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Administration of drugs through oral and intravenous routes is a mainstay of modern medicine, but this approach suffers from limitations associated with off-target side effects and narrow therapeutic windows. It is often apparent that a controlled delivery of drugs, either localized to a specific site or during a specific time, can increase efficacy and bypass problems with systemic toxicity and insufficient local availability. To overcome some of these issues, local delivery systems have been devised, but most are still restricted in terms of elution kinetics, duration, and temporal control. Ultrasound-targeted drug delivery offers a powerful approach to increase delivery, therapeutic efficacy, and temporal release of drugs ranging from chemotherapeutics to antibiotics. The use of ultrasound can focus on increasing tissue sensitivity to the drug or actually be a critical component of the drug delivery. The high spatial and temporal resolution of ultrasound enables precise location, targeting, and timing of drug delivery and tissue sensitization. Thus, this noninvasive, non-ionizing, and relatively inexpensive modality makes the implementation of ultrasound-mediated drug delivery a powerful method that can be readily translated into the clinical arena. This review covers key concepts and areas applied in the design of different ultrasound-mediated drug delivery systems across a variety of clinical applications.

Conventional cross-sectional imaging done shortly after radioembolization of hepatocellular carcinoma (HCC) does not reliably predict long-term response to treatment. This study evaluated whether quantitative contrast-enhanced ultrasound (CEUS) can predict the long-term response of HCC to yttrium-90 (Y-90) treatment. Fifteen patients underwent CEUS at three time points: immediately following treatment and 1 and 2 wk post-treatment. Response 3–6 mo after treatment was categorized on contrast-enhanced magnetic resonance imaging by two experienced radiologists using the Modified Response Evaluation Criteria in Solid Tumors. CEUS data were analyzed by quantifying tumor perfusion and residual fractional vascularity using time–intensity curves. Patients with stable disease on magnetic resonance imaging had significantly greater fractional vascularity 2 wk post-treatment (65.15%) than those with partial or complete response (13.8 ± 9.9%, p = 0.007, and 14.9 ± 15.4%, p = 0.009, respectively). Complete responders had lower tumor vascularity at 2 wk than at post-operative examination (–38.3 ± 15.4%, p = 0.045). Thus, this pilot study suggests CEUS may provide an earlier indication of Y-90 treatment response than cross-sectional imaging.

BACKGROUND: US contrast agents are gas-filled microbubbles (MBs) that can be locally destroyed by using external US. Among other bioeffects, US-triggered MB destruction, also known as UTMD, has been shown to sensitize solid tumors to radiation in preclinical models through localized insult to the vascular endothelial cells. PURPOSE: To evaluate the safety and preliminary efficacy of combining US-triggered MB destruction and transarterial radioembolization (TARE) in participants with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: In this pilot clinical trial, participants with HCC scheduled for sublobar TARE were randomized to undergo either TARE or TARE with US-triggered MB destruction 1–4 hours and approximately 1 and 2 weeks after TARE. Enrollment took place between July 2017 and February 2020. Safety of US-triggered MB destruction was evaluated by physiologic monitoring, changes in liver function tests, adverse events, and radiopharmaceutical distribution. Treatment efficacy was evaluated by using modified Response Evaluation Criteria in Solid Tumors (mRECIST) on cross-sectional images, time to required next treatment, transplant rates, and overall survival. Differences across mRECIST reads were compared by using a Mann-Whitney U test, and the difference in prevalence of tumor response was evaluated by Fisher exact test, whereas differences in time to required next treatment and overall survival curves were compared by using a log-rank (Mantel-Cox) test. RESULTS: Safety results from 28 participants (mean age, 70 years ± 10 [standard deviation]; 17 men) demonstrated no significant changes in temperature (P = .31), heart rate (P = .92), diastolic pressure (P = .31), or systolic pressure (P = .06) before and after US-triggered MB destruction. No changes in liver function tests between treatment arms were observed 1 month after TARE (P > .15). Preliminary efficacy results showed a greater prevalence of tumor response (14 of 15 [93%; 95% CI: 68, 100] vs five of 10 [50%; 95% CI: 19, 81]; P = .02) in participants who underwent both US-triggered MB destruction and TARE (P = .02). CONCLUSION: The combination of US-triggered microbubble destruction and transarterial radioembolization is feasible with an excellent safety profile in this patient population and appears to result in improved hepatocellular carcinoma treatment response. © RSNA, 2020

