A bio-inspired, asynchronous, time-domain, multispectral imaging system for high dynamic range near-infrared fluorescence image-guided surgery

As surgery has become the standard-of-care for cancer, surgeons have been left underequipped to identify tumors in the operating room, causing many operations to end in positive margins and necessitating secondary treatments to remove remaining tumor tissue. Near-infrared fluorescence image-guided surgery utilizes near-infrared fluorescent markers and near-infrared sensitive cameras to highlight cancerous tissues. Unfortunately, state-of-the-art imaging systems are unable to handle the high dynamic range between strong surgical lighting and weak fluorescent emission and suffer from temperature-dependent co-registration error. To provide a cost-effective and space-efficient imaging system with sufficient dynamic range and no co-registration error, this work analyzes the required dynamic range for a single-sensor imaging system used for near-infrared fluorescence image-guided surgery and reports the development of a single-chip snapshot multispectral imaging system that meets this specification. By monolithically integrating an asynchronous time-domain image sensor and pixelated interference filters, this system achieves a dynamic range of 120 dB without co-registration error in four channels across the visible and near-infrared spectra. The imager can detect less than 100 nM of the FDA-approved fluorescent dye indocyanine green under surgical lighting conditions, making it a promising candidate for image-guided surgery clinical trials

Bio-Inspired Multi-Spectral Image Sensor and Augmented Reality Display for Near-Infrared Fluorescence Image-Guided Surgery

Background: Cancer remains a major public health problem worldwide and poses a huge economic burden. Near-infrared (NIR) fluorescence image-guided surgery (IGS) utilizes molecular markers and imaging instruments to identify and locate tumors during surgical resection. Unfortunately, current state-of-the-art NIR fluorescence imaging systems are bulky, costly, and lack both fluorescence sensitivity under surgical illumination and co-registration accuracy between multimodal images. Additionally, the monitor-based display units are disruptive to the surgical workflow and are suboptimal at indicating the 3-dimensional position of labeled tumors. These major obstacles have prevented the wide acceptance of NIR fluorescence imaging as the standard of care for cancer surgery. The goal of this dissertation is to enhance cancer treatment by developing novel image sensors and presenting the information using holographic augmented reality (AR) display to the physician in intraoperative settings. Method: By mimicking the visual system of the Morpho butterfly, several single-chip, color-NIR fluorescence image sensors and systems were developed with CMOS technologies and pixelated interference filters. Using a holographic AR goggle platform, an NIR fluorescence IGS display system was developed. Optoelectronic evaluation was performed on the prototypes to evaluate the performance of each component, and small animal models and large animal models were used to verify the overall effectiveness of the integrated systems at cancer detection. Result: The single-chip bio-inspired multispectral logarithmic image sensor I developed has better main performance indicators than the state-of-the-art NIR fluorescence imaging instruments. The image sensors achieve up to 140 dB dynamic range. The sensitivity under surgical illumination achieves 6108 V/(mW/cm2), which is up to 25 times higher. The signal-to-noise ratio is up to 56 dB, which is 11 dB greater. These enable high sensitivity fluorescence imaging under surgical illumination. The pixelated interference filters enable temperature-independent co-registration accuracy between multimodal images. Pre-clinical trials with small animal model demonstrate that the sensor can achieve up to 95% sensitivity and 94% specificity with tumor-targeted NIR molecular probes. The holographic AR goggle provides the physician with a non-disruptive 3-dimensional display in the clinical setup. This is the first display system that co-registers a virtual image with human eyes and allows video rate image transmission. The imaging system is tested in the veterinary science operating room on canine patients with naturally occurring cancers. In addition, a time domain pulse-width-modulation address-event-representation multispectral image sensor and a handheld multispectral camera prototype are developed. Conclusion: The major problems of current state-of-the-art NIR fluorescence imaging systems are successfully solved. Due to enhanced performance and user experience, the bio-inspired sensors and augmented reality display system will give medical care providers much needed technology to enable more accurate value-based healthcare

Bio-Inspired Multi-Spectral and Polarization Imaging Sensors for Image-Guided Surgery

