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6
Health and Medicine
INTRODUCTION
The U.S. health care industry representing approximately $3 trillion of annual
expenditures1 and employing roughly 15 million people2 comprises one of the
largest sectors of the national economy. Our nation boasts the most technologically
advanced, and the most costly, health care system in the world: almost 20 cents of
every dollar is spent on health care. To remain the world leader in developing and
introducing innovative medical instrumentation while improving and bringing
down the cost of health care will require continued investment in research and
development. Photonics technology plays a key role in providing the most effec-
tive, lowest-cost approaches for diagnosing, treating, and preventing disease and
maintaining a healthy U.S. citizenry.3 In the nearly 15 years since the publication
of the National Research Council’s (NRC’s) Harnessing Light: Optical Science and
Engineering for the 21st Century,4 advances in photonics technologies and develop-
1 Centers for Medicare and Medicaid Services. 2012. “National Health Expenditures 2010 High-
lights.” Available at http://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-
Reports/NationalHealthExpendData/Downloads/highlights.pdf. Accessed August 1, 2012.
2 SelectUSA. 2012. “The Health and Medical Technology Industry in the United States.” Available at
http://selectusa.commerce.gov/industry-snapshots/health-and-medical-technology-industry-united-
states. Accessed August 1, 2012.
3 For a more detailed description of the optics and photonics in the service of health and medicine,
see the full description in Appendix C of this report.
4 National Research Council. 1998. Harnessing Light: Optical Science and Engineering for the 21st
Century. Washington, D.C.: National Academy Press.
163
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164 Optics and Photonics: Essential Technologies for O u r N at i o n
ments in the field of biophotonics have created many opportunities for significant
improvements in the quality of health care as well as for substantial reductions in
the overall cost.
The discipline of biophotonics deals with the interaction of light, or electro-
magnetic radiation, with living organisms and biologically active macromolecules:
proteins (hemoglobin), nucleic acids (DNA and RNA), and metabolites (glucose
and lactose). Light interacts with biological material and organisms in many diverse
ways, depending primarily on the energy or color of the photon. At both high (x
ray) and low (radio frequency [RF]) energies the body is mostly transparent, thus
allowing the non-invasive imaging of the internal structure of organs and bones.
In contrast, certain colors or wavelengths in the infrared (IR) and ultraviolet (UV)
regions are absorbed strongly by biological tissues. The intense, focused light of
lasers with these colors can be used for a wide variety of unique therapeutic inter-
ventions: making incisions, cauterizing and sealing wounds, and selectively heating
or even vaporizing specific regions of organs and tissues. In the visible region of
the spectrum, some biologically active macromolecules naturally absorb specific
photon energies or colors. The amount of this intrinsic absorption can be used to
determine the physiological health of an organ—for example, whether the tissue
is getting sufficient oxygenated blood flow. Non-absorbing macromolecules can be
labeled using specifically engineered dyes that selectively bind to macromolecules.
These dyes or biomarkers can be used in conjunction with visible and near-infrared
light to highlight specific cell and tissue types, such as metastatic cancer cells cir-
culating in the bloodstream. Modern biomedical instrumentation takes advantage
of this wide range of interactions between photons and biological materials and
provides a remarkably broad set of tools for the physician and life scientist.
HISTORICAL OVERVIEW OF THE IMPACT
OF TECHNOLOGY ON MEDICINE
Prior to the modern age of medicine, physicians primarily used their five senses
directly to determine the causes of ill health.5 For example:
• The color of a person’s eyes was studied to detect jaundice and possible liver
failure.
• The urine of patients was tasted for sweetness, to detect the presence of
glucose and diagnose diabetes.
• An ammonia-like odor in urine implied possible kidney failure.
5 Berger, D. 1999. A brief history of medical diagnosis and the birth of the clinical laboratory.
Part 1—Ancient times through the 19th century. Medical Laboratory Observer 31(7):28-30, 32, 34-40.
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H e a lt h and Medicine 165
• The chest was struck or thumped and the resulting sound analyzed to iden-
tify the presence of fluid in the lungs, implying tuberculosis or pneumonia.
• The abdomen and breasts were palpated to detect cancerous lumps.
Currently biomedical technology extends and enhances the senses of the physi-
cian and thus dramatically increases the ability of the physician to diagnose disease.
Considering that the primary sense used by physicians in diagnosis was sight, it
is understandable that optics and imaging have played a critical role in improving
health care. Over the past 100 years, optics and imaging have allowed the clinician
to see the previously unseen. For example, observation of bacteria and microbial
parasites led to the development of antibiotics, and direct imaging of skeleton and
organs with x ray aided in observing and setting bone fractures and diagnosing
traumatic injuries to other organs. For example, laser-based flow cytometers pro-
vide detailed quantification of critical blood cell types, which is one of the primary
tools for diagnosing and monitoring the treatment of AIDS patients.6
In addition to allowing the physician to see what could not be seen unaided,
state-of-the-art optical technologies increase the sensitivity and specificity of mea-
surements far beyond the physician’s sense of taste, smell, hearing, and touch.7
Photonics plays a major role in many modern molecular diagnostic instruments.
Optical technologies now provide precise measurements of blood serum chemistry
for maintaining safe glucose levels in patients with diabetes, replacing urine taste
tests.8 Kidney function tests rely on accurate optical measurements of the glo-
merular filtration rate (GFR) rather than smelling a patient’s urine. Lung diseases
such as emphysema, lung cancer, and tuberculosis are detected using computed
tomography (CT) and chest x ray imaging. In addition, these imaging modalities
provide more complete diagnosis of potential tumors detected by palpation.
