Research
Dr. de Boer is an international authority in the field of Biomedical Optics and Optical Coherence Tomography (OCT). After his PhD in Experimental Physics, he focused on translational research, bringing physics from bench to bedside, motivated by a desire to provide a direct benefit to society. He combines both fundamental research on the unique imaging capabilities of light-based interferometry with a clear eye for bringing these innovations to clinical practice and to commercial implementation. He has made many key contributions to OCT technology, most noticeable Polarization Sensitive OCT, Spectral Domain OCT, attenuation imaging in OCT and Digital Holographic Metrology for wafer metrology. Non-invasive quantitative in vivo 3D imaging of the retina by SD-OCT has revolutionized ophthalmology clinical care leading to a paradigm shift in improved diagnosis and disease monitoring. SD-OCT has saved vision in millions of people worldwide. Patients with common blinding diseases, such as glaucoma, age-related macular degeneration, diabetic retinopathy have a chance for better vision because of SD-OCT.
The paradigm shift of Spectral Domain OCT (SD-OCT)
Before 1993, the invention of Optical Coherence Tomography (OCT), there was no technology available to ophthalmologists to examine the eye, and in particular the retina, with high resolution in 3D. Before the clinical introduction of OCT, only 2-dimensional information (a photo) could be acquired, through e.g., fundus photography or slit lamp examination. Before 2003/2004 the existing OCT technology was too slow to become widely clinically accepted by the ophthalmic community.
Key contributions
The research of Dr. de Boer has provided a paradigm shift in ophthalmology. SD-OCT is an indispensable imaging technology in ophthalmology. Nowadays, every ophthalmic clinic in the developed world has at least one OCT device which is based on the video rate Spectral Domain OCT (SD-OCT) design first published by de Boer in 2004. Video rate SD-OCT imaging was a breakthrough with respect to OCT imaging at that time, providing a 100 to 1000-fold increase in sensitivity, which allowed a 100-1000 fold increase in imaging speed without loss of image quality. The experimental proof of this 100-1000 fold increase in sensitivity was first described by de Boer in patent application US20050018201A1 and WO2003062802A2 with priority date Jan 24, 2002, and subsequently virtually simultaneously published by a number of groups in 2003 (Leitgeb et al., de Boer et al., Choma et al.). Dr. de Boer was the first to realise comprehensive in vivo video-rate 3-D volumetric imaging of the human retina in Jan. 2004, providing a blueprint for the optimal technical implementation and the convincing proof of the potential for clinical care in ophthalmology. Since these publications in 2003-2004, SD-OCT technology has not only provided improved care in ophthalmology and saved vision in millions of patients, but also paved the way for Optical Frequency Domain imaging (OFDI) or Swept Source OCT, which has the same two to three orders improvement in sensitivity but is better suited for endoscopic applications.
Since 2006, with the rollout of the first commercial SD-OCT systems, OCT has penetrated the ophthalmic community by storm. Nowadays, for nearly all diagnostic procedures in ophthalmology, OCT is included as a standard. OCT even has penetrated the optometrist market, where increasingly OCT is offered as part of an eye exam to prescribe glasses. Several research reports estimate the global market of OCT technologies at $1.5 billion by 2023 from $1 billion in 2018. His fundamental contributions to Spectral Domain Optical Cohernce Tomography (SD-OCT) and his blueprint for the optimal technical implementation still forms the basis of nearly all current clinical systems in ophthalmology. He actively pursued licensing and knowledge transfer to two ophthalmic companies (Nidek and Heidelberg Engineering) to make the technology available to the ophthalmic community.
Functional Extensions
At the same time, he has pushed innovation of the technology for blood flow detection (Doppler OCT), and imaging of fibrous structures such as nerves, collagen and muscle with Polarization Sensitive OCT (PS-OCT). These developments provide unique contrast at micrometer resolution, not achievable with current clinical techniques, that will benefit glaucoma, asthma, and interstitial lung disease patients. He pursues implementing these innovations into clinical systems in ophthalmology, pulmonology and gastroenterology, having brought several systems to METC approval for in human clinical pilot studies.
Molecular sensitivity: Immuno-OCT
OCT provides structural cross-sectional information of tissue. OCT shows the natural layered structure of tissue, but is poor at discriminating benight from malicious abnormalities. Dr. de Boer’s current research program is focused on this topic, exploring the combination of OCT with targeted fluorescence (Immuno-OCT), which provides molecular specificity. Immuno-therapies provide the most promising innovation in cancer care, with specific monoclonal antibodies (mAb’s) that target cell surface receptors overexpressed in tumor cells. PET-CT/MRI imaging with radioactively labeled mAbs’s has significantly improved clinical care by locating tumors and evaluating therapy. Since 2010 de Boer is working on the optical equivalent of PET-CT/MRI, developing novel endoscopic catheters specifically designed to combine OCT with fluorescent detection of fluorescently labeled mAb’s. To this end, he initiated a collaboration with the VUmc medical center and TracerLab. The aim is to label monoclonal antibodies with fluorescent markers, to provide molecular contrast in combination with structural OCT imaging. This optical equivalent to PET-CT/MRI provides a 10 – 100 times better resolution. This effort has resulted in an awarded patent on the combined technology, the first ex vivo paper on OCT combined with targeted fluorescence (Immuno-OCT), and the first in vivo demonstration of catheters with a 1 mm diameter motor at the tip in pulmonology.
