a genesequence of interest onto an “enhancing”functions for only 3 percentof the postulatedmicrostructured metal surface greatlystrengthens the Raman signal, allowing aresearcher to detect minute quantities of80,000 to 100,000 genes. specific DNA sequences with a spectroscope.When a gene sequence of interest isintroduced into the reaction, the SERSprobe seeks out its complementary partner on the reaction plate; thisprocess is known as hybridization. Hybridization indicates that a matchhas been made between two complementary strands of DNA. The doublestrandedhybrids give a unique Raman signal, distinguishing them fromthe single-stranded, unmatched sequences.54MEDICAL SIGNIFICANCEThere are many areas in which SERGen would prove useful because of itsrapidity and sensitivity. For example, in our era of increasing antibioticresistance, SERGen may prove a boon to doctors who want to quicklyidentify resistant organisms. In this way, the proper medication can be prescribedand a wasted course of ineffective antibiotics can be avoided. Thereare many known resistance genes in bacteria. With a simple probe that representsthe sequence of the resistance gene, SERGen can immediately identifythis unique biochemical tag to narrow drug treatment choices.Chapter 2 - Observation TechnologiesSection C - DiagnosisBMDO Technologies for Biomedical Applications

SERGen has already been used in the laboratory to detect sequences fromthe genomes of HIV-1, hepatitis B, and Mycobacterium tuberculosis (theorganism that causes tuberculosis). Therefore, SERGen can serve as a fastprobe for diagnosing infections without the long wait for cultures or antibodyassays.A much more newsworthy application of SERGen is in the HumanGenome Project, for which discussions are under way. Gene sequencingand identification timetables have accelerated impressively; however, theseincremental improvements have been variations on a few themes of conventionalmolecular biology techniques. SERGen could offer a drasticimprovement in methodology.VENTURES OR PRODUCT AVAILABILITYSERGen won a 1996 R&D 100 award, and a patent for the technology ispending.CONTACTOak Ridge National LaboratoryTuan Vo-Dinh, Ph.D.P.O. Box 2008Mail Stop 6101Oak Ridge, TN 37831Telephone: (423) 574-6249Facsimile: (423) 576-7651Email: tvo@ornl.govWWW: http://www.ornl.gov55BMDO Technologies for Biomedical ApplicationsChapter 2 - Observation TechnologiesSection C - Diagnosis

NANOPHOSPHORS• Nanophosphors may someday beused to tag genes in chromosomes.BMDO HISTORYStructured Materials Industries, Inc. (SMI; Piscataway, NJ), collaboratingwith Rutgers University, developed a deposition and processing technologyto form, control, and study a variety of nanocrystal powders and nanostructuredfilms, several of which are luminescent when in the nanocrystal structure.After conducting preliminary research into porous silicon and germaniumnanocrystal structures with BMDOSBIR Phase I funding in 1992, SMI receivedThe late, great physicistRichard Feynman wasa vocal proponent ofPhase II funding in 1993 to continue thenanophosphor research. SMI has demonstratedluminescence from several nanocrystalsand is pursuing full-color electroluminescentdisplays (ELDs). Recently, SMInanotechnology. With demonstrated luminescence from severaldoped-oxide compounds as well. With thesuch technology, he help of two additional BMDO STTR awards,and with the Massachusetts Institute ofonce declaimed, theTechnology and Lawrence Livermorecomplete contents of theEncyclopedia BritannicaNational Laboratory, SMI is also developingan annealing technology for phosphors onglass, as well as zinc oxide epitaxy. Two morePhase I awards support development of p-could be written on the type transparent conductors and nanostructuredfilms, and a Phase II award supportshead of a pin.alternative conductive and transparentoxides. A Phase II STTR contract supportsnanopowder development.56HOW IT WORKSA new patented, dry chemical-vapor-condensation process that can be customizedfor each particular type of nanoparticle is being marketed by SMI’snew division, Nanopowder Enterprises, Inc. (NEI). The reactant chemicalsare fed into the system on an inert carrier gas and then pass through a heatedreaction chamber. During the reaction phase, the by-products dissipateas vapors. This leaves only the desired product: the dry, nonagglomeratednanoparticles. The condensation of the nanoparticles from the superheated,supersaturated vapor in the reaction chamber is so rapid that the particlesdo not have a chance to agglomerate. This rapid condensation producesnanoparticles with a narrow size distribution. The particular compound’schemistry is controlled by selecting an atmosphere that is oxidizing,reducing, carburizing, or nitridizing, as required. Multicomponent ormultiphasic particles are formed by using multiple chemical reactantsources. This method controllably produces nanopowders from 3 to 50nanometers in size. When materials are restricted to this small size, theyChapter 2 - Observation TechnologiesSection C - DiagnosisBMDO Technologies for Biomedical Applications

can have dramatically different properties from their larger counterparts.Some materials’ strength approaches the calculated theoretical limit; someceramic and intermetallic materials exhibit ductility, a property usuallyseen only in metals; some exhibit superplasticity; some exhibit quantumconfinement effects; and some exhibit dramatically enhanced magnetic,electronic, and optical properties.MEDICAL SIGNIFICANCENanocrystal light emission has other uses besides ELD componentry. NEIis exploring other, more efficient nanophosphors that are brighter at lowerexcitation voltages and in each primary color: red, blue, and green. Thenanophosphors are electroluminescent at 1000 volts and are brighter thanstandard CRT phosphors at that voltage. A promising biotechnology applicationfor nanophosphors is molecular tagging to “up-convert” infraredradiation to visible photoluminescence. Laboratories now use taggingcompounds that luminesce when exposed to either visible or ultravioletlight—shorter wavelengths that can destroy the sample material quickly.Using the up-converting nanophosphors to tag and visualize the DNA, forexample, may provide an advantage because the nanophosphors are activatedby infrared light, which is less destructive than ultraviolet or visiblelight. With three colors, researchers can choose from or combine thenanophosphors to create a wide-range spectrum for identifying differentmolecules such as specific DNA sequences or cellular proteins.VENTURES OR PRODUCT AVAILABILITYFounded in 1993, SMI established NEI as a division in 1995 specifically tomanufacture and market nanocrystalline materials, Nanomyte powders,and Nanomyte One processing equipment. NEI has received patentsand has patents pending for the production method and apparatus fornanostructured ceramic powders and whiskers; the method for large-areadeposition and processing of nanoparticle powders on sheet substrates;and for high-volume, low-pressure combustion flame synthesis ofnanophase materials. SMI and NEI offer a variety of films, powders, andprocessing equipment and have generated several hundred thousand dollarsin matching funds for these program areas.CONTACTStructured Materials Industries, Inc./Nanopowder Enterprises, Inc.Gary S. Tompa, Ph.D.120 Centennial AvenuePiscataway, NJ 08854Telephone: (908) 885-5909Facsimile: (908) 885-5910Email: 75031.1321@compuserve.com57BMDO Technologies for Biomedical ApplicationsChapter 2 - Observation TechnologiesSection C - Diagnosis

OPTICAL BIOPSYBMDO HISTORYFunding for surface-enhanced Raman optical data storage (SERODS) at OakRidge National Laboratory (ORNL) also led to a different sort of biologicalprobe (see previous article on SERGen). Tuan Vo-Dinh, Ph.D., conductedstudies with SERODS-associated lasers that have contributed to the use oflasers for a cancer detection method that substitutes light for the scalpel ofsurgical biopsy. Using the body’s own emissionin reaction to certain wavelengths of laserThe average age of alight, it is possible to detect unique fluorescencesignals with a spectrometer. As demonstratedin studies conducted by Vo-Dinh atcancer patient at diagnosisis 60; this fact probably ORNL and his co-developers, MasoudPanjehpour, M.D. and Bergein Overholt,reflects long-term exposureto environmental demonstrate cancerous “hot spots” withoutM.D., at the Thompson Cancer SurvivalCenter (Knoxville, TN), this activity canremoving tissue. Optical biopsy, as this techniquehas come to be known, has gainedinsults and carcinogens,tremendous momentum within the last twoas well as the aging body’syears. Major trials are under way in manydeclining ability to repair U.S. cancer treatment centers, such asMemorial-Sloan Kettering (New York, NY),genetic mutations. Roswell Park (Buffalo, NY), WellmanLaboratories of Photomedicine (Boston, MA),and Beckman Laser Institute (Irvine, CA).58• Optical biopsy holds the key to earlycancer diagnosis.HOW IT WORKSThe tissue under investigation is illuminated with laser light via a fiberopticprobe. Electrons in the tissue are temporarily kicked into a higherquantum state, or energy level; when they relax to a lower energy level,photons are emitted for a short time (fluorescence). A spectrometer recordsthe wavelength of the fluorescence. Cancerous tissue fluoresces at peakwavelengths different from those seen in normal tissue. By comparing thepeak readings, the fluorescence signatures can be converted into a realcolorimage that shows precisely where normal tissue ends and canceroustissue begins. This method is also sensitive to precancerous changes andinflammation.MEDICAL SIGNIFICANCEEarly diagnosis is the key to effective therapy and long-term cancer survival.Optical biopsy can help to diagnose cancers before they have had achance to spread and can also alert the clinician to precancerous conditionsthat can thereafter be carefully monitored. Slender fiber-optic lightdelivery can also reach hard-to-access regions, can be used with conven-Chapter 2 - Observation TechnologiesSection C - DiagnosisBMDO Technologies for Biomedical Applications

