Trends and Opportunities in Photonics Technologies: Solid-State Lighting and Healthcare (NISTIR 7305)

III. PHOTONICS IN HEALTHCARE

A. Current Status

Although our understanding of both photonics and biology has made tremendous advances in the last few years, optical techniques have been used in healthcare applications throughout human history. From cave drawings that image deadly wounds via drawings of figures with arrows protruding from their bodies through descriptions of plague-generated lesions during the Middle Ages and the development of the optical microscope, optical techniques have been used to diagnose health problems and to monitor the progress of healing.

In light of the extensive history relating optical approaches to health monitoring and diagnosis, a comprehensive discussion of the entire range of optical techniques currently used in healthcare lies outside the scope of this document. Rather, we will focus on recent developments in which optical techniques are used in new ways as diagnosis, treatment, or monitoring tools. While many of these tools are associated with aspects of imaging, photonics approaches should not be considered as synonymous with imaging. As will be discussed, photonic tools are being developed for treatment and chemical diagnosis as well as for imaging. In this section we will address both techniques already being developed for clinical applications and approaches still restricted to the laboratory environment. The expectation is that many of the latter approaches will soon make the transition to clinical application as commercialization efforts mature.

Before the discussion of specific applications, it should be pointed out that, like all tools, optical techniques have both benefits and limitations (Table 3). In practice, most of the benefits and limitations are application specific. For example, surface applicationsof optical techniques, i.e., those for the skin or eye, can usually be viewed as non-contact. However, for internal imaging, the limited penetration depth of optical techniques usually requires optical probes to bring the source light into the region to be interrogated, thus losing the non-contact aspect.  Similarly, without the use of probes, the benefits of variable wavelength range are limited; typically, to achieve greater penetration, specific wavelengths are used, thereby pre-determining resolution and optical interaction with features of interest. Conversely, tuning the interrogation wavelength to interact with a specific feature of interest automatically places restrictions on the possible penetration depths. If the applications are intended to be used for diagnosis in vitro rather than in vivo, these restrictions are considerably relaxed, since penetration depth is less of an issue.

TABLE 3: Benefits and limitations of optical techniques

1.  Clinical:

The development of lasers and light emitting diodes has had a major effect on medical treatment. From retinal mapping, eye surgery and epidermal ablation to more prosaic hair removal, lasers are routinely used for a range of surface medical treatments. Concurrent development of optical fibers has led to internal imaging capabilities such as endoscopy, permitting inspection of intestinal and esophageal passages to detect cancerous and precancerous conditions, and laparoscopy, allowing examination of abdominal and ovarian cavities. Combining laser sources and fiber catheters has given rise to capabilities such as laser angioplasty, in which plaque deposits are destroyed by focused optical radiation. In addition to these techniques, major advances in the understanding of cell chemistry for both healthy and diseased cells have resulted in increasingly sophisticated spectroscopic analyses of blood and tissue samples. In vitro tools are currently being used for a variety of applications: e.g., to check glucose levels for diabetes monitoring, to detect troponin T and myoglobin as a monitor for heart attacks in real time, using turbidimetry for distributed clot detection.

2.  Research and Development:

Although the words in vivo and in vitro are used throughout the medical and biological communities, their precise meanings are somewhat context dependent. While in vitro means "in glass", i.e., in a laboratory setting, and in vivo means "in life", i.e., in a living body, the distinction is somewhat blurred. Some scientists consider studies of fixed cells to be in vitro and studies of living cells to be in vivo. In contrast, other scientists consider the study of living cells removed from a host to be in vitro, because they are in an artificial environment, and the study of cells in a living creature, e.g., mouse, human, to be in vivo. For this document, we use the latter definition; i.e., living cells that have been removed from their host are considered in vitro and not in vivo.

a) In vitro

While the predominant goal for research into biophotonics is the development of tools to be used eventually in vivo for healthcare,12 there are a number of technical advances that will almost certainly be limited to in vitro applications but that, nonetheless, will provide new understanding of life processes. This understanding will include both the behavior of healthy tissue as well as cellular and sub-cellular behavior associated with the onset of disease. The results of such an understanding could lead to the development of in vivo tools and procedures for identifying and treating diseases such as cancer at the very onset of cellular damage, i.e., low grade dysplasia. For the in vitro research areas, photonic activities are divided into three components: Optical Microscopy, Spectroscopy, and Combinatorial approaches.

