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

Theoretical and experimental characterisation of magnetic microbubbles.

In addition to improving image contrast, microbubbles have shown great potential in molecular imaging and drug/gene delivery. Previous work by the authors showed that considerable improvements in gene transfection efficiency were obtained using microbubbles loaded with magnetic nanoparticles under simultaneous exposure to ultrasound and magnetic fields. The aim of this study was to characterise the effect of nanoparticles on the dynamic and acoustic response of the microbubbles. High-speed video microscopy indicated that the amplitude of oscillation was very similar for magnetic and nonmagnetic microbubbles of the same size for the same ultrasound exposure (0.5 MHz, 100 kPa, 12-cycle pulse) and that this was minimally affected by an imposed magnetic field. The linear scattering to attenuation ratio (STAR) was also similar for suspensions of both bubble types although the nonlinear STAR was ~50% lower for the magnetic microbubbles. Both the video and acoustic data were supported by the results from theoretical modelling

Ultrasound mediated delivery of quantum dots from a 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 focussed ultrasound. These findings suggest that the use of focused ultrasound together with microbubbles could play a role in the oral delivery of biologic therapeutics

Gelation Landscape Engineering Using a Multi-Reaction Supramolecular Hydrogelator System

Simultaneous control of the kinetics and thermodynamics of two different types of covalent chemistry allows pathway selectivity in the formation of hydrogelating molecules from a complex reaction network. This can lead to a range of hydrogel materials with vastly different properties, starting from a set of simple starting compounds and reaction conditions. Chemical reaction between a trialdehyde and the tuberculosis drug isoniazid can form one, two, or three hydrazone connectivity products, meaning kinetic gelation pathways can be addressed. Simultaneously, thermodynamics control the formation of either a keto or an enol tautomer of the products, again resulting in vastly different materials. Overall, this shows that careful navigation of a reaction landscape using both kinetic and thermodynamic selectivity can be used to control material selection from a complex reaction network

Traditional multiwell plates and petri dishes limit the evaluation of the effects of ultrasound on cells in vitro

Ultrasound accelerates healing in fractured bone; however, the mechanisms responsible are poorly understood. Experimental setups and ultrasound exposures vary or are not adequately characterized across studies, resulting in inter-study variation and difficulty in concluding biological effects. This study investigated experimental variability introduced through the cell culture platform used. Continuous wave ultrasound (45 kHz; 10, 25 or 75 mW/cm2, 5 min/d) was applied, using a Duoson device, to Saos-2 cells seeded in multiwell plates or Petri dishes. Pressure field and vibration quantification and finite-element modelling suggested formation of complex interference patterns, resulting in localized displacement and velocity gradients, more pronounced in multiwell plates. Cell experiments revealed lower metabolic activities in both culture platforms at higher ultrasound intensities and absence of mineralization in certain regions of multiwell plates but not in Petri dishes. Thus, the same transducer produced variable results in different cell culture platforms. Analysis on Petri dishes further revealed that higher intensities reduced vinculin expression and distorted cell morphology, while causing mitochondrial and endoplasmic reticulum damage and accumulation of cells in sub-G1 phase, leading to cell death. More defined experimental setups and reproducible ultrasound exposure systems are required to study the real effect of ultrasound on cells for development of effective ultrasound-based therapies not just limited to bone repair and regeneration

Traditional multiwell plates and petri dishes limit the evaluation of the effects of ultrasound on cells in vitro

Ultrasound accelerates healing in fractured bone; however, the mechanisms responsible are poorly understood. Experimental setups and ultrasound exposures vary or are not adequately characterized across studies, resulting in inter-study variation and difficulty in concluding biological effects. This study investigated experimental variability introduced through the cell culture platform used. Continuous wave ultrasound (45 kHz; 10, 25 or 75 mW/cm2, 5 min/d) was applied, using a Duoson device, to Saos-2 cells seeded in multiwell plates or Petri dishes. Pressure field and vibration quantification and finite-element modelling suggested formation of complex interference patterns, resulting in localized displacement and velocity gradients, more pronounced in multiwell plates. Cell experiments revealed lower metabolic activities in both culture platforms at higher ultrasound intensities and absence of mineralization in certain regions of multiwell plates but not in Petri dishes. Thus, the same transducer produced variable results in different cell culture platforms. Analysis on Petri dishes further revealed that higher intensities reduced vinculin expression and distorted cell morphology, while causing mitochondrial and endoplasmic reticulum damage and accumulation of cells in sub-G1 phase, leading to cell death. More defined experimental setups and reproducible ultrasound exposure systems are required to study the real effect of ultrasound on cells for development of effective ultrasound-based therapies not just limited to bone repair and regeneration

Temperature behaviour of ultrasound contrast agents

Accurate characterization of ultrasound contrast agents (USCAs) is of increasing importance as their use for quantitative imaging and therapeutic application is explored. In the laboratory, such investigations are frequently undertaken in a water bath at room temperature. The effect of temperature on single bubbles has previously been demonstrated [1]. However, the effect on the acoustic properties of bulk suspensions is not presented in the literature. The acoustic and physical properties of bulk SonoVue (Bracco, Milan) suspensions over a range of temperatures (20-45°C) are investigated. Attenuation and scattering both increased with temperature over the range 20-40°C, for example at an insonation pressure of 100 kPa, signal attenuation increased from 1.5 dB to 2.5 dB, and scattering by 2 dB. The frequency spectra of the attenuated signals revealed a decrease in the frequency of peak attenuation (fa) with increasing temperature, suggesting an increase in bubble diameter. Above 40°C, attenuation was again decreased, and fa increased, implying that bubbles increased to a critical diameter and were destroyed, resulting in a decrease in signal attenuation. This effect was most apparent at 45°C. Additionally, increasing temperature from 20 - 40°C was shown to affect bubble stability by influencing bubble dissolution. We show that the acoustic characteristics of the USCA SonoVue are significantly influenced by temperature. The results suggest that measurements made at room temperature require careful interpretation before conclusions can be drawn regarding contrast agent behaviour in vivo. ©2009 IEEE

The Importance of Bubble-wall Interaction for Physiologically Relevant Simulations of Ultrasound-mediated Targeted Drug Delivery

No abstract available

Temperature dependent behavior of ultrasound contrast agents

Recent interest in ultrasound contrast agents (UCAs) as tools for quantitative imaging and therapy has increased the need for accurate characterization. Laboratory investigations are frequently undertaken in a water bath at room temperature; however, implications for in vivo applications are not presented. Acoustic investigation of a bulk suspension of SonoVue (Bracco Research, Geneva, Switzerland) was made in a water bath at temperatures of 20–45 °C. UCA characteristics were significantly affected by temperature, particularly between 20 and 40 °C, leading to an increase in attenuation from 1.7–2.5 dB, respectively (p = 0.002) and a 2-dB increase in scattered signal over the same range (p = 0.05) at an insonation pressure of 100 kPa. Optical data supported the hypothesis that a temperature-mediated increase in diameter was the dominant cause, and revealed a decrease in bubble stability. In conclusion, measurements made at room temperature require careful interpretation with regard to behavior in vivo