Thomas D. O'Sullivan

Photodynamic therapy (PDT) is a promising treatment for triple-negative breast cancer (TNBC), but clinical translation is limited by poor light penetration into deep-seated tumors. This study employed a miniature wireless implantable light-emitting device (WILD) for localized red-light activation of PDT after oral administration of the clinical drug 5-aminolevulinic acid (5-ALA). Cancer cell studies showed that WILD-mediated 5-ALA PDT induced phototoxicity and production of immunogenic cell death (ICD) biomarkers. Studies using a mouse model of TNBC revealed that WILD-mediated 5-ALA PDT reduced total tumor burden, with evidence suggesting immune activation. These findings support the feasibility of WILD-mediated 5-ALA PDT for treating deep-seated solid tumors.

The use of noninvasive near-infrared spectroscopy (NIRS) has grown significantly over the past few decades for use in the characterization of tissue optical properties and derived physiological parameters such as tissue oxygen saturation and hemoglobin composition to support human health and wellness. Wearable NIRS devices have been developed in recent years that enable real-time continuous monitoring. These devices have been enabled by advances in the dense integration of miniature integrated circuits, light sources and detectors, embedded processing, and wireless technologies. The most attractive aspect of wearable NIRS devices is that they enable real-time sensing both inside and outside of laboratory and clinical settings. This review paper focuses on recent hardware developments related to fully integrated wearable NIRS devices, including continuous wave (CW), time domain (TD), and frequency domain (FD) NIRS techniques, and their enabling technologies. We also review their application in biomedical fields such as neuroscience, musculoskeletal physiology, and others. We provide our perspective on the future technology research opportunities and direction of the field.

Frequency-domain near-infrared spectroscopy (FD-NIRS) is a noninvasive in vivo sensing and imaging technique that is used to quantify tissue composition and oxygen metabolism in the brain, muscle, and other tissues. However, the size and complexity of FD-NIRS instrumentation have largely limited its use to laboratory and clinical research settings. To expand the use of FD-NIRS into continuous monitoring applications and in naturalistic environments, we report a novel real-time multi-frequency (50–350 MHz) wearable FD-NIRS system based on a custom application-specific integrated circuit (ASIC). The wearable device includes 685 nm and 850 nm laser diodes and a silicon photomultiplier (SiPM) detector. The system has an optical property accuracy of 0.0007 mm ⁻¹ for absorption and 0.08 mm ⁻¹ for reduced scattering at a 14.7 Hz measurement rate, evaluated using tissue-simulating phantoms, and is capable of capturing single-frequency measurements up to 1 kHz with both wavelengths. Without a battery, it weighs 37 grams and measures less than 7 x 3 x 3 cm in size. For proof-of-concept, we demonstrate measurement of an arteriovenous occlusion of the human forearm. Overall, this work demonstrates the feasibility of quantitative FD-NIRS tissue optical spectroscopy for wearable health monitoring.

We present a preclinical study that demonstrates that deep photodynamic therapy using a minimally-invasive wireless light-emitting implant with orally-administered 5-ALA can reduce tumor volume in an aggressive triple-negative model of breast cancer.

Light‐mediated healthcare has several very attractive features, including minimally invasive administration, reduced possibility of side effects, and potential for patient‐specific treatment. However, the shallow penetration of light into skin and tissue is an inherent physical limitation that restricts the use of phototherapy to superficial sites of disease. To mitigate this major problem, researchers and clinicians are developing miniature light devices that can be implanted at strategic deep‐tissue locations within a living subject. The work is leveraged by emerging new classes of light‐absorbing drugs and light‐activated drug delivery methods. This Perspective summarizes the major concepts and recent technical advances in this interdisciplinary subfield of advanced phototherapeutics. Fundamental factors are described, such as the wavelength dependence of light penetration and scattering through tissue, and the required power levels for the desired phototherapeutic effect. The implanted devices can be powered by an attached wire or otherwise powered wirelessly, and each approach has its own engineering challenges to produce desired performance features. A forward‐looking conclusion section envisions future phototherapies that use implanted miniature light devices with the capacity to deliver phototherapy and monitor therapeutic response using sensors that provide immediate feedback and dose control.