tional endoscopy, and is minimally invasive. Visual confirmation of atumor before surgery can prevent tumor excision that is too wide of themark—often, clinicians remove extra margins around the primary tumorto ensure that no cancerous tissue has been left behind, with results thatare disfiguring.VENTURES OR PRODUCT AVAILABILITYVo-Dinh’s optical biopsy method, BiOptics, has been licensed to OpticalBiopsy, LLC, a joint venture of Venture Alliance (Knoxville, TN) andPioneer Surgical (Loxahatchee, FL). The technique is being evaluated at theThompson Cancer Survival Center in cancers of the esophagus. More than100 patients have been studied, with a detection rate of 98 percent. Inaddition, the BiOptics technology won a 1997 award from the AmericanMuseum of Science and Energy.CONTACTOak Ridge National LaboratoryTuan Vo-Dinh, Ph.D.P.O. Box 2008Mail Stop 6101Oak Ridge, TN 37831Telephone: (423) 574-6249Facsimile: (423) 576-7651Email: tvo@ornl.govWWW: http://www.ornl.gov59BMDO Technologies for Biomedical ApplicationsChapter 2 - Observation TechnologiesSection C - Diagnosis

SAGEBRUSH GIMBALFOR NEEDLE BIOPSY• The Roto-Lok rotary drive helpedFischer Imaging make a better needlebiopsy device.BMDO HISTORYSagebrush Technology Inc. (Albuquerque, NM) developed a novel rotarydrive system to precisely position laser beam transmitters and receivers in acommunications network. The device, called the Roto-Lok ® rotary drive,has both military and commercial applications in the angular positioning ofmechanical components. The Roto-Lok rotary drive was originally designedto control large, heavy astronomical telescopes.The BMDO Laser CommunicationsNeedle aspiration(LaserCom) program, however, providedkey support to develop the drive into a highvisibilityproduct. In the LaserCom project,cytopathology wasoriginally developed in the Sagebrush used the Roto-Lok drive to controlthe precision angular alignment of laserUnited States in the 1920s, beam transmitters and receivers in a communicationsnetwork. The drive also servedbut Scandinavian studies to position a telescope on BMDO’s HighAltitude Balloon Experiment.from the 1940s through theFischer Imaging (Denver, CO) recently1970s led to U.S. acceptanceof the needle biopsy tem, used to sample breast tissue. Thisacquired a Roto-Lok drive to improve theaccuracy of its needle biopsy guidance sys-adaptation has allowed Fischer engineers tofor breast tissue.provide accurate, smooth needle delivery tothe region of concern.60HOW IT WORKSThe drive uses spring-loaded cables to accurately turn a cylinder (drum)that positions the equipment. The cables are wound around the drivemotor shaft (a capstan) and attached by a spring at one end to the drum.As the capstan turns, friction from the cables forces rotation of the drumand the components mounted on it. The tensioned cables provide hightorsional stiffness without backlash (a design problem in precision gearsthat reduces pointing accuracy and transmission efficiency). They also providesmooth operation. Because the cables do not slide on the drum orcapstan, there is virtually no wear. Any imperfections on a single cable oron the drum are averaged over the multiple cables, so the drive is extremelysmooth. In addition, performance does not degrade with use. The drivecan position the drum to within 1 microradian of arc. Further, it transmitsrotation at efficiency rates greater than 98 percent and runs more quietlythan any other mechanical transmission system.Chapter 2 - Observation TechnologiesSection C - DiagnosisBMDO Technologies for Biomedical Applications

MEDICAL SIGNIFICANCERoto-Lok drives are now lending precision and reliability to FischerImaging’s specialized needle biopsy driver. The device is a semiautomatedultrasound imager that displays the breast lesion and helps to position aneedle for minimally invasive breast biopsy. The Roto-Lok drive enablesthe physician to aim and deliver the needle with great accuracy andsmooth motion, which are of utmost importance in any biopsy. In addition,the driver’s performance does not degrade with repeated procedures,significantly reducing overall maintenance. The simpler mechanics of thedrive also allow for improved housing so that the unit is easier to manipulateand sterilize between procedures.When a mammogram or self-exam reveals a suspicious area, needle biopsyis the least invasive way to sample the region of concern and yield a coreof tissue for a histopathological examination. If the sample is positive forcancer, then mastectomy or breast-conserving lumpectomy may be performed,with adjuvant therapy. If the sample is negative, then the patientwill have avoided more painful, costly, and cosmetically unsatisfactory surgicalbiopsy.VENTURES OR PRODUCT AVAILABILITYSagebrush currently custom-designs Roto-Lok drives for a variety of applications.Sagebrush has received several patents for the Roto-Lok drive.Patent applications also have been filed. At present, Fischer is finishing itsadaptation of the Roto-Lok drive into its needle biopsy unit.CONTACTSagebrush Technology, Inc.Donald G. Carson10300A Constitution Avenue, NEAlbuquerque, NM 87112Telephone: (505) 299-6623Facsimile: (505) 298-207261BMDO Technologies for Biomedical ApplicationsChapter 2 - Observation TechnologiesSection C - Diagnosis

CHAPTER 3INTERVENTION TECHNOLOGIESWhen living systems fail because of disease or aging, medicine hasat its disposal some truly amazing remedies. These nostrumsrange from outright replacement of the defective part, to modificationof an existing one, to the general practice that most of us arefamiliar with. To effect these healing changes, a wide range of technologydevelopments have been used. Microelectromechanical systemsengineering, ion beam implanting techniques, new biocompatiblematerials, ultrashort electrical pulses, and lasers all play apart in these medical advances.THIS CHAPTER INCLUDES THE FOLLOWINGSECTIONS AND THEIR STORIES:Section A - ImplantsMEMS Sensor for Balance DisordersIon-Beam Surface Treatment for ImplantsAdvanced Material for Orthotics and ImplantsSpire’s Ion-Beam ApplicationsNovel Material for Spinal ImplantsSection B - TreatmentWellman Laboratories of PhotomedicineBeckman Laser Institute AdvancesBaylor Photosensitizing AgentsHigh-Energy Capacitors to Help Zap MicrobesCarbon Dioxide Lasers for Medical ApplicationsUltrafast Light-Activated Switches

SECTI0N AIMPLANTSHearts can be replaced, but only with a donation from anotherhuman being. Luckily, less vital parts can be strengthenedor supplanted by artificial components designed to produceminimal reaction from the host. The exception in the followingseries of stories is a miniature inertial unit that may beworn on the outside of the body, but the remainder are variationson the theme of better materials for biocompatibility,based on modifying the surface and structural characteristicsof the implantable object.1. A vest fitted with sensors that can provide tactile feedbacksignals to persons with balance disorders.2. Stronger material components for hip replacementsurgery.3. Lightweight orthotics for knee and leg braces.4. An ion-beam method for increasing battery lifetimes forpacemakers, meaning fewer surgeries.5. Inserts to stabilize the spine to ameliorate the pain of traumaor degenerative disease.

66MEMS SENSOR FOR BALANCEDISORDERS• The lightweight MEMS sensor maysomeday act as a cue to patients withinner-ear disorders.BMDO HISTORYThe Charles Stark Draper Laboratories (Cambridge, MA) developed amicromachining process for the manufacture of miniature inertial sensorsusing microelectromechanical systems (MEMS). The low-cost sensorscombined the functions of a gyroscope and an accelerometer with an informationprocessor to provide inertial guidance components for BMDO’sLightweight Exoatmospheric AdvancedProjectiles program. The lightweight sensorshave numerous applications in militaryVestibular disease can beand commercial technology, including precision-guidedmunitions, autopilot con-detected by observingrhythmic movements of trols, airbag deployment, and medical electronics.In this last category, the micromachininginnovation may lead to a uniquethe eyes while instillingway to help patients with balance disorders.warm or cool water intoHOW IT WORKSthe ears. In a normal Draper Labs’ micromachining process usescontrolled chemical etching that can placesubject, cool water causes up to 10,000 devices on a single siliconchip. The chips can be mass-produced,the eyes to move in thekeeping production costs to a minimum. Inaddition, the low power requirements, smallopposite direction of thesize, and complexity of the chip make it airrigated ear, and warm versatile component for a lightweight feedbacksystem. The chip’s features have lentwater causes movement themselves well to a collaborative projectinvolving the restoration of balance cues totoward it. The clinician can patients with inner-ear disturbances.judge certain aspects of MEDICAL SIGNIFICANCEVestibular (inner-ear) disorder is an uncommonbut sometimes very debilitating condi-disease by watching howtion that can be caused by transient viralfast or how slowly theinfections, tumors, or trauma to thevestibular organs and nerves. Signals abouteye movements occurthe body’s orientation in space (particularlyrotational changes) are processed by a systemof hair cells that are moved about byand whether movement issuppressed in a particular fluid flow within the inner ear’s semicircularcanals. These signals are relayed by thedirection.vestibular nerves to the brain, which in turnsignals the body to make postural adjustmentsto maintain balance. Damage to theChapter 3 - Intervention TechnologiesSection A - ImplantsBMDO Technologies for Biomedical Applications

