Fraser Stewart

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.

CHAPTER 8:Theranostics in the Gut

As a part of the body that is considered external, the gastrointestinal (GI) tract should allow easy access, but it remained relatively obscure, particularly the small intestine, until video capsule endoscopy (VCE) emerged in the past 20 years, uniquely able to view the entire length routinely. Additionally, drawing on contemporary topics including miniaturisation of electronics, wireless communications and efficient electrical power delivery, VCE provides a model for future devices. However, research in therapeutic capsule endoscopy (TCE) has been limited and poorly integrated with diagnostics. This chapter reviews relevant progress, highlighting ultrasound (US) as particularly promising for GI TCE. A description of the GI tract at different length scales is given, including the common, multi-layered structure maintained from mouth to anus and its variation down to cellular and sub-cellular level. Recent developments in multimodal capsule endoscopy are described, including US for imaging within tissue, and targeted drug delivery (TDD) is highlighted for TCE, particularly with US-mediation, because of the potential perforation associated with simpler ablation techniques. This is exemplified by a proof-of-concept theranostic device with the potential to treat conditions such as inflammatory bowel disease and colon cancer. Finally, with significant development ahead, relevant areas are highlighted, including further capsule development and nanotechnology.

A Prototype Therapeutic Capsule Endoscope for Ultrasound-mediated Targeted Drug Delivery

The prevalence of gastrointestinal (GI) diseases such as Crohn’s disease, which is chronic and incurable, are increasing worldwide. Treatment often involves potent drugs with unwanted side effects. The technological–pharmacological combination of capsule endoscopy with ultrasound-mediated targeted drug delivery (UmTDD) described in this paper carries new potential for treatment of these diseases throughout the GI tract. We describe a proof-of-concept UmTDD capsule and present preliminary results to demonstrate its promise as an autonomous tool to treat GI diseases.

A fully-automated insonation system for in vitro investigations of ultrasound-mediated targeted drug delivery

Focused ultrasound (US) produces clinically useful bioeffects such as hyperthermia, cavitation and radiation force. A focused US mediated targeted drug delivery (UmTDD) capsule endoscope was developed previously to explore treatment of gastrointestinal conditions such as Crohns disease (SonoCAIT [1]). This included focused US transducers to enhance drug uptake into the bowel wall. In further development, a benchtop system was developed [2] using the same ultrasound sources. However, this system was limited and could only insonate single samples, required significant human intervention, and could only work on therapeutic agents in suspension rather than introduce them selectively. This paper describes the development of a fully automated system to overcome these issues and describes the development of application-specific focused US transducers.

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.

An in vitro sonication system for applications in ultrasound-mediated targeted drug delivery

Ultrasound is a well-established imaging modality used in clinics worldwide for many different applications. It has also experienced recent growth in interest for therapeutic applications in the form of high-intensity focused ultrasound (HIFU) or focused ultrasound (focused-US), including in capsules for use in drug delivery in the gut. The work described here aimed to support the investigation of its usefulness for drug delivery further. An in vitro sonication system was designed, comprising a focused-US transducer, a cell plate on a vertical stage and transepithelial electrical resistance (TER) meter. Miniature focused-US transducers were fabricated with PZ26 and PZ54 materials (Meggitt Sensing Systems, Kvistgaard, Denmark). The active elements in both transducers have outer diameter, OD = 5 mm, and radius of curvature, RC = 15 mm. US field mapping indicated that output acoustic pressures are in the range 25 kPa <; Pac <; 210 kPa and acoustic powers in the range 8 mW <; Powerac <; 80 mW. Feasibility testing with Caco-2 colon cancer cells involved measuring TER during and after sonication. Sonication produced a drop in TER of 6.7% after 6 min. Recovery to the starting TER value was observed 14 min after sonication indicating that the sonication system can be used to measure the effect of ultrasound on tissue barrier function as expected.

Ultrasound facilitated marking of gastrointestinal tissue with fluorescent material

The epithelial lining of the gastrointestinal (GI) mucosal layer is an effective barrier to the contents of the gut lumen. Selective channels and tight junctions prevent contamination of the sterile internal environment of the body. Conversely, the gut barrier also prevents desired agents from entering the GI tissue. This hinders marking of tissue for further clinical follow-up. Focused ultrasound (US) may provide a potential means of overcoming the gut barrier and allowing penetration of material beyond it which was explored in a series of tests. Experiments were carried out on 14 individual postmortem-obtained murine small bowel samples for a total of 23 sonication/control paired tests. A favourable result of 80% indicated that focused US can pass a nanoscale fluorescent agent through the gut barrier. Further work is required to elucidate where the agent resides, intercellular or intracellular, post-sonication.

Nanotechnology in multimodal theranostic capsule endoscopy

Video capsule endoscopy (VCE) has become a clinically accepted diagnostic modality in the last 20 years and has established a technological roadmap for other capsule endoscopy (CE) devices, incorporating microscale technology, a local power supply and wireless communication. However, VCE does not provide a therapeutic function and research in therapeutic capsule endoscopy (TCE) has been limited. This paper proposes a new route towards viable TCE based on multiple CE devices including essential nanoscale components. A first device is used for multimodal diagnosis, with quantitative microultrasound as a complement to video imaging. Ultrasound-enhanced fluorescent marking of sites of pathology allows follow-up with a second device for therapy. This is based on fluorescence imaging and ultrasound-mediated targeted drug delivery. Subsequent treatment verification and monitoring with a third device exploits the minimally invasive nature of CE. Clinical implementation of a complete patient pathway remains the subject of research but several key components have been prepared in early prototype form. These are described, along with gaps that remain to be filled.

Development of a therapeutic capsule endoscope for treatment in the gastrointestinal tract: Bench testing to translational trial

Video capsule endoscopy (VCE) is a widely accepted clinical alternative to conventional endoscopy for diagnosis in the gut. Its advantages are that it can visualise the entire gastrointestinal tract including the small bowel (SB) and it is less invasive for the patient. However, VCE is suitable only for diagnosis, with little research into therapeutic capsule endoscopy (TCE). Like VCE, TCE has great potential to reach locations that would previously have been difficult, such as the SB. Ultrasound-mediated targeted drug delivery (UmTDD) is a promising modality for TCE: the power required is low compared with ultrasound (US) ablation and focused US can manipulate the position of therapeutic agents using radiation forces, increase uptake into and through cell layers, and thus deliver a higher dose safely to specifically targeted sites of action.

Acoustic radiation pressure as a versatile tool for cell compression and mechanobiology studies

Cells not only sense their biochemical and biological environment, they also respond to physical cues. To study the effect of mechanical inputs on cells, techniques commonly rely on growing cells on stretchable substrates or exerting force via directly contacting cells. Our work suggests that acoustic radiation pressure applied with ultrasonic devices can be used to compress cells without requiring direct contact.