First-in-Man Study of a Cardiac Extracellular Matrix Hydrogel in Early and Late Myocardial Infarction Patients.

This study evaluated the safety and feasibility of transendocardial injections of VentriGel, a cardiac extracellular matrix hydrogel, in early and late post-myocardial infarction (MI) patients with left ventricular (LV) dysfunction. VentriGel was delivered in 15 patients with moderate LV dysfunction (25% ≤ LV ejection fraction ≤ 45%) who were between 60 days to 3 years post-MI and were revascularized by percutaneous coronary intervention. The primary endpoints were incidence of adverse events and abnormal clinical laboratory results. This first-in-man study established the safety and feasibility of delivering VentriGel in post-MI patients, thus warranting further evaluation in larger, randomized clinical trials.

Safety and efficacy of an injectable extracellular matrix hydrogel for treating myocardial infarction.

New therapies are needed to prevent heart failure after myocardial infarction (MI). As experimental treatment strategies for MI approach translation, safety and efficacy must be established in relevant animal models that mimic the clinical situation. We have developed an injectable hydrogel derived from porcine myocardial extracellular matrix as a scaffold for cardiac repair after MI. We establish the safety and efficacy of this injectable biomaterial in large- and small-animal studies that simulate the clinical setting. Infarcted pigs were treated with percutaneous transendocardial injections of the myocardial matrix hydrogel 2 weeks after MI and evaluated after 3 months. Echocardiography indicated improvement in cardiac function, ventricular volumes, and global wall motion scores. Furthermore, a significantly larger zone of cardiac muscle was found at the endocardium in matrix-injected pigs compared to controls. In rats, we establish the safety of this biomaterial and explore the host response via direct injection into the left ventricular lumen and in an inflammation study, both of which support the biocompatibility of this material. Hemocompatibility studies with human blood indicate that exposure to the material at relevant concentrations does not affect clotting times or platelet activation. This work therefore provides a strong platform to move forward in clinical studies with this cardiac-specific biomaterial that can be delivered by catheter.

Catheter-deliverable hydrogel derived from decellularized ventricular extracellular matrix increases endogenous cardiomyocytes and preserves cardiac function post-myocardial infarction.

OBJECTIVES: This study evaluated the use of an injectable hydrogel derived from ventricular extracellular matrix (ECM) for treating myocardial infarction (MI) and its ability to be delivered percutaneously. BACKGROUND: Injectable materials offer promising alternatives to treat MI. Although most of the examined materials have shown preserved or improved cardiac function in small animal models, none have been specifically designed for the heart, and few have translated to catheter delivery in large animal models. METHODS: We have developed a myocardial-specific hydrogel, derived from decellularized ventricular ECM, which self-assembles when injected in vivo. Female Sprague-Dawley rats underwent ischemia reperfusion followed by injection of the hydrogel or saline 2 weeks later. The implantation response was assessed via histology and immunohistochemistry, and the potential for arrhythmogenesis was examined using programmed electrical stimulation 1 week post-injection. Cardiac function was analyzed with magnetic resonance imaging 1 week pre-injection and 4 weeks post-MI. In a porcine model, we delivered the hydrogel using the NOGA-guided MyoStar catheter (Biologics Delivery Systems, Irwindale, California), and utilized histology to assess retention of the material. RESULTS: We demonstrate that injection of the material in the rat MI model increases endogenous cardiomyocytes in the infarct area and maintains cardiac function without inducing arrhythmias. Furthermore, we demonstrate feasibility of transendocardial catheter injection in a porcine model. CONCLUSIONS: To our knowledge, this is the first in situ gelling material to be delivered via transendocardial injection in a large animal model, a critical step towards the translation of injectable materials for treating MI in humans. Our results warrant further study of this material in a large animal model of MI and suggest this may be a promising new therapy for treating MI.

Transurethral ultrasound applicators with dynamic multi-sector control for prostate thermal therapy: in vivo evaluation under MR guidance.

