Ultrasound mediated delivery of quantum dots from a proof of concept capsule endoscope to the gastrointestinal wall.

Biologic drugs, defined as therapeutic agents produced from or containing components of a living organism, are of growing importance to the pharmaceutical industry. Though oral delivery of medicine is convenient, biologics require invasive injections because of their poor bioavailability via oral routes. Delivery of biologics to the small intestine using electronic delivery with devices that are similar to capsule endoscopes is a promising means of overcoming this limitation and does not require reformulation of the therapeutic agent. The efficacy of such capsule devices for drug delivery could be further improved by increasing the permeability of the intestinal tract lining with an integrated ultrasound transducer to increase uptake. This paper describes a novel proof of concept capsule device capable of electronic application of focused ultrasound and delivery of therapeutic agents. Fluorescent markers, which were chosen as a model drug, were used to demonstrate in vivo delivery in the porcine small intestine with this capsule. We show that the fluorescent markers can penetrate the mucus layer of the small intestine at low acoustic powers when combining microbubbles with focused ultrasound during in vivo experiments using porcine models. This study illustrates how such a device could be potentially used for gastrointestinal drug delivery and the challenges to be overcome before focused ultrasound and microbubbles could be used with this device for the oral delivery of biologic therapeutics.

Ultrasound Capsule Endoscopy With a Mechanically Scanning Micro-ultrasound: A Porcine Study.

Wireless capsule endoscopy has been used for the clinical examination of the gastrointestinal (GI) tract for two decades. However, most commercially available devices only utilise optical imaging to examine the GI wall surface. Using this sensing modality, pathology within the GI wall cannot be detected. Micro-ultrasound (µUS) using high-frequency (>20 MHz) ultrasound can provide a means of transmural or cross-sectional image of the GI tract. Depth of imaging is approximately 10 mm with a resolution of between 40-120 µm that is sufficient to differentiate between subsurface histologic layers of the various regions of the GI tract. Ultrasound capsule endoscopy (USCE) uses a capsule equipped with µUS transducers that are capable of imaging below the GI wall surface, offering thereby a complementary sensing technique to optical imaging capsule endoscopy. In this work, a USCE device integrated with a ∼30 MHz ultrasonic transducer was developed to capture a full 360° image of the lumen. The performance of the device was initially evaluated using a wire phantom, indicating an axial resolution of 69.0 µm and lateral resolution of 262.5 µm. Later, in vivo imaging performance was characterised in the oesophagus and small intestine of anaesthetized pigs. The reconstructed images demonstrate clear layer differentiation of the lumen wall. The tissue thicknesses measured from the B-scan images show good agreement with ex vivo images from the literature. The high-resolution ultrasound images in the in vivo porcine model achieved with this device is an encouraging preliminary step in the translation of these devices toward future clinical use.

Intelligent magnetic manipulation for gastrointestinal ultrasound.

Diagnostic endoscopy in the gastrointestinal tract has remained largely unchanged for decades and is limited to the visualization of the tissue surface, the collection of biopsy samples for diagnoses, and minor interventions such as clipping or tissue removal. In this work, we present the autonomous servoing of a magnetic capsule robot for in-situ, subsurface diagnostics of microanatomy. We investigated and showed the feasibility of closed-loop magnetic control using digitized microultrasound (µUS) feedback; this is crucial for obtaining robust imaging in an unknown and unconstrained environment. We demonstrated the functionality of an autonomous servoing algorithm that uses µUS feedback, both on benchtop trials as well as in-vivo in a porcine model. We have validated this magnetic-µUS servoing in instances of autonomous linear probe motion and were able to locate markers in an agar phantom with 1.0 ± 0.9 mm position accuracy using a fusion of robot localization and µUS image information. This work demonstrates the feasibility of closed-loop robotic µUS imaging in the bowel without the need for either a rigid physical link between the transducer and extracorporeal tools or complex manual manipulation.

Gastrointestinal diagnosis using non-white light imaging capsule endoscopy.

