Stuart B. Mitchell

Preclinical in vivo Evaluation of an Extracorporeal HIFU Device for Ablation of Pancreatic Tumors

Extracorporeal high-intensity focused ultrasound (HIFU) can be used to ablate tissue noninvasively by delivering focused ultrasound energy from an external source. HIFU for clinical treatment of pancreatic cancer has been reported; however, systematic evaluation of the safety and efficacy of pancreatic ablation with HIFU has not been performed. The objectives of this in vivo study are as follows: (1) assess the safety and feasibility of targeting and ablating pancreatic tissue using the FEP-BY02 HIFU system (Yuande Bio-Medical Engineering, Beijing, China); (2) evaluate a method for estimating in situ acoustic treatment energy in an in vivo setting; and (3) identify the optimal treatment parameters that result in safe and effective ablation of the pancreas. The pancreata of 12 common swine were treated in vivo. Prior to therapy, blood was drawn for laboratory analysis. Animals were then treated with extracorporeal HIFU at three different acoustic treatment energies (750, 1000 and 1250 J). Endoscopy was performed prior to and immediately following HIFU therapy to assess for gastric injury. Blood was drawn after completion of the treatment and on days 2 and 7 following treatment to assess for biochemical evidence of pancreatitis. Animals were then euthanized 7 d following treatment and a necropsy was performed to assess for unintended injury and to obtain pancreatic tissue for histology to assess efficacy of HIFU ablation. Histologic scoring of pancreatic tissue changes was performed by a pathologist blinded to the treatment energy delivered. The degree of ablation identified on histology correlated with the treatment energy. No collateral tissue damage was seen at treatment energies of 750 and 1000 J. At 1250 J, thermal injury to the abdominal muscles and gastric ulcers were observed. There were no premature deaths, serious illnesses, skin burns or evidence of pancreatitis on biochemical analysis. HIFU treatment of the pancreas is feasible, safe and can be used to ablate tissue noninvasively. A clinical trial in humans examining the use of extracorporeal HIFU for palliation of pain related to pancreatic cancer is planned.

A device to apply user-specified strains to biomaterials in culture

An apparatus was developed to apply user-specified displacements to biomaterial samples in culture. The device allowed cyclic waveforms of bandwidth 0 Hz to 20 Hz to be applied under physiologic thermal (37.5/spl deg/C) and [CO/sub 2/] (5%) conditions. For a 0 Hz to 20 Hz bandwidth signal similar in shape to a ventricular pressure waveform, the mean displacement error was 0.26% of the full-scale output. The maximum overshoot was 0.700%. Environmental system evaluation tests demonstrated a specimen cartridge temperature of 37.20/spl plusmn/0.15/spl deg/C during cyclic loading and 37.23/spl plusmn/0.21/spl deg/C during static conditions, [CO/sub 2/] was 5.29/spl plusmn/0.54% during cyclic loading and 5.25/spl plusmn/0.61% during static conditions. Laminar flow applied at the loading rod entrances to the specimen cartridge ensured the sample remained sterile during testing. As a preliminary evaluation, polyurethane samples were seeded with fetal foreskin fibroblasts and subject to intermittent cyclic displacements. Results demonstrated enhanced cell proliferation and increased [PGE/sub 2/] for samples subjected to 10% strain compared with unstrained controls. A next step will be to evaluate cell response sensitivity to strain magnitude, duration, direction, and frequency. The long-term intent is to establish mechanical loading configurations that induce acceptable or adaptation-inducing responses for use in implant design and tissue engineering applications.

A digitizer with exceptional accuracy for use in prosthetics research: a technical note.

A mechanical digitizer was developed for use in prosthetics research where measurements of small differences in shape are of interest. Root-mean-square error was 0.075 mm in the radial direction, 0.05 degrees in the tangential direction, and 0.1 mm in the vertical direction. The system has potential use for time-dependent assessment of changes in socket and residuum cast shape, assessment of socket fabrication systems, and development of accurate prosthetic finite element models.