Penile prosthesis (PP) is a gold standard for treatment of erectile dysfunction given its reliability and efficacy. Infection remains the most feared complication of prosthetic surgery, which usually results in device removal, and places a significant economic burden on the healthcare system. While biofilms have shown to support the persistence of microorganisms, the degree by which this matrix is truly pathogenic remains unknown given its high prevalence even in asymptomatic patients. We aim to review and summarize the current literature pertaining to biofilm formation in the setting of PP surgeries in clinically infected and non-infected cases.Searches were performed in the MEDLINE online database through PubMed using a combination of keywords "penile prosthetic" OR "penile prosthesis" OR "penile implant" AND "biofilm" OR "revision" OR "removal" OR "infection" OR "explant". Eleven articles met inclusion criteria. There were only three studies that explicitly listed the number of biofilms identified in their cohort, but we also included eight articles that mentioned swabbing and culturing of any bacterial biofilm during revision procedures for both clinically infected and non-infected implants.Infected PP yielded a 11-100% rate of biofilm presence, while non-infected PP yielded a 3-70% rate of biofilm presence. Time to reoperation from initial PP placement were also largely variable, ranging from 2 weeks to over 2 years. Coagulase-negative staphylococcus (i.e.,Since the advent of PP surgery, diabetes control, revision washout protocols and antibiotic-impregnated devices have led to an overall decrease in biofilm formation and infectious complications. There is an overall paradigm shift in microbial profiles with more virulent organisms, such as

Neuroblastoma (NB) is the most common extracranial solid tumor in infants and children, and imposes significant morbidity and mortality in this population. The aggressive chemoradiotherapy required to treat high-risk NB results in survival of less than 50%, yet is associated with significant long-term adverse effects in survivors. Boosting efficacy and reducing morbidity are therefore key goals of treatment for affected children. We hypothesize that these may be achieved by developing strategies that both focus and limit toxic therapies to the region of the tumor. One such strategy is the use of targeted image-guided drug delivery (IGDD), which is growing in popularity in personalized therapy to simultaneously improve on-target drug deposition and assess drug pharmacodynamics in individual patients. IGDD strategies can utilize a variety of imaging modalities and methods of actively targeting pharmaceutical drugs, however in vivo imaging in combination with focused ultrasound is one of the most promising approaches already being deployed for clinical applications. Over the last two decades, IGDD using focused ultrasound with “microbubble” ultrasound contrast agents (UCAs) has been increasingly explored as a method of targeting a wide variety of diseases, including cancer. This technique, known as sonopermeation, mechanically augments vascular permeability, enabling increased penetration of drugs into target tissue. However, to date, methods of monitoring the vascular bioeffects of sonopermeation in vivo are lacking. UCAs are excellent vascular probes in contrast-enhanced ultrasound (CEUS) imaging, and are thus uniquely suited for monitoring the effects of sonopermeation in tumors. Methods: To monitor the therapeutic efficacy of sonopermeation in vivo, we developed a novel system using 2D and 3D quantitative contrast-enhanced ultrasound imaging (qCEUS). 3D tumor volume and contrast enhancement was used to evaluate changes in blood volume during sonopermeation. 2D qCEUS-derived time-intensity curves (TICs) were used to assess reperfusion rates following sonopermeation therapy. Intratumoral doxorubicin (and liposome) uptake in NB was evalauted ex vivo along with associated vascular changes. Results: In this study, we demonstrate that combining focused ultrasound therapy with UCAs can significantly enhance chemotherapeutic payload to NB in an orthotopic xenograft model, by improving delivery and tumoral uptake of long-circulating liposomal doxorubicin (L-DOX) nanoparticles. qCEUS imaging suggests that changes in flow rates are highly sensitive to sonopermeation and could be used to monitor the efficacy of treatment in vivo. Additionally, initial tumor perfusion may be a good predictor of drug uptake during sonopermeation. Following sonopermeation treatment, vascular biomarkers show increased permeability due to reduced pericyte coverage and rapid onset of doxorubicin-induced apoptosis of NB cells but without damage to blood vessels. Conclusion: Our results suggest that significant L-DOX uptake can occur by increasing tumor vascular permeability with microbubble sonopermeation without otherwise damaging the vasculature, as confirmed by in vivo qCEUS imaging and ex vivo analysis. The use of qCEUS imaging to monitor sonopermeation efficiency and predict drug uptake could potentially provide real-time feedback to clinicians for determining treatment efficacy in tumors, leading to better and more efficient personalized therapies. Finally, we demonstrate how the IGDD strategy outlined in this study could be implemented in human patients using a single case study.

OBJECTIVES—: This pilot study evaluated whether contrast-enhanced subharmonic imaging (SHI) could be used to characterize adnexal masses before surgical intervention. METHODS—: Ten women (with 12 lesions) scheduled for surgery of an ovarian mass underwent an SHI examination of their adnexal region using a modified LOGIQ E9 scanner (GE Healthcare, Waukesha, WI) with an endocavitary transducer, in which digital clips were acquired by pulse destruction-replenishment SHI across the lesions. Time-intensity curves were