ARCNL and ASML
Since 2017 Dr. de Boer is involved in a collaboration with ARCNL and ASML, focusing on improving metrology for wafer alignment. De Boer has made significant contributions to publications at ARCNL and IP assigned to ASML. Together with Dr. den Boef, Dr de Boer is initiator of holographic metrology, as of now one of the two most successful research lines at ARCNL, has made significant contributions to publications at ARCNL and is the lead inventor on a key patent related to holographic metrology and co-inventor on subsequent filings. This IP was assigned to ASML.
Imaging center
He is a founding member of the Amsterdam UMC/VUmc imaging Center, a center that is unique in the Netherlands and Europe, where the most innovative medical imaging techniques come together for health care and scientific research. The Amsterdam UMC/VUmc imaging Center has dedicated optical lab space for translational research and a clean room facility for the fabrication of catheters.
Publication highlights
J. F. de Boer, T. E. Milner, M. J. C. van Gemert, J. S. Nelson. Two-dimensional birefringence imaging in biological tissue by polarization-sensitive optical coherence tomography. Optics Lett. 22: 934-936, 1997.
Hallmark paper on polarization sensitive OCT, establishing the potential of PS-OCT to image fibrous structures in tissue
J. F. de Boer, B. Cense, B. H. Park, M.C. Pierce, G. T. Tearney, B.E. Bouma, “Improved signal to noise ratio in spectral domain compared with time domain optical coherence tomography.” Opt. Lett. (21) 28, 2067-2069, 2003.
This paper is the among the first experimental and theoretical descriptions of the paradigm shift that SD-OCT provided. Cited over 1000 times
N. A. Nassif, B. Cense, B. H. Park, M. C. Pierce, S. H. Yun, B. E. Bouma, G. J. Tearney, T. C. Chen, and J. F. de Boer, “In vivo high-resolution video-rate spectral-domain optical coherence tomography of the human retina and optic nerve,” Opt. Express 12, 367-376 (2004), http://www.opticsexpress.org/abstract.cfm?URI=OPEX-12-3-367.
The first demonstration of the paradigm shift provided by SD-OCT, leading to video-rate imaging of the human retina. The paper is a blueprint on how to achieve high speed, shot noise limited detection, with commercially available components. The paper showed that sensor electron well depth and 12 bit A/D range were no limitation to achieving the ultimate shot noise limited sensitivity. First large area 3D acquisition of retinal volumes. This paper introduced the acronym SD-OCT for this technology.
F. Feroldi, M. Verlaan, H. Knaus, V. Davidoiu, D. J. Vugts, G. A. M. S. van Dongen, C. F. M. Molthoff, and J. F. de Boer, “High resolution combined molecular and structural optical imaging of colorectal cancer in a xenograft mouse model,” Biomed Opt Express 9, 6186-6204 (2018).
First demonstration in an animal model of the Immuno-OCT concept, the combination of structural OCT imaging with targeted fluorescence to provide simultaneously molecular sensitivity. The first demonstration of the optical analogue of PET/CT and PET/MRI imaging with a 10-100 fold higher resolution.
F. Feroldi, J. Willemse, V. Davidoiu, M.G.O. Grafe, D.J. van Iperen, A.W.M. Goorsenberg, J.T. Annema, J.M.A. Daniels, P.I. Bonta, and J.F. de Boer, In vivo multifunctional optical coherence tomography at the periphery of the lungs. Biomedical Optics Express, 2019. 10(6): p. 3070-3091. https://doi.org/10.1364/BOE.10.003070
First in vivo in human demonstration of a motorized catheter with a 1 mm micromotor at the tip for OCT imaging in pulmonology.
Margherita Vaselli, Pieta C Wijsman, Joy Willemse, Annika WM Goorsenberg, Fabio Feroldi, Julia NS d’Hooghe, Jouke T Annema, Johannes F de Boer*, Peter I Bonta*, Polarization Sensitive Optical Coherence Tomography for Bronchoscopic Airway Smooth Muscle Detection in Bronchial Thermoplasty-Treated Patients With Asthma. Chest ,vol. 160, (2), p432-435, Aug. 01, 2021.
First in vivo human study showing the potential of PS-OCT to determine the airway smooth muscle layer thickness in vivo.
Christos Messinis, Theodorus TM van Schaijk, Nitesh Pandey, Vasco T Tenner, Stefan Witte, Johannes F de Boer, Arie den Boef, Diffraction-based overlay metrology using angular-multiplexed acquisition of dark-field digital holograms. Optics Express 28 (25), 37419-37435, 2020.
First paper showing angular multiplexed dark field holography for wafer metrology.
M.G.O. Grafe, O. Nadiarnykh, and J.F. De Boer, Optical coherence tomography velocimetry based on decorrelation estimation of phasor pair ratios (DEPPAIR). Biomedical Optics Express, 2019. 10(11): p. 5470-5485.
Paper settling the long-standing dispute if phase or intensity decorrelation is superior for flow quantification. The complex phasor decorrelation approach (including analytical derivation of the Probability Density Function) is superior, but simultaneously demonstrates that phase decorrelation is superior to intensity decorrelation.