The Development, Commercialization, and Impact of Optical Coherence Tomography

Abstract

This review was written for the special issue of IOVS to describe the history of optical coherence tomography (OCT) and its evolution from a nonscientific, historic perspective. Optical coherence tomography has become a standard of care in ophthalmology, providing real-time information on structure and function - diagnosing disease, evaluating progression, and assessing response to therapy, as well as helping to understand disease pathogenesis and create new therapies. Optical coherence tomography also has applications in multiple clinical specialties, fundamental research, and manufacturing. We review the early history of OCT describing how research and development evolves and the important role of multidisciplinary collaboration and expertise. Optical coherence tomography had its origin in femtosecond optics, but used optical communications technologies and required advanced engineering for early OCT prototypes, clinical feasibility studies, entrepreneurship, and corporate development in order to achieve clinical acceptance and clinical impact. Critical advances were made by early career researchers, clinician scientists, engineering experts, and business leaders, which enabled OCT to have a worldwide impact on health care. We introduce the concept of an "ecosystem" consisting of research, government funding, collaboration and competition, clinical studies, innovation, entrepreneurship and industry, and impact - all of which must work synergistically. The process that we recount is long and challenging, but it is our hope that it might inspire early career professionals in science, engineering, and medicine, and that the clinical and research community will find this review of interest.

Figure 1

Photographing light in flight 1971. (Left) A high-speed laser optical shutter is created using a CS2 cell between crossed polarizers. An intense laser pulse induces transient birefringence (the Kerr effect) and opens the shutter. (Center) An ultrashort laser pulse propagating through a cell of milk and water, “frozen” by ultrahigh speed photography. The shutter speed was 10 ps. (Right) “Gated picture ranging” sees only the image light to recover an image behind scattering material. These early studies suggested that high speed optical gating could be used to “see inside” biological tissues. Reprinted with permission from Duguay MA, Mattick AT. Ultrahigh speed photography of picosecond light pulses and echoes. Appl Opt. 1971;10:2162–2170. © 1971 Optical Society of America.

Figure 2

(Top) The colliding pulse femtosecond dye laser was state of the art in the 1980s and could generate record pulse durations of less than 100 fs. This technology enabled fundamental studies of ultrafast phenomena in physics, chemistry, and photobiology. We began to explore biomedical applications at MIT in the mid-1980s. (Bottom) Early experiment measuring femtosecond light echoes in an ex vivo bovine eye.

Figure 3

Early demonstration of femtosecond optical ranging (A-scans). (Left) Femtosecond echoes of backscattered light (signal) are detected using nonlinear cross correlation, mixing the signal with a delayed reference pulse. (Right) Measurement of corneal thickness in an in vivo rabbit eye, showing an axial scan (A-scan) of backscattering versus depth. An axial resolution of 15 μm (in air) was achieved using 65 fs pulses at 625-nm wavelength. Detection sensitivity was −70 dB or 10⁻⁷ (Ref. 6). Reprinted with permission from Fujimoto JG, De Silvestri S, Ippen EP, Puliafito CA, Margolis R, Oseroff A. Femtosecond optical ranging in biological systems. Opt Lett. 1986;11:150–152. © 1986 Optical Society of America.

Figure 4

Low coherence interferometry can measure optical echoes with more scalability and lower cost than femtosecond optics. (Left) Drawing from Bachelor's thesis by John Apostolopolous (MIT 1989) showing a schematic interferometer for measuring multilayer structures in the eye [Reprinted with permission]. (Right) Measurement from Huang et al. demonstrating A-scans of the anterior chamber in an ex vivo bovine eye. A 10-μm axial resolution was achieved using a low-coherence diode light source at approximately 800 nm. Detection sensitivity was −100 dB or 10⁻¹⁰⁰ (Ref. 16). Reprinted with permission from Huang D, Wang J, Lin CP, Puliafito CA, Fujimoto JG. Micron-resolution ranging of cornea anterior chamber by optical reflectometry. Lasers Surg Med. 1991;11:419–425. © 1991 Wiley-Liss, Inc.

Figure 5

The first OCT images from Huang et al. Imaging was performed at 830-nm wavelength with 15-μm axial resolution in tissue and displayed on a log false color scale spanning −60 to −90 dB of the incident intensity. (A) Optical coherence tomography of the human retina ex vivo and corresponding histology. Optical coherence tomography shows the optic nerve head contour with retinal nerve fiber layer visible as a high scattering layer. (B) Optical coherence tomography of human artery ex vivo and corresponding histology. Optical coherence tomography shows fibrocalcific plaque (right three-quarters of specimen) and fibroatheromatous plaque (left). After 20 years, we were able to realize Duguay's proposal to “see inside” tissue. Reprinted with permission from Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science. 1991;254;1178–1181. © American Association for the Advancement of Science.

