Christopher Stephen Hall

Ultrasound triggered image-guided drug delivery

The integration of therapeutic interventions with diagnostic imaging has been recognized as one of the next technological developments that will have a major impact on medical treatments. Important advances in this field are based on a combination of progress in guiding and monitoring ultrasound energy, novel drug classes becoming available, the development of smart delivery vehicles, and more in depth understanding of the mechanisms of the cellular and molecular basis of diseases. Recent research demonstrates that both pressure sensitive and temperature sensitive delivery systems hold promise for local treatment. The use of ultrasound for the delivery of drugs has been demonstrated in particular the field of cardiology and oncology for a variety of therapeutics ranging from small drug molecules to biologics and nucleic acids.

Oil-filled polymer microcapsules for ultrasound-mediated delivery of lipophilic drugs

The use of ultrasound contrast agents as local drug delivery systems continues to grow. Current limitations are the amount of drug that can be incorporated as well as the efficiency of drug release upon insonification. This study focuses on the synthesis and characterisation of novel polymeric microcapsules for ultrasound-triggered delivery of lipophilic drugs. Microcapsules with a shell of fluorinated end-capped poly(L-lactic acid) were made through pre-mix membrane emulsification and contained, apart from a gaseous phase, different amounts of hexadecane oil as a drug-carrier reservoir. Mean number weighted diameters were between 1.22 microm and 1.31 microm. High-speed imaging at approximately 10 million fames per second showed that for low acoustic pressures (1 MHz, 0.24 MPa) microcapsules compressed but remained intact. At higher diagnostic pressures of 0.51 MPa, microcapsules cracked, thereby releasing the encapsulated gas and model lipophilic drug. Using conventional ultrasound B-mode imaging at a frequency of 2.5 MHz, a marked enhancement of scatter intensity over a tissue-mimicking phantom was observed for all differently loaded microcapsules. The partially oil-filled microcapsules with high drug loads and well-defined acoustic activation thresholds have great potential for ultrasound-triggered local delivery of lipophilic drugs under ultrasound image-guidance.

Interlaboratory Comparison of Ultrasonic Backscatter Coefficient Measurements From 2 to 9 MHz

As are the attenuation coefficient and sound speed, the backscatter coefficient is a fundamental ultrasonic property that has been used to characterize many tissues. Unfortunately, there is currently far less standardization for the ultrasonic backscatter measurement than for the other two, as evidenced by a previous American Institute of Ultrasound in Medicine (AIUM)–sponsored interlaboratory comparison of ultrasonic backscatter, attenuation, and speed measurements (J Ultrasound Med 1999; 18:615–631). To explore reasons for these disparities, the AIUM Endowment for Education and Research recently supported this second interlaboratory comparison, which extends the upper limit of the frequency range from 7 to 9 MHz.

Three-dimensional spatial and temporal temperature imaging in gel phantoms using backscattered ultrasound

Thermal therapies such as radio frequency, heated saline, and high-intensity focused ultrasound ablations are often performed suboptimally due to the inability to monitor the spatial and temporal distribution of delivered heat and the extent of tissue necrosis. Ultrasound-based temperature imaging recently was proposed as a means to measure noninvasively the deposition of heat by tracking the echo arrival time shifts in the ultrasound backscatter caused by changes in speed of sound and tissue thermal expansion. However, the clinical applicability of these techniques has been hampered by the two-dimensional (2-D) nature of traditional ultrasound imaging, and the complexity of the temperature dependence of sound speed for biological tissues. In this paper, we present methodology, results, and validation of a 3-D spatial and temporal ultrasound temperature estimation technique in an alginate-based gel phantom to track the evolution of heat deposition over a treatment volume. The technique was experimentally validated for temperature rises up to ~10degC by comparison with measurements from thermocouples that were embedded in the gel. Good agreement (rms difference=0.12degC, maximum difference=0.24degC) was observed between the noninvasive ultrasound temperature estimates and thermocouple measurements. Based on the results obtained for the temperature range studied in this paper, the technique demonstrates potential for applicability in image guidance of thermal therapy for determining the location of the therapeutic focal spot and assessing the extent of the heated region at subablative intensities.

Targeted Ultrasound-Mediated Delivery of Nanoparticles: On the Development of a New HIFU-Based Therapy and Imaging Device

Ultrasound-mediated delivery (USMD) is an active research topic, as researchers develop applications for therapeutic ultrasound in addition to thermal ablation. In USMD, ultrasound is used in conjunction with microbubbles and drugs, nanoparticles, siRNA, pDNA, stem cells, etc., to facilitate their cellular delivery and uptake using pressure and temperature-mediated mechanisms to bring about a desired therapeutic effect. To investigate the potential of targeted USMD of nanoparticles, pDNA, and stem cells for cardiovascular and other applications, a general-purpose preclinical research tool, therapy imaging probe system (TIPS) was designed. It consists of a wideband annular array, a small-animal acoustic coupler, a motorized positioning system, integrated control software for ultrasound image-guided treatment planning and execution, and triggering electronics that allow ECG and respiration-gated ultrasound exposures. TIPS was then used to enhance delivery of nanoparticles into the murine myocardium and heart vessel walls to demonstrate the feasibility of the technology, pave the way for additional basic research in cardiovascular USMD, and begin to explore the requirements that USMD devices will have to meet to be useful in a clinical setting.