Capsule endoscopy (CE) has proved to be a powerful tool in the diagnosis and management of small bowel disorders since its introduction in 2001. However, white light imaging (WLI) is the principal technology used in clinical CE at present, and therefore, CE is limited to mucosal inspection, with diagnosis remaining reliant on visible manifestations of disease. The introduction of WLI CE has motivated a wide range of research to improve its diagnostic capabilities through integration with other sensing modalities. These developments have the potential to overcome the limitations of WLI through enhanced detection of subtle mucosal microlesions and submucosal and/or transmural pathology, providing novel diagnostic avenues. Other research aims to utilize a range of sensors to measure physiological parameters or to discover new biomarkers to improve the sensitivity, specificity and thus the clinical utility of CE. This multidisciplinary Review summarizes research into non-WLI CE devices by organizing them into a taxonomic structure on the basis of their sensing modality. The potential of these capsules to realize clinically useful virtual biopsy and computer-aided diagnosis (CADx) is also reported.

Design and Simulation of a Ring-Shaped Linear Array for Microultrasound Capsule Endoscopy.

Video capsule endoscopy (VCE) has significantly advanced visualization of the gastrointestinal tract since its introduction in the last 20 years. Work is now under way to combine VCE with microultrasound imaging. However, small maximum capsule dimensions, coupled with the electronics required to integrate ultrasound imaging capabilities, pose significant design challenges. This paper describes a simulation process for testing transducer geometries and imaging methodologies to achieve satisfactory imaging performance within the physical limitations of the capsule size and outlines many of the tradeoffs needed in the design of this new class of ultrasound capsule endoscopy (USCE) device. A hybrid MATLAB model is described, incorporating Krimholtz-Leedom-Matthaei circuit elements and digitizing and beamforming elements to render a gray-scale B-mode. This model is combined with a model of acoustic propagation to generate images of point scatterers. The models are used to demonstrate the performance of a USCE transducer configuration comprising a single, unfocused transmit ring of radius 5 mm separated into eight segments for electrical impedance control and a 512-element receive linear array, also formed into a ring. The MATLAB model includes an ultrasonic pulser circuit connected to a piezocrystal composite transmit transducer with a center frequency of 25 MHz. B-scan images are simulated for wire target phantoms, multilayered phantoms, and a gut wall model. To demonstrate the USCE system's ability to image tissue, a digital phantom was created from single-element ultrasonic transducer scans of porcine small bowel ex vivo obtained at a frequency of 45 MHz.

In Vivo Characterization of a Wireless Telemetry Module for a Capsule Endoscopy System Utilizing a Conformal Antenna.

This paper describes the design, fabrication, packaging, and performance characterization of a conformal helix antenna created on the outside of a capsule endoscope designed to operate at a carrier frequency of 433 MHz within human tissue. Wireless data transfer was established between the integrated capsule system and an external receiver. The telemetry system was tested within a tissue phantom and in vivo porcine models. Two different types of transmission modes were tested. The first mode, replicating normal operating conditions, used data packets at a steady power level of 0 dBm, while the capsule was being withdrawn at a steady rate from the small intestine. The second mode, replicating the worst-case clinical scenario of capsule retention within the small bowel, sent data with stepwise increasing power levels of -10, 0, 6, and 10 dBm, with the capsule fixed in position. The temperature of the tissue surrounding the external antenna was monitored at all times using thermistors embedded within the capsule shell to observe potential safety issues. The recorded data showed, for both modes of operation, a low error transmission of 10-3 packet error rate and 10-5 bit error rate and no temperature increase of the tissue according to IEEE standards.

Acoustic Sensing and Ultrasonic Drug Delivery in Multimodal Theranostic Capsule Endoscopy.

