Light in diagnosis, therapy and surgery

Abstract

Light and optical techniques have made profound impacts on modern medicine, with numerous lasers and optical devices being currently used in clinical practice to assess health and treat disease. Recent advances in biomedical optics have enabled increasingly sophisticated technologies - in particular those that integrate photonics with nanotechnology, biomaterials and genetic engineering. In this Review, we revisit the fundamentals of light-matter interactions, describe the applications of light in imaging, diagnosis, therapy and surgery, overview their clinical use, and discuss the promise of emerging light-based technologies.

Figure 1

Light–tissue interactions. a, Representative optical mechanisms used in diagnosis and imaging (left), and surgery and therapy (right). Circular objects denote incoming and outgoing photons, with their trajectories indicated by solid and dotted lines with arrowheads. Circle colours represent the spectrum of the light; dotted circles indicate the absorption of input photons. For the case of therapy, specific effects of light on tissue and cells are indicated. b, Optical techniques mapped according to their optical fluence and exposure time (either total illumination time for cw light, or pulse duration for pulses). Background colours represent medical areas: green for diagnostics, magenta for surgery, and cyanine for therapy. MPE, maximum permissible exposure.

Figure 2

Medical application areas of light. a, Representative applications of light in the human body for diagnosis and imaging (green), surgery (magenta) and therapy (cyanine). b, Global market in 2014 for medical lasers by therapeutic application. Photosensitizer drugs are included as part of the PDT market. c, Equipment spending in 2013 for leading laser-treatment procedures. d, Global market in 2013–2014 for several major diagnostic devices. Data sources: BCC Research reports HLC093C, HLC072C, and HLC172A (with permission of BCC Research, Wesley, MA, USA).

Figure 3

Surgical and therapeutic applications of light. a, Photoablation. The scanning electron micrograph shows stepwise ablated patterns (arrows) in an experimental cornea by excimer laser irradiation. b, Photocoagulation. Laser-induced damage spots around a retinal tear region (dashed-line circle). c, Photothermal ablation. Histology of porcine skin tissues harvested 0 min (left) and 60 min (right) after fractional, pulsed CO₂ laser exposure in vivo. The arrow indicates the laser channel, which is filled with fibrin plug within minutes. d, Photothermal ablation (vaporization). A fibre-optic catheter delivers high-power continuous-wave laser (arrow) to remove excess prostate tissue in a patient with benign prostate hyperplasia [from Feldman, RG. Prostata laser verde green light. www.youtube.com/watch?v=jAbSwtSN9xE. License at http://creativecommons.org/license/by/3.0]. e, Blue-light therapy for the treatment of neonatal jaundice. f, Photodynamic therapy. Close-up image of a surgeon’s hands in an operating room. Panel e reproduced with permission from Photobiological Sciences Online. Panel f courtesy of the National Cancer Institute.

Figure 4

Current and emerging optical imaging. Top row, Established microscopy and endoscopy in routine clinical use. Immunohistochemistry shows c-Met expression in an adenomatous polyp. Laparoscopy visualizes the peritoneal cavity for minimally invasive surgery. Endoscopy reveals a mucosal lesion (arrow) in gastric body. Colonoscopy shows a large, 3-cm sigmoid polyp (arrow). Otoscopy visualizes the eardrum and middle ear. Ophthalmoscopy fundus camera image of the human retina. Optical coherence tomography (OCT) allows microscopic cross-sectional imaging of the retina. Middle row, Imaging technologies currently in clinical adoption phases. Diffuse optical tomography (DOT) shows oxygen saturation map for a breast with a 2.5-cm malignant tumor (arrow). Speckle contrast image reveals meningeal artery (arrow) in the cortex and dura. Fluorescence image shows colorectal polyps labelled with fluorescent peptides. Fluorescence angiography shows loss of blood perfusion (arrow) in the foot. Catheter OCT shows plaque rupture in a human coronary artery, identified by a broken fibrous cap (arrow). Confocal laser endomicroscopy shows intramucosal bacteria (bright spots, inset) in the small intestine of a patient with ulcerative colitis. Reflectance confocal microscopy shows an aggregate of neoplastic cells appearing as a focus of bright nuclei in the dermal–epidermal junction. Bottom row, Technologies under development or in clinical testing. Microscopy of optically cleared thick-tissue blocks holds promise for the high-content mapping and phenotyping of normal and pathological tissue samples. Functional connectivity maps of three sensory-motor networks generated with high-density DOT and fMRI (ref ). Intraoperative imaging of gliomas under white-light and fluorescence imaging with 5-aminolevulinic acid. Multimodal (OCT plus fluorescence) image shows a three-dimensional rendering of the stented right iliac artery of a living rabbit. Red, artery wall; white, stent; purple, thrombus; yellow, NIR fluorescent fibrin. Photoacoustic image of oxygen saturation of haemoglobin (sO₂) in the murine brain vasculature. Clinically viable stimulated Raman microscopy shows hypercellularity and nuclear atypia of tumour, in correspondence with conventional H&E microscopy. Brillouin microscopy shows a longitudinal modulus map of the cornea in a keratoconus patient. DOT image in the middle row courtesy of Qianqian Fang at Massachusetts General Hospital.

Figure 5

Various implantable photonic devices at the proof-of-concept stage. a, Nanoparticles for drug delivery and treatment monitoring. Left, Light-activated drug release. Right, photothermal-polymer-coated gold nanocages. b, Nanorobots. Left, Transmission electron microscope image of an aptamer-gated DNA nanorobot capable of transporting 5-nm gold nanoparticles (black dots) to cells. Right, Light-controllable microrobot with nanoscale phototactic machinery. c, Optogenetic devices. Left, Optical pattern illuminated on cultured neuronal cells. Right, Miniaturized, wireless, soft optoelectronic systems implanted in the spinal cord for performing optogenetics. d, Wearables. Top, Thermo-chromic liquid-crystal-based temperature imaging device on the skin. Bottom, Epidermal optoelectronic device powered by, and communicating with, a smartphone. e, Microprobes. Left, Multifunctional, implantable optoelectronic device with LEDs and microelectrodes. Middle, optoelectronic drug-delivery probe. Right, multifunctional endoscope system based on transparent bioelectronic sensors and theranostic nanoparticles. f, Vision prosthetics. Retinal prosthetic system using a head-mounted camera and a goggle, which projects NIR (880–915 nm) images to photodiode arrays implanted in the retina. g, Wirelessly-powered, subcutaneously implanted LED in a mouse. h, Biomaterial devices. Left, biodegradable polymer waveguide implanted in tissue for efficient light delivery. Right, Fibre-pigtailed hydrogel waveguide implanted in a freely moving mouse for sensing and therapy. i, Human cell containing an intracellular fluorescent-bead laser (green).