The purpose of this study was to explore the feasibility and performance of a multi-sectored tubular array transurethral ultrasound applicator for prostate thermal therapy, with potential to provide dynamic angular and length control of heating under MR guidance without mechanical movement of the applicator. Test configurations were fabricated, incorporating a linear array of two multi-sectored tubular transducers (7.8-8.4 MHz, 3 mm OD, 6 mm length), with three 120 degrees independent active sectors per tube. A flexible delivery catheter facilitated water cooling (100 ml min(-1)) within an expandable urethral balloon (35 mm long x 10 mm diameter). An integrated positioning hub allows for rotating and translating the transducer assembly within the urethral balloon for final targeting prior to therapy delivery. Rotational beam plots indicate approximately 90 degrees-100 degrees acoustic output patterns from each 120 degrees transducer sector, negligible coupling between sectors, and acoustic efficiencies between 41% and 53%. Experiments were performed within in vivo canine prostate (n = 3), with real-time MR temperature monitoring in either the axial or coronal planes to facilitate control of the heating profiles and provide thermal dosimetry for performance assessment. Gross inspection of serial sections of treated prostate, exposed to TTC (triphenyl tetrazolium chloride) tissue viability stain, allowed for direct assessment of the extent of thermal coagulation. These devices created large contiguous thermal lesions (defined by 52 degrees C maximum temperature, t43 = 240 min thermal dose contours, and TTC tissue sections) that extended radially from the applicator toward the border of the prostate (approximately15 mm) during a short power application (approximately 8-16 W per active sector, 8-15 min), with approximately 200 degrees or 360 degrees sector coagulation demonstrated depending upon the activation scheme. Analysis of transient temperature profiles indicated progression of lethal temperature and thermal dose contours initially centered on each sector that coalesced within approximately 5 min to produce uniform and contiguous zones of thermal destruction between sectors, with smooth outer boundaries and continued radial propagation in time. The dimension of the coagulation zone along the applicator was well-defined by positioning and active array length. Although not as precise as rotating planar and curvilinear devices currently under development for MR-guided procedures, advantages of these multi-sectored transurethral applicators include a flexible delivery catheter and that mechanical manipulation of the device using rotational motors is not required during therapy. This multi-sectored tubular array transurethral ultrasound technology has demonstrated potential for relatively fast and reasonably conformal targeting of prostate volumes suitable for the minimally invasive treatment of BPH and cancer under MR guidance, with further development warranted.

Monitoring prostate thermal therapy with diffusion-weighted MRI.

For MR-guided minimally invasive therapies, it is important to have a repeatable and reliable tissue viability evaluation method. The use of diffusion-weighted MRI (DWI) to evaluate tissue damage was assessed in 19 canine prostates with cryoablation or high-intensity ultrasound (HIU) ablation. The apparent diffusion coefficient (ADC) trace value was measured in the treated tissue immediately upon the procedure and on the posttreatment follow-up. For the acute lesions, the ADC value decreased to (1.05+/-0.25)x10(-3) mm2/s, as compared to (1.64+/-0.24)x10(-3) mm2/s before the treatment. There was no statistical difference between previously frozen or previously ultrasound-heated lesions in terms of the 36% ADC reduction (P=0.66). The ADC decrease occurred early during the course of the treatment, which appears to complicate DWI-based thermometry. Over time, the ADC value increased as the tissue recovered and regenerated. This study shows that DWI could be a promising method to monitor prostate thermal therapies and to provide insight on tissue damage and tissue remodeling after injury.

Referenceless MR thermometry for monitoring thermal ablation in the prostate.

Referenceless proton resonance frequency (PRF) shift thermometry provides a means to measure temperature changes during minimally invasive thermotherapy that is inherently robust to motion and tissue displacement. However, if the referenceless method is used to determine temperature changes during prostate ablation, phase gaps between water and fat in image regions used to determine the background phase can confound the phase estimation. We demonstrate an extension to referenceless thermometry which eliminates this problem by allowing background phase estimation in the presence of phase discontinuities between aqueous and fatty tissue. In this method, images are acquired with a multiecho sequence and binary water and fat maps are generated from a Dixon reconstruction. For the background phase estimation, water and fat regions are treated separately and the phase offset between the two tissue types is determined. The method is demonstrated feasibile in phantoms and during in vivo thermal ablation of canine prostate.

Multisectored interstitial ultrasound applicators for dynamic angular control of thermal therapy.

