Deep bleeder acoustic coagulation (DBAC)-Part I: development and in vitro testing of a research prototype cuff system.

BACKGROUND: Bleeding from limb injuries is a leading cause of death on the battlefield, with deep wounds being least accessible. High-intensity focused ultrasound (HIFU) has been shown capable of coagulation of bleeding (cautery). This paper describes the development and refereed in vitro evaluation of an ultrasound (US) research prototype deep bleeder acoustic coagulation (DBAC) cuff system for evaluating the potential of DBAC in the battlefield. The device had to meet quantitative performance metrics on automated operation, therapeutic heating, bleeder detection, targeting accuracy, operational time limits, and cuff weight over a range of limb sizes and bleeder depths. These metrics drove innovative approaches in image segmentation, bleeder detection, therapy transducers, beam targeting, and dose monitoring. A companion (Part II) paper discusses the in vivo performance testing of an animal-specific DBAC system. MATERIALS AND METHODS: The cuff system employed 3D US imaging probes ("Ix") for detection and localization (D&L) and targeting, with the bleeders being identified by automated spectral Doppler analysis of flow waveforms. Unique high-element-count therapeutic arrays ("Tx") were developed, with the final cuff prototype having 21 Tx's and 6 Ix's. Spatial registration of Ix's and Tx's was done with a combination of image-registration, acoustic time-of-flight measurement, and tracking of the cuff shape via a fiber optic sensor. Acoustic radiation force impulse (ARFI) imaging or thermal strain imaging (TSI) at low-power doses were used to track the HIFU foci in closed-loop targeting. Recurrent neural network (RNN) acoustic thermometry guided closed-loop dosing. The cuff was tested on three phantom "limb" sizes: diameters = 25, 15, and 7.5 cm, with bleeder depths from 3.75 to 12.5 cm. "Integrated Phantoms" (IntP) were used for assessing D&L, closed-loop targeting, and closed-loop dosing. IntPs had surrogate arteries and bleeders, with blood-mimicking fluids moved by a pulsatile pump, and thermocouples (TCs) on the bleeders. Acoustic dosing was developed and tested using "HIFU Phantoms" having precisely located TCs, with end-of-dose target ∆T = 33-58 °C, and skin temperature ∆T ≤ 20 °C, being required. RESULTS: Most DBAC cuff performance requirements were met, including cuff weight, power delivery, targeting accuracy, skin temperature limit, and autonomous operation. The automated D&L completed in 9 of 15 tests (65 %), detecting the smallest (0.6 mm) bleeders, but it had difficulty with the lowest flow (3 cm/sec) bleeders, and in localizing bleeders in the smallest (7.5 cm) phantoms. D&L did not complete within the 9-min limit (results ranged 10-21 min). Closed-loop targeting converged in 20 of 31 tests (71 %), and closed-loop dosing power shut-off at preset ∆Ts was operational. SUMMARY AND CONCLUSION: The main performance objectives of the prototype DBAC cuff were met, however the designs required a number of challenging new technology developments. The novel Tx arrays exhibited high power with significant beam steering and focusing flexibility, while their integrated electronics enabled the required compact, lightweight configurability and simplified driving controls and cable/connector architecture. The compounded 3D imaging, combined with sophisticated software algorithms, enabled automated D&L and initial targeting and closed-loop targeting feedback via TSI. The development of RNN acoustic thermometry made possible feedback-controlled dosing. The lightweight architecture required significant design and fabrication effort to meet mechanical functionalities. Although not all target specifications were met, future engineering solutions addressing these performance deficiencies are proposed. Lastly, the program required very complex limb test phantoms and, while very challenging to develop, they performed well.

Deep Bleeder Acoustic Coagulation (DBAC)-part II: in vivo testing of a research prototype system.

BACKGROUND: Deep Bleeder Acoustic Coagulation (DBAC) is an ultrasound image-guided high-intensity focused ultrasound (HIFU) method proposed to automatically detect and localize (D&L) and treat deep, bleeding, combat wounds in the limbs of soldiers. A prototype DBAC system consisting of an applicator and control unit was developed for testing on animals. To enhance control, and thus safety, of the ultimate human DBAC autonomous product system, a thermal coagulation strategy that minimized cavitation, boiling, and non-linear behaviors was used. MATERIAL AND METHODS: The in vivo DBAC applicator design had four therapy tiles (Tx) and two 3D (volume) imaging probes (Ix) and was configured to be compatible with a porcine limb bleeder model developed in this research. The DBAC applicator was evaluated under quantitative test conditions (e.g., bleeder depths, flow rates, treatment time limits, and dose exposure time limits) in an in vivo study (final exam) comprising 12 bleeder treatments in three swine. To quantify blood flow rates, the "bleeder" targets were intact arterial branches, i.e., the superficial femoral artery (SFA) and a deep femoral artery (DFA). D&L identified, characterized, and targeted bleeders. The therapy sequence selected Tx arrays and determined the acoustic power and Tx beam steering, focus, and scan patterns. The user interface commands consisted of two buttons: "Start D&L" and "Start Therapy." Targeting accuracy was assessed by necropsy and histologic exams and efficacy (vessel coagulative occlusion) by angiography and histology. RESULTS: The D&L process (Part I article, J Ther Ultrasound, 2015 (this issue)) executed fully in all cases in under 5 min and targeting evaluation showed 11 of 12 thermal lesions centered on the correct vessel subsection, with minimal damage to adjacent structures. The automated therapy sequence also executed properly, with select manual steps. Because the dose exposure time limit (t dose ≤ 30 s) was associated with nonefficacious treatment, 60-s dosing and dual-dosing was also pursued. Thrombogenic evidence (blood clotting) and collagen denaturation (vessel shrinkage) were found in necropsy and histologically in all targeted SFAs. Acute SFA reductions in blood flow (20-30 %) were achieved in one subject, and one partial and one complete vessel occlusion were confirmed angiographically. The complete occlusion case was achieved with a dual dose (90 s total exposure) with focal intensity ≈500 W/cm(2) (spatial average, temporal average). CONCLUSIONS: While not meeting all in vivo objectives, the overall performance of the DBAC applicator was positive. In particular, D&L automation workflow was verified during each of the tests, with processing times well under specified (10 min) limits, and all bleeder branches were detected and localized. Further, gross necropsy and tissue examination confirmed that the HIFU thermal lesions were coincident with the target vessel locations in over 90 % of the multi-array dosing treatments. The SFA/DFA bleeder models selected, and the protocols used, were the most suitable practical model options for the given DBAC anatomical and bleeder requirements. The animal models were imperfect in some challenging aspects, including requiring tissue-mimicking material (TMM) standoffs to achieve deep target depths, thereby introducing device-tissue motion, with resultant imaging artifacts. The model "bleeders" involved intact vessels, which are subject to less efficient heating and coagulation cascade behaviors than true puncture injuries.

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 x 5.5-cm skin explant at an air interface with controlled temperature, relative humidity (RH), and carbon dioxide concentration [CO2] 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 degrees C of the 37.5 degrees C set point, RH within 5% of the user-specified set point (range of 5% to 95%), and [CO2] within 1% of the 5% [CO2] 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 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.

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.

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.

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.