Diffuse optical tomography (DOT) performed using deep-learning allows high-speed reconstruction of tissue optical properties and could thereby enable image-guided scanning, e.g., to enhance clinical breast imaging. Previously published models are geometry-specific and, therefore, require extensive data generation and training for each use case, restricting the scanning protocol at the point of use. A transformer-based architecture is proposed to overcome these obstacles that encode spatially unstructured DOT measurements, enabling a single trained model to handle arbitrary scanning pathways and measurement density. The model is demonstrated with breast tissue-emulating simulated and phantom data, yielding - for 24 mm-deep absorptions (μ _a ) and reduced scattering (μ _s ′) images, respectively - average RMSEs of 0.0095±0.0023 cm⁻¹ and 1.95±0.78 cm⁻¹, Sørensen-Dice coefficients of 0.55±0.12 and 0.67±0.1, and anomaly contrast of 79±10% and 93.3±4.6% of the ground-truth contrast, with an effective imaging speed of 14 Hz. The average absolute μ _a and μ _s ′ values of homogeneous simulated examples were within 10% of the true values.

The goal of this prospective clinical study was to determine if quantitative broadband (600-1000nm) diffuse optical spectroscopy (DOS) can differentiate suspicious benign and malignant breast lesions and compare various optical biomarkers. To accomplish this goal, N=68 subjects were measured using a custom probe-based hybrid broadband continuous-wave and frequency domain diffuse optical spectroscopic imaging device. Lesion concentrations of oxyhemoglobin, deoxyhemoglobin, methemoglobin, water, lipid, fat, and collagen were estimated from tissue optical absorption. We found that absolute concentrations of collagen were significantly elevated (p=0.037) in malignant lesions versus normal tissue, while elevated methemoglobin approached significance (p=0.058). In addition, elevated water concentrations were a significant differentiator (p=0.039) of malignant versus benign lesions when applying Zscore normalization and a previously published model of malignancy probability.

The design and evaluation of an integrated circuit (IC) that provides gain and phase measurements for a broad modulation bandwidth frequency-domain near-infrared spectroscopy (fd-NIRS) system is described. This circuit includes a voltage-controlled oscillator (VCO) that provides modulating frequencies from 50 MHz up to 1 GHz, as well as analog measurements of amplitude and phase. The phase detector is based on an N-path filter and allows for accurate phase measurement. The IC works with a laser diode and an avalanche photodiode (APD) to implement a complete fd-NIRS spectroscopy system. The IC-based system was used to characterize tissue-simulating phantoms with varying absorption and reduced scattering properties with modulation frequencies of 105-405 MHz with the upper frequency limited by the APD used in the system. Mean optical property accuracy was within 0.00064 and ${0.054}~\text {mm}^{-{1}}$ for absorption and reduced scattering, respectively, compared to a reference system. These results show a promising path toward scalable and wearable optical sensing systems based on fd-NIRS.

Welcome to the 2024 Feature Issue on Diffuse Optical Spectroscopy: Technology and Applications in Biomedical Optics Express! This feature issue provides an exemplary sample of established and emerging DOS technologies as well as their biomedical applications through 27 contributed research papers and 1 invited review article. DOS researchers are inherently multidisciplinary, advancing topics spanning the basic theory of light-tissue interactions, computational modeling, technique and system development and preclinical and clinical applications. You will find this full range of topics represented in this feature issue.

Achieving negative surgical margins, defined as no tumor found on the edges of the resected tissue, during lumpectomy for breast cancer is critical for mitigating the risk of local recurrence. To identify nonpalpable tumors that cannot be felt, pre-operative placements of wire and wire-free localization devices are typically employed. Wire-free localization approaches have significant practical advantages over wired techniques. In this study, we introduce an innovative localization system comprising a light-emitting diode (LED)-based implantable device and handheld system. The device, which is needle injectable and wire free, utilizes multiple wirelessly powered LEDs to provide direct visual guidance for lumpectomy. Two distinct colors, red and blue, provide a clear indication of tissue depth: blue light is absorbed strongly in tissue, visible within a close range of 2 cm of ex vivo chicken breast and bovine muscle tissue using less than 4 W of transmitted power from a handheld antenna. These miniaturized needle-injectable localization devices show promise for improving surgical guidance of nonpalpable breast tumors.