Influence of Atherosclerotic Risk Factors on the Effectiveness of Therapeutic Ultrasound Cavitation for Flow Augmentation
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J. Todd Belcik↗
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Results for “Therapeutic Ultrasound”
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Vessel Rupture Thresholds for Vessel–Bubble Interactions Using an Earthworm Vasculature Model
Intravenous microbubble oscillation in the presence of ultrasound has the potential to yield a wide range of therapeutic benefits. However, the likelihood of vessel damage caused by mechanical effects has not been quantified as a function of the numerous important parameters in therapeutic ultrasound procedures. In this study, we examined the effects of microbubbles injected into the vasculature of the earthworm. It was found that the elastic properties of earthworm blood vessels are similar to those of arteries in older humans, and that earthworms are well suited to the large number of experiments necessary to investigate safety of procedures involving microbubble oscillation in sonicated vessels. Microbubbles were infused into earthworm vessels, and the rupture time during sonication was recorded as a function of ultrasound frequency, pulse repetition frequency and acoustic pressure. A modified mechanical index (MMI) was defined that successfully captured the trends in rupture probability and rupture time for the different parameter values, creating a database of vessel rupture thresholds. In the absence of bubbles, the product of MMI squared and rupture time was approximately constant, indicating a possible radiation-force effect. Here, the MMI was an effective correlating parameter in the presence of bubbles, though the mathematical dependence is not yet apparent. The results of the study are expected to be valuable in designing more refined studies in vertebrate models, as well as informing computational models.
59 BASIC BIOLOGICAL SCIENCES↗
(Phospho)Proteomic dataset of ischemia- and ultrasound- stimulated mouse cardiac endothelial cells in vitro
Cardiac endothelial cells respond to both ischemia and therapeutic ultrasound; the proteomic changes underlying these responses are unknown. This data article provides raw and processed data resulting from our global, unbiased phosphoproteomics investigation conducted on primary mouse cardiac endothelial cells exposed to ischemia (2-hour oxygen glucose deprivation) and ultrasound (250 kHz, 1.2 MPa) in vitro [1]. Proteins were extracted from cell lysates and enriched phosphopeptides were analyzed with a high mass accuracy liquid chromatrography (LC) - tandem mass spectrometry (MS/MS) proteomic platform, yielding multiple alterations in both total protein levels and phosphorylation events in response to ischemic injury and ultrasound. This dataset can be used as a reference for future studies on the cardiac endothelial response to ischemia and the mechanistic underpinnings of the cellular response to ultrasound, with the potential to yield clinically relevant therapeutic targets.
59 BASIC BIOLOGICAL SCIENCES↗
Poly( N -vinylpyrrolidone)- block -Poly(dimethylsiloxane)- block -Poly( N -vinylpyrrolidone) Triblock Copolymer Polymersomes for Delivery of PARP1 siRNA to Breast Cancers
Nearly 20% of HER2-positive breast cancers develop resistance to HER2-targeted therapies requiring the use of advanced therapies. Silencing RNA therapy may be a powerful modality for treating resistant HER2 cancers due to its high specificity and low toxicity. However, the systemic administration of siRNAs requires a safe and efficient delivery platform because of siRNA’s low stability in physiological fluids, inefficient cellular uptake, immunoreactivity, and rapid clearance. We have developed theranostic polymeric vesicles to overcome these hurdles for encapsulation and delivery of small functional molecules and PARP1 siRNA for in vivo delivery to breast cancer tumors. The 100 nm polymer vesicles were assembled from biodegradable and non-ionic poly(N-vinylpyrrolidone) 14 -block-poly(dimethylsiloxane) 47 -block-poly(N-vinylpyrrolidone) 14 triblock copolymer PVPON 14 -PDMS 47 -PVPON 14 using nanoprecipitation and thin-film hydration. We demonstrated that the vesicles assembled from the copolymer covalently tagged with the Cy5.5 fluorescent dye for in vivo imaging could also encapsulate the model drug with high loading efficiency (40%). The dye-loaded vesicles were accumulated in tumors after 18 h circulation in 4TR breast tumor-bearing mice via passive targeting. We found that PARP1 siRNA encapsulated into the vesicles was released intact (13%) into solution by the therapeutic ultrasound treatment as quantified by gel electrophoresis. Additionally, the PARP1 siRNA-loaded polymersomes inhibited the proliferation of MDA-MB-361TR cells by 34% after 6 days of treatment by suppressing the NF-kB signaling pathway, unlike their scrambled siRNA-loaded counterparts. Finally, the treatment by PARP1 siRNA-loaded vesicles prolonged the survival of the mice bearing 4T1 breast cancer xenografts, with the 4-fold survival increase, unlike the untreated mice after 3 weeks following the treatment. These biodegradable, non-ionic PVPON 14 -PDMS 47 -PVPON 14 polymeric nanovesicles capable of the efficient encapsulation and delivery of PARP1 siRNA to successfully knock down PARP1 in vivo can provide an advanced platform for the development of precision-targeted therapeutic carriers, which could help develop highly effective drug delivery nanovehicles for breast cancer gene therapy.