During the 20th century, improvements in medical technology have doubled
the life expectancy9 of individuals in high-income countries, changing the primary
causes of death for a typical individual. One hundred years ago, infectious diseases
often killed most individuals before the age of 50, whereas today the typical indi-
vidual in a high-income country lives until the age of 80. Optics and photonics have
been essential technologies leading to this dramatic increase in life expectancy. For
example, the microscope was the key technology allowing discoveries in microbi-
6 Hazenberg, M.D., S.A. Otto, B.H. van Benthem, M.T. Roos, R.A. Coutinho, J.M. Lange, D.
H
amann, M. Prins, and F. Miedema. 2003. Persistent immune activation in HIV-1 infection is asso
ciated with progression to AIDS. AIDS 17(13):1881-1888.
7 Bynum, W.F., and Roy Porter, eds. 1933. Medicine and the Five Senses. Cambridge, Mass.:
C
ambridge University Press.
8 For more information, see Appendix C in this report.
9 See, for example, the CIA’s World Factbook, available at https://www.cia.gov/library/publications/
the-world-factbook/. Accessed December 1, 2011.
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166 Optics and Photonics: Essential Technologies for O u r N at i o n
FIGURE 6.1 Life expectancy: 2011 estimates by CIA World Factbook. SOURCE: CIA. 2011. World Factbook.
Available at https://www.cia.gov/library/publications/the-world-factbook/rankorder/2102rank.html.
ology which determined that germs are the underlying cause of most infectious
diseases, leading to the development of effective antibiotic drugs.
The primary causes of death today (heart disease, cancer, diabetes, and neuro-
degenerative diseases) are diseases that are more prevalent at older ages. The success
of modern medicine has therefore created a series of new challenges, requiring
further innovation.
Many of these challenges are being met using optics and photonics instrumen-
tation, which is providing scientific insights into the underlying molecular biology
causing these diseases as well as quantitative new diagnostic instruments to help
steer effective interventional therapies.
In low-income countries, infectious diseases, such as tuberculosis, malaria, and
AIDS, remain leading causes of death. This is due in large part to the absence of
low-cost diagnostic tests that can detect these diseases at an early stage when the
infections can be more easily contained and cost-effective intervention strategies
can be employed. (See Figure 6.1.)
OPTICS AND PHOTONICS IN MEDICAL PRACTICE TODAY
A patient entering the emergency room (ER) with chest pains or a severe
headache almost invariably receives a high-resolution, three-dimensional scan us-
ing CT or magnetic resonance imaging (MRI) as an initial diagnostic screening,
which can assist in the diagnosis of a heart attack, pulmonary embolism, or stroke.
CT and MRI both use photons with wavelengths for which the human body is very
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H e a lt h and Medicine 167
transparent, creating comprehensive, high-resolution, three-dimensional images
of the anatomy: CT uses x-ray photons and MRI uses RF photons.10 Stroke and
heart attack can lead to sudden death, but effective interventions exist if the condi-
tions can be diagnosed swiftly. If a nonresponsive patient comes to the ER with an
unlabeled prescription in his or her pocket, how can the ER attendant determine
whether or not the patient’s drugs have contributed to his or her condition? New
technology using lasers has the potential to provide a fast method for identifying
drugs by exposing the pills to laser light and observing the spectra emitted in re-
sponse to the laser excitation. The colors emitted by the sample provide a unique
fingerprint, which can be compared with a database of more than 5,000 common
pharmaceuticals to determine the precise makeup of the patient’s prescription and
to determine quickly whether these drugs contributed to the patient’s condition.11
In the surgical suite, brain damage occurs in less than 5 minutes in anesthetized
patients during surgery if sufficient oxygen levels are not maintained. During the
early and mid-20th century, the monitoring of blood oxygen levels required taking
a blood sample and sending it to the hospital laboratory for analysis. This process
typically took tens of minutes to complete, presenting significant hazards to the
patient with such slow feedback. These procedures were revolutionized by opti-
cal pulse oximeters, developed in the 1980s, which precisely measure the ratio of
the absorption levels of the blood at two wavelengths, using convenient, low-cost,
disposable optical probes based on light-emitting diodes (LEDs) and inexpensive
solid-state detectors.12 In the past, mortality rates of 1 in 2,000 to 1 in 7,000 were
reported in developed countries, and many patients suffered brain damage owing
to oxygen deprivation during surgery;13 today such deaths and injuries have es-
sentially been eliminated.
Surgery almost always results in some unavoidable trauma to the patient.
Minimizing the size of the surgical incision reduces this trauma and can dramati-
cally speed recovery. Modern optical endoscopes provide a close-up view of organs
and a method for implementing laser surgery, utilizing incisions of less than a few
centimeters. In addition, endoscopic visualization is now the standard of care for
screening for colon cancer and for diagnosing esophageal cancer. Commonly used
today in orthopedic surgery for repairing injuries in almost all of the major joints
10 For more information about developments in CT instruments, see Appendix C.
11 Gendrin, C., Y. Roggo, and C. Collet. 2008. Pharmaceutical applications of vibrational chemi-
cal imaging and chemometrics: A review. Journal of Pharmaceutical and Biomedical Analysis 48(3):
533-553.
12 For more information about O saturation measurements, see Appendix C in this report.
2
13 World Health Organization (WHO). 2008. Global Pulse Oximetry Project. Background docu-
ment. First International Consultation Meeting. WHO Headquarters, Geneva, CH. Available at
http://www.who.int/patientsafety/events/08/1st_pulse_oximetry_meeting_background_doc.pdf. Ac-
cessed August 1, 2012.