vestibular system can cause some patients to lose their sense of balance,resulting in recurrent dizziness that can greatly inhibit lifestyle and causeinjury. In February 1997, researchers at Draper Labs, the MassachusettsEye and Ear Infirmary (MEEI), and the Massachusetts Institute ofTechnology (MIT), with the support of the W. M. Keck Foundation of LosAngeles, began to consider the MEMS chip as a component in a feedbackloop system that alerts patients when they begin to lose their balance. Aninitial system design would incorporate MEMS devices into a vest that canbe comfortably worn by a patient. When one of the MEMS chips senses adeviation of a few degrees from vertical (indicating that the wearer isfalling), a vibration is induced that alerts the wearer to correct the situation.An arrangement of chips can take the place of normal cues providedby the ailing vestibular system. Eventually, researchers hope that such aninertial guidance device could be inserted in the inner ear itself, much ascochlear implants are implanted in deaf patients.VENTURES OR PRODUCT AVAILABILITYThis nascent work is part of the Balance Project in the W. M. Keck NeuralProsthesis Research Center at Massachusetts General Hospital. The centerincludes investigators from MIT, MEEI, and Draper Labs. The center’sdirector is Donald Eddington, Ph.D., of the Cochlear Implant ResearchLaboratory at MEEI. Draper Labs is contributing internal funding to thisproject as well.CONTACTCharles Stark Draper LaboratoriesDonald K. Eddington, Ph.D.Cochlear Implant LaboratoryMassachusetts Eye and Ear Infirmary243 Charles StreetBoston, MA 02114Telephone: (617) 573-3766Facsimile: (617) 573-3023Email: dke@cirl.meei.harvard.eduWWW: http://www.draper.com67BMDO Technologies for Biomedical ApplicationsChapter 3 - Intervention TechnologiesSection A - Implants

ION-BEAM SURFACETREATMENT FOR IMPLANTS• IBEST can help strengthen the surfacesof weight-bearing artificial joints.BMDO HISTORYSandia National Laboratories (Albuquerque, NM) developed an ion-beamtreatment technique called IBEST (ion-beam surface treatment) to modifysurfaces of metals, ceramics, and plastic to make them more durable.The repetitive high-energy pulsed-power (RHEPP) accelerator developedfor this treatment was funded in part by BMDO’s Free Electron Laserweapons program and the Department ofEnergy’s Inertial Confinement Fusion program.IBEST does not produce environmen-More than 90 percenttally harmful waste products or residue,of hip replacements lastunlike predecessor technologies such asat least 10 years. This electroplating and other chemical processes.To commercialize the patented IBEST technology,two Sandia scientists obtained exclu-statistic is expected tosive worldwide rights to IBEST and formedimprove as materials and a new company called QM Technologies,Inc. (Albuquerque, NM).techniques evolve further.HOW IT WORKSRHEPP accelerators deliver short-duration,high-intensity ion beams. This combination of rapid pulsing and high energyallows controlled melting and surface modification of various materials.The heart of the RHEPP accelerator is a magnetically confined anode plasma(MAP) diode, invented at Cornell University. Through this device, anelectrical pulse is delivered to a pre-ionized gas inside the MAP diode. Theelectrical pulse kicks ions out of the plasma that then travel through a vacuumto the surface to be modified. The IBEST ion beam can cover severalhundred square centimeters at once. Very thin surface layers (2 to 20micrometers thick) are rapidly melted and cooled, forming nanocrystallinegrain layers without changing the atomic composition of the treated surface.68MEDICAL SIGNIFICANCEMedical implants, especially weight-bearing hip joints for replacement surgeries,need to be durable. The longer a joint remains functional, the longerthe patient can avoid a second surgery to replace a failed or worn implant.Modern artificial hips are often made of composite material, usually aceramic that is coated with a durable metal, such as titanium, at the femurhead (the “ball” of the ball-and-socket hip arrangement). Minute cracks inthe metal coating allow calcium ions from the synovial fluid (lubricatingfluid in the joint) to migrate through to the composite material of thereplacement, causing the material to break down. IBEST treatment can minimizeor eliminate these cracks, resulting in a longer-lived joint.Chapter 3 - Intervention TechnologiesSection A - ImplantsBMDO Technologies for Biomedical Applications

VENTURES OR PRODUCT AVAILABILITYQM Technologies is currently evaluating materials used by companiesmanufacturing artificial joints with an eye to improving knee and hip jointswith IBEST technology. IBEST also has many applications in the nonmedicalarena, with development projects in the automotive, aerospace, andtool-and-die industries.CONTACTQM Technologies, Inc.Phillip Maloy3701 Hawkins Street, NEAlbuquerque, NM 87109Telephone: (505) 342-2851Facsimile: (505) 342-2852Email: pwmaloy@QMInc.com69BMDO Technologies for Biomedical ApplicationsChapter 3 - Intervention TechnologiesSection A - Implants

ADVANCED MATERIAL FORORTHOTICS AND IMPLANTSBMDO HISTORYSPARTA, Inc. (San Diego, CA), has developed composite materials forstronger, lighter-weight orthotics and medical implants. BMDO fundedSPARTA’s work in structural materials. The requirements for high stiffnessand strength in a ground-based missile interceptor led to a compositematerial of graphite fiber and resin.• SPARTA’s technology has beeninstrumental in improving hip, knee,and ankle joints.HOW IT WORKSApproximately 43 million SPARTA begins designing each orthotic orimplant by selecting appropriate compositeAmericans are regarded thermoset and thermoplastic compoundsfor the application, including those that areas having some sort offormable at low temperatures, lightweight,and low cost. Then it selects the length ofphysical disability. Newthe fibers. SPARTA’s technology combinesmaterials and both functionaland anatomical yet retains the high strength of the materi-the best of continuous and chopped fibers,which provides the necessary formabilityals. These materials can also be constructedmodeling based on magneticresonance imagingfor stiffness without malleability whenneeded, as in the ankle joints, knee joints,and foot plates.and computed tomography MEDICAL SIGNIFICANCESPARTA’s technology is especially usefulhave brought much reliefwhen strong, lightweight materials areneeded for full-leg braces, ankle joints, kneeto such individuals.joints, foot plates, hip implants, boneimplants, and spinal implants. Externalbracing is designed primarily for patientswho have lower-extremity paralysis after spinal cord injury, with some limitedapplications for post-polio syndrome and congenital disorders.Composite orthopedic implants for repairing long-bone fractures and stabilizingspines are also under study.70The medical community’s interest encouraged SPARTA to developimplantable biomimetic components, including femur and spinalimplants. SPARTA—with the National Science Foundation; the Universityof California at Davis; Mekanika, Inc. (Miami, FL); the University ofMiami, Department of Orthopedics; and Brent Adamson, M.D., (Kearney,NE)—studied repairing long-bone fractures with composite devices. Thestudy used a composite femur implant for testing because of the strengthrequired and the large amount of readily available data on steel implants.The information, methods, and synthetic materials used in the compositefemur implant are also applicable to other long bones.Chapter 3 - Intervention TechnologiesSection A - ImplantsBMDO Technologies for Biomedical Applications

SPARTA, in a joint venture with Mekanika, is developing a spinal implantto immobilize vertebrae and has worked with the Defense AdvancedResearch Projects Agency to generate Food and Drug Administration dataand commercialize the spinal implant. Mechanical testing is continuingalong with cadaver studies. SPARTA is now working on testing the completesystem, rather than the individual components, and is directing itsenergies to lowering the system cost.VENTURES OR PRODUCT AVAILABILITYSPARTA has worked with the National Rehabilitation Hospital (NRH;Washington, DC), the General Reinsurance Corporation, and BeckerOrthopedic Appliance Company (Troy, MI) to develop lightweight kneeand ankle joints. In particular, this effort resulted in an articulating droplockknee joint that can be either locked in the upright position for walkingor unlocked for sitting, allowing the leg to bend. Both joints passedmechanical static and fatigue testing. The knee joint is in clinical trials, andthe ankle joint is now in clinical evaluation at NRH. SPARTA has met itsgoal of reducing materials costs for the ankle joint.The National Institutes of Health (NIH) is in discussion with SPARTA andthe inventors of the “Seattle foot” for a prosthetic study. The Seattle foot isnotable for its appearance in television advertisements in which doubleamputees play basketball. Currently, this venture is on hold because ofSPARTA’s transformation from small business to large, which makes it ineligiblefor NIH Phase II SBIR funding. Proof of concept was successfullydemonstrated under a Phase I SBIR contract.SPARTA’s program manager for bioengineering of advanced material productsis Moreno White, whose awards for bioengineering include the 1989SDIO/ADPA Technology Transfer Award, the 1993 DuPont/ASMComposite Systems Award for the composite leg brace, and the 1996Composites Institute’s Award of Excellence.CONTACTSPARTA, Inc.Moreno White10540 Heater CourtSan Diego, CA 92121-1964Telephone: (619) 455-1650Facsimile: (619) 455-1698Email: moreno_white@sparta.comWWW: http://www.sparta.com71BMDO Technologies for Biomedical ApplicationsChapter 3 - Intervention TechnologiesSection A - Implants