60 APPLIED LIFE SCIENCES↗
Assessing the Added Value of Miniature X-Ray in the Setting of Portable Ultrasound in Spaceflight
INTRODUCTION: Point-of-care ultrasound (POCUS) has become the standard of care for imaging diagnosis and management in low-Earth Orbit (LEO) spaceflight and it has long been hypothesized that POCUS will also be the standard of care for exploration spaceflight. However, like the trajectory for which ultrasound became more portable and user-friendly, the mass, volume, and power requirements of radiography devices for both diagnostic and therapeutic applications have also been dramatically reduced. This study seeks to determine the clinical utility and added value of miniature x-ray (XR) for the diagnosis and management of each of the 119 conditions within NASA Exploration Medical Capability’s IMPACT Condition List (ICL) given that the medical system is presumed to already be carrying a handheld portable POCUS device. METHODS: For each condition, a team of reviewers performed a rapid systematic literature review seeking sensitivity and specificity data for both handheld portable ultrasound and miniature XR. When there was a paucity of data, subject matter expertise and clinical experience was added to semi-quantitatively score the added value of miniature XR, given an US was already available for both diagnosis and management. Diagnostic utility of a modality for a condition was evaluated in the setting of both the best- and worst-case scenario definitions included and defined by the ICL. Evidence tracing and quality of evidence scores were also recorded. RESULTS/DISCUSSION: Conditions for which it was determined that miniature XR added diagnostic or therapeutic value are provided in this presentation. Previously presented work by our team has demonstrated that XR provides diagnostic and management capabilities that are hypothesized to complement or surpass ultrasound for over one-third of medical conditions that may arise during exploration spaceflight (i.e., diagnosis of injuries to the axial skeleton, teeth, and lungs as well as management of orthopedic reductions, endotracheal tube placement, and drain placement confirmation). In the setting of known inclusion of a handheld portable POCUS device, there remains significant added value of portable miniature XR. Whether or not this added clinical benefit is worth the mass, volume, and power requirements of the radiography system remains yet unknown and is the focus of future work. LEARNING OBJECTIVES: 1) Understand the value of ultrasound and radiography in the diagnosis and management of medical comorbidities that may arise in exploration spaceflight; 2) Understand the medical conditions of highest concern on exploration class missions for which miniature x-ray may provide added value to portable ultrasound.
