Bionanotechnology and bioMEMS (BNM): state-of-the-art applications, opportunities, and challenges.

The development of micro- and nanotechnology for biomedical applications has defined the cutting edge of medical technology for over three decades, as advancements in fabrication technology developed originally in the semiconductor industry have been applied to solving ever-more complex problems in medicine and biology. These technologies are ideally suited to interfacing with life sciences, since they are on the scale lengths as cells (microns) and biomacromolecules (nanometers). In this paper, we review the state of the art in bionanotechnology and bioMEMS (collectively BNM), including developments and challenges in the areas of BNM, such as microfluidic organ-on-chip devices, oral drug delivery, emerging technologies for managing infectious diseases, 3D printed microfluidic devices, AC electrokinetics, flexible MEMS devices, implantable microdevices, paper-based microfluidic platforms for cellular analysis, and wearable sensors for point-of-care testing.

Laser-Enabled Surface Treatment of Disposable Endoscope Lens with Superior Antifouling and Optical Properties.

Endoscopes are ubiquitous in minimally invasive or keyhole surgeries globally. However, frequent removal of endoscopes from the patient's body due to the lens contaminations results in undesirable consequences. Therefore, a cost-effective process chain to fabricate thermoplastic-based endoscope lenses with superior antifouling and optical properties is proposed in this research. Such multifunctional surface response was achieved by lubricant impregnation of nanostructures. Two types of topographies were produced by femtosecond laser processing of metallic molds, especially to produce single-tier laser-induced periodic surface structures (LIPSS) and two-tier multiscale structures (MS). Then, these two LIPSS and MS masters were used to replicate them onto two thermoplastic substrates, namely polycarbonate and cyclic olefin copolymer, by using hot embossing. Finally, the LIPSS and MS surfaces of the replicas were infiltrated by silicone oils to prepare lubricant-impregnated surfaces (LIS). Droplet sliding tests revealed that the durability of the as-prepared LIS improved with the increase of the lubricant viscosity. Moreover, the single-tier LIPSS replicas exhibited longer-lasting lubricant conservation properties than the MS ones. Also, LIPSS-LIS replicas demonstrated an excellent optical transparency, better than the MS-LIS ones, and almost match the performance of the reference polished ones. Furthermore, the LIPSS-LIS treatment led to superior antifouling characteristics, i.e., regarding fogging, blood adhesion, protein adsorption, and microalgae attachment, and thus demonstrated its high suitability for treating endoscopic lenses. Finally, a proof-of-concept LIPSS-LIS treatment of endoscope lenses was conducted that confirmed their superior multifunctional response.

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.

Wireless Power Transfer Techniques for Implantable Medical Devices: A Review.

Wireless power transfer (WPT) systems have become increasingly suitable solutions for the electrical powering of advanced multifunctional micro-electronic devices such as those found in current biomedical implants. The design and implementation of high power transfer efficiency WPT systems are, however, challenging. The size of the WPT system, the separation distance between the outside environment and location of the implanted medical device inside the body, the operating frequency and tissue safety due to power dissipation are key parameters to consider in the design of WPT systems. This article provides a systematic review of the wide range of WPT systems that have been investigated over the last two decades to improve overall system performance. The various strategies implemented to transfer wireless power in implantable medical devices (IMDs) were reviewed, which includes capacitive coupling, inductive coupling, magnetic resonance coupling and, more recently, acoustic and optical powering methods. The strengths and limitations of all these techniques are benchmarked against each other and particular emphasis is placed on comparing the implanted receiver size, the WPT distance, power transfer efficiency and tissue safety presented by the resulting systems. Necessary improvements and trends of each WPT techniques are also indicated per specific IMD.

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.

In-Vivo Evaluation of Microultrasound and Thermometric Capsule Endoscopes.