SPIRE’S ION-BEAMAPPLICATIONSBMDO HISTORYWith the help of BMDO SBIR contracts, Spire Corporation (Bedford, MA)developed an ion-beam texturization method that can create intricate surfaceson a variety of materials. For BMDO’s Advanced Optical Baffles program,Spire used its patented SPI-TEXT method to create random patternson optical sensors that aid in rejecting stray light. These sensors were usedin BMDO’s moon-orbiting spacecraft,Clementine, as part of the light collectionBacterial endocarditis issystem for star tracking. The same texturizationmethod plays an integral role inan infrequent complicationSpire’s biomaterial product line.• SPI-TEXT creates random patternson surfaces that can be useful for manybiomaterials.of valve replacementsurgery, but once acquiredit can be fatal to nearly60 percent of patients. Itcan also be acquired byrheumatic heart patientsafter simple surgery ordental procedures. In bothcases it can usually beHOW IT WORKSSpire developed an advanced surface modificationtechnology based on ion-beamimplantation and ion-beam-assisted depositiontechniques. To produce optically darksurfaces, metals are bombarded with ions tocreate micrometer-scale textures, increasingsurface area and providing light-trappingpores. For biomaterials that are either polymericor metallic, this etching can alter surfacesfor all manner of applications—forexample, providing better anchoring forbacteria in petri dishes or, conversely, bycoating and smoothing a catheter surface toprevent bacterial adherence.72MEDICAL SIGNIFICANCEprevented with antibiotics.While medical procedures certainly savelives and alleviate suffering, many of thephysical invasions associated with modernpractices automatically introduce new problems. Any device that is insertedinto the body carries with it a threat of infection. Bacteria are often particularlyattracted to polymers in portions of hip and knee implants, as wellas indwelling catheters and heart valve sewing cuffs. They easily take upresidence on these devices in a resistant covering called a biofilm. Evenbacteria that are normally eradicable by antibiotics can avoid harm by colonizingimplants in this manner. In addition, rough surfaces on medicaldevices can promote the formation of clots that can travel to the lung,heart, and brain, with devastating consequences.One of Spire’s latest efforts has been in impregnating replacement heartvalve sewing cuffs with silver metal through an ion-beam process calledSPI-ARGENT. This coating of elemental metal helps prevent bacterialChapter 3 - Intervention TechnologiesSection A - ImplantsBMDO Technologies for Biomedical Applications

growth on the cuff, thus lowering the incidence of postreplacement endocarditis,a life-threatening infection of the heart’s inner lining. In early June1997, Spire announced an exclusive agreement with St. Jude Medical, Inc.,to develop the heart-valve sewing cuff. St. Jude produces mechanical heartvalves that are considered the gold standard in the industry. Using relatedtechnology, Spire also treats central venous catheters and surgical guidewires to reduce the likelihood of clot formation and increase lubricity,which eases the insertion process.VENTURES OR PRODUCT AVAILABILITYSpire’s registered and trademarked techniques include the following:IONGUARD enhances the mechanical and chemical surface properties oftitanium alloy, cobalt-chromium, and other metal and ceramic orthopedicor dental devices. Overall, this process makes artificial joints more durableby increasing wettability and reducing friction; it also enhances adhesionto biocompatible cements.SPI-TEXT texturizes electrodes used in cardiac pacemaker batteries. Theincreased surface area improves tissue attachment and decreases electricalresistance at the contacts. Testing showed that battery lifetimes wereincreased by 300 percent, electrode resistance was reduced, and batteryweight was decreased. SPI-TEXT was licensed by a cardiac pacemakermanufacturer in 1993.SPI-ARGENT treats polymer, metal, and ceramic medical devices to reducethe material’s ability to induce blood clotting (increase thromboresistance),to reduce bacterial adhesion, and to improve hardness, slickness, andbondability of surfaces.Spire’s recently introduced line of central venous catheters is treated with aprocess called SPI-POLYMER. The process is designed to create a slick andthromboresistant surface for catheters.CONTACTSpire CorporationJohn E. BarryOne Patriots ParkBedford, MA 01730-2396Telephone: (617) 275-6000Facsimile: (617) 275-7470Email: email@spirecorp.comWWW: http://www.spirecorp.com73BMDO Technologies for Biomedical ApplicationsChapter 3 - Intervention TechnologiesSection A - Implants

NOVEL MATERIAL FOR SPINALIMPLANTSBMDO HISTORYUltramet (Pacoima, CA) received SBIR funding from BMDO to develop insulatormaterials for rocket nozzles. From this research, the company successfullymanufactured synthetic cellular foams that can serve both as insulatorsand as kinetic energy absorbers. The foams are made of ceramic, metal, and glassand can be used for biomedical, environmental, and construction applications.• Ultramet’s synthetic cellular materialsare readily compatible with natural bone.In evolutionary terms,the human spine is animperfect support systembecause of our fairlyrecent adaptation to theupright position. It wasreally designed for creatureswho move on allfours. Back pain andspinal disorders areprevalent in human lives,largely because of thisengineering glitch.HOW IT WORKSUltramet’s materials are composed of a carbonfoam skeleton that is treated by a chemicalvapor deposition (CVD) method to laydown a coating of various compounds andelements. Through CVD, a continuous thinfilm of metals such as rhenium or tantalum,or compounds such as silicon carbide, canbe distributed throughout the interior of theconstruct, lending certain thermal or tensileproperties to the carbon foam substrate andto the structure as a whole. The resultingproducts are characterized by low cost, lowdensity, high chemical purity, controlledthermal expansion, and high thermal stability.Depending on the coating used, the materialcan be made resistant to oxidation andcan withstand temperatures of up to 6,000°F. The high strength and porous structure ofone Ultramet product, Hedrocel ® , makes itespecially useful as a biocompatible replacementfor the vertebral bodies that make upthe spinal column. Hedrocel is a tantalumcoatedcarbon porous matrix product thatmimics the properties of, and is compatiblewith, bone.74MEDICAL SIGNIFICANCEThe problems of the aging spine can be traced, at times, to loss of soft tissuebetween the vertebrae. This can lead to pain from compressed spinalnerves. Cancer that has metastasized to the spine, degenerative diseasessuch as arthritis, and trauma can also compromise soft tissue. Hedrocelwas licensed by Implex Corporation (Allendale, NJ) to be used in replacementdiscs for the spinal column. Specifically, the replacement acts as aspacer in support of the vertebral body, or the round portion of the disc.The porous natural structure of bone is simulated by Hedrocel, and bonecan gradually infiltrate into the artificial disc just as it would into a dam-Chapter 3 - Intervention TechnologiesSection A - ImplantsBMDO Technologies for Biomedical Applications

aged section of natural bone. The vertebral body implant is screwed intoplace, sometimes with a cement accompaniment, and consolidation takesplace as the bone and Hedrocel implant fuse together. The fusion obviatesthe necessity for the soft tissue disc, and the two bony processes growtogether, reducing the possibility of nerve compression and therefore pain.VENTURES OR PRODUCT AVAILABILITYEarly animal studies funded by the National Institutes of Health spurredImplex to build facilities specifically for Hedrocel implant products.Hedrocel vertebral implants were then used in eight European patients inlate 1994. They are currently being used in a United Kingdom trial of 25patients, specifically for replacement of the lower cervical vertebrae.Implex is also planning to manufacture devices for the small joints of thefingers, as well as components for hip replacements.Ultramet owns the patent on the carbon foam process. Ultramet licensedthe technology to Implex, which trademarked Hedrocel.CONTACTUltramet, Inc.Robert H. Tuffias, Ph.D.12173 Montague StreetPacoima, CA 91331Telephone: (818) 899-0236Facsimile: (818) 890-1946Email: ultramet@earthlink.comWWW: http://www.ultramet.com75BMDO Technologies for Biomedical ApplicationsChapter 3 - Intervention TechnologiesSection A - Implants

SECTION BTREATMENTLasers have found their way into medicine, replacingscalpels in some cases, augmenting drug-tissue interactions,reducing discomfort in dental procedures, and reshapingthe surface of the eye. Based on funding from BMDO’sMedical Free Electron Laser (MFEL) program in the mid-1980s through the early 1990s, photomedicine became atrue specialty. In 1996, the first photodynamic therapy drug,Photofrin, was approved for the treatment of esophagealcancer. This drug, its cognates, and second-generationderivatives were studied in depth at a number of clinical centersand universities, thanks in large part to the MFEL program.Also represented here is a sterilization method for liquidand solid foods, a timely subject in light of the recentrash of food- and water-borne illness in the United States.1. Two world-recognized facilities that perform state-of-theartphotomedical research and provide clinical treatmentsfor skin disorders and cancer and develop laser-based imagingtechnologies.2. New collagen-bonding treatments for joint disorders andimproved outcomes for lens replacement surgery.3. A “cool” sterilization technology that kills deadlyCryptosporidium and leaves foods and liquids unaltered.4. New laser therapy for effective cavity prevention andpractically painless root canal treatment.5. Ultrafast switches for lasers, electroporation devices, anda novel tomographic imaging technique.