J G Steller↗
Assessing the Added Value of Miniature X-Ray in the Setting of US in Spaceflight
INTRODUCTION: Point-of-care ultrasound (POCUS) has become the standard of care for imaging diagnosis and management in lowEarth Orbit (LEO) spaceflight and it has long been hypothesized that POCUS will also be the standard of care for exploration spaceflight. However, like the trajectory for which ultrasound became more portable and user-friendly, the mass, volume, and power requirements of radiography devices for both diagnostic and therapeutic applications have also been dramatically reduced. This study seeks to determine the clinical utility and added value of miniature x-ray (XR) for the diagnosis and management of each of the 119 conditions within NASA Exploration Medical Capability’s IMPACT Condition List (ICL) given that the medical system is presumed to already be carrying a handheld portable POCUS device. METHODS: For each condition, a team of reviewers performed a rapid systematic literature review seeking sensitivity and specificity data for both handheld portable ultrasound and miniature XR. When there was a paucity of data, subject matter expertise and clinical experience was added to semi-quantitatively score the added value of miniature XR, given an US was already available for both diagnosis and management. Diagnostic utility of a modality for a condition was evaluated in the setting of both the best- and worst-case scenario definitions included and defined by the ICL. Evidence tracing and quality of evidence scores were also recorded. RESULTS/DISCUSSION: Conditions for which it was determined that miniature XR added diagnostic or therapeutic value are provided in this presentation. Previously presented work by our team has demonstrated that XR provides diagnostic and management capabilities that are hypothesized to complement or surpass ultrasound for over one-third of medical conditions that may arise during exploration spaceflight (i.e., diagnosis of injuries to the axial skeleton, teeth, and lungs as well as management of orthopedic reductions, endotracheal tube placement, and drain placement confirmation). In the setting of known inclusion of a handheld portable POCUS device, there remains significant added value of portable miniature XR. Whether or not this added clinical benefit is worth the mass, volume, and power requirements of the radiography system remains yet unknown and is the focus of future work. LEARNING OBJECTIVES: 1) Understand the value of ultrasound and radiography in the diagnosis and management of medical comorbidities that may arise in exploration spaceflight; 2) Understand the medical conditions of highest concern on exploration class missions for which miniature x-ray may provide added value to portable ultrasound.
Jon Steller↗
Focused Ultrasound-Mediated Blood-Brain Barrier Opening Increases Delivery and Efficacy of Etoposide for Glioblastoma Treatment
Glioblastoma (GBM) is a devastating disease. With the current treatment of surgery followed by chemoradiation, outcomes remain poor, with median survival of only 15 months and a 5-year survival rate of 6.8%. A challenge in treating GBM is the heterogeneous integrity of the blood-brain barrier (BBB), which limits the bioavailability of systemic therapies to the brain. There is a growing interest in enhancing drug delivery by opening the BBB with the use of focused ultrasound (FUS). We hypothesize that an FUS-mediated BBB opening can enhance the delivery of etoposide for a therapeutic benefit in GBM.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Magnetic Microspheres for Therapeutical Applications
Hyperthermia is a well known cancer therapy and consists of heating a tumor region to the elevated temperatures in the range of 40-45 C for an extended period of time (2-8 hours). This leads to thermal inactivation of cell regulatory and growth processes with resulting widespread necrosis, carbonization and coagulation. Moreover, heat boosts the tumor response to other treatments such as radiation, chemotherapy or immunotherapy. Of particular importance is careful control of generated heat in the treated region and keeping it localized. Higher heating, to about 56 C can lead to tissue thermo-ablation. With accurate temperature control, hyperthermia has the advantage of having minimal side effects. Several heating techniques are utilized for this purpose, such as whole body hyperthermia, radio-frequency (RF) hyperthermia, ultrasound technique, inductive microwave antenna hyperthermia, inductive needles (thermoseeds), and magnetic fluid hyperthermia (MFH).MFH offers many advantages as targeting capability by applying magnets. However, this technology still suffers significant inefficiencies due to lack of thermal control. This paper will provide a review of the topic and outline the ongoing work in this area. The main emphasis is in devising ways to overcome the technical difficulty in hyperthermia therapy of achieving a uniform therapeutic temperature over the required region of the body and holding it steady. The basic obstacle of the present heating methods are non-uniform thermal properties of the tissue. Our approach is to develop a novel class of magnetic fluids which have inherent thermoregulating properties. We have identified a few magnetic alloys which can serve as a suitable nano-particle material. The objective is to synthesize, characterize and evaluate the efficacy of TRMF for hyperthermia therapy.