Effect of molecular weight, crystallinity, and hydrophobicity on the acoustic activation of polymer-shelled ultrasound contrast agents.

Polymer-shelled microbubbles are applied as ultrasound contrast agents. To investigate the effect of the polymer on microbubble preparation and acoustic properties, polylactides with systematic variations in molecular weight, crystallinity, and end-group hydrophobicity were used. Polymer-shelled cyclodecane filled capsules were prepared by emulsification, and the cyclodecane was removed by lyophilization to obtain hollow capsules. Complete removal of cyclodecane from the microcapsules was only achieved for short chain (about M(w) 6000) crystalline polymers. The pressure threshold for acoustic destruction of the microbubbles was found to increase with molecular weight. Noncrystalline polymers showed a higher threshold for destruction than crystalline polymers. Hydrophobically modified short chain crystalline polymers showed the steepest increase in acoustic destruction after the threshold as a function of the applied pressure, which is a favorable characteristic for ultrasound mediated drug delivery. Microcapsules made with such polymers had an inhomogeneous surface including pores through which cyclodecane was lyophilized efficiently.

New mold manufacturing techniques

Typically, optical molds have been made from silicon carbide (SiC) or tungsten carbide (WC). Magnetorheological Finishing (MRF) polishing results of SiC and WC molds will be reviewed. Impressive figure corrections have been demonstrated on both types of materials. The roughness performance of CVD-SiC, WC and binderless WC will be compared. However, the hardness and polycrystalline nature of these materials make them difficult to manufacture. In this paper we report positive initial results using an alternate mold material, glassy carbon. Test samples have been ground, pre-polished and finish polished to a 38 nm surface figure peak-to-valley (PV) and a 6 Å rms surface roughness, with improved cycle times versus SiC and WC. Glassy carbon is a promising mold material candidate as an amorphous material of lower hardness. The lower hardness leads to more effective diamond grinding process and results in a better surface rms roughness following MRF. After reviewing key material properties of glassy carbon material, this paper will describe some collaborative activities between Toshiba Machine Co., Ltd. and QED Technologies (QED) to manufacture representative examples of glassy carbon. Details of the grinding, pre-polishing and final polishing process will be provided along with the resultant metrology results after key steps. Molding experiments based on these developments will also be presented.

9B-5 Ultrasound Therapy with Drug Loaded Microcapsules

A novel class of acoustically active microcapsules that partially contain drug-bearing oil with gas offers great potential for localized drug release. The acoustical activation threshold and rate of such microcapsules with different oil-to-gas ratios were measured in vitro. Drug loaded microcapsules were prepared from which the anti-cancer drug paclitaxel was delivered in murine tumors. For recovered mice each with two tumors on the left and right hind legs, the growth rate of the acoustically treated tumors was substantially reduced in comparison to that of the untreated tumor on the same mouse. These initial results showed that lipophilic drugs can be packaged in microcapsules and released locally using focused ultrasound.

Ultrasound mediated drug delivery

For patients with ulcerative colitis, the most common form of inflammatory bowel disease (IBD), aminosalicylates such as mesalamine provide first line anti-inflammatory therapy. Since efficacy is related to tissue concentration, when administered as a rectal enema lack of retention challenges topical formulation effectiveness. To address this problem, Schoellhammer and his colleagues (Schoellhammer et al 2015) recently described the development and pre-clinical testing of a novel delivery system in which they incorporated low frequency ultrasound (LFU) as a means to enhance transmucosal drug delivery through the gastrointestinal mucosa.

Ultrasound therapy transducers with space-filling non-periodic arrays

Ultrasound transducers designed for therapeutic purposes such as tissue ablation, histotripsy, or drug delivery require large apertures for adequate spatial localization while providing sufficient power and steerability without the presence of secondary grating lobes. In addition, it is highly preferred to minimize the total number of channels and to maintain simplicity in electrical matching network design. To this end, we propose array designs that are both space-filling and non-periodic in the placement of the elements. Such array designs can be generated using the mathematical concept of non-periodic or aperiodic tiling (tessellation) and can lead to reduced grating lobes while maintaining full surface area coverage to deliver maximum power. For illustration, we designed two 2-D space-filling therapeutic arrays with 128 elements arranged on a spherical shell. One was based on the two-shape Penrose rhombus tiling, and the other was based on a single rectangular shape arranged non-periodically. The steerability performance of these arrays was studied using acoustic field simulations. For comparison, we also studied two other arrays, one with circular elements distributed randomly, and the other a periodic array with square elements. Results showed that the two space-filling non-periodic arrays were able to steer to treat a volume of 16 × 16 × 20 mm while ensuring that the grating lobes were under -10 dB compared with the main lobe. The rectangular non-periodic array was able to generate two and half times higher power than the random circles array. The rectangular array was then fabricated by patterning the array using laser scribing methods and its steerability performance was validated using hydrophone measurements. This work demonstrates that the concept of space-filling aperiodic/non-periodic tiling can be used to generate therapy arrays that are able to provide higher power for the same total transducer area compared with random arrays while maintaining acceptable grating lobe levels.