WELLMAN LABORATORIES OFPHOTOMEDICINEBMDO HISTORYDuring the late 1980s, BMDO funded the MFEL program to allow medicineto leverage the Defense Department’s advanced laser technology. Withhelp from this initiative, Massachusetts General Hospital (Boston, MA)nurtured a combined research and clinical laboratory that came to beknown as the Wellman Laboratories of Photomedicine. In this brief period,Wellman has achieved worldwiderecognition for its excellence in light-basedLasers have revolutionized medicine, as well as a pioneering milestonein cancer treatment called photodynamicthe lucrative practice of therapy. Thus, technology transfer from thehigh-powered free electron laser, originallycosmetic surgery andconceived to kill enemy missiles, hasenabled destruction of a different sort.related services. ForHOW IT WORKSdepilation alone, whereThe discrete wavelengths and short, wellcontrolledpulses of laser devices allow cliniciansto investigate and observe specific phys-lasers have just made anical interactions. For instance, certain skinentry, the U.S. market ispigments such as melanin absorb light at aparticular wavelength, as does the hemoglobinin red blood cells. Researchers can takeestimated at $1 billion.advantage of these particular traits and tailornew therapies to old disorders. The MFEL program allowed researchers accessto powerful free electron lasers, which in turn led to insights for new applicationsof Nd:YAG, carbon dioxide, and other medically useful lasers.78• Photodynamic therapy can selectivelydestroy cancerous cells.Chapter 3 - Intervention TechnologiesSection B - TreatmentMEDICAL SIGNIFICANCEPhotodynamic Therapy. Wellman Laboratories of Photomedicine has developeda wide range of light-based therapies. The most notable among these isphotodynamic therapy (PDT), a method of killing tumors and other diseasedtissues that has been approved by the Food and Drug Administration (FDA).Lasers are a critical part of PDT because a precise wavelength of light is neededto activate the tumoricidal drug. In this case, the drug is Photofrin, a compoundthat is preferentially absorbed by cancer cells. The drug remains inactiveuntil exposed to light, whereupon it releases high-energy oxidationproducts that kill the tumor, in a manner similar to how the immune systemeliminates damaged or diseased cells. Normal tissue is spared, and there arefew undesirable side effects. Second-generation photoactive drugs such asbenzoporphyrin derivative are also being tested for efficacy in PDT, and theapplications are not limited to cancer. Rheumatoid arthritis, psoriasis,endometriosis, macular degeneration, and regrowth of arterial plaque afterangioplasty are all conditions that are being treated experimentally with PDT.Laser Treatment of Skin Lesions. Before lasers were accepted as a clinicaltool, pigmented skin lesions such as the purplish-red port-wine stain andthe common hemangioma, or “strawberry mark,” were not satisfactorilyBMDO Technologies for Biomedical Applications

treatable. Lesions that appear on the face are cosmetically disturbing to thepatient, and occasionally a hemangioma can threaten eyesight or obstructthe nose or mouth. Researchers at Wellman have achieved truly remarkableresults with laser treatment of these lesions. Copper vapor lasers andNd:YAG lasers are used to deliver a 585-nanometer laser beam to theaffected area. After repeated treatments, the red pigment (from hemoglobinmostly) fades away, and the normal color of the skin emerges.In a related therapy, superficial capillaries, or spider veins, can also be treatedwith lasers. Wellman uses a 595-nanometer laser to obliterate theseunsightly but usually harmless veins. The alternative treatment, called sclerotherapy,involves injection of saline solution or other sclerosing compoundthat collapses the blood vessel walls. Sclerotherapy can be painfuland can result in discoloration that is more objectionable than the originalcondition. For cosmetic concerns of another sort, Wellman is also developinga method of laser depilation, similar to a technique that is now on themarket. The difference in Wellman’s technique is that the laser is used withoutpreapplication of a light-absorbing lotion. Thus far, studies have shownthat the laser method can prevent hair regrowth for up to 31 weeks.Laser-Induced Fluorescence of Cancerous Lesions. Laser-induced fluorescencespectroscopy has become an exciting window into the cell. Precisewavelengths induce precise excitations, and cancerous lesions can be seen asbright spots that can be well distinguished from their normal surroundings.In endoscopically accessible regions of the body, such as the bladder, esophagus,and lungs, a fiber-optic probe can deliver laser light and then transmitthe fluorescence response to a spectrometer, which analyzes the returninglight. At Wellman, doctors are using this technique to inspect the bladderwall in order to distinguish cancerous lesions from normal tissue. After comparingunique fluorescence patterns, a false-color imager can show the doctora well-defined picture of the tumor, allowing successful excision andavoiding surgical damage to the nondiseased portion of the bladder.VENTURES OR PRODUCT AVAILABILITYWellman continues to develop and implement novel treatments involvingthe use of light and photochemicals. Approximately $250 million in commercialrevenues have been generated by the laboratory’s photomedicineactivities, mostly through sales of medical lasers.79CONTACTMassachusetts General Hospital Laser CenterLynn OsbornBartlett Hall X 630Boston, MA 02114Telephone: (617) 726-2327Facsimile: (617) 726-4103Email: lyn@wlp.mgh.harvard.eduWWW: http://mghlc.mgh.harvard.eduBMDO Technologies for Biomedical ApplicationsChapter 3 - Intervention TechnologiesSection B - Treatment

BECKMAN LASERINSTITUTE ADVANCES• Beckman’s researchers use “lasertweezers” to isolate and examinesingle cells.BMDO HISTORYAlong with other centers of excellence such as Stanford and Baylor ResearchInstitute, the Beckman Laser Institute (BLI; Irvine, CA) received fundingthrough the MFEL program. Like the Wellman Laboratories of Photomedicine(Boston, MA), this institute has made many advances in photomedicine inareas such as photodynamic therapy (PDT) and laser treatment of dermatologicdiseases. BLI was established in 1982 as an international center for laserstudies and includes a medical clinic thatfunctions as an outpatient facility of theRecent in vitro studies Medical School of the University of Californiaat Irvine. Other areas of interest include treatmentof cataracts, glaucoma, and gynecologi-suggest that low-levelcal conditions, and novel imaging modalities.ultrasound can be usedin place of light to activatePDT drugs. An advantageof this approach would beHOW IT WORKSMost living tissues exhibit some wavelengthdependentabsorption, reflection, andtransmission. By taking advantage of thesediscrete differences in laser-matter behavior,researchers can tailor laser-beam wavelengthsto a particular target without harming surroundingtissue. The laser-matter interactioncan be direct or can be assisted with drugs thatare preferentially absorbed by a target tissue.to eliminate invasive fiberopticlight delivery systems In addition to treating diseases, laser light energycan be used to create optical traps and to cutand laparoscopic access cellular components. “Laser tweezers” and“laser scissors” are now becoming a recognizedto internal structures. part of the biological tool kit. Laser transmission,reflectance, and scatter through tissue canalso be used to create both macroscopic andmicroscopic images and to collect data for spectral analysis.80MEDICAL SIGNIFICANCEPhotodynamic Therapy. PDT will very likely be adapted as a regular partof the cancer treatment pharmacopoeia in short order. For reasons not yetwell understood, abnormal tissues collect the photosensitive drug preferentially,while normal tissues collect far less. When light of a specific wavelengthis applied to the treated area, a toxic oxidative reaction takes place.The reaction kills tumor cells but spares normal tissue—a “surgical strike”without surgery. So far, PDT has shown itself to be generally nontoxic tohealthy tissues when compared with conventional chemotherapy, whichdamages all tissue. PDT also seems not to encourage drug resistance, aproblem that frequently occurs in repeated cancer treatments. A recentlyapproved drug, Photofrin, is part of a newly FDA-approved PDT regimen(currently limited to end-stage esophageal cancer) and is just one of thedrugs being tested at BLI. The institute’s researchers are using a number ofPDT protocols, along with second-generation PDT compounds, to treatcancers and gynecological disorders.Novel Imaging Device. Bruce Tromberg, Ph.D., and a group of medicalresearchers at BLI have developed a fast, portable near-infrared spectrometerto probe for tissue abnormalities, such as breast tumors. The opticaldevice uses a new optical imaging modality, called frequency-domain pho-Chapter 3 - Intervention TechnologiesSection B - TreatmentBMDO Technologies for Biomedical Applications