Mazuruk, K.↗
Magnetic Microspheres and Tissue Model Studies for Therapeutical Applications
Hyperthermia is a well known cancer therapy and consists of heating a tumor region to the elevated temperatures in the range of 40-45 C for an extended period of time (2-8 hours). This leads to thermal inactivation of cell regulatory and growth processes with resulting widespread necrosis, carbonization and coagulation. Moreover, heat boosts the tumor response to other treatments such as radiation, chemotherapy or immunotherapy. Of particular importance is careful control of generated heat in the treated region and keeping it localized. Higher heating, to about 56 C can lead to tissue thermo-ablation. With accurate temperature control, hyperthermia has the advantage of having minimal side effects. Several heating techniques are utilized for this purpose, such as whole body hyperthermia, radio-frequency (RF) hyperthermia, ultrasound technique, inductive microwave antenna hyperthermia, inductive needles (thermoseeds), and magnetic fluid hyperthermia (MFH).MFH offers many advantages as targeting capability by applying magnets. However, this technology still suffers significant inefficiencies due to lack of thermal control. This paper will provide a review of the topic and outline the ongoing work in this area. The main emphasis is in devising ways to overcome the technical difficulty in hyperthermia breast therapy of achieving a uniform therapeutic temperature over the required region of the body and holding it steady for an extended period (2-3 hours). The basic shortcomings of the presently utilized heating methods stem from the non-uniform thermal properties of the tissue and the point heating characteristics of the techniques without any thermal control. Our approach is to develop a novel class of magnetic fluids, which have inherent thermoregulating properties. We have identified a few magnetic alloys which can serve as suitable nano to micron-size particle material. The objective is to synthesize, characterize and evaluate the efficacy of Thermo Regulating Magnetic Fluids (TRMF) for hyperthermia therapy. The development of a tissue model and testing the fluid dynamics of particle motion, settling, distribution in the tissue matrix and heat generation will be discussed.
Ramachandran, N.↗
Piezoelectric Charging and Wireless Communication
Modern medicine is undergoing a revolution in the application of new sensor capabilities for aiding in diagnosis of specific conditions and monitoring a variety of informative vital signs. In the past, many of the measurements were limited by what could be accomplished externally. A shift toward in-vivo monitoring for both diagnostic and therapeutic sensing and actuation [1] has created a need for low power electronics, high energy density batteries and methods to successfully power devices embedded in the body. For a review of the field and sensing capabilities see [2]. Recent studies suggest that charging with ultrasound is more efficient at longer transmission distance (> 10cm) than inductive charging [3]. In this manuscript, we discuss the modeling and experimentation that we have accomplished and demonstrate in ultrasonic charging of sensors having the form and fit of in-vivo sensors. The task goal has been to use piezoelectric transducers for wireless communication and powering of sensors internal to the human body with a goal to transmit power levels of 100 W a receiver with receiving area of 3x3 mm2 over a distance of 16 cm equivalent to human body interior. The results suggest that we can transmit power levels that exceed this baseline requirement.
Jackson, Shannon↗
Breast tumor-targeted drug delivery via polymer nanocarriers: Endogenous and exogenous strategies
Breast cancer, one of the most common types of cancer worldwide, has a high degree of malignancy while lacking efficient treatments. The off-target events frequently occurring in drug administration have been a major obstacle, which causes severe side effects to patients and reduces the therapeutic efficacy. An ideal medication should precisely target the specific site with precise control over concentration and duration. In recent years, there has been immense progress in polymer nanocarriers that demonstrate great potential in the targeted delivery. These nanocarriers are constructed from materials sensitive to a wide range of endogenous (e.g., pH, enzyme, redox) and exogenous stimuli (e.g., light, ultrasound, magnetic waves), driving cargo release to the targeted tissue or cells. Here, we elucidate the mechanism of current targeting strategies and the engineering methods to construct these targeting systems or to improve their targeting efficiency. Here we capture the recent progress in the targeted nanocarriers derived from polymers which span hydrogels and micelles, demonstrating their design and applications in chemo, hyperthermia, immuno, and gene therapies.