An explant model for the investigation of skin adaptation to mechanical stress

A test apparatus was developed to investigate the effects of mechanical stress application on collagen remodeling in skin. The system maintained a 4.5-cm /spl times/ 5.5-cm skin explant at an air interface with controlled temperature, relative humidity (RH), and carbon dioxide concentration [CO/sub 2/] while allowing controlled compressive and shear forces to be applied to the skin surface. For environmental control, a custom-designed flow system under proportional-integral-derivative (PID) control was used. Evaluation tests demonstrated that the system maintained air above the explant at a temperature within 1/spl deg/C of the 37.5/spl deg/C set point, RH within 5% of the user-specified set point (range of 5% to 95%), and [CO/sub 2/] within 1% of the 5% [CO/sub 2/] set point. Least-squares errors in cyclic compressive and shear forces (0- to 20-Hz bandwidth) delivered to the explant were 0.9% and 2.8%, respectively, of user-specified values. Pig skin samples cyclically stressed for 1 hr/day for 3 days with either compressive force only or a combined compressive and shear force had significantly smaller collagen fibril densities compared with an unstressed control, a result consistent with in vivo test data. Collagen fibril diameters were significantly larger for stressed versus control for some of the samples, but the changes were not as substantial as from previous in vivo testing . This result may have been due to the shorter study duration in vitro (3 d versus 20 d in vivo). The system allows insight into the mechanisms of skin adaptation to mechanical stress to be investigated on a cellular and molecular level, potentially leading to therapies to encourage adaptation in at-risk patients.

Characterizing an Agar/Gelatin Phantom for Image Guided Dosing and Feedback Control of High-Intensity Focused Ultrasound

The temperature dependence of an agar/gelatin phantom was evaluated. The purpose was to predict the material property response to high-intensity focused ultrasound (HIFU) for developing ultrasound guided dosing and targeting feedback. Changes in attenuation, sound speed, shear modulus and thermal properties with temperature were examined from 20°C to 70°C for 3 weeks post-manufacture. The attenuation decreased with temperature by a power factor of 0.15. Thermal conductivity, diffusivity and specific heat all increased linearly with temperature for a total change of approximately 16%, 10% and 6%, respectively. Sound speed had a parabolic dependence on temperature similar to that of water. Initially, the shear modulus irreversibly declined with even a slight increase in temperature. Over time, the gel maintained its room temperature shear modulus with moderate heating. A stable phantom was achieved within 2 weeks post-manufacture that possessed quasi-reversible material properties up to nearly 55°C.

Novel High-Intensity Focused Ultrasound Clamp—Potential Adjunct for Laparoscopic Partial Nephrectomy

BACKGROUND AND PURPOSE Partial nephrectomy (PN) can be technically challenging, especially if performed in a minimally invasive manner. Although ultrasound technology has been shown to have therapeutic capabilities, including tissue ablation and hemostasis, it has not gained clinical use in the PN setting. The purpose of this study is to evaluate the ability of a high-intensity ultrasound clamp to create an ablation plane in the kidney providing hemostasis that could potentially aid in laparoscopic PN. METHODS A new instrument was created using a laparoscopic Padron endoscopic exposing retractor. Ultrasound elements were engineered on both sides of the retractor to administer high-intensity ultrasound energy between the two sides of the clamp. This high-intensity focused ultrasound (HIFU) clamp was placed 2 to 2.5 cm from the upper and lower poles of 10 porcine kidneys to evaluate its effectiveness at different levels and duration of energy delivery. PN transection was performed through the distal portion of the clamped margin. Kidneys postintervention and after PN were evaluated and blood loss estimated by weighing gauze placed at the defect. Histologic analysis was performed with hematoxylin and eosin and nicotinamide adenine dinucleotide staining to evaluate for tissue viability and thermal spread. RESULTS Gross parenchymal changes were seen with obvious demarcation between treated and untreated tissue. Increased ultrasound exposure time (10 vs 5 and 2 min), even at lower power settings, was more effective in causing destruction and necrosis of tissue. Transmural ablation was achieved in three of four renal units after 10 minutes of exposure with significantly less blood loss (<2 g vs 30-100 g). Nonviable tissue was confirmed histologically. There was minimal thermal spread outside the clamped margin (1.2-3.2 mm). CONCLUSION In this preliminary porcine evaluation, a novel HIFU clamp induced hemostasis and created an ablation plane in the kidney. This technology could serve as a useful adjunct to laparoscopic PN in the future and potentially obviate the need for renal hilar clamping.