ton migration, which is safe, noninvasive, inexpensive, and potentiallymore sensitive and accurate than other imaging techniques.To detect abnormal breast tissue, the handheld laser diode instrumentsends near-infrared light through the tissue to determine its optical properties.As light propagates through tissue, the researchers measure howmany photons were scattered or absorbed. These data can then be interpretedto yield tissue hemoglobin levels, blood volume, and water content.With this information, certain diagnoses can be made.For example, a great deal of scattering might signal high cell density, a signof cancer. Malignant tumors also may absorb more light because they containmore hemoglobin than normal tissue. Fluid-filled cysts should havelower than usual scattering, because the density of fluid is lower than thatof normal tissue.Laser Tweezers and Scissors. Beckman’s director, Michael Berns, Ph.D.,and Tromberg have collaborated to develop devices such as laser tweezersand scissors that can be used to immobilize and manipulate cells and theircontents. Berns’s early interest in chromosome cutting has led to the abilityto optically cut lengths of DNA and selectively amplify these sequences.Currently, molecular biologists use a variety of wet chemistry techniques toenzymatically cut DNA (with restriction endonucleases derived frommicrobes). The laser scissors device, if cost-effective, is a cleaner, moredirect alternative to endonuclease cutting; moreover, restriction endonucleasescan be used at only a limited set of four- to eight-nucleotidesequences in the genome. The laser tweezer, scissors, and the free electronlaser based microscope are basic research tools at present.VENTURES OR PRODUCT AVAILABILITYPhotofrin, manufactured by QLT Photopharmaceuticals (Vancouver, BC)was approved for treating late-stage esophageal cancer in late 1996 and isbeing used in a number of clinical centers, including BLI, for PDT. PDT fornoncancerous conditions such as endometrial hyperplasia is also beingassessed, as well as novel photosensitive drugs.Through a collaboration with the Chao Family Clinical Cancer ResearchCenter (Orange, CA), Tromberg is testing the tissue spectrometer’s abilityto differentiate between normal and abnormal tissue. He and John Butler,M.D., have gathered and analyzed data on about 30 patients. Theresearchers are now correlating these data to such conventional techniquesas mammography and histopathology.Tromberg says that the results look promising at this point: the data correctlypredicted a fluid-filled cyst in one patient and a fibrous tumor inanother. He anticipates more extensive clinical trials within two years.Ultimately, he hopes the research will result in a needle-free breast cancerdetection device to complement, not replace, mammography. Tromberg’steam received a patent for frequency-domain photon migration in 1992.81CONTACTBeckman Laser InstituteBruce Tromberg, Ph.D.1002 Health Sciences Road EastIrvine, CA 92715Telephone: (714) 856-6996Facsimile: (714) 856-8413Email: bjtrombe@bli.uci.eduWWW: http://bli.uci.eduBMDO Technologies for Biomedical ApplicationsChapter 3 - Intervention TechnologiesSection B - Treatment

BAYLORPHOTOSENSITIZING AGENTSBMDO HISTORYIn the early to mid-1980s, BMDO supported the MFEL program, designedto transfer military expertise in laser development to the medical sector.Baylor Institute (Dallas, TX) was just one recipient of MFEL funding.Large, expensive free electron lasers were not (and indeed are still not)commonly available, and the biological benefits of the lasers’ broad wavelengthrange were therefore hard to realize.The MFEL program offered medical scientistsa chance to use the lasers’ versatileApproximately 40,000characteristics, and attendant observationscorneal transplants areof tissue-wavelength interactions, to furtherperformed every year develop their hypotheses. A very largenumber of clinically significant outcomeson an outpatient basis resulted from this collaboration. Amongthem were the development of photosensitiveagents that can be used in treatingunder local anesthetic.cataracts and even cancers.• Baylor has a new drug that can helpmaintain vision clarity in lens replacementpatients.HOW IT WORKSThe wide wavelength range afforded by free electron lasers helpedresearchers explore a greater variety and more discrete assortment of laserenergies and frequencies. Most materials, including biological tissues,absorb light markedly well at a certain wavelength, while handily reflectinglight at others. Hemoglobin, for instance, absorbs very strongly atbetween 580 and 600 nanometers, corresponding to the green-yellow partof the spectrum. For this reason, laser therapy of hemoglobin-rich birthmarkssuch as port-wine stains has found resounding success in recentyears. The hemoglobin, and not the surrounding healthy skin, absorbs theintense energy of the coherent light, and the unsightly red marks breakdown and fade. Similarly, other cellular components react in predictableways when they absorb light, and through the activity of photochemicals,they can be targeted by light activation.82MEDICAL SIGNIFICANCEThe latest advances at Baylor include a photochemical method of removingtumor cells from bone marrow in preparation for autologous transplant. Inpatients who have a relapse following chemotherapy for cancer, a more vigorousand potentially toxic chemotherapy protocol is now used. To preventirreparable damage to the marrow stem cells, the marrow is removed andstored while the patient undergoes therapy. Baylor researchers are studyingthe use of photochemicals and light on the marrow cells as a means ofensuring that the marrow will be purged of any residual tumor cells. Thuswhen the marrow is returned to the patient to reconstitute the blood andimmune system, the danger of cancer recurrence is reduced. Other chemicalmethods of purifying marrow stem cells kill about 80 percent of the stemChapter 3 - Intervention TechnologiesSection B - TreatmentBMDO Technologies for Biomedical Applications

cells. The photochemical method preserves 80 percent of the stem cells. Itis projected that a larger number of surviving stem cells will increase thelikelihood of a successful take of the cells upon transplantation.Researchers at Baylor have also developed a photochemical treatment forcataract patients. Cataracts, or proteinaceous growths on the lens of theeye, can obscure vision to the point of blindness. Lenses can be replacedwith surgery, but 30 percent of patients experience exuberant regrowth oftissue over the lens as a result of an overactive healing process. A new surgicaladjunct method uses naphthalimide dye and blue laser light to treatthe capsule, or lens implant site, before placement of the new artificial lens.This intervention reduces tissue regrowth that can obscure the new lens.A novel photoactive dye that inhibits the activity of collagenase and linksadjacent collagen fibrils together is also under investigation. Collagen is afibrous protein that serves as a connecting and supporting structure in connectivetissues throughout the body. Collagen is the primary protein foundin the tendons, ligaments, bone, cartilage, skin, organ capsules, and corneaand sclera (white) of the eye. During tissue remodeling and following trauma,collagenase, an enzyme that disrupts the bonds between collagenstrands, is released to digest the collagen. The photochemical bonding isachieved by painting a photochemical on a damaged surface of a torn tissue,such as the cartilage meniscus in the knee joint or a torn surface of acornea, and then exposing these surfaces to a blue laser light. This causesthe formation of new bonds between adjacent collagen fibrils and alsomakes them resistant to further degradation by collagenase. This newapproach to tissue bonding offers a sutureless system that is more efficientat healing the treated surface.VENTURES OR PRODUCT AVAILABILITYThe ophthalmology applications are being investigated further in a jointeffort between Baylor researchers and investigators at the Kansas EyeInstitute. Additional studies on the toxicity and metabolism of the photochemicalsare in progress to enable clinical testing of the stem cell procedureand collagen bonding procedure in humans. Work on the collagen linkingwas partly supported by the MFEL program and the Arthritis Foundation.Patents on the dye synthesis and applications are issued to the inventors.83CONTACTBaylor InstituteLes Matthews, M.D.P.O. Box 7106993812 Elm StreetDallas, TX 75226Telephone: (214) 820-4951Facsimile: (214) 820-4952WWW: http://www.bcm.tcm.eduBMDO Technologies for Biomedical ApplicationsChapter 3 - Intervention TechnologiesSection B - Treatment

HIGH-ENERGY CAPACITORS TOHELP ZAP MICROBESBMDO HISTORYPurePulse Technologies, Inc., a subsidiary of Maxwell Technologies (SanDiego, CA), has developed a highly efficient FDA-approved method forkilling parasites, bacteria, and viruses in water, on the surfaces of medical andfood packaging, and in liquid foods. Dubbed PureBright ® and CoolPure ® ,the two systems deliver, respectively, microsecond bursts of intense light ora pulsed electric field to rupture the membranesof pathogenic microbes. Based onA major outbreak of waterborneCryptosporidiumadvanced high-energy capacitors, the systemsoffer kill rates 100 to 10,000 timesthose of conventional mercury lamp ultraviolettreatments. BMDO partially fundedoccurred in the summerdevelopment of these capacitors to produceof 1993, sickening about a compact, lightweight device that couldprovide pulsed power for space-based lasers400,000 people in the and accelerators.• PurePulse has introduced a fastand effective method for eliminatingdeadly bacteria, viruses, and othermicroorganisms.Milwaukee area. There isno effective treatment forthis parasite, which canalso be spread throughfoods, juices, and personalcontact. Water filtering andhand washing are goodpreventive measures.HOW IT WORKSCapacitors accumulate electrical charge andenergy on the surfaces of conducting platesthat are insulated from each other by adielectric material. Maxwell developed itscapacitors by using insulating materials witha higher dielectric constant, reducing thethickness of the insulating material, increasingthe voltage between the conductors, andreducing the thickness of the conductingplates. Through this combination, Maxwellsuccessfully produced its high-density thinfilmcapacitors, which have been used topower implantable cardiac fibrillators.PurePulse used this same technology todevelop its purification systems.84MEDICAL SIGNIFICANCEPureBright has been shown to kill the deadly Cryptosporidium, a recentlyresurgent pathogen in municipal water systems. Moreover, the organism iskilled in the oocyst phase, a particularly resistant stage in its life cycle.Viruses are also eliminated by the system. PureBright is designed to treatclear fluids, but it also effectively kills bacteria, mold spores, and viruses inair ducts and on filter surfaces. Used with ultraviolet-transmissive polymerssuch as polypropylene or polyethylene, PureBright can also sterilizesaline solutions in intravenous bags, making sterilization a one-stepprocess. Other applications include sterilizing packaged foods, decontam-Chapter 3 - Intervention TechnologiesSection B - TreatmentBMDO Technologies for Biomedical Applications