36 MATERIALS SCIENCE↗
Programmatic Considerations to Reduce the Risk of Adverse Renal Stone Events in Spaceflight
Introduction: Microgravity exposure may alter the likelihood that astronauts will experience renal stones. The potential risk includes both acute and chronic health issues, with the potential for significant impact on mission objectives. Methods: To understand the role of the NASA's Human Research Program (HRP) research agenda in both preventing and addressing renal stones in spaceflight, current astronaut epidemiologic data and a summary of programmatic considerations are reviewed. Results: Although there has never been a symptomatic renal stone event in a U.S. crewmember during spaceflight, urine chemistry has been altered - likely due to induced changes in renal physiology as a result of exposure to microgravity. This may predispose astronauts to stone formation, leading the HRP to conduct and sponsor research to: 1) understand the risk of stone formation in space; 2) prevent stones from forming; and 3) address stones that may form by providing novel diagnostic and therapeutic approaches. Discussion: The development of a renal stone during spaceflight is a significant medical concern that requires the HRP to minimize this risk by providing the ability to prevent, diagnose, monitor and treat the condition during spaceflight. A discussion of the risk as NASA understands it is followed by an overview of the multiple mitigations currently under study, including novel ultrasound techniques for stone detection and manipulation, and how they may function as part of a larger exploration medical system.
Antonsen, Erik↗
Clinical Outcome Metrics for Optimization of Robust Training
Introduction: The emphasis of this research is on the Human Research Program (HRP) Exploration Medical Capability's (ExMC) "Risk of Unacceptable Health and Mission Outcomes Due to Limitations of In-Flight Medical Capabilities." Specifically, this project aims to contribute to the closure of gap ExMC 2.02: We do not know how the inclusion of a physician crew medical officer quantitatively impacts clinical outcomes during exploration missions. The experiments are specifically designed to address clinical outcome differences between physician and non-physician cohorts in both near-term and longer-term (mission impacting) outcomes. Methods: Medical simulations will systematically compare success of individual diagnostic and therapeutic procedure simulations performed by physician and non-physician crew medical officer (CMO) analogs using clearly defined short-term (individual procedure) outcome metrics. In the subsequent step of the project, the procedure simulation outcomes will be used as input to a modified version of the NASA Integrated Medical Model (IMM) to analyze the effect of the outcome (degree of success) of individual procedures (including successful, imperfectly performed, and failed procedures) on overall long-term clinical outcomes and the consequent mission impacts. The procedures to be simulated are endotracheal intubation, fundoscopic examination, kidney/urinary ultrasound, ultrasound-guided intravenous catheter insertion, and a differential diagnosis exercise. Multiple assessment techniques will be used, centered on medical procedure simulation studies occurring at 3, 6, and 12 months after initial training (as depicted in the following flow diagram of the experiment design). Discussion: Analysis of procedure outcomes in the physician and non-physician groups and their subsets (tested at different elapsed times post training) will allow the team to 1) define differences between physician and non-physician CMOs in terms of both procedure performance (pre-IMM analysis) and overall mitigation of the mission medical impact (IMM analysis); 2) refine the procedure outcome and clinical outcome metrics themselves; 3) refine or develop innovative medical training products and solutions to maximize CMO performance; and 4) validate the methods and products of this experiment for operational use in the planning, execution, and quality assurance of the CMO training process The team has finalized training protocols and developed a software training/testing tool in collaboration with Butler Graphics (Detroit, MI). In addition to the "hands on" medical procedure modules, the software includes a differential diagnosis exercise (limited clinical decision support tool) to evaluate the diagnostic skills of participants. Human subject testing will occur over the next year.
Ebert, D.↗