Therapeutic Ultrasound for Enhanced Corneal Permeability to Macromolecules.

Objectives: Topically applied macromolecules have the potential to provide vision-saving treatments for many of the leading causes of blindness in the United States. The aim of this study was to determine if ultrasound can be applied to increase transcorneal drug delivery of macromolecules without dangerously overheating surrounding ocular tissues.

Methods: Dissected corneas of adult rabbits were placed in a diffusion cell between a donor compartment filled with a solution of macromolecules (40, 70 kDa, or 150 kDa) and a receiver compartment.

Review of the Delivery Kinetics of Thermosensitive Liposomes.

Thermosensitive liposomes (TSL) are triggered nanoparticles that release the encapsulated drug in response to hyperthermia. Combined with localized hyperthermia, TSL enabled loco-regional drug delivery to tumors with reduced systemic toxicities. More recent TSL formulations are based on intravascular triggered release, where drug release occurs within the microvasculature.

Selecting ideal drugs for encapsulation in thermosensitive liposomes and other triggered nanoparticles.

Objective: Thermosensitive liposomes (TSL) and other triggered drug delivery systems (DDS) are promising therapeutic strategies for targeted drug delivery. However, successful designs with candidate drugs depend on many variables, including nanoparticle formulation, drug properties, and cancer cell properties. We developed a computational model based on experimental data to predict the potential efficacies of drugs when used with triggered DDS, such as TSL.

Extracorporeal Removal of Thermosensitive Liposomal Doxorubicin from Systemic Circulation after Tumor Delivery to Reduce Toxicities.

Thermosensitive liposomal doxorubicin (TSL-Dox) combined with localized hyperthermia enables targeted drug delivery. Tumor drug uptake occurs only during hyperthermia. We developed a novel method for removal of systemic TSL-Dox remaining after hyperthermia-triggered delivery to reduce toxicities.

Untargeted Large Volume Hyperthermia Reduces Tumor Drug Uptake From Thermosensitive Liposomes.

Goal: The impact of hyperthermia (HT) method on tumor drug uptake with thermosensitive liposomes (TSL) is not well understood.

Methods: We created realistic three-dimensional (3-D) computer models that simulate TSL-encapsulated doxorubicin (TSL-DOX) delivery in mouse tumors with three HT methods (thermistor probe (T), laser (L) and water bath (WB), at 15 min and 60 min HT duration), with corroborating studies.

Results: Average computer model-predicted tumor drug concentrations (g/g) were 8.

Computer simulations of an irrigated radiofrequency cardiac ablation catheter and experimental validation by infrared imaging.

Purpose: To develop and validate a three-dimensional (3-D) computer model based on accurate geometry of an irrigated cardiac radiofrequency (RF) ablation catheter with microwave radiometry capability, and to test catheter performance.

Methods: A computer model was developed based on CAD geometry of a RF cardiac ablation catheter prototype to simulate electromagnetic heating, heat transfer, and computational fluid dynamics (blood flow, open irrigation, and natural convection). Parametric studies were performed; blood flow velocity (0-25 cm/s) and irrigation flow (0-40 ml/min) varied, both with perpendicular (PE) and parallel (PA) catheter orientations relative to tissue.

Drug transport kinetics of intravascular triggered drug delivery systems.

Intravascular triggered drug delivery systems (IV-DDS) for local drug delivery include various stimuli-responsive nanoparticles that release the associated agent in response to internal (e.g., pH, enzymes) or external stimuli (e.

Closed-loop trans-skull ultrasound hyperthermia leads to improved drug delivery from thermosensitive drugs and promotes changes in vascular transport dynamics in brain tumors.

Effective drug delivery in brain tumors remains a major challenge in oncology. Although local hyperthermia and stimuli-responsive delivery systems, such as thermosensitive liposomes, represent promising strategies to locally enhance drug delivery in solid tumors and improve outcomes, their application in intracranial malignancies remains unexplored. We hypothesized that the combined abilities of closed-loop trans-skull Magnetic Resonance Imaging guided Focused Ultrasound (MRgFUS) hyperthermia with those of thermosensitive drugs can alleviate challenges in drug delivery and improve survival in gliomas.

Externally triggered smart drug delivery system encapsulating idarubicin shows superior kinetics and enhances tumoral drug uptake and response.

Increasing the bioavailable drug level in a tumor is the key to enhance efficacy of chemotherapy. Thermosensitive smart drug delivery systems (SDDS) in combination with local hyperthermia facilitate high local drug levels, thus improving uptake in the tumor. However, inability to rapidly and efficiently absorb the locally released drug results in reduced efficacy, as well as undesired redistribution of the drug away from the tumor to the system.

Computer Modeling of Drug Delivery with Thermosensitive Liposomes in a Realistic Three-Dimensional Geometry.

Thermosensitive liposomes (TSL) are nanoparticles that can encapsulate therapeutic drugs, and release those drugs when exposed to hyperthermic temperatures (>40 °C). Combined with localized hyperthermia, TSL enable focused drug delivery. In this study, we created a three-dimensional (3D) computer model for simulating delivery with TSL-encapsulated doxorubicin (TSL-Dox) to mouse tumors.

Real-time fluorescence imaging for visualization and drug uptake prediction during drug delivery by thermosensitive liposomes.

Thermosensitive liposomal doxorubicin (TSL-Dox) is a promising stimuli-responsive nanoparticle drug delivery system that rapidly releases the contained drug in response to hyperthermia (HT) (>40 °C). Combined with localized heating, TSL-Dox allows highly localized delivery. The goals of this study were to demonstrate that real-time fluorescence imaging can visualize drug uptake during delivery, and can predict tumor drug uptake.

Therapeutic Systems and Technologies: State-of-the-Art Applications, Opportunities, and Challenges.