inating cup and lid packaging, and treating fresh meats, fruits, and vegetablesto prevent microbial degradation and eliminate contamination.CoolPure preserves opaque liquids such as milk, soups, and juices withoutheating and therefore without denaturing the treated product. As most peopleare accustomed to the flavor of heat-pasteurized milk, they may findCoolPure-treated raw milk an acquired taste. However, retention of rawmilk components such as rennin, the curdling enzyme, is important forcheese production. CoolPure is bactericidal at temperatures from 25°F to60°F and is designed to treat pumped liquids as they are flowing. The quicktreatment time ensures an acceptable product flow rate. CoolPure may alsoenhance the yields of some pharmaceutical and biotechnical processes.VENTURES OR PRODUCT AVAILABILITYPurePulse is in discussion with leading medical manufacturers for varioussterilization applications. The company has contracted with a large internationalfast-food chain for decontaminating water, the U.S. Army for sterilizingfood, and a manufacturer for treating liquid whole eggs. PurePulseconfigures its systems to the user’s needs and welcomes inquiries.CONTACTMaxwell Technologies/PurePulse TechnologiesBrian Vandemark4241 Ponderosa AvenueSan Diego, CA 92123Telephone: (619) 514-1262Facsimile: (619) 576-1377WWW: http://www.maxwell.com85BMDO Technologies for Biomedical ApplicationsChapter 3 - Intervention TechnologiesSection B - Treatment

CARBON DIOXIDE LASERS FORMEDICAL APPLICATIONSBMDO HISTORYQSource, Inc. (East Hartford, CT), received both Phase I and II SBIR fundingfor building compact, lightweight carbon dioxide (CO2) lasers forLADAR systems. In 1996, QSource won a Phase II contract through thenew SBIR Fast Track program, with Medical Optics, Inc. (MOI; Carlsbad,CA), providing the matching funds.Although a third of today’syoungsters between 5 and17 are cavity free, toothdecay remains secondonly to the common coldHOW IT WORKSQSource has licensed its radiofrequency,direct-current (RF-DC) CO2 laser to MOIfor medical and dental applications. Dentalapplications are one of the initial target marketsfor QSource’s modular laser technology,which also has good industrial potential.In addition, these lasers are suitable forexistent and emerging soft-tissue medicaltreatments, such as laser skin resurfacing.• QSource’s air-cooled lasers arepoised to enter the medical anddental markets.in disease prevalence.QSource’s sealed, air-cooled CO2 laser is amodular, repetitively pulsed instrumentthat employs a sealed tube configurationand a hybrid RF-DC electrical discharge lasing mechanism. The design’sadvantages are system reliability, ease of maintenance, and device life overconventional CO2 lasers. The design makes possible less costly manufacturingmethods in production. It achieves high power output with its combinedRF-DC excitation mode, which produces peak pulsed power levels(as high as 1 kilowatt) several orders of magnitude higher than the averageoutput power. The sealed design also allows system flexibility and portability,since the laser need not be connected to an umbilical gas line. It canalso operate in a continuous-wave mode and boasts a lifetime of more than1,000 hours in the product configuration.86MEDICAL SIGNIFICANCECO2 lasers are already in widespread use in the medical realm, and withthe pulsed power capability of QSource’s design, these lasers have promisingdental applications. In MOI-sponsored research at the University ofCalifornia at San Francisco Dental School, 9.3-micrometer-wavelengthlaser pulses are being investigated as a way to seal tooth enamel and inhibitdental caries (cavities). Studies suggest that rapid pulsing of teeth canmake them five times more resistant to caries formation, and in some cases,the laser treatment can even remineralize areas of incipient decay. The brieftreatment is less time-consuming than fluoride treatment (which can discolorteeth) and polymer sealant application.Chapter 3 - Intervention TechnologiesSection B - TreatmentBMDO Technologies for Biomedical Applications

Another significant research area is laser pulpotomy, or laser treatment ofdental pulp, the vital portion of the tooth. At Beckman Laser Institute(Irvine, CA), MOI’s CO2 lasers (also designed with QSource technology)are being used in dogs to treat pulp infections. The laser method removesinflamed tissue before infection can destroy the whole tooth, and it leaveshealthy tissue intact so that the tooth remains functional and retains its livingroot. The method may become an alternative to root canal therapy, apainful procedure that millions of human patients undergo each year.Unlike the forceful physical debridement methods of conventional rootcanal therapy, laser treatment is expected to result in better tooth retentionand reduced future complications.VENTURES OR PRODUCT AVAILABILITYDavid Nielsen, D.V.M., a Manhattan Beach, CA, veterinarian, has beenusing the CO2 laser in his canine dental practice since 1995. He works incollaboration with Petra Wilder-Smith, D.V.M., and George Peavy, D.V.M.,of the Beckman Laser Institute. Documentation of this work will eventuallybe used to justify human trials.MOI, a subsidiary of Kaiser Aerospace and Electronics, has agreed to providematching funds for technology development in the Fast Track PhaseII agreement, the total of which amounts to $1 million over two years.MOI sponsors research at the University of California at San Francisco indental applications and plans to market QSource technology for the manyprocedures that the FDA has already approved for CO2 lasers.CONTACTQSource, Inc.Howard Knickerbocker91 Prestige Park CircleEast Hartford, CT 06108Telephone: (860) 291-0120Facsimile: (860) 291-0124Medical Optics, Inc.Larry M. Osterink2752 Loker AvenueCarlsbad, CA 92008Telephone: (619) 438-9361Facsimile: (619) 438-916787BMDO Technologies for Biomedical ApplicationsChapter 3 - Intervention TechnologiesSection B - Treatment

ULTRAFAST LIGHT-ACTIVATED SWITCHESBMDO HISTORYEnergy Compression Research (ECR; San Diego, CA) has developed a revolutionaryultrafast semiconductor switching technology called light-activatedsilicon switching (LASS). With contracts from the early days of BMDOresearch, ECR focused its efforts on developing photoconductive switchesthat have applications in electronics, electro-optics, and photonics forweapons such as the electromagnetic gun.88• The minuscule silicon switch hasmultiple applications in biotechnologyand medical imaging.Electroporation is now a HOW IT WORKSECR’s LASS technology involves semiconductordevices that use laser light to switchworkhorse application fora current on or off. Semiconductors aremolecular biology, whereubiquitous in the electronics industry,where they function as power amplifiers,it is used to transformstorage modules, and switches. Switchingbacteria, yeast, and human current on and off is the most general functionof the semiconductor. Conventionalcells with foreign DNA, semiconductor switching time is governedby the speed at which electrons traverse theenabling E. coli, for switch. The LASS device uses the absorptionof laser light to create the conductinginstance, to secreteelectrons within the semiconductor, resultingin a thousandfold increase in switchingmammalian proteins liketime compared with conventional switches.insulin or interferon. The high-speed, low-jitter, and zero-delayLASS device can be used to power lasers,route signals in fiber-optic communicationsdevices, control industrial motors, and power high-frequency radar communications.LASS technology offers high efficiency and cost savings inthese areas.MEDICAL SIGNIFICANCEECR is currently developing LASS technology for applications in the medicalindustry. One area of concentration includes analytical instrumentssuch as flow cytometers, mass spectrometers, and fluorescence lifetimespectrometers. Lasers designed by ECR provide high reliability as well as acompact footprint for these devices.A second medical application is in imaging systems. ECR is looking to thefar-future application of optical diffuse tomography, a technology that mayenable doctors to perform mammography without ionizing radiation. Thistechnology was envisioned more than a generation ago as “diaphanography,”a method that is familiar to anyone who has shone a flashlightthrough his or her hand. For breast tissue, however, high-intensity visible-Chapter 3 - Intervention TechnologiesSection B - TreatmentBMDO Technologies for Biomedical Applications

to-infrared light is necessary for penetration and visualization, and a meansof optical gating must be used to reconstruct the image. Technologies suchas LASS devices and better understanding of the optical properties of livingtissue are stimulating interest in this field.ECR lasers offer well-defined short pulses with high repetition rates forsurgery, particularly eye surgery.In electroporation, an intense short pulse of electricity is used to providethe force that opens cellular pores, enabling the insertion of macromoleculeslike DNA into cells of interest. It is a commonly used method forbasic research in biology and for “transfecting” cells in genetic studies.However, many cells are sacrificed in the process; up to 50 percent aredestroyed when using a DC power source to induce pore formation. LASStechnology can reduce cell loss to 10 percent by using a square-wave pulseto effect rapid and reversible pore formation.VENTURES OR PRODUCT AVAILABILITYECR manufactures microlasers, fast Pockels cell drivers, and laser diode drivers.The microlaser series is an established commercial product that is distributedworldwide. Microlasers are being used in temperature sensor systems,scientific instruments, and a broad range of product development areas,including biomedical, electrical utility, micromachining, and defense systems.The Pockels cell driver is also a commercial product that uses ECR’s LASStechnology as the heart of the system. It is used in a variety of lasers andswitches at megawatt power levels and picosecond speeds.ECR also manufactures and distributes solid-state, high-current pulse generatorsdesigned to drive laser diodes. Applications include biomedicalsensors, fiber-optic systems, and LIDAR measurements. Several new productsincorporating LASS technology are under development and areplanned for release in the coming year.CONTACTEnergy Compression Research CorporationLori Cobb6355 Nancy Ridge DriveSan Diego, CA 92121Telephone: (619) 450-6612Facsimile: (619) 450-9351Email: ECRCorp@aol.com89BMDO Technologies for Biomedical ApplicationsChapter 3 - Intervention TechnologiesSection B - Treatment