Figure 6

The first OCT retinal imaging prototype instrument was designed by (EAS) at MIT Lincoln Laboratory in 1993. The imaging engine was reduced in size from a 1-m² lab table to a compact and robust 19-inch wide unit. High speed A-scanning at 160 mm/s enabled rapid acquisition of retinal images. The patient interface was designed around a slit-lamp biomicroscope. The OCT beam is scanned using a pair of galvanometer actuated mirrors. This system was designed for use at the NEEC and imaged several thousand patients during the mid-1990s. Image courtesy of Eric Swanson.

Figure 7

First in vivo OCT image of the normal retina in a human subject. Imaging was approximately 15-μm axial resolution (in tissue) at approximately 840-nm wavelength. The image shows the retinal architectural morphology including the choroid, retinal pigment epithelium, nuclear layers, plexiform layers, and retinal nerve fiber layer. Reprinted with permission from Swanson EA, Izatt JA, Hee MR, et al. In vivo retinal imaging by optical coherence tomography. Opt Lett. 1993;18:1864–1866. © 1993 Optical Society of America.

Figure 8

The evolution of early OCT ophthalmic instruments. Humphrey (Zeiss) introduced the first OCT instrument in 1996. Optical coherence tomography 2 was introduced in 2000, but limited sales almost caused OCT to be abandoned. After the introduction of the Stratus OCT in 2006, OCT became a standard of care in ophthalmology.

Figure 9

Photographs from the 2006 American Academy of Ophthalmology Annual Meeting. Numerous companies have developed SD-OCT instruments and it is widely available to the ophthalmic community.

Figure 10

Wide-field retinal and choroidal OCT imaging. Swept-source OCT using VCSEL light source at 580-kHz axial scan rate. (a) Rendering of volumetric wide-field 3D-OCT data. (b) Virtual (arbitrary) cross-sectional image showing deep image penetration and ability to visualize choroid and sclera. Arrow indicates scleral vessel. (c) En face OCT image of the choroid obtained by integrating signal below the RPE. Red line indicates orientation of cross section in (b). En face OCT images at depths (d) 30, (e) 80, and (f) 200 μm below the RPE showing choroidal layers and sclera. Signal integrated from 40-μm thick slices. Reprinted with permission from Grulkowski I, Liu JJ, Potsaid B, et al. Retinal, anterior segment and full eye imaging using ultrahigh speed swept source OCT with vertical-cavity surface emitting lasers. Biomed Opt Exp. 2012;3:2733–2751. © 2012 Optical Society of America.

Figure 11

The ecosystem required to impact healthcare. Many factors drove the success of OCT, starting with clinical needs for new, cost-effective, high-resolution imaging solutions for diagnostic and therapeutic applications, the underlying physics of the high-sensitivity, high-resolution, interferometric imaging process behind OCT and the worldwide ecosystem consisting of researchers, clinician scientists, government funding, innovation at the boundaries, entrepreneurs, venture capitalists, and small and large corporations in biomedical optics as well as other industries.

Figure 12

Government funding has been critical for the success of OCT. The National Institutes of Health and National Science Foundation funded grants that list OCT in the title or abstract amounts to approximately $590 million. If the search criterion is reduced to OCT in the title (not abstract), the cost drops to less than $100 million and is probably more indicative of the cumulative US OCT research funding for OCT technology, a small amount compared to return on investment.

Figure 13

Graphical representations of some of the organizations involved in OCT research, where the node size represents publication volume and the lines represent collaboration. (Left) OCT Publications from 1998 (PUBMED), (Right) 2015 OCT Global Footprint (OCTNews). Government funding allowed researchers to pursue creative ideas and the collaborative and competitive process of scientific research rapidly moved OCT forward. Image courtesy of B. Potsaid, compiled from PUBMED and OCTNews search.

Figure 14

Growth of journal publications involving OCT. Publications are an indicator of scientific and clinical progress. Ophthalmology and cardiovascular imaging are currently the largest applications of OCT. Optical coherence tomography technology remains an active area and was in second place until 2010 when cardiology applications increased. The growth in clinical publications is closely linked to commercial development of technology and is one indicator for clinical impact. Image courtesy of E. Swanson, complied from PUBMED search.

Figure 15

Examples of OCT system companies. Approximately 40% of these companies are associated with institutions receiving government funding for OCT research and is an indicator that government dollars are having a positive translational impact on society. Approximately 75% of the OCT companies (blue dots) are, or originated as, startups. Zeiss and St. Jude are today the market leaders in their respective segments. The risks that these business took accelerated the introduction of OCT by perhaps as much as a decade.

Figure 16

Estimated OCT system revenue (including biometry) is approaching $1 billion/year. Since the first commercial product was released in 1996, cumulative revenue has likely exceeded $5 billion. Estimated tax revenues are over $500 million, yielding an excellent return on research investment.

Figure 17

Yearly and cumulative direct OCT jobs at system and component companies. Seventy OCT system and component companies were contacted and asked to supply their individual historic OCT direct employment data. By the end of 2016, the OCT industry will have provided approximately 20,000 person-years of cumulative direct high quality jobs. Not included is an estimated approximately 1000 additional jobs per year associated with the numerous OCT research groups around the world supporting faculty, post-docs, students, and related university staff.