Video capsule endoscopy (VCE) is now a clinically accepted diagnostic modality in which miniaturized technology, an on-board power supply and wireless telemetry stand as technological foundations for other capsule endoscopy (CE) devices. However, VCE does not provide therapeutic functionality, and research towards therapeutic CE (TCE) has been limited. In this paper, a route towards viable TCE is proposed, based on multiple CE devices including important acoustic sensing and drug delivery components. In this approach, an initial multimodal diagnostic device with high-frequency quantitative microultrasound that complements video imaging allows surface and subsurface visualization and computer-assisted diagnosis. Using focused ultrasound (US) to mark sites of pathology with exogenous fluorescent agents permits follow-up with another device to provide therapy. This is based on an US-mediated targeted drug delivery system with fluorescence imaging guidance. An additional device may then be utilized for treatment verification and monitoring, exploiting the minimally invasive nature of CE. While such a theranostic patient pathway for gastrointestinal treatment is presently incomplete, the description in this paper of previous research and work under way to realize further components for the proposed pathway suggests it is feasible and provides a framework around which to structure further work.

Ultrasound capsule endoscopy: sounding out the future.

Video capsule endoscopy (VCE) has been of immense benefit in the diagnosis and management of gastrointestinal (GI) disorders since its introduction in 2001. However, it suffers from a number of well recognized deficiencies. Amongst these is the limited capability of white light imaging, which is restricted to analysis of the mucosal surface. Current capsule endoscopes are dependent on visual manifestation of disease and limited in regards to transmural imaging and detection of deeper pathology. Ultrasound capsule endoscopy (USCE) has the potential to overcome surface only imaging and provide transmural scans of the GI tract. The integration of high frequency microultrasound (µUS) into capsule endoscopy would allow high resolution transmural images and provide a means of both qualitative and quantitative assessment of the bowel wall. Quantitative ultrasound (QUS) can provide data in an objective and measurable manner, potentially reducing lengthy interpretation times by incorporation into an automated diagnostic process. The research described here is focused on the development of USCE and other complementary diagnostic and therapeutic modalities. Presently investigations have entered a preclinical phase with laboratory investigations running concurrently.

High Resolution Microultrasound (µUS) Investigation of the Gastrointestinal (GI) Tract.

High resolution, microultrasound (µUS) scanning of the gastrointestinal (GI) tract has potential as an important transmural imaging modality to aid in diagnosis. Operating at higher frequencies than conventional clinical ultrasound instruments, µUS is capable of providing scanned images of the GI tract with higher resolution. To investigate the use of µUS for this application, a phantom which is cost effective, within ethical guidelines and, most importantly, similar in histology to the human GI tract is necessary. Therefore, a phantom utilizing porcine small bowel tissue has been developed for custom assembled µUS scanning systems. Two such systems, a stepping scanner and a continuous sweep scanner were utilized to repeatedly scan regions of prepared samples of porcine small bowel tissue. The porcine small bowel tissue phantom was perfused with degassed phosphate buffer saline (dPBS) solution through a cannula inserted in its mesenteric vessel to simulate in vivo conditions and achieve better µUS mucosal characterization. The µUS system scans a transducer across the tissue phantom to acquire RF echo data, which is then processed using MATLAB. A B-scan reconstruction produces 2D images with relative echo strength mapped to a color map of the user's choice. The phantom developed also allows for modifications such as the insertion of fiducial markers to detect tissue change over time and simultaneous perfusion and scanning, providing a platform for more detailed research and investigation into µUS scanning of the GI tract.

Comparative ergonomic workflow and user experience analysis of MRI versus fluoroscopy-guided vascular interventions: an iliac angioplasty exemplar case study.