Clinical endoscopy and colonoscopy are commonly used to investigate and diagnose disorders in the upper gastrointestinal tract and colon, respectively. However, examination of the anatomically remote small bowel with conventional endoscopy is challenging. This and advances in miniaturization led to the development of video capsule endoscopy (VCE) to allow small bowel examination in a noninvasive manner. Available since 2001, current capsule endoscopes are limited to viewing the mucosal surface only due to their reliance on optical imaging. To overcome this limitation with submucosal imaging, work is under way to implement microultrasound (µUS) imaging in the same form as VCE devices. This paper describes two prototype capsules, termed Sonocap and Thermocap, which were developed respectively to assess the quality of µUS imaging and the maximum power consumption that can be tolerated for such a system. The capsules were tested in vivo in the oesophagus and small bowel of porcine models. Results are presented in the form of µUS B-scans as well as safe temperature readings observed up to 100 mW in both biological regions. These results demonstrate that acoustic coupling and µUS imaging can be achieved in vivo in the lumen of the bowel and the maximum power consumption that is possible for miniature µUS systems.

Nanocomposite-Based Microstructured Piezoresistive Pressure Sensors for Low-Pressure Measurement Range.

Piezoresistive pressure sensors capable of detecting ranges of low compressive stresses have been successfully fabricated and characterised. The 5.5 × 5 × 1.6 mm³ sensors consist of a planar aluminium top electrode and a microstructured bottom electrode containing a two-by-two array of truncated pyramids with a piezoresistive composite layer sandwiched in-between. The responses of two different piezocomposite materials, a Multiwalled Carbon Nanotube (MWCNT)-elastomer composite and a Quantum Tunneling Composite (QTC), have been characterised as a function of applied pressure and effective contact area. The MWCNT piezoresistive composite-based sensor was able to detect pressures as low as 200 kPa. The QTC-based sensor was capable of detecting pressures as low as 50 kPa depending on the contact area of the bottom electrode. Such sensors could find useful applications requiring the detection of small compressive loads such as those encountered in haptic sensing or robotics.

Sensors for Fetal Hypoxia and Metabolic Acidosis: A Review.

This article reviews existing clinical practices and sensor research undertaken to monitor fetal well-being during labour. Current clinical practices that include fetal heart rate monitoring and fetal scalp blood sampling are shown to be either inadequate or time-consuming. Monitoring of lactate in blood is identified as a potential alternative for intrapartum fetal monitoring due to its ability to distinguish between different types of acidosis. A literature review from a medical and technical perspective is presented to identify the current advancements in the field of lactate sensors for this application. It is concluded that a less invasive and a more continuous monitoring device is required to fulfill the clinical needs of intrapartum fetal monitoring. Potential specifications for such a system are also presented in this paper.

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.

Challenges in developing collaborative interdisciplinary research between gastroenterologists and engineers.

The role of technology in healthcare is rapidly evolving. However, it can be argued that gastroenterology has not kept pace with other medical fields due to the multifaceted needs of this speciality and other issues. Innovation in healthcare technology increasingly requires interdisciplinary collaboration between engineers and clinicians. Nevertheless, working in such an interdisciplinary environment can be challenging due to factors such as working culture, communication and difference in priorities. We surveyed the views of clinicians specialising in gastroenterology and engineers on interdisciplinary health research. The 21 respondents expressed a range of opinions on the perceived benefits and challenges of interdisciplinary collaboration. Though engineers and clinicians recognised its advantages, they expressed a need for further improvement. However, engineers and clinicians differed in how best this could be achieved. The results of this survey are discussed with reference to the literature on interdisciplinary collaboration.

Luminally expressed gastrointestinal biomarkers.

INTRODUCTION: A biomarker is a measurable indicator of normal biologic processes, pathogenic processes or pharmacological responses. The identification of a useful biomarker is challenging, with several hurdles to overcome before clinical adoption. This review gives a general overview of a range of biomarkers associated with inflammatory bowel disease or colorectal cancer along the gastrointestinal tract. Areas covered: These markers include those that are already clinically accepted, such as inflammatory markers such as faecal calprotectin, S100A12 (Calgranulin C), Fatty Acid Binding Proteins (FABP), malignancy markers such as Faecal Occult Blood, Mucins, Stool DNA, Faecal microRNA (miRNA), other markers such as Faecal Elastase, Faecal alpha-1-antitrypsin, Alpha2-macroglobulin and possible future markers such as microbiota, volatile organic compounds and pH. Expert commentary: There are currently a few biomarkers that have been sufficiently validated for routine clinical use at present such as FC. However, many of these biomarkers continue to be limited in sensitivity and specificity for various GI diseases. Emerging biomarkers have the potential to improve diagnosis and monitoring but further study is required to determine efficacy and validate clinical utility.

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.