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168 Optics and Photonics: Essential Technologies for O u r N at i o n
(knee, elbow, hip, wrist), this technology has allowed many surgeries to become
outpatient procedures, eliminating hospital stays and greatly reducing health care
costs.
Besides being ubiquitous in the hospital, optical methods and instruments are
also used in monitoring chronic conditions and in many outpatient surgical proce-
dures.14 The most pervasive use of optics and lasers in surgery is in ophthalmology.
Laser treatments are standard therapy for treating blindness due to diabetes as
well as age-related degenerative disease. One of the most common laser cosmetic
surgeries today is the correction of focus of the eye lens by the precise shaping of
the cornea, a procedure that has been performed on tens of millions of patients.
Lasers and optics are also used in many outpatient elective cosmetic procedures,
such as skin resurfacing and hair and tattoo removal.
Almost everyone has had blood drawn and sent to the clinical laboratory for
blood tests, but few people are aware that these blood samples are analyzed using
lasers and optical imaging to provide the measurements characterizing the status of
the patient’s blood and circulatory system. Many types of blood cells have distinct
shapes and unique internal structures, which can be detected by illuminating the
cells with a laser beam and analyzing the transmitted and scattered laser light. The
laser-based instruments used for these purposes can count many thousands of cells
per second and are used to measure with great precision the different types of cells
present in the bloodstream.
A doctor detecting a suspicious lump in a patient will often order an explor-
atory biopsy, which is sent to the pathology laboratory. High-resolution imaging of
the excised tissue and analysis of the size and shape of the cells provide the most
precise diagnosis of tumor malignancy and aggressiveness. These images also can
help determine the boundaries between healthy and diseased tumor tissue, provid-
ing a surgeon with guidance about how much tissue needs to be removed to fully
excise a tumor.
ADVANCES IN TECHNOLOGY PROVIDING THE OPPORTUNITY
FOR NEW APPLICATIONS OF PHOTONICS
New optical technology has accelerated the translation of remarkable new
capabilities into medical practice. As an example, just 30 years ago the standard
technique for sequencing genes involved the radioactive labeling (using a radioac-
tive isotope of phosphorous) of the gene bases, gel electrophoresis to separate the
gene fragments by size, and the overnight exposure of an optical film placed in close
proximity to the gel. This laborious and time-consuming process allowed the se-
quencing of only several hundred bases during a typical day. With the introduction
of optical methods in the 1980s, including four-color sequencing and optical scan-
14 For more information, see Appendix C.
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H e a lt h and Medicine 169
ning of the gel, the speed of sequencing increased by a factor of 10. The develop-
ment of superior separation technologies, including capillary electrophoresis and
better optical designs using confocal laser scanning, increased sequencing speed by
about another factor of 10. Recently, single molecular fluorescence detection dur-
ing single-strand DNA synthesis, synthesis-based sequencing (SBS), has replaced
electrophoresis. Low-noise, high-resolution charge-coupled device (CCD) imaging
devices allow the simultaneous sequencing of millions of individual DNA strands.
These technologies have increased the speed of sequencing by a factor of 1,000.
(See Figure 6.2.) Not only has the speed increased by 100,000-fold, but the cost
of sequencing the genome has decreased from billions of dollars to under $1,000.
Data collected during 1 day in a typical sequencing laboratory in 1970 would fill
approximately half of a single page in a lab notebook. In 1990, the technology
produced enough data to fill a chapter of a lab book, or about 20 pages in a single
day. In the year 2000, a single day’s data would fill a whole lab book.
Present-day technology, driven by advances in laser sources, nanophotonics,
and detectors, generate enough data in 1 hour to fill the contents of 10, 24-volume
encyclopedias.
ADVANCES IN TECHNOLOGY PROVIDING THE OPPORTUNITY
FOR FUTURE APPLICATIONS OF PHOTONICS
Continuing advances in several critical areas of technology have dramatically
increased the capabilities of biomedical optical instrumentation and herald a new
era of innovation in biomedical optics, leading to improvements in treating many
types of diseases. New optical sources and materials, imaging devices, microfluidic
technologies, and detection methods will provide remarkable increases in speed,
sensitivity, and precision for biomedical optical instrumentation.
Nucleic Acid Sequence Detection and Mutation Detection
Predilections for many diseases are the result of the specific makeup of an in-
dividual’s inherited genetic code. Specific alterations in certain genes can dramati-
cally increase the likelihood of cancer, cognitive impairment, and severe allergic
reactions to certain types of food. Early identification of these inherited tendencies
allows preventive strategies to be in place before the disease causes significant dam-
age. With the advent of rapid and much-lower-cost methods for whole genome
sequencing, many of which rely on optical methods, the possibility exists that a
wide range of correlations between genetic makeup and disease predilection can
be detected earlier, and appropriate interventions put in place.15
Today, sequencing a complete human genome costs less than $5,000; it is
15 For more information, see Appendix C.
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170 Optics and Photonics: Essential Technologies for O u r N at i o n
(a)
FIGURE 6.2 Technologies have increased the speed of
s
equencing by a factor of 1,000. Time to sequence a sin-
gle human genome with (a) pre-laser DNA sequencers
(1970s), (b) 1990s laser-based DNA sequencers, and (c)
second- eneration laser-based DNA sequencers. SOURCE:
g
(b)
C
ongressional briefing by Thomas Baer, Executive Director,
Stanford Photonics Research Center, Stanford University, Palo
Alto, Calif. November 30, 2010. Available at http://portal.acs.
org/preview/fileFetch/C/CNBP_026401/pdf/CNBP_026401.
pdf. Accessed November 8, 2012.
(c)
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H e a lt h and Medicine 171
projected that the next generation of instruments will reduce the cost to $1,000
over the next few years.16 The new generation of SBS sequencers (see Box 6.1 and
Figure 6.3) combines nanotechnology with photonics to achieve this remarkable
increase in speed.17 To reach their full potential, these instruments will require fur-
ther investment in research to develop higher-speed and -sensitivity CCD cameras,
more efficient labeling dyes, high-speed software to extract quantitative informa-
tion from large, high-resolution images, and nanophotonic structures optimized
to localize the fluorescent signals from the individual DNA strands.
Proteomic Analysis Through Protein and Tissue Arrays
Detecting cancer recurrence early, determining the most appropriate drug
therapy to slow tumor growth, and detecting and/or diagnosing a number of
deadly infectious diseases are all examples of diagnostic tests that rely on measuring
specific proteins in the blood serum. Recent advances in protein detection using
photonics technology platforms are providing dramatic increases in sensitivity
and specificity.
Microfluidics and robotics combined with optics provide the technology to
create arrays of tissue samples on slides that can be automatically laser scanned
and analyzed after exposure to fluorescently labeled antibodies which attach to
tumor-specific proteins. These tissue arrays are analyzed using laser scanners and
automated image analysis of the digital images. Drug interactions and molecular
structures can be studied across hundreds of diseased and healthy patient samples
all located on a single slide. This technology has the potential for greatly accelerat-
ing the drug development process and reducing development costs.
These protein-measuring instruments use automated, high-resolution micros-
copy, wide-field-of-view, low-noise imaging devices, and quantitative fluorescence
microscopy. The performance of these instruments will improve greatly with ad-
vances in the areas of optics and photonics technology.
High-Throughput Screening
The development of new drugs based on small molecules is often limited by
the rate at which candidate molecules can be screened for their therapeutic effect
on target cell cultures. In recent years, optical technology has been combined with
16 Bio-ITWorld Staff. 2011. “Illumina Announces $5,000 Genome Pricing.” Available at http://
www.bio-itworld.com/news/05/09/2011/Illumina-announces-five-thousand-dollar-genome.html.
Accessed August 1, 2012.
17 Margulies, M., M. Egholm, and W.E. Altman, et al. 2005. Genome sequencing in microfabricated
high-density picolitre reactors. Nature 437:376-380.
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172 Optics and Photonics: Essential Technologies for O u r N at i o n
BOX 6.1
Nucleic Acid Synthesis-Based Sequencing
The first human genome was sequenced using technology based on electrophoresis, a process by
which molecules of different sizes and chemical makeup are separated spatially in special gelatins by
running an electric current through the gel. This process allowed different nucleic acid sequences to be
isolated and the genetic code to be read out using fluorescent tags and laser scanners.
The newest approaches to gene sequencing use a radically different approach—called synthesis-
based sequencing (SBS)—which relies on several key photonics technologies. A sample containing a
quantity of DNA molecules with unknown sequences is placed in a special microfluidics chamber. In
this chamber separate strands of DNA are captured in different locations and then are copied by special
enzymes. As the copy is created, each added base is incorporated into the growing DNA strand along
with a fluorescent dye. Each of the four bases is coupled to a different-colored dye. The addition of each
new base is detected by exciting the fluorescence dye with a laser and detecting the color of the fluores-
cence using a high-resolution, high-sensitivity CCD (charge-coupled device) camera. After the dye color
is detected and the added base is identified, the dye molecule is enzymatically cleaved from the DNA
strand. This process is repeated until the all of the bases have been added and identified and the DNA
sequence has been determined.
This synthesis of copies of the various DNA molecules in the sample takes place simultaneously in
hundreds of thousands of distinct locations, all of which can be monitored in parallel by high-sensitivity
cameras that can detect signals as low as a single photon from each synthesis site. This approach has
increased the speed of the sequencing of nucleic acids by many orders of magnitude. Currently, a single
instrument can sequence the 3 billion base pairs in a human genome in less than a day. In contrast, the hu-
man genome project employed many hundreds of instruments and took more than 10 years to complete.
SOURCE: Fuller, C.W., L.R. Middendorf, S.A. Benner, G.M. Church, T. Harris, X. Huang, S.B.
Jovanovich, J.R. Nelson, J.A. Schloss, D.C. Schwartz, and D.V. Vezenov. 2009. The challenges of
equencing by synthesis. Nature Biotechnology 27(11):1013-1023.
s
robotics to provide the ability to screen hundreds of thousands of drug candidates
per day, dramatically accelerating the drug discovery process. This high-throughput
screening technology relies on robotic sample-handling automation for the precise
and rapid parallel processing of multiple samples as well as on optical technology
for high-speed quantitative data collection. Optical methods, including fluores-
cence, bioluminescence, and colorimetry, are used to identify and count viable
and nonviable cells affected by the candidate compounds, determine activated
molecular pathways in target cells, and detect the overall cellular response to po-
tential small-molecule drugs. An example of an approach that allows very low con-
centrations of proteins to be detected by actually counting the protein molecules
individually is seen in Figure 6.4. More recently, by combining microfluidics with
microscopic imaging to enhance protein quantification, researchers have increased
sample throughput by 1,000-fold, to an astounding 10 million samples per day,
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H e a lt h and Medicine 173
FIGURE 6.3 The Pacific Biosciences PacBio RS platform is used for single-molecule sequence data. SOURCE:
© Pacific Biosciences. Reprinted with permission.
FIGURE 6.4 Showing single occupancy:
reaction wells approximately 5 microns in
diameter contain a single bead coated with
antibodies that trap a single target protein
molecule. This single protein in turn binds a
fluorescent enzyme that creates a fluorescent
signal localized in the well, which is detected
by laser scanning the well array. This
approach allows very low concentrations of
proteins to be detected by actually counting
the protein molecules individually. SOURCE:
Subbaraman, N. 2010. “Detecting Single
Cancer Molecules.” Technology Review.
Available at http://www.technologyreview.
com/biomedicine/25462/. Reprinted with
permission.
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174 Optics and Photonics: Essential Technologies for O u r N at i o n
and radically reduced the sample volume and the time required for analysis.18
These instruments utilize and will benefit from improvements in high-sensitivity,
quantum-limited imaging detectors and new, compact, long-lived laser sources.
Flow Cytometry Mass Spectrometry
Although essential to survival, the human immune system also is a key factor
in a number of common diseases, such as rheumatoid arthritis, childhood or Type
I diabetes, and arteriosclerosis. Understanding the complex processes that make up
an immune response requires the simultaneous monitoring of the activity and con-
centration of dozens of immune-system cell types. Lasers have traditionally been
used in flow cytometer instruments to evaluate patient blood samples, identifying
and counting the immune-system cell types. These instruments were limited in the
past to quantifying only a few different cell types simultaneously. A new generation
of flow cytometry instruments combines optical detection with mass spectrometry.
This new technology promises to allow a status check of a patient’s immune system
by simultaneously quantifying all of the major cellular constituents. When com-
bined with other advanced proteomic technologies, including tissue microarrays
and protein mass spectrometry, the CyTOF instrument (see Figure 6.5) will provide
the most complete understanding of the immune system to date.19 Identifying
immune cell types along with their associated functions in affected tissues—that
is arthritic joints, inflammatory tissues, and pancreatic islets—will allow the most
complete understanding of the local and systemic processes that underlie many
degenerative diseases such as rheumatoid arthritis, diabetes, Alzheimer’s disease,
and heart disease.20
Ophthalmology
Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are
two of the leading causes of blindness, particularly in older patients.21 Laser-based
surgical and drug therapies can slow the disease progression, particularly if the
disease is detected prior to major damage to the retina. Early detection is difficult
because the disease primarily impacts tissue beneath the surface of the retina, which
18 Agrestia, J.J., E. Antipov, A.R. Abate, K. Ahn, A.C. Rowat, J.-C. Baret, M. Marquez, A.M. Klibanov,
A.D. Griffiths, and D.A. Weitz. 2009. Ultrahigh-throughput screening in drop-based microfluidics
for directed evolution. Proceedings of the National Academy of Sciences of the United States of America
107(9):4004-4009.
19 Cheung, R.K., and P.J. Utz. 2011. Screening: CyTOF—the next generation of cell detection.
Nature Reviews Rheumatology 7(9):502-503.
20 For information about use in HIV status, see Appendix C.
21 For more information, see the section on “Ophthalmology” in Appendix C.
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H e a lt h and Medicine 175
(a)
(b)
FIGURE 6.5 (a) A CyTOF instrument, which extends the capability of multi-parameter flow cytometry
by atomic mass spectrometry to measure up to 100 biomarkers simultaneously in single cells at a rate
of 1,000 cells per second; (b) data: 138-178 segment of mass spectrum for a homogeneous sample
of several enriched isotopes of lanthanides. SOURCE: DVS Sciences, Inc. Available at http://www.
dvssciences.com/index.html. Reprinted with permission.
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176 Optics and Photonics: Essential Technologies for O u r N at i o n
is not easily observed in the early stage. New optical methods employing optical
coherence tomography (OCT), a type of microscopic laser radar imaging that can
probe beneath the surface of the retina, provide a method for precise subsurface
imaging. OCT provides a high-resolution, three-dimensional image of the interior
of the eye, allowing subsurface structures to be resolved down to a depth of about 1
millimeter below the surface of the retina. This capability allows early diagnosis and
early intervention, which can stop or slow down the disease progression, provid-
ing the potential for many additional years of visual acuity to affected individuals.
The number of cases of AMD and DR has increased greatly due to the aging of
the population and the obesity epidemic.22 Early detection and intervention with
new anti-angiogenesis drugs have proven to be remarkably effective in treating
AMD. Moreover, the efficacy of new drugs currently under development can be
quantitatively assessed and compared using the three-dimensional OCT images,
which accurately define the volume of the lesions in the retina caused by AMD.
Changes in the lesion volumes provide a direct measure of the drug efficacy and
can help determine effective and safe dosage levels.
OCT also provides the capability for the accurate mapping of the lens and sur-
rounding tissue capsule, which can be measured with great precision in all three
dimensions. This information, when combined with laser surgery using ultrafast
lasers, has the potential to revolutionize the protocol for treating cataracts. Using
OCT guidance, femtosecond lasers can be precisely focused on the capsule and
automatically cut close to perfectly round incisions in the capsule. These precise
incisions greatly assist in locating and centering the replacement lens. The same
ultrafast pulsed laser can also be used to segment the original occluded lens, which
can then be much more easily extracted from the patient’s eye. This combination
of OCT for precise measurement of eye morphology, along with precision fem-
tosecond ultrafast laser machining, is setting a new standard for quality in these
ophthalmic procedures, as seen in Figure 6.6.23
Image-Guided Surgery
For most solid tumor cancers, surgical excision is often the optimal interven-
tion strategy when it is feasible. Most often it is very important to balance the
22 AMD Alliance International. 2011. Increasing Understanding of Wet Age-Related Macular Degen-
eration (AMD) as a Chronic Disease to ensure that all patients have access to early intervention, regular
proactive treatment, and integrated care, and that research is ongoing for improved treatment options.
Available at http://www.amdalliance.org/user_files/documents/AMD_ChronicDiseasePolicy_M03_
NoCrops_Low_Res.pdf. Accessed August 1, 2012.
23 Friedman, N.J., D.V. Palanker, G. Schuele, D. Andersen, G. Marcellino, B.S. Seibel, J. Batlle, R.
Feliz, J.H. Talamo, M.S. Blumenkranz, and W.W. Culbertson. 2011. Femtosecond laser capsulotomy.
Journal of Cataract and Refractive Surgery 37(7):1189-1198.
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H e a lt h and Medicine 177
FIGURE 6.6 Excised and stained lens capsule samples from (top) a manual capsulorhexis and (bot-
tom) a laser capsulotomy with clearly improved boundaries of lens capsule cutting with optical coher-
ence tomography (OCT)-guided femtosecond laser surgery. SOURCE: Reprinted with permission from
Friedman, N.J., D.V. Palanker, G. Schuele, D. Andersen, G. Marcellino, B.S. Seibel, J. Batlle, R. Feliz,
J.H. Talamo, M.S. Blumenkranz, and W.W. Culbertson. 2011. Femtosecond laser capsulotomy. Journal
of Cataract and Refractive Surgery 37(7):1189-1198.
need to remove the tumor completely versus the desire to maintain the integrity
and function of the surrounding tissue. This is of particular importance in organs
such as the brain, liver, and pancreas. Currently many surgical procedures require
the excision of a sample portion of the affected organ, which is then sent to the
pathology lab for analysis to determine the tumor boundaries, which then help
guide the surgeon’s decision as to how much tissue to remove. This process is
time-consuming and is typically performed while the patient is anesthetized. New
optical techniques are being developed24 that provide real-time images of the tu-
mor boundaries. These techniques employ fluorescent biomarkers (see Figure 6.7),
which selectively bind to the tumor cells, providing a clear demarcation between
the healthy and diseased tissues that can be visualized directly by the surgeon
during the operation. Similar techniques can be used to highlight nearby nerves
24 For additional information, see Appendix C.
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178 Optics and Photonics: Essential Technologies for O u r N at i o n
FIGURE 6.7 Comparisons highlighting different fluorescent biomarkers. (a) White light reflectance
only used in (a-c); (b) Cy5 fluorescence (pseudocolored cyan, overlaid on reflectance) image high-
lighting deeply buried nerve (long-stemmed arrow); (c) yellow fluorescent compound (YFP) fluores-
cence (pseudocolored yellow, overlaid on reflectance) image highlights additional branches (large
arrowhead); (d) white light reflectance only used in (d-f); (e) FAM fluorescence (pseudocolored cyan,
overlaid on reflectance) image highlighting a stained buried nerve branch (large arrowhead); (f) Cy5
fluorescence (pseudocolored green, overlaid on reflectance) image highlighting a tumor (small arrow-
heads). SOURCE: Reprinted with permission from Whitney, M.A., J.L. Crisp, L.T. Nguyen, B. Friedman,
L.A. Gross, P. Steinbach, R.Y. Tsien, and Q.T. Nguyen. 2011. Fluorescent peptides highlight peripheral
nerves during surgery in mice. Nature Biotechnology 29:352-356.
and lymph nodes that may need to be carefully avoided or excised as part of the
operational procedure.25
Dual Energy CT and Quantitative Image Analysis
The primary causes of death in the United States today are heart disease, cancer,
and pulmonary disease, such as emphysema.26 In all of these modern ailments,
early detection is the key to effective intervention. Since, in their early stages, these
diseases often develop with minor or no symptoms, appropriate routine screen-
ing of at-risk populations must be implemented to detect disease in apparently
healthy individuals. These screens must be low-cost, minimally invasive, and have
low false-positive results in order to prevent unnecessary follow-on procedures.
Imaging methods can provide a very effective approach to meeting these criteria.
Recent large-scale clinical trials have demonstrated the ability of low-dose
x ray CT scanning as a very effective method to screen for lung cancer tumors,
25 For information about the use of optic and photonics in biopsies, see Appendix C.
26 Centers for Disease Control and Prevention (CDC). 2012. “Leading Causes of Death.” Available
at http://www.cdc.gov/nchs/fastats/lcod.htm/. Accessed August 1, 2012.
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H e a lt h and Medicine 179
cardiovascular disease, and early signs of emphysema. High-resolution CT scans of
the chest provide data sets that allow precise measurement of the size of lesions in
the lung and allow tracking of changes in the size of these lesions, which is a very
specific indication of malignancy. These CT data sets can also provide measures of
occlusions or obstruction in cardiac vasculature (early indication of heart attack
risk) and assessment of pulmonary function (indicative of emphysema).
CT imaging is a fast (a scan takes less than 10 seconds), non-invasive, and
low-cost method for obtaining critical data that can be used to determine effec-
tive early intervention, preventing disease progression and greatly reducing the
cost of treatment and improving the quality of life for the patient. To achieve the
full potential of this technology will require new approaches to data analysis and
quantitative feature extraction. For example, to deploy effective screening services,
more precise methods for quantifying tumor size, determining the level of calcifi-
cation in cardiac vasculature, and extracting measures of lung expiration capacity
must be developed.
The critical contributions of optical technology to CT instrumentation (and
other imaging platforms such as MRI and ultrasound) are often overlooked. Fun-
damentally, CT devices are optical instruments, employing photons chosen with
wavelengths for which the body is partially transparent to precisely image the inter-
nal physiology of the patient. The x ray photon sources, the optics for focusing the
x rays, and the detectors used to detect the x ray photons are designed employing
many of the same techniques developed for the design of imaging instruments
using visible light. Similarly, the mathematical methods for analyzing the raw trans-
mitted x ray data, for reconstructing and visualizing three-dimensional models
of internal anatomy, are almost identical to comparable techniques employed in
other imaging modalities using visible or infrared light. Thus advances in detector
technology, image reconstruction models, and techniques for quantitative feature
extraction from large three-dimensional data sets will greatly enhance the perfor-
mance of CT, MRI, and ultrasound imaging platforms.27
In general, advances in developing quantitative imaging data analysis pro-
cedures are hindered by the inability of the scientific community to access com-
mon data sets useful for comparing the performance of automated computerized
methods to analyze the data. Establishment of the infrastructure to support public
access to large data sets of image data and open-source software tools to extract
clinically significant features from these data should be a national priority. Such an
infrastructure is vital to accelerating advances in many different imaging modali-
ties, including OCT, CT, MRI, ultrasound, x ray, diffuse optical imaging, and others.
27 Baer, T.M., J.L. Mulshine, and J.J. Jacobs. 2007. Biomedical Imaging Archive Network. Skeletal
Radiology 36(9):799-801.
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180 Optics and Photonics: Essential Technologies for O u r N at i o n
Biomedical Optics in Regenerative Medicine
One of the most active frontiers of modern medicine is in the field of stem cell
research. As more is learned about the fundamental processes behind how progeni-
tor cells differentiate and develop into cell types that make up specific tissues and
how tissue expands and develops into organs, the potential arises for using this
knowledge to repair or replace organs that are damaged due to aging or traumatic
injury. Time-lapse microscopic imaging of stem cells as they differentiate into dif-
ferent cells types is playing a key role in identifying specific stages that characterize
both normal and abnormal growth pathways. These data can potentially be used
to determine which cells are safe to transplant into patients and which may be give
rise to tumors.28
Biomedical Optics in Research
Advances in technology and the application of new instruments often provide
the basis for further insights and discoveries that lead to a deeper understanding of
the causes and the molecular basis of diseases. Significant improvements in optical
technology have dramatically increased the ability to measure and study biological
processes in both in vitro and in vivo environments.
The past few years have witnessed the birth and genesis of a whole new field
of biophotonics called optogenetics.29 (This field was declared the Method of the
Year in 2010 by the journal Nature Methods.30) As defined by Carl Deisseroth, one
of its primary developers: “Optogenetics is the combination of genetic and optical
methods to achieve gain or loss of function of well-defined events in specific cells
of living tissue.”31 This technique has seen primary application in neuroscience,
where the function of single neurons or groups of neurons can be monitored and
controlled by specific wavelengths of light. Neurons in live, behaving animals can
be genetically programmed to fire or be prevented from firing by exposure to dif-
ferent colors of light. Moreover, the active or inactive state of the neuron can be
detected by observing fluorescence from the neuron. This provides neuroscientists
with tools very analogous to those used by engineers to study electronic circuits:
specific neural circuits can be activated or deactivated, and the overall circuit re-
28 Wong, C.C., K.E. Loewke, N.L. Bossert, B. Behr, C.J. De Jonge, T.M. Baer, R.A. Reijo Pera. 2010.
Non-invasive imaging of human embryos before embryonic genome activation predicts development
to the blastocyst stage. Nature Biotechnology 28:1115-1121.
29 For additional information, see Appendix C.
30 Nature Methods. 2011. “Method of the Year 2010.” Editorial. Available at http://www.nature.com/
nmeth/journal/v8/n1/full/nmeth.f.321.html. Accessed July 27, 2012.
31 Lin, S.-C., K. Deisseroth, and J.M. Henderson. 2011. Optogenetics: Background and Concepts
for Neurosurgery. Neurosurgery 69(1):1-3.
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sponse to these changes and the changes to information flow through the neuronal
circuit can be monitored in real time. All of these types of measurements have been
performed in a wide variety of alert, active animals.
These remarkable capabilities are made possible by the combination of the
development of new forms of bioengineered, light-sensitive proteins and the ap-
plication of two photon imaging instruments that allow the subsurface probing
of neural anatomies. These new bioengineered materials and optical techniques
have revolutionized the field of neuroscience and provide, essentially for the first
time, the possibility of reverse engineering and modeling of the neural circuitry of
complex brains in live animals.
One of the fundamental principles of imaging that has limited the size of ob-
jects that can be resolved is the diffraction limit. In essence, objects smaller than
the wavelength of light used to illuminate the sample cannot be imaged clearly.
Over the past 10 years, several techniques have been developed that allow the pre-
cise location of single molecules to be determined to a fraction of a wavelength
of light. These approaches allow startlingly vivid images illustrating the locations
of proteins and small molecules in organelles and other structures within cells,
providing a new capability for gaining insight into the mechanisms and functions
of proteins within cells.
Several other areas of biophotonics are in early stages of development but show
great promise. These include the use of free electron laser coherent x ray sources to
probe the structure of membrane bound proteins in situ. These proteins are often
key drug targets, since they control signaling pathways within the cell that are in-
volved with a number of diseases. Laser tweezers and atomic force microscopy are
being used to measure what the impact of localized forces on cell membranes is and
how these forces can initiate biochemical signaling within the cell. This research
has important ramifications on the engineering of tissue structures to support the
appropriate growth of specific cell types for organ transplantation.
FINDINGS
Key Finding: Many chronic, debilitating, and often fatal degenerative diseases
impacting the aging population are mediated or exacerbated by the patient’s own
immune system. Understanding and controlling the immune system are thus
among the major challenges facing modern medicine today. Optical instrumenta-
tion will continue to be the principal enabling technology allowing advances in the
understanding of the immune system.
Key Finding: Stem cell science is advancing rapidly, providing great insight into
how cells progress from progenitor cells (capable of transforming into any tissue
type) to cells of a phenotype characteristic of a specific tissue. Controlling these
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182 Optics and Photonics: Essential Technologies for O u r N at i o n
processes in vivo and developing confidence that once the cells are transplanted
into a patient they will continue to develop normally, present a major remaining
challenge that must be overcome before stem cells can be used broadly in regen-
erative medicine. Microscopic imaging technologies will provide key non-invasive
methods to monitor the growth process of stem-cell-derived tissues and help en-
sure their safety and efficacy for transplantation.
Finding: Optical techniques using solid-state light sources and detectors com-
bined with microfluidics are the ideal technology base for automated, low-cost,
portable devices that can be operated by personnel without their needing extensive
training. In high-income countries the primary causes of death and patient mor-
bidity are degenerative diseases due to longer life expectancy; in contrast, in low-
income countries the infectious diseases remain leading causes of death. One of the
primary challenges for infectious diseases in low-income countries is to develop
low-cost diagnostic methods that can identify disease in its pre-symptomatic and
pre-infectious early stage. Additionally, diseases such as malaria and tuberculosis
have different phenotypes that can be identified using optically based diagnostic
methods and thus help determine the most effective course of therapy.
Finding: The current generation of imaging instruments (CT, MRI, OCT, and
ultrasound) provides unprecedented resolution, allowing spectacular three-dimen-
sional, non-invasive images of human anatomy. These data sets contain informa-
tion that will allow early diagnosis of many potentially fatal diseases, including lung
cancer, heart disease, emphysema, and Alzheimer’s disease. Early detection often
provides the opportunity for the most effective intervention. However, these images
contain an enormous amount of information, at times overwhelming the ability
of the radiologist or clinician to effectively evaluate and digest all the information
available from the raw images. Similar challenges are faced by ophthalmologists in-
terpreting three-dimensional data sets generated by OCT instruments, and likewise
by pathologists dealing with large data sets generated by the automated scanning of
large tissue sections imaged with subcellular resolution. Automated image-analysis
software can provide reliable quantitative measurement of key features from these
complex data sets, improving the diagnostic reliability, decreasing the amount of
time required, and lowering cost. Clearly all of these new image approaches have
many challenges in common and could benefit from a centralized infrastructure
for sharing data and image-analysis software algorithms.
Finding: A person’s genes determine, in part, that person’s tendency to succumb
to specific diseases. Developing more cost-effective methods to sequence human
genomes could lead to effective identification of an individual’s risk factors and
potentially to effective early intervention and preventative strategies. Almost all of
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H e a lt h and Medicine 183
the most recent generation of high-throughput sequencing instruments are based
on optical methods.
RECOMMENDATIONS
Key Recommendation: The U.S. optics and photonics community should develop
new instrumentation to allow simultaneous measurement of all immune-system
cell types in a blood sample. Many health issues could be addressed by an improved
knowledge of the immune system, which represents one of the major areas requir-
ing better understanding.
Key Recommendation: New approaches, or dramatic improvements in existing
methods and instruments, should be developed by industry and academia to in-
crease the rate at which new pharmaceuticals can be safely developed and proved
effective. Developing these approaches will require investment by the government
and the private sector in optical methods integrated with high-speed sample-
handling robotics, methods for evaluating the molecular makeup of microscopic
samples, and increased sensitivity and specificity for detecting antibodies, enzymes,
and important cell phenotypes.
Recommendation: The U.S. health care diagnostics industry, in cooperation with
academia, should prioritize the development of low-cost diagnostics for extremely
drug-resistant and multi-drug-resistant TB, malaria, HIV, and other dangerous
pathogens, and low-cost blood-serum- and tissue-analysis technology to poten-
tially save millions of lives per year.
Recommendation: The U.S. health care industry, in cooperation with academia,
should prioritize the development of new optical instruments and integrated incu-
bation technology capable of imaging expanding and differentiating cell cultures in
vitro and in vivo, to provide important tools for predicting the safety and efficacy
of stem-cell-derived tissue transplants.
Recommendation: The U.S. software and information technology industry, in
cooperation with academia, should prioritize the development of new software
methods automating the extracting, quantifying, and highlighting of important
features in large, two- and three-dimensional data sets to optimize the utility of
the latest generation of imaging instruments.
Recommendation: The U.S. life science instrumentation industry, in cooperation
with academia and the federal government, should prioritize the development of
the next generation of super-high-throughput sequencing devices, required for
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184 Optics and Photonics: Essential Technologies for O u r N at i o n
lowering the cost of sequencing down to the target cost of $1,000 per genome.
This will require advances in high-sensitivity, low-noise, high-resolution CCD
cameras, high-efficiency laser sources, and nanophotonic devices integrated with
microfluidics and automated systematic analysis.
Recommendation: The U.S. government should expand investment in multidis-
ciplinary centers (e.g., at universities with medical and engineering schools) at
which critical developments combining medical and engineering discoveries can
be efficiently fostered.
Recommendation: The U.S. government, in cooperation with scientific and medi-
cal societies, should facilitate the creation of an information technology infra-
structure for sharing large amounts of medical and clinical data (e.g., quantitative
imaging and molecular data) and open-source analysis tools.