PURPOSE: A methodological framework is introduced to assess and compare a conventional fluoroscopy protocol for peripheral angioplasty with a new magnetic resonant imaging (MRI)-guided protocol. Different scenarios were considered during interventions on a perfused arterial phantom with regard to time-based and cognitive task analysis, user experience and ergonomics. METHODS: Three clinicians with different expertise performed a total of 43 simulated common iliac angioplasties (9 fluoroscopic, 34 MRI-guided) in two blocks of sessions. Six different configurations for MRI guidance were tested in the first block. Four of them were evaluated in the second block and compared to the fluoroscopy protocol. Relevant stages' durations were collected, and interventions were audio-visually recorded from different perspectives. A cued retrospective protocol analysis (CRPA) was undertaken, including personal interviews. In addition, ergonomic constraints in the MRI suite were evaluated. RESULTS: Significant differences were found when comparing the performance between MRI configurations versus fluoroscopy. Two configurations [with times of 8.56 (0.64) and 9.48 (1.13) min] led to reduce procedure time for MRI guidance, comparable to fluoroscopy [8.49 (0.75) min]. The CRPA pointed out the main influential factors for clinical procedure performance. The ergonomic analysis quantified musculoskeletal risks for interventional radiologists when utilising MRI. Several alternatives were suggested to prevent potential low-back injuries. CONCLUSIONS: This work presents a step towards the implementation of efficient operational protocols for MRI-guided procedures based on an integral and multidisciplinary framework, applicable to the assessment of current vascular protocols. The use of first-user perspective raises the possibility of establishing new forms of clinical training and education.

Preclinical feasibility of a technology framework for MRI-guided iliac angioplasty.

PURPOSE: Interventional MRI has significant potential for image guidance of iliac angioplasty and related vascular procedures. A technology framework with in-room image display, control, communication and MRI-guided intervention techniques was designed and tested for its potential to provide safe, fast and efficient MRI-guided angioplasty of the iliac arteries. METHODS: A 1.5-T MRI scanner was adapted for interactive imaging during endovascular procedures using new or modified interventional devices such as guidewires and catheters. A perfused vascular phantom was used for testing. Pre-, intra- and post-procedural visualization and measurement of vascular morphology and flow was implemented. A detailed analysis of X-ray fluoroscopic angiography workflow was conducted and applied. Two interventional radiologists and one physician in training performed 39 procedures. All procedures were timed and analyzed. RESULTS: MRI-guided iliac angioplasty procedures were successfully performed with progressive adaptation of techniques and workflow. The workflow, setup and protocol enabled a reduction in table time for a dedicated MRI-guided procedure to 6 min 33 s with a mean procedure time of 9 min 2 s, comparable to the mean procedure time of 8 min 42 s for the standard X-ray-guided procedure. CONCLUSIONS: MRI-guided iliac vascular interventions were found to be feasible and practical using this framework and optimized workflow. In particular, the real-time flow analysis was found to be helpful for pre- and post-interventional assessments. Design optimization of the catheters and in vivo experiments are required before clinical evaluation.

Wireless mobile technology to improve workflow and feasibility of MR-guided percutaneous interventions.

PURPOSE: A wireless interactive display and control device combined with a platform-independent web-based user interface (UI) was developed to improve the workflow for interventional magnetic resonance imaging (iMRI). METHODS: The iMRI-UI enables image acquisition of up to three independent slices using various pulse sequences with different contrast weighting. Pulse sequence, scan geometry and related parameters can be changed on the fly via the iMRI-UI using a tablet computer for improved lesion detection and interventional device targeting. The iMRI-UI was validated for core biopsies with a liver phantom ([Formula: see text] [Formula: see text] 40) and Thiel soft-embalmed human cadavers ([Formula: see text] [Formula: see text] 24) in a clinical 1.5T MRI scanner. RESULTS: The iMRI-UI components and setup were tested and found conditionally MRI-safe to use according to current ASTM standards. Despite minor temporary touch screen interference at a close distance to the bore ([Formula: see text]20 cm), no other issues regarding quality or imaging artefacts were observed. The 3D root-mean-square distance error was [Formula: see text] (phantom)/[Formula: see text] mm (cadaver), and overall procedure times ranged between 12 and 22 (phantom)/20 and 55 min (cadaver). CONCLUSION: The wireless iMRI-UI control setup enabled fast and accurate interventional biopsy needle placements along complex trajectories and improved the workflow for percutaneous interventions under MRI guidance in a preclinical trial.

Wireless MR tracking of interventional devices using phase-field dithering and projection reconstruction.