Image-guided surgery (IGS) can enhance cancer treatment by decreasing, and ideally eliminating, positive tumor margins and iatrogenic damage to healthy tissue. Current state-of-the-art near-infrared fluorescence imaging systems are bulky, costly, lack sensitivity under surgical illumination, and lack co-registration accuracy between multimodal images. As a result, an overwhelming majority of physicians still rely on their unaided eyes and palpation as the primary sensing modalities to distinguish cancerous from healthy tissue. In my thesis, I have addressed these challenges in IGC by mimicking the visual systems of several animals to construct low power, compact and highly sensitive multi-spectral and color-polarization sensors. I have realized single-chip multi-spectral imagers with 1000-fold higher sensitivity and 7-fold better spatial co-registration accuracy compared to clinical imaging systems in current use by monolithically integrating spectral tapetal and polarization filters with an array of vertically stacked photodetectors. These imaging sensors yield the unique capabilities of imaging simultaneously color, polarization, and multiple fluorophores for near-infrared fluorescence imaging. Preclinical and clinical data demonstrate seamless integration of this technologies in the surgical work flow while providing surgeons with real-time information on the location of cancerous tissue and sentinel lymph nodes, respectively. Due to its low cost, the bio-inspired sensors will provide resource-limited hospitals with much-needed technology to enable more accurate value-based health care

Development of Portable Diffuse Optical Spectroscopic Systems For Treatment Monitoring

The goal of this dissertation is to demonstrate the utility of portable, small-scale diffuse optical spectroscopic (DOS) systems for the diagnosis and treatment monitoring of various diseases. These systems employ near-infrared light (wavelength range of 650nm to 950nm) to probe human tissue and are sensitive to changes in scattering and absorption properties of tissues. The absorption is mainly influenced by the components of blood, namely oxy- and deoxy-hemoglobin (HbO2 and Hb) and parameters that can be derived from them (e.g. total hemoglobin concentration [THb] and oxygen saturation, StO2). Therefore, I focused on diseases in which these parameters change, which includes vascular diseases such as Peripheral Atrial Disease (PAD) and Infantile Hemangiomas (IH) as well as musculoskeletal autoimmune diseases such as Rheumatoid Arthritis (RA). In each of these specific diseases, current monitoring techniques are limited by their sensitivity to disease progression or simply do not exist as a quantitative metric. As part of this project, I first designed and built a wireless handheld DOS device (WHDD) that can perform DOS measurements at various tissue depths. This device was used in a 15-patient pilot study for infantile hemangiomas (IH) to differentiate diseased skin from normal skin and monitor the vascular changes during intervention. In another study, I compare the ultra-small form- factor WHDD’s ability to monitor synovitis and disease progression during a patient’s treatment of RA against the capabilities of a proven frequency domain optical tomographic (FDOT) system that has shown to differentiate patients with and without RA. Learning from clinical utility of the WHDD from these two studies, I adapted the WHDD technology to develop a compact multi- channel DOS measurement system to monitor perfusion changes in the lower extremities before and after surgical intervention for patients with peripheral artery disease (PAD). Using this multi- channel system, which we called the vascular optical spectroscopic measurement (VOSM) system, our group conducted a 20-subject pilot study to quantify its ability to monitor blood perfusion before and after revascularization of stenotic arteries in the lower extremities. This proof-of- concept study demonstrated how DOS may help vascular surgeons perform revascularization procedures in the operating room and assists in post-operative treatment monitoring of vascular diseases

Dynamic Digital Optical Tomography for Cancer Imaging and Therapy Monitoring

Diffuse optical tomography is a non-invasive imaging technique that uses near-infrared light to create three-dimensional images of tissue. This dissertation presents the design and validation of an instrument for rapid optical imaging using digital detection techniques. In addition to a detailed description of the instrument, three studies are presented: a clinical study detecting breast cancer using dynamic optical imaging; a pre-clinical study monitoring early tumor response to anti-angiogenic therapy; and a clinical study monitoring individual patient response to neoadjuvant chemotherapy. These studies show that diffuse optical tomography is a valuable imaging modality that can play an important role in cancer detection and treatment