In this review, we present current state-of-the-art developments and challenges in the areas of thermal therapy, ultrasound tomography, image-guided therapies, ocular drug delivery, and robotic devices in neurorehabilitation. Additionally, intellectual property and regulatory aspects pertaining to therapeutic systems and technologies are addressed.

In vitro Measurement of Release Kinetics of Temperature Sensitive Liposomes with a Fluorescence Imaging System.

Temperature sensitive liposomes (TSL) are a promising type of nanoparticles for localized drug delivery. TSL typically release the contained drug at mild hyperthermic temperatures (40-42 °C). Combined with localized hyperthermia, this allows for local drug delivery.

Permanent and Transient Electrophysiological Effects During Cardiac Cryoablation Documented by Optical Activation Mapping and Thermal Imaging.

Objective: Cardiac catheter cryoablation is a safer alternative to radiofrequency ablation for arrhythmia treatment, but electrophysiological (EP) effects during and after freezing are not adequately characterized. The goal of this study was to determine transient and permanent temperature induced EP effects, during and after localized tissue freezing.

Methods: Conduction in right (RV) and left ventricles (LV) was studied by optical activation mapping during and after cryoablation in paced, isolated Langendorff-perfused porcine hearts.

Thermosensitive Liposomes for Image-Guided Drug Delivery.

Liposomes have been employed as cancer therapy clinically since the 1990s, with the primary benefit of reduced toxicity but no appreciable efficacy improvement. Thermosensitive liposomes (TSLs) are specifically formulated such that they release the encapsulated drug when exposed to hyperthermic temperatures in the fever range (~40-42°C) and have been investigated as cancer therapy for several decades, with first clinical trials initiated in the last decade. Combined with localized hyperthermia, TSLs allow precise drug delivery to a targeted region.

Localized delivery of therapeutic doxorubicin dose across the canine blood-brain barrier with hyperthermia and temperature sensitive liposomes.

Most drugs cannot penetrate the blood-brain barrier (BBB), greatly limiting the use of anti-cancer agents for brain cancer therapy. Temperature sensitive liposomes (TSL) are nanoparticles that rapidly release the contained drug in response to hyperthermia (>40 °C). Since hyperthermia also transiently opens the BBB, we hypothesized that localized hyperthermia can achieve drug delivery across the BBB when combined with TSL.

A Unified Mathematical Model for Nano-Liposomal Drug Delivery to Solid Tumors.

Nanoparticles, such as liposomes, allow more targeted drug delivery for improved efficacy and/or reduced toxicity in both passive (e.g., Doxil) or active [e.

Lesion modeling, characterization, and visualization for image-guided cardiac ablation therapy monitoring.

In spite of significant efforts to improve image-guided ablation therapy, a large number of patients undergoing ablation therapy to treat cardiac arrhythmic conditions require repeat procedures. The delivery of insufficient thermal dose is a significant contributor to incomplete tissue ablation, in turn leading to the arrhythmia recurrence. Ongoing research efforts aim to better characterize and visualize RF delivery to monitor the induced tissue damage during therapy.

Technical Note: On Cardiac Ablation Lesion Visualization for Image-guided Therapy Monitoring.

The delivery of insufficient thermal dose is a significant contributor to incomplete tissue ablation and leads to arrhythmia recurrence and a large number of patients requiring repeat procedures. In concert with ongoing research efforts aimed at better characterizing the RF energy delivery, here we propose a method that entails modeling and visualization of the lesions in real time. The described image-based ablation model relies on classical heat transfer principles to estimate tissue temperature in response to the ablation parameters, tissue properties, and duration.

Drug release kinetics of temperature sensitive liposomes measured at high-temporal resolution with a millifluidic device.

Purpose: Current release assays have inadequate temporal resolution ( ∼ 10 s) to characterise temperature sensitive liposomes (TSL) designed for intravascular triggered drug release, where release within the first few seconds is relevant for drug delivery.

Materials And Methods: We developed a novel release assay based on a millifluidic device. A 500 µm capillary tube was heated by a temperature-controlled Peltier element.

Temperature sensitive liposomes combined with thermal ablation: Effects of duration and timing of heating in mathematical models and in vivo.

Background: Temperature sensitive liposomes (TSL) are nanoparticles that rapidly release the contained drug at hyperthermic temperatures, typically above ~40°C. TSL have been combined with various heating modalities, but there is no consensus on required hyperthermia duration or ideal timing of heating relative to TSL administration. The goal of this study was to determine changes in drug uptake when heating duration and timing are varied when combining TSL with radiofrequency ablation (RF) heating.

Lyso-thermosensitive liposomal doxorubicin for treatment of bladder cancer.

Purpose: To evaluate lyso-thermosensitive liposomal doxorubicin (LTLD, ThermoDox) in combination with loco-regional mild hyperthermia (HT) for targeted drug delivery to the bladder wall and potential treatment of bladder cancer.

Material And Methods: Porcine in vivo studies were performed with the following groups: (i) intravenous (IV) LTLD with hyperthermia (LTLD + HT); (ii) IV doxorubicin (DOX) with hyperthermia (IV DOX + HT) and (iii) IV LTLD without hyperthermia (LTLD - HT). Drug formulations were delivered via 30 min IV infusion coinciding with 1-h bladder irrigation (45 °C water for HT groups, 37 °C for non-HT group), followed by immediate bladder resection.

Experimental measurement of microwave ablation heating pattern and comparison to computer simulations.

Introduction: For computational models of microwave ablation (MWA), knowledge of the antenna design is necessary, but the proprietary design of clinical applicators is often unknown. We characterised the specific absorption rate (SAR) during MWA experimentally and compared to a multi-physics simulation.

Methods: An infrared (IR) camera was used to measure SAR during MWA within a split ex vivo liver model.