Acoustic hemostasis of porcine superficial femoral artery: Simulation and in-vivo experimental studies

In-vivo focused ultrasound studies were computationally simulated and conducted experimentally with the aim of occluding porcine superficial femoral arteries (SFA) via thermal coagulation. A multi-array HIFU applicator was used which electronically scanned multiple beam foci around the target point. The spatio-temporally averaged acoustic and temperature fields were simulated in a fluid dynamics and acousto-thermal finite element model with representative tissue fields, including muscle, vessel and blood. Simulations showed that with an acoustic power of 200W and a dose time of 60s, perivascular tissue reached 91°C; and yet blood reached a maximum 59°C, below the coagulation objective for this dose regime (75°C). Per simulations, acoustic-streaming induced velocity in blood reached 6.1cm/s. In in-vivo experiments, several arteries were treated. As simulated, thermal lesions were observed in muscle surrounding SFA in all cases. In dosing limited to 30 to 60 seconds, it required 257W to provide occlusion (o...

Ultrasound induced mechanical induction of mesenchymal stem cells.

Low‐intensity pulsed ultrasound (LIPUS) has been used to accelerate fracture healing and tissue regeneration but the biological mechanism of these responses is not completely understood. Stem cell activity can be induced through biochemical and mechanical mechanisms. Despite the common use of LIPUS in fracture healing and tissue regeneration, there are only a few studies that examine the mechanical induction of stem cells with ultrasound. The purpose of this study is to determine the effects of ultrasound‐generated mechanical stimulus on the behavior of human mesenchymal stem cells (hMSCs) in vitro. In our preliminary studies low‐intensity pulsed ultrasound was used to induce mechanical strains on hMSCs in vitro. Amplitudes, pulse durations, and pulse repetition frequencies were varied such that different radiation pressures were generated on hMSCs in culture. Results indicated a significant increase in cell proliferation after 4 consecutive days of treatment as well as a significant difference in the cel...

High intensity focused ultrasound laparoscopic instrument for partial nephrectomy

Partial nephrectomy (PN) is the gold standard for small clinically localized renal masses because of equal oncologic outcomes and greater preservation of renal function compared with radical nephrectomy (RN). However, it is a complex operation due to the challenges of cutting into a well-vascularized organ and the need for reconstruction of the remaining kidney following excision. PN is associated with higher blood loss, risk of transfusion, and longer operative time compared to RN. High intensity focused ultrasound (HIFU) affords the ability to ablate tissue and perform hemostasis, thus potentially mitigating some of the challenges associated with PN. The purpose of this paper is to introduce a new HIFU clamp as an adjunctive tool for PN. A HIFU device was created to conform to the shape of a commonly used laparoscopic instrument. Characterization studies were conducted using ex vivo tissue. Histology was performed to evaluate thermal damage. Ex vivo studies indicated that complete ablation planes could ...

Understanding changes in tissue phantom material properties with temperature.

Phantoms used for high intensity focused ultrasound (HIFU) applications require rigorous evaluation of material properties since, locally, the material experiences extreme changes in temperature and stresses with the HIFU treatment. Here we present the testing of an agar/gelatin phantom intended for both acoustic radiation force imaging (ARFI) and HIFU applications. The phantom shear modulus, speed of sound, attenuation, and thermal properties were all evaluated over the range of room temperature to 80 °C. With the exception of the thermal properties, all measurements were taken during both heating and cool down. Cavitation threshold and melting point were also tested. The change in material sound speed and thermal properties with temperature were quasireversible and similar to that of water. Material attenuation showed a slight decrease with temperature, but appeared to also be reversible. Shear modulus decreased significantly with temperature, going to near zero. The response was not reversible, returni...