Dynamic angular control of thermal ablation and hyperthermia therapy with current interstitial heating technology is limited in capability, and often relies upon nonadjustable angular power deposition patterns and/or mechanical manipulation of the heating device. The objective of this study was to investigate the potential of multisectored tubular interstitial ultrasound devices to provide control of the angular heating distribution without device manipulation. Multisectored tubular transducers with independent sector power control were incorporated into modified versions of internally cooled (1.9 mm OD) and catheter-cooled (2.4 mm OD) interstitial ultrasound applicators in this work. The heating capabilities of these multisectored devices were evaluated by measurements of acoustic output properties, measurements of thermal lesions produced in ex vivo tissue samples, biothermal simulations of thermal ablation and hyperthermia treatments, and MR temperature imaging of ex vivo and in vivo experiments. Acoustic beam measurements of each applicator type displayed a 35 degrees -40 degrees acoustic dead zone between each independent sector, with negligible mechanical or electrical coupling. Thermal lesions produced in ex vivo liver tissue with one, two, or three sectors activated ranged from 13-18 mm in radius with contiguous zones of coagulation between active sectors. The simulations demonstrated the degree of angular control possible by using variable power levels applied to each sector, variable duration of applied constant power to individual sectors, respectively, or a multipoint temperature controller to vary the power applied to each sector. Despite the acoustic dead zone between sectors, the simulations also showed that the variance from the maximum lesion radius with three elements activated is within 4%-13% for tissue perfusions from 1-10 kg m(-3) s(-1). Simulations of hyperthermia with maximum tissue temperatures of 45 degrees C and 48 degrees C displayed radial penetration up to 2 cm of the 40 degrees C steady-state contour. Thermal characterizations of trisectored applicators in ex vivo and in vivo muscle, using real-time MR thermal imaging, reinforced angular controllability and negligible radial variance of the heating pattern from the applicators, demonstrated effective heating penetration, and displayed MR compatibility. The multisectored interstitial ultrasound applicators developed in this study demonstrated a significant degree of dynamic angular control of a heating pattern without device manipulation, while maintaining heat penetration consistent with previously reported results from other interstitial ultrasound applicators.

Magnetic resonance-guided high-intensity ultrasound ablation of the prostate.

OBJECTIVES: This paper describes our work in developing techniques and devices for magnetic resonance (MR)-guided high-intensity ultrasound ablation of the prostate and includes review of relevant literature. METHODS: Catheter-based high-intensity ultrasound applicators, in interstitial and transurethral configurations, were developed to be used under MR guidance. Magnetic resonance thermometry and the relevant characteristics and artifacts were evaluated during in vivo thermal ablation of the prostate in 10 animals. Contrast-enhanced MR imaging (MRI) and diffusion-weighted MRI were used to assess tissue damage and compared with histology. RESULTS: During evaluation of these applicators, MR thermometry was used to monitor the temperature distributions in the prostate in real time. Magnetic resonance-derived maximum temperature thresholds of 52 degrees C and thermal dose thresholds of 240 minutes were used to control the extent of treatment and qualitatively correlated well with posttreatment imaging studies and histology. The directional transurethral devices are selective in their ability to target well-defined regions of the prostate gland and can be rotated in discrete steps to conform treatment to prescribed boundaries. The curvilinear applicator is the most precise of these directional techniques. Multisectored transurethral applicators, with dynamic angular control of heating and no rotation requirements, offer a fast and less complex means of treatment with less selective contouring. CONCLUSIONS: The catheter-based ultrasound devices can produce spatially selective regions of thermal destruction in prostate. The MR thermal imaging and thermal dose maps, obtained in multiple slices through the target volume, are useful for controlling therapy delivery (rotation, power levels, duration). Contrast-enhanced T1-weighted MRI and diffusion-weighted imaging are useful tools for assessing treatment.

Interstitial ultrasound applicators with dynamic angular control for thermal ablation of tumors under MR-guidance.

Thermal ablation has been investigated as a treatment for a variety of cancers. Heat treatments have not gained large-scale clinical acceptance due to inconsistencies in controlling heat deposition in vivo and the lack of precise temperature measurement. Interstitial ultrasound provide a good method of controlling the radial depth of a thermal lesion and the applicator designs evaluated in this study allow for dynamic angular control of the shape of the lesion. A trisectored internally water-cooled applicator (TriAD) and a rotating catheter water-cooled applicator (RIUS) angularly controlled thermal dose to a target area. Both devices were small in diameter (1.8 mm-2.4 mm), making them clinically feasible for minimally invasive treatment in device size-sensitive tissues. A biothermal model accounting for changes in acoustic attenuation and perfusion as a function of thermal dose was used to evaluate and predict applicator performance. The MR susceptibility artifact of the applicators was examined with MR temperature imaging (MRTI) sequences at 1.5 T and 0.5 T. Ex vivo experiments in turkey and beef muscle with realtime MRTI correlated well with results from the biothermal model. These results display the feasibility of thermally treating tumors with controllable interstitial ultrasound applicators under real-time MRTI and bracket the applicators' predicted performance in vivo.