PURPOSE: Device tracking is crucial for interventional MRI (iMRI) because conventional device materials do not contribute to the MR signal, may cause susceptibility artifacts and are generally invisible if moved out of the scan plane. A robust method for wireless tracking and dynamic guidance of interventional devices equipped with wirelessly connected resonant circuits (wRC) is presented. METHODS: The proposed method uses weak spatially-selective excitation pulses with very low flip angle (0.3°), a Hadamard multiplexed tracking scheme and employs phase-field dithering to obtain the 3D position of a wRC. RF induced heating experiments (ASTM protocol) and balloon angioplasties of the iliac artery were conducted in a perfused vascular phantom and three Thiel soft-embalmed human cadavers. RESULTS: Device tip tracking was interleaved with various user-selectable fast pulse sequences receiving a geometry update from the tracking kernel in less than 30ms. Integrating phase-field dithering significantly improved our tracking robustness for catheters with small diameters (4-6 French). The volume root mean square distance error was 2.81mm (standard deviation: 1.31mm). No significant RF induced heating (<0.6°C) was detected during heating experiments. CONCLUSION: This tip tracking approach provides flexible, fast and robust feedback loop, intuitive iMRI scanner interaction, does not constrain the physician and delivers very low specific absorption rates. Devices with wRC can be exchanged during a procedure without modifications to the iMRI setup or the pulse sequence. A drawback of our current implementation is that position information is available for a single tracking coil only. This was satisfactory for balloon angioplasties of the iliac artery, but further studies are required for complex navigation and catheter shapes before animal trials and clinical application.

The sympathetic nervous system induces a metastatic switch in primary breast cancer.

Metastasis to distant tissues is the chief driver of breast cancer-related mortality, but little is known about the systemic physiologic dynamics that regulate this process. To investigate the role of neuroendocrine activation in cancer progression, we used in vivo bioluminescence imaging to track the development of metastasis in an orthotopic mouse model of breast cancer. Stress-induced neuroendocrine activation had a negligible effect on growth of the primary tumor but induced a 30-fold increase in metastasis to distant tissues including the lymph nodes and lung. These effects were mediated by ß-adrenergic signaling, which increased the infiltration of CD11b(+)F4/80(+) macrophages into primary tumor parenchyma and thereby induced a prometastatic gene expression signature accompanied by indications of M2 macrophage differentiation. Pharmacologic activation of ß-adrenergic signaling induced similar effects, and treatment of stressed animals with the ß-antagonist propranolol reversed the stress-induced macrophage infiltration and inhibited tumor spread to distant tissues. The effects of stress on distant metastasis were also inhibited by in vivo macrophage suppression using the CSF-1 receptor kinase inhibitor GW2580. These findings identify activation of the sympathetic nervous system as a novel neural regulator of breast cancer metastasis and suggest new strategies for antimetastatic therapies that target the ß-adrenergic induction of prometastatic gene expression in primary breast cancers.

SIV infection decreases sympathetic innervation of primate lymph nodes: the role of neurotrophins.

The sympathetic nervous system regulates immune responses in part through direct innervation of lymphoid organs. Recent data indicate that viral infections can alter the structure of lymph node innervation. To determine the molecular mechanisms underlying sympathetic denervation during Simian Immunodeficiency Virus (SIV) infection, we assessed the expression of neurotrophic factors and neuromodulatory cytokines within lymph nodes from experimentally infected rhesus macaques. Transcription of nerve growth factor (NGF), brain-derived neurotropic factor (BDNF) and neurotrophin-4 (NT4) decreased significantly in vivo during chronic SIV infection, whereas expression of the neuro-inhibitory cytokine interferon-gamma (IFN gamma) was up-regulated. Acute SIV infection of macaque leukocytes in vitro induced similar changes in the expression of neurotrophic and neuro-inhibitory factors, indicative of an innate immune response. Statistical mediation analyses of data from in vivo lymph node gene expression suggested that coordinated changes in expression of multiple neuromodulatory factors may contribute to SIV-induced depletion of catecholaminergic varicosities within lymphoid tissue. Given previous evidence that lymph node catecholaminergic varicosities can enhance SIV replication in vivo, these results are consistent with the hypothesis that reduced expression of neurotrophic factors during infection could constitute a neurobiological component of the innate immune response to viral infection.