INDEX3-D image ....................................................................10, 11, 12, 13, 513-D chip architecture ......................................................................16, 173-D displays ........................................................................10, 11, 12, 133-D Technology Laboratories ..........................................................10, 11A B CAcousto-optic tunable filters............................................................36, 37Adaptive optics ..................................................................44, 45, 46, 47Applied Modern Technologies Corporation....................................44, 45AstroTerra Corporation....................................................................12, 13Baylor Institute ................................................................................82, 83Beckman Laser Institute ............................................................80, 81, 87Biocompatible implants....................................................................68-75Bioluminescence..............................................................................50, 5190Cancer diagnosis ................................................................37, 51, 52, 53Capacitors, high-density..................................................................84, 85Carbon-13 ........................................................................................28,29Cardiac pacemaker ................................................................................73Catheters ..................................................................................30, 31, 73CD-Scan and Ratiometer ................................................................52, 53Cell transfection ..............................................................................88, 89Cellular function....................................................................................37Charles Stark Draper Laboratories ..................................................66, 67Chemical signature ............................................................36, 37, 48, 49Ciencia, Inc. ....................................................................................36, 37Coated carbon foam ........................................................................74, 75Collagen linkage, photochemical reaction ............................................83Computer-aided diagnosis ....................................................................17CoolPure..........................................................................................84, 85Cryptosporidium ..............................................................................84, 85IndexBMDO Technologies for Biomedical Applications

D E FData fusion ............................................................................................21Deformable mirror ..........................................................................46, 47Dental caries, prevention ................................................................86, 87Diabetic retinopathy ..............................................................................45DNA-DNA hybrids..........................................................................54, 55E. coli detection......................................................................................51Electroluminescent displays ............................................................56, 57Electronic images ............................................................................20, 21Electroporation................................................................................88, 89Endoscope ......................................................................................52, 53Endoscopic procedures ..................................................................30, 31Energy Compression Research ........................................................88, 89Essex Corporation ..........................................................................26, 27External brace, knee and leg ..........................................................70, 71Eye disorders ......................................................................44, 45, 46, 47Fiber-optic testbed ................................................................................20Fischer Imaging ..............................................................................60, 61Flow cytometer ........................................................................40, 41, 88Fluorescence lifetime sensor............................................................36, 37Foster-Miller, Inc. ............................................................................30, 31Fourier transform ............................................................................26, 48Frequency-domain photon migration ..................................................81Full-color display ......................................................................10, 11, 12G H IGigabit-per-second ..........................................................................20, 21Gimbal ............................................................................................60, 61Heart valve cuffs ..............................................................................72, 73Heat-pasteurization................................................................................85Hedrocel ..........................................................................................74, 75Helicobacter pylori ..................................................................................28High-speed image processing ............................................14, 15, 16, 17Hip joint, artificial ..............................................................68, 69, 70, 75HIV detection ........................................................................................55Human Genome Project ........................................................................5591BMDO Technologies for Biomedical ApplicationsIndex

IBEST ion-beam treatment ..............................................................68, 69Imaging spectrometer......................................................................50, 51Implex Corporation ........................................................................74, 75Inertial guidance device ..................................................................66, 67Infrared laser....................................................................................10, 11Infrared microscope ........................................................................48, 49Ion-beam surface treatment ................................................68, 69, 72, 73Irvine Sensors Corporation..............................................................16, 17J K LJet Propulsion Laboratory ........................................................16, 32, 33Laser scissors ..................................................................................80, 81Laser, root canal treatment ..............................................................86, 87Laser tweezers..................................................................................80, 81Laser depilation ....................................................................................79Lasers ....................................................10, 11, 12, 58, 59, 78-83, 86-89Lasers, dental applications ..............................................................86, 87Lasers, carbon dioxide ....................................................................86, 87Lasers, radiofrequency-direct current..............................................86, 87Lens implant, photochemical treatment..........................................82, 83Ligand-receptor interaction ......................................................38, 39, 41Light-activated silicon switch ..........................................................88, 89LiSAF laser ......................................................................................40, 41Loma Linda Proton Therapy Facility ....................................................32M N O92Magnetic resonance imaging (MRI) ..........................................26, 27, 29Maxwell Technologies ....................................................................84, 85Medical Free Electron Laser program ..............................................78-83Medical Optics, Inc. ........................................................................86, 87Mediscience Technology Corporation ............................................52, 53Mercury cadmium telluride ..................................................................48Microelectromechanical systems (MEMS) ......................................66, 67Microlasers ......................................................................................88, 89Microorganisms, sterilization of ......................................................84, 85Moldyn, Inc. ..........................................................................................39Molecular modeling ........................................................................38, 39Multispectral sensor ........................................................................50, 51Nanocrystalline materials ................................................................56, 57NanoDynamics, Inc.........................................................................28, 29IndexBMDO Technologies for Biomedical Applications

Nanophosphors ..............................................................................56, 57Nanopowder Enterprises, Inc. ........................................................56, 57National Institutes of Health ..........................................................48, 49Needle biopsy..................................................................................60, 61Neural network......................................................................................16Nondestructive analysis ..................................................................26, 27Oak Ridge National Laboratory ..........................................54, 55, 58, 59Ocular Vergence and Accommodation Sensor (OVAS) ..................44, 45Optical mammography ......................................................53, 81, 88, 89Optical processor ............................................................................14, 15Optical biopsy ..............................37, 51, 52, 53, 58, 59, 78, 79, 80, 81Ordered polymers ..........................................................................30, 31Oriel Instruments ............................................................................36, 37P Q RP-FET chip ......................................................................................32, 33Pacific Advanced Technology, Inc. ..................................................50, 51Pharmaceutical design ....................................................................38, 39Photodynamic therapy ....................................................................78-83Photofrin ..........................................................................................78-83Photon Research Associates ............................................................38, 39Piezoelectric actuators ....................................................................46, 47Pockels cell drivers ................................................................................89Pollution detection ..........................................................................50, 51Premalignant changes ........................................................52, 53, 58, 59Proton beam therapy ............................................................................32PureBright........................................................................................84, 85PurePulse Technologies, Inc. ..........................................................84, 85Q-switched laser ....................................................................................40QM Technologies ............................................................................68, 69Qsource, Inc. ..................................................................................86, 87Quantum cryptography ........................................................................21Radiation monitor ..........................................................................32, 33Radiation exposure..........................................................................32, 33Radiology displays ..........................................................................20, 21Raman spectroscopy........................................................................36, 37Rare earth ..............................................................................................10Remote diagnosis ............................................................................44, 45Retinal imaging................................................................................46, 4793BMDO Technologies for Biomedical ApplicationsIndex

Retinal camera ................................................................................46, 47Retinopathy of prematurity....................................................................46Rheumatoid arthritis........................................................................78, 79Roto-Lok rotary drive......................................................................60, 61S T USagebrush Technology Inc...............................................................60, 61Sandia National Laboratories ..........................................................68, 69Science and Engineering Services, Inc.............................................40, 41SERGen gene probe ........................................................................54, 55Silicon Mountain Design, Inc. ........................................................14, 15Silicone implant leakage..................................................................48, 49Skin lesions, laser treatment............................................................78, 79SPARTA, Inc.....................................................................................70, 71Spectrometer, near-infrared ..................................................................81Spectroscopic imaging ........................................................36, 37, 48, 49Spire Corporation............................................................................72, 73Stem cell transplant, photochemical treatment ..............................82, 83Structured Materials Industries, Inc. ..............................................56, 57Superex Polymer, Inc.......................................................................30, 31Surface-enhanced Raman spectroscopy ..........................................54, 55Synthetic aperture radar ..................................................................26, 27Terabit-per-second data rate ............................................................16, 17Thompson Cancer Survival Center ................................................58, 59Tissue fluorescence..........................................................................52, 53Ultramet ..........................................................................................74, 75University of Rochester....................................................................46, 47University of California at San Diego ..............................................20, 21Unstable plaque ..............................................................................36, 37Upconversion ........................................................................................5794V W X Y ZVertebral inserts, artificial....................................................70, 71, 74, 75Vestibular disorder ..........................................................................66, 67Virtual Lens Microscope..................................................................26, 27Wavefront sensor ............................................................................44, 45Wellman Laboratories of Photomedicine ........................................78, 79Xinetics, Inc.....................................................................................46, 47IndexBMDO Technologies for Biomedical Applications