Environmental enteric dysfunction (EED) is a pathological condition of the small intestine that is endemic to low- and middle-income countries (LMICs). EED is thought to interfere with nutrient absorption and enteropathogen exclusion, resulting in altered immune response, increased infection, and limited neurological and physical development. Biopsy of the small intestine is the current diagnostic gold standard for diagnosis yet is untenable due to lack of availability in these countries. Endoscopic biopsy is further problematic since EED-related stunting can only be reversed if diagnosed in the first two years of life when endoscopy must be conducted under anesthesia in advanced medical care settings. Thus, there is an unmet need for a minimally invasive technology for obtaining small intestinal biopsies in unsedated infants in LMICs. To address this need, we have developed an OCT image-guided trans-nasal cryobiopsy device. The device comprises a dual-lumen 1.2 mm outer diameter (OD) probe, terminated by a metal tip, through which Freon is injected. The device is introduced through the lumen of a novel liquid-metal transnasal imaging tube that passively transits to the small intestine. M-mode OCT image guidance is used to determine when the metal tip is in contact with the mucosa so that cryobiopsies may be efficiently acquired. We have conducted feasibility experiments using this device in 10 swine in vivo, demonstrating residual bleeding that is comparable to conventional excisional biopsy, tissue sampling volumes that are greater than or equal to those of conventional biopsy, and high-quality histopathology. These results suggest that this transnasal cryobiopsy technique may be suitable for infants in low-resource settings where EED is prevalent, due to its simplicity and its ability to be used in unsedated subjects.
Prior research in photoacoustic tomography has consistently demonstrated its ability to image structures near the surface of tissue with a high degree of optical contrast. However, despite significant advancements in the field, there has been little to no development of clinical applications for photoacoustic tomography, principally due to the requirement for backwardmode operation, i.e., it must detect the photoacoustic signal on the same side of the tissue as the incident laser light. This results in the standard ultrasonic transducer occluding the path of the inciting laser beam. Therefore, developing a technique to deliver light into the tissue, while incorporating commonly available ultrasonic detection equipment without occluding the beam propagation or modifying the equipment in any way, would provide a significant benefit to the field, and potentially improve its clinical applicability. Here, we propose a new method to accomplish this aim, using planar optical waveguides that employ the optical tunneling phenomenon to transmit light directly into tissue (pig skin) through physical contact with the sample. A commercially available, 10MHz, unfocused ultrasonic transducer was positioned on the rear face of the waveguide and was used to detect photoacoustic signals generated within the tissue as the signals propagated perpendicularly through the waveguide substrate. Unlike alternative solutions to the occlusion problem, this modality does not necessitate the use of custom manufactured transducers, expensive dichroics, or additional laser systems, and thereby represents a viable approach for the easy implementation of photoacoustic tomography in a clinical setting.
Lasers have demonstrated widespread applicability in clinical dermatology as minimally invasive instruments that achieve photogenerated responses within tissue. However, before reaching its target, the incident light must first transmit through the surface layer of tissue, which is interspersed with chromophores (e.g. melanin) that preferentially absorb the light and may also generate negative tissue responses. These optical absorbers decrease the efficacy of the procedures. In order to ensure that the target receives a clinically relevant dose, most procedures simply increase the incident energy; however, this tends to exacerbate the negative complications of melanin absorption. Here, we present an alternative solution aimed at increasing epidermal energy uence while mitigating excess absorption by unintended targets. Our technique involves the combination of a waveguide-based contact transmission modality with simultaneous high-frequency ultrasonic pulsation, which alters the optical properties of the tissue through the agglomeration of dissolved gasses into micro-bubbles within the tissue. Doing so effectively creates optically transparent pathways for the light to transmit unobstructed through the tissue, resulting in an increase in forward scattering and a decrease in absorption. To demonstrate this, Q-switched nanosecond-pulsed laser light at 532nm was delivered into pig skin samples using custom glass waveguides clad in titanium and silver. Light transmission through the tissue was measured with a photodiode and integrating sphere for tissue with and without continuous ultrasonic pulsation at 510 kHz. The combination of these techniques has the potential to improve the efficiency of laser procedures while mitigating negative tissue effects caused by undesirable absorption.