Dynamic Hyperspectral and Polarized Endoscopic Imaging

The health of rich, developed nations has seen drastic improvement in the last two centuries. For it to continue improving at a similar rate new or improved diagnostic and treatment technologies are required, especially for those diseases such as cancer which are forecast to constitute the majority of disease burden in the future. Optical techniques such as microscopy have long played their part in the diagnostic process. However there are several new biophotonic modalities that aim to exploit various interactions between light and tissue to provide enhanced diagnostic information. Many of these show promise in a laboratory setting but few have progressed to a clinical setting. We have designed and constructed a flexible, multi-modal, multi-spectral laparoscopic imaging system that could be used to demonstrate several different techniques in a clinical setting. The core of this system is a dynamic hyperspectral illumination system based around a supercontinuum laser and Digital Micromirror Device that can provide specified excitation light in the visible and near infra-red ranges. This is a powerful tool for spectroscopic techniques as it is not limited to interrogating a fixed range of wavelengths and can switch between excitation bands instantaneously. The excitation spectra can be customised to match particular fluorophores or absorption features, introducing new possibilities for spectral imaging. A standard 10 mm diameter rigid endoscope was incorporated into the system to reduce cost and demonstrate compatibility with existing equipment. The polarization properties of two commercial endoscopes were characterised and found to be unsuited to current polarization imaging techniques as birefringent materials used in their construction introduce complex, spatially dependent transformations of the polarization state. Preliminary exemplar data from phantoms and ex vivo tissue was collected and the feasibility and accuracy of different analysis techniques demonstrated including multiple class classification algorithms. Finally, a novel visualisation method was implemented in order to display the complex hyperspectral data sets in a meaningful and intuitive way to the user

Miniaturized Optical Probes for Near Infrared Spectroscopy

RÉSUMÉ L’étude de la propagation de la lumière dans des milieux hautement diffus tels que les tissus biologiques (imagerie optique diffuse) est très attrayante, car elle offre la possibilité d’explorer de manière non invasive le milieu se trouvant profondément sous la surface, et de retrouver des informations sur l’absorption (liée à la composition chimique) et sur la diffusion (liée à la microstructure). Dans la gamme spectrale 600-1000 nm, également appelée gamme proche infrarouge (NIR en anglais), l'atténuation de la lumière par le tissu biologique (eau, lipides et hémoglobine) est relativement faible, ce qui permet une pénétration de plusieurs centimètres dans le tissu. En spectroscopie proche infrarouge (NIRS en anglais), de photons sont injectés dans les tissus et le signal émis portant des informations sur les constituants tissulaires est mesuré. La mesure de très faibles signaux dans la plage de longueurs d'ondes visibles et proche infrarouge avec une résolution temporelle de l'ordre de la picoseconde s'est révélée une technique efficace pour étudier des tissus biologiques en imagerie cérébrale fonctionnelle, en mammographie optique et en imagerie moléculaire, sans parler de l'imagerie de la durée de vie de fluorescence, la spectroscopie de corrélation de fluorescence, informations quantiques et bien d’autres. NIRS dans le domaine temporel (TD en anglais) utilise une source de lumière pulsée, généralement un laser fournissant des impulsions lumineuses d'une durée de quelques dizaines de picosecondes, ainsi qu'un appareil de détection avec une résolution temporelle inférieure à la nanoseconde. Le point essentiel de ces mesures est la nécessité d’augmenter la sensibilité pour de plus grandes profondeurs d’investigation, en particulier pour l’imagerie cérébrale fonctionnelle, où la peau, le crâne et le liquide céphalo-rachidien (LCR) masquent fortement le signal cérébral. À ce jour, l'adoption plus large de ces techniques optique non invasives de surveillance est surtout entravée par les composants traditionnels volumineux, coûteux, complexes et fragiles qui ont un impact significatif sur le coût et la dimension de l’ensemble du système. Notre objectif est de développer une sonde NIRS compacte et miniaturisée, qui peut être directement mise en contact avec l'échantillon testé pour obtenir une haute efficacité de détection des photons diffusés, sans avoir recours à des fibres et des lentilles encombrantes pour l'injection et la collection de la lumière. Le système proposé est composé de deux parties: i) une unité d’émission de lumière pulsée et ii) un module de détection à photon unique qui peut être activé et désactivé rapidement. L'unité d'émission de lumière utilisera une source laser pulsée à plus de 80 MHz avec une largeur d'impulsion de picoseconde.----------ABSTRACT The study of light propagation into highly diffusive media like biological tissues (Diffuse Optical Imaging) is highly appealing due to the possibility to explore the medium non-invasively, deep beneath the surface and to recover information both on absorption (related to chemical composition) and on scattering (related to microstructure). In the 600–1000 nm spectral range also known as near-infrared (NIR) range, light attenuation by the biological tissue constituents (i.e. water, lipid, and hemoglobin) is relatively low and allows for penetration through several centimeters of tissue. In near-infrared spectroscopy (NIRS), a light signal is injected into the tissues and the emitted signal carrying information on tissue constituents is measured. The measurement of very faint light signals in the visible and near-infrared wavelength range with picosecond timing resolution has proven to be an effective technique to study biological tissues in functional brain imaging, optical mammography and molecular imaging, not to mention fluorescence lifetime imaging, fluorescence correlation spectroscopy, quantum information and many others. Time Domain (TD) NIRS employs a pulsed light source, typically a laser providing light pulses with duration of a few tens of picoseconds, and a detection circuit with temporal resolution in the sub-nanosecond scale. The key point of these measurements is the need to increase the sensitivity to higher penetration depths of investigation, in particular for functional brain imaging, where skin, skull, and cerebrospinal fluid (CSF) heavily mask the brain signal. To date, the widespread adoption of the non-invasive optical monitoring techniques is mainly hampered by the traditional bulky, expensive, complex and fragile components which significantly impact the overall cost and dimension of the system. Our goal is the development of a miniaturized compact NIRS probe, that can be directly put in contact with the sample under test to obtain high diffused photon harvesting efficiency without the need for cumbersome optical fibers and lenses for light injection and collection. The proposed system is composed of two parts namely; i) pulsed light emission unit and ii) gated single-photon detection module. The light emission unit will employ a laser source pulsed at over 80MHz with picosecond pulse width generator embedded into the probe along with the light detection unit which comprises single-photon detectors integrated with other peripheral control circuitry. Short distance source and detector pairing, most preferably on a single chip has the potential to greatly expedites the traditional method of portable brain imaging