i. Optical microscopy:

Advances in optical microscopy have made it possible to image features on the 100's and even 10's of nanometer scale. Taking advantage of the nonlinear optical properties of biological material, in some cases new techniques have been able to make use of contrast mechanisms that do not require dyes or external tracers. In other cases, optical tracers that are designed to attach to specific cellular sites, providing optical contrast through mechanisms such as fluorescence provide information regarding cellular dynamics. Finally, optical tools have been developed that allow manipulation of cell components on the micrometer and sub-micrometer level. While most of the tools that use these techniques can be purchased from commercial vendors, new applications are continually being devised and reported. The following is an overview of optical microscopy procedures being developed specifically directed towards healthcare.

Figure 3: Schematic of a confocal microscope. The spatial filter in front of the detector provides resolution. Three-dimensional images can be generated by scanning the specimen at different focus positions within the specimen.

Figure 4: Energy diagram of two-photon process. Excitation wavelength is longer that emitted wavelength; a single incident photon has insufficient energy to excite an electron and is not absorbed.

Figure 5: Incident light on the nonlinear region results in scattered light at twice (2n or three times (third harmonic) the frequency of the incident light.

Figure 6: Schematic of FRET. As the two particles approach each other, the laser-induced fluorescence in the dye in particle 1 induces a secondary fluorescence in the dye in particle 2 through non-radiative dipole interactions.

The primary advantage of FRET is its extreme sensitivity to the spacing between fluorophores. Because the energy transfer is a non-radiative resonance phenomenon, it is very short range and the efficiency of the transfer is strongly dependent upon the separation between the cell components. Measurements of the intensity ofλfl or Xn can give very precise information regarding that separation; monitoring the polarization of the emissions can give information regarding relative orientations. A disadvantage of the technique is that interactions between cell components must be inferred and the type of interaction is unknown. In addition, the effects of the fluorophores attached to the components on their subsequent interactions are unknown.

Figure 7: Schematic of TIR fluorescence

ii. Spectroscopy:

A number of the techniques mentioned above are powerful tools that can provide much more information than is contained in optical contrast images. For example, Raman, near-field Raman, fluorescence, and light scattering measurements can all be used spectroscopically, i.e., as a function of wavelength, to provide chemical, orientation, and structural information in addition to the time-dependent location information that images provide.   The combination of spectroscopic information with imaging information has the potential of providing detailed information regarding intercellular and intracellular mechanisms under varying conditions. Currently, however, spectroscopic tools are predominately used independently of imaging techniques in their traditional role of performing chemical assay, albeit at increasingly reduced size scales. Sample sizes are being reduced to ^liters, and under carefully controlled laboratory conditions, even single molecules have been interrogated.

iii. Combinatorial approaches:

The enhancement of spectroscopic techniques that allows single cell or even sub-cell interrogation makes it possible for researchers to apply parallel measurements to reduce noise³⁴ or quickly to evaluate new markers or drugs under differing conditions.³⁵,³⁶    One of the easiest approaches is to use optical fiber arrays, applying separate fibers to individual cells. In this way, identical measurements can be made simultaneously on identical cells to reduce noise within a measurement, or individual cells can be modified, e.g., to contain a different marker or modification of a drug, and a wide parameter space can be mapped rapidly. The measurements can be as simple as monitoring fluorescence intensity or as sophisticated as measuring entire Raman spectra for each fiber. An alternate approach that does not require fibers could make use of uniform illumination of an array of cells or sub-cellular components. The scattered light from the specimens could then be individually imaged, via an array of micro-lenses, onto an array detector, or, alternatively, the light could be scanned rapidly into a single detector. All of these approaches have the advantage of high-speed assessment capability. However, there are also limitations. The major limitation is spectroscopic techniques provide a great deal of data on each cell but there is currently no mechanism for rapidly quantifying, assessing, and efficiently accessing all of the chemical and structural information obtained for each element of the array when a large array of data is being obtained with rapid throughput.¹² Therefore, while in principle a great deal of knowledge could be obtained regarding marker or drug interactions within a cell under various conditions, typically such data are not obtained. Rather, a spectroscopic peak is chosen and its intensity, position, or width is monitored for each element of the detector array and the remaining data are discarded.³⁷ This leads directly to the second limitation of the technique. The procedure requires a precise knowledge of the type of interaction to be investigated. Without this knowledge, simultaneous relevant processes that occur may not be detected.

b) In vivo

Challenges associated with in-vivo measurements are of a different nature than those found in in-vitro work. In particular, the primary goal of in-vivo research is to develop procedures that will not generate more damage in the host than the intended treatment cures. The second goal is to generate sensing schemes that will detect specific responses, via imaging or chemical sensing techniques, in an inhomogeneous environment that has a dynamic background filled with a wide range of chemical species, pH values, densities, sizes, and optical properties. The third goal is to improve understanding of the interworkings of the living system, thereby developing criteria for earlier, more precise, disease indicators and minimizing the extent of required medical interventions. Current procedures generally use a chemical test or some form of an image to detect a problem, then, if feasible, an image to localize the problem, a medical intervention, and finally, an image or chemical test to evaluate the consequences of the intervention (see Figure 2). Consequently, we will divide the following discussion into the categories of Imaging, Diagnosis, and Treatment.

Figure 8: Flowchart showing sequential, semi-independent relationship between diagnosis, intervention/treatment, and treatment evaluation in current medical practice.

i. Imaging:

Because of the difficulties listed above, a living body is a very difficult object in which to discover defects via photonic imaging. Problems are minimized to some degree in procedures such as x-ray imaging of bone, because the penetration of the x-rays is relatively high in a living creature and the contrast between the high density, high atomic number (i.e., high capture cross section) bone and the low density, relatively low atomic number soft tissue allows for good signal intensity and reasonable high contrast. However, use of visible optical techniques to obtain images is much more difficult. Water and hemoglobin in the body combine to absorb light over the entire near-UV to near-IR range³⁸ with the exception of two windows centered at approximately 800 nm and 1200 nm. In these windows, light can penetrate about 12 cm.   However, for wavelengths of 700 nm, 600 nm, or 500 nm, the penetration depths resulting in half the initial intensity are 10 cm, 1 cm, and 0.5 cm, respectively (see Figure 3). Clearly, there is a trade-off between resolution and penetration depth, with penetration depth falling off dramatically as wavelength decreases. However, absorption is only one of the factors governing the use of visible or near visible optical techniques in vivo. The second major limiting factor in using optical techniques is that bodies are highly heterogeneous systems, filled with scattering objects ranging in size from tens of nanometers, e.g., membranes, to objects such as organelles and whole cells on the tens of micrometers scale. Consequently, even in the absence of absorption, reflected and transmitted signals are highly attenuated due to multiple scattering events at all wavelengths. Finally, living bodies are not static. Muscles twitch, blood flows, chemical processes occur. Therefore, any optical technique used in-vivo must be designed to accommodate such motion, or else must be limited to detection of defects large compared to the scale of motion-induced displacement.

Figure 9: Penetration depth through water and hemoglobin across the visible wavelength range. Values represent the depth at which the intensity is 50% of the original value.

ii. Diagnostics:

Optical tools in use or being researched for in vivo diagnostics typically fall into one of two categories: imaging⁴⁷ or spectroscopy⁴⁸. Imaging, by far the most widely researched aspect of optical diagnosis techniques, is used, often with disease or organ specific tracers, to generate high contrast images for diseases detection and concomitant size and location information. By making measurements over time with a contrast agent or molecular tracer, relative severity of the disease can sometimes be assessed. However, the information is typically visual only and, consequently, relatively qualitative in nature. Spatial dimensions can be obtained but detailed information will still have to be determined by a biopsy.   Spectroscopy tools, i.e., tools used to obtain chemical information rather than images, are being recognized as potentially very powerful for in-vivo applications but are still relatively rare. As mentioned previously, when spectroscopic tools are used for imaging, e.g., fluorescence or Raman spectroscopy, typically a major peak position or intensity is monitored and the remaining information is discarded for processing speed and data storage reasons.³⁷

iii. Treatment:

As might be expected, photonic tools in medical treatment lag behind those being developed for imaging and diagnostics. One treatment with potentially broad applications is photodynamic therapy (PDT). In PDT, light sensitive agents, e.g., systemic photosensitive dye, quantum dots (QDs), nanoscale spheres, collect at a region of interest such as a tumor. A laser or high intensity diode lamp illuminates the region either locally activating a toxin or generating local heating that kills the surrounding tissue. Although the technique has clear benefits, there remain a number of issues that must be addressed. First, monitoring the dosage of the optically active agents relative to the dosage⁴⁹ required for treatment in absolute terms and as a function of time is difficult. Second, systemic dyes are undesirable because the patient remains light sensitive until the body eliminates the dye, which can take several hours or even a few days for complete elimination. Third, as mentioned previously, the material composing most QDs is toxic. The QDs can be coated but the lifetime and reliability of the coating in the chemically active environment of the body as well as during optical heating must be ascertained. Nanoscale spheres made of Au, alumina, or polymers are more inert, although the long-term biological response to these materials is not known. Equally important for all of the nanoscale materials is the fact that both their dispersal in the body and their optical absorption are strongly dependent upon sphere size. Therefore, material issues such as purity, size, size distribution, agglomeration, and reactivity must be controlled very well.

B. Long-term issues

Long-term issues associated with healthcare are predominately related to safety, reliability, efficiency, and effectiveness. In addition, there is a growing sense that the traditional distinctions between imaging/detection, diagnosis, and treatment will become blurred in the future.   Figure 4 shows schematically this blurring of previously independent aspects of medical treatment. As mentioned previously, current medical practice typically separates diagnosis, treatment, and evaluation into distinct categories. Frequently, practitioners in the three categories do not even speak together; written reports are passed between them or placed on the patient's chart. Consequently, subtle effects in diagnosis or changes in treatment may not be communicated among the different groups of people, leading to confusion in treatment. Improvements in imaging and spectroscopic techniques are expected to provide true chemical information across the entire image and to provide it in real time. Such capabilities could lead to in-situ biopsies, real time analysis during intervention (e.g., surgery, PDT), and immediate post-treatment biopsies. Increased knowledge of the chemistries associated with precursors to disease coupled with spectroscopic imaging on the sub-cellular level might even allow detection, treatment, and follow-up of pre-cancerous areas without the need for traditional surgical procedures even arising.

Figure 10: Schematic of future use of photonics in medical care. Advances in both imaging and spectroscopy procedures will a linking of the formerly distinct areas of Diagnosis, Treatment, and Evaluation into a more monolithic structure. As spectroscopic imaging tools improve to allow chemical analysis across entire images, distinctions between imaging and chemical tests will tend to disappear, as well.

1.  Implant/biotracer/imaging agent issues:

The long-term issues associated with insertion of foreign material into the body are similar to those discussed above for short-term tests. The primary concern is for biocompatibility.¹² What are the degradation mechanisms?⁵⁰ What occurs at the interface between the body and the implant? What time frames are important? What are the failure probabilities and implications? Are there fouling mechanisms that need to be considered?   With nanoparticle tracers, the time frame in the body is intended to be on the order of hours or days. Yet, some of the nanoparticles may become trapped and remain indefinitely. For those materials and their debris, the toxicity issues touched on previously remain important, and moreover, the time frame over which interactions must be considered is extended considerably. Some of the parameters that need to be monitored for toxicity assessment are:⁵¹ composition, size, shape, deformability, stability, and coatings.

2.  Imaging/spectroscopy:

As shown in Figure 4, a long-term goal for imaging is to combine real-time spectroscopic information with image formation. Implied in that goal is the need to develop a direct relationship between measurements and cellular behavior.³⁷ A second critical long-term need for imaging that is expressed by everyone from the pharmaceutical industry through diagnosticians, all the way to the FDA is the need for standards, procedures, and techniques that will provide validated image interpretation.⁵²   Among the necessary improvements are instrument-to-instrument reproducibility, operator-to-operator reproducibility, and even reproducibility of the same operator on the same instrument and the same patient from one measurement to the next.⁴⁰ In fact, there appears to be a widespread sense that image analysis tools need to be developed to the extent that the judgment of the human operator can be removed from the image analysis process.⁴⁰,⁵² This goal implies that interactions of the physics, chemistry, biology, and statistics used to create the image need to be more rigorously understood to allow automation of image analysis.¹²   Combining these requirements, the future of imaging requires, on its simplest level, that:

1. the engineering of the instrumentation must be well enough defined that images made of standard reference specimens on instruments from different manufacturers or different models from the same manufacturer can be related in a meaningful and understandable way;
2. analysis algorithms must provide at least a core set of imaging tools common to all instruments to allow image comparisons between instruments and to confirm consistency

1. the image probe should provide cellular and sub-cellular chemical information; the information should be directly connected to cellular processes of interest;
2. the information should provide quantitative information regarding the presence or absence of a disease and, if present, a measure of the disease progress.

The implications of the last three items are that detailed spectroscopy information needs to be obtained as part of the image. This, in turn, requires that spectroscopic techniques need to be improved in speed, signal/noise, and spatial resolution for them to be useful as imaging tools on the cellular level while retaining their use as spectroscopic instruments.

In addition, because these data sets will contain three-dimensional coordinate information, spectra containing up to 1000 points of wavelength versus intensity (and possibly phase) information, possibly a temporal axis, and fitting parameters, data handling tools need to be developed to optimize data storage, data retrieval, and data viewing, as well as general data manipulation for n-dimensional data sets. Finally, data analysis techniques need to be standardized and automated. While relatively large, isolated peaks can be fitted automatically with reasonable accuracy, analysis of complicated spectra still requires operator input and judgment. This last statement leads to a point only recently recognized; all image analyses should include quantitative, standardized, and well-defined uncertainty discussions and medical practitioners need to be trained to understand those discussions.

C. NIST Interaction Opportunities in Photonics in Healthcare

Unlike SSL, which is predominately a commercial driven activity that also has benefits to society at large in terms of increased energy efficiency, increased reliability, and reduction in greenhouse gas production, healthcare is viewed as primarily a matter of public safety and only secondarily as a commercial enterprise. Consequently, the area of photonics in healthcare is dominated by government agencies tasked with the responsibility of assuring safety and effectiveness of medical treatment and is less driven by large consortia of businesses. This is not meant to imply that business does not play a large role in healthcare in the United State, from large pharmaceutical companies down to small start-ups, nor does it mean to downplay the importance of university research, particularly those universities with associated teaching hospitals, in medical R&D. However, for the subject of Photonics in Healthcare, unlike SSL, it is difficult to isolate one or two consortia that drive research directions and guide government agencies that monitor this topic. Rather, two government agencies, the National Institutes of Health (NIH) and the Food and Drug Administration (FDA) function as the primary drivers for progress through their funding and regulatory practices. These two organizations act as the main mechanism for research concepts and devices to reach commercialization. A third organization, the National Science Foundation (NSF) provides funding for research that is typically less applied.

1. Food and Drug Administration (FDA)

The FDA is a regulatory agency that monitors medicines, devices, and procedures for safety and compliance with regulatory requirements. Its mission involves assuring near-term and long-term safety and research conducted at the FDA is closely focused on this mission.

a)  NIST Laboratories
Most of the work at the FDA is too applied and too near term for research collaborations between NIST and FDA to be easily formed. However, some areas of mutual concern are readily apparent; the FDA is highly concerned with reliability, degradation, degradation mechanisms, and lifetimes associated with any foreign material implanted or injected into the body. There are many materials and chemistry issues that could reasonably be addressed by NIST. In addition, there are a number of areas (e.g., OCT) in which the FDA would benefit from standards work and metrology that could be done at NIST. It should be noted that, because of the large level of device, drug, and treatment monitoring which is the ongoing responsibility of the FDA, external collaborations need to be directly related to the FDA mission.

b) ATP
The FDA could provide a large reservoir of reviewers, and potentially, ATP proposal evaluation board members who have an outstanding knowledge of current medical technology and associated barriers and pitfalls. The aspects of the FDA that make scientific collaboration somewhat difficult for the NIST laboratories (i.e., short term, applied research) provide the FDA scientists with an excellent view of needed improvements and recognition of innovative thinking regarding technologies soon to be introduced into the marketplace.