Blind Source Separation for the Processing of Contact-Less Biosignals

(Spatio-temporale) Blind Source Separation (BSS) eignet sich für die Verarbeitung von Multikanal-Messungen im Bereich der kontaktlosen Biosignalerfassung. Ziel der BSS ist dabei die Trennung von (z.B. kardialen) Nutzsignalen und Störsignalen typisch für die kontaktlosen Messtechniken. Das Potential der BSS kann praktisch nur ausgeschöpft werden, wenn (1) ein geeignetes BSS-Modell verwendet wird, welches der Komplexität der Multikanal-Messung gerecht wird und (2) die unbestimmte Permutation unter den BSS-Ausgangssignalen gelöst wird, d.h. das Nutzsignal praktisch automatisiert identifiziert werden kann. Die vorliegende Arbeit entwirft ein Framework, mit dessen Hilfe die Effizienz von BSS-Algorithmen im Kontext des kamera-basierten Photoplethysmogramms bewertet werden kann. Empfehlungen zur Auswahl bestimmter Algorithmen im Zusammenhang mit spezifischen Signal-Charakteristiken werden abgeleitet. Außerdem werden im Rahmen der Arbeit Konzepte für die automatisierte Kanalauswahl nach BSS im Bereich der kontaktlosen Messung des Elektrokardiogramms entwickelt und bewertet. Neuartige Algorithmen basierend auf Sparse Coding erwiesen sich dabei als besonders effizient im Vergleich zu Standard-Methoden.(Spatio-temporal) Blind Source Separation (BSS) provides a large potential to process distorted multichannel biosignal measurements in the context of novel contact-less recording techniques for separating distortions from the cardiac signal of interest. This potential can only be practically utilized (1) if a BSS model is applied that matches the complexity of the measurement, i.e. the signal mixture and (2) if permutation indeterminacy is solved among the BSS output components, i.e the component of interest can be practically selected. The present work, first, designs a framework to assess the efficacy of BSS algorithms in the context of the camera-based photoplethysmogram (cbPPG) and characterizes multiple BSS algorithms, accordingly. Algorithm selection recommendations for certain mixture characteristics are derived. Second, the present work develops and evaluates concepts to solve permutation indeterminacy for BSS outputs of contact-less electrocardiogram (ECG) recordings. The novel approach based on sparse coding is shown to outperform the existing concepts of higher order moments and frequency-domain features

Cumulative index to NASA Tech Briefs, 1986-1990, volumes 10-14

Tech Briefs are short announcements of new technology derived from the R&D activities of the National Aeronautics and Space Administration. These briefs emphasize information considered likely to be transferrable across industrial, regional, or disciplinary lines and are issued to encourage commercial application. This cumulative index of Tech Briefs contains abstracts and four indexes (subject, personal author, originating center, and Tech Brief number) and covers the period 1986 to 1990. The abstract section is organized by the following subject categories: electronic components and circuits, electronic systems, physical sciences, materials, computer programs, life sciences, mechanics, machinery, fabrication technology, and mathematics and information sciences

Concepts and Approaches for Mars Exploration

Abstracts describe missions, mission elements or experiments for consideration in the 2005-2020 time frame. Also the technologies and the support necessary to achieve the results are discussed.NASA Headquarters; Lunar and Planetary Institutehosted by Lunar and Planetary Institute ; sponsored by NASA Headquarters, Lunar and Planetary Institute ; convener Scott Hubbard