2. National Institutes of Health (NIH)

The National Institutes of Health are formed of a group of semi-autonomous Institutes, each of which has its own mission, typically, the study and treatment of a specific disease. Although most of these Institutes probably have applications that could be considered as biophotonics, it appears that bulk of the work on photonics in healthcare is funded by either the National Cancer Institute (NCI) or the National Institute for Biomedical Imaging and Bioengineering (NIBIB).

a) NIST Laboratories
Interactions with NIH benefit the NIST laboratories in three areas. First, NIH provides an important mechanism for generating collaborations between NIST scientists and the medical community, either NIH staff or researchers funded by NIH. This mechanism has been strengthened considerably by the joint NIST/NIH postdoctoral program. The second benefit of working with NIH is credibility. NIST is well recognized as a metrology laboratory but is not well known for its research in medical or biological applications. Therefore, collaborating with the medical staff at NIH provides that dimension of capabilities to the joint research. The third benefit is that proposals that advance both the health mission of NIH and the metrology mission of NIST can result in funding for equipment and guest scientists. It should be mentioned that there are a number of ongoing interactions between different groups at NIST and NIH.

b) ATP
Interactions with NIH benefit ATP in ways similar to those described for DOE in the SSL section. Not only does NIH form a source of potential reviewers for biology/health related ATP proposals, close relations with NIH provide insight into near-term and longer-term research and development issues associated with healthcare. In addition, it may be possible to develop a relationship with program managers at NIH in which they shepherd researchers who have commercialization proposals that are inappropriate for NIH funding toward ATP competitions. Finally, the NIH provides both the ATP and the laboratories an additional mechanism for outreach and education through the many workshops that the NIH provides on a wide range of current topics.

3. National Science Foundation (NSF)

The NSF is a government funding organization directed to providing resources for basic research. In this regard, the NSF might be considered on the opposite side of NIH from the FDA. The NSF is less concerned about commercialization than NIH and far more concerned with expanding the basic knowledge base than the FDA is.

a)  NIST Laboratories
Although the NSF does not provide funding for NIST staff time, it does fund proposals that would cover guest scientist, travel, and publication costs. More importantly, the NSF has a huge number of contacts with colleges and universities and, consequently, could provide a great deal of information that would lead to collaborations between NIST staff and universities. The NSF can also provide an additional resource: information regarding current research trends.

b) ATP
As with other government agencies discussed previously, the NSF can provide reviewers for proposals. In addition, the NSF funds technology centers that act as incubators for new companies. Contact information for the NSF Center for Biophotonics Science and Technology is provided in Section VI: Appendix II.

D. NIST Research Opportunities

As mentioned above, there are a number of groups at NIST already involved in biophotonics research and active collaborations with NIH or other organizations. Some of the research issues in the outline below are being addressed by these groups. However, the listed items remain important topics to enhance current understanding of biological behavior in general as well as specific instrument/biology interactions. In addition, many of the topics listed below address metrology needs and, consequently fall directly into the NIST mission.

1.   Imaging

1. Resolution
   i.   Signal/Noise (S/N)
         1.  Physics of interactions
         2. Statistical tools
         3. Uncertainty analysis
   ii.   Contrast
         1.  Physics of interactions
         2. Markers
               a. Sensitivity
               b. Specificity
               c. Toxicity (material properties)
               d. Uniformity
               e. Material/tissue interface chemistry

2. Reproducibility
   i.   Operator to operator
         1. Measurement protocols
         2. Technique metrology (e.g., OCT, fluorescence, Raman)
   ii.   Single operator repeatability (same is operator to operator)
   iii.   Instrument to instrument
         1. Measurement protocols
         2. Standard sources, detectors
         3. Calibration procedures
   
   
3. Spectroscopy
   i.   Spatial resolution
   ii.   Relationship to biological functions
   iii.   Sensitivity
   iv.   Data handling

2.    Implants

1. Biological compatibility
2. Reliability
   i.   Degradation mechanisms
         1. Encapsulation
         2. Mechanical
         3. Chemical
               a.    Interface interactions
               b.    Particle/ion diffusion
   ii.   Lifetime prediction
   iii.   Accelerated test procedures

3.    Single cell investigation

1. Near field techniques
   i.   Metrology
   ii.   S/N
   iii.   Apply to living cells
2. Measurement physics relationship to biological function

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Date created: May 22, 2006
Last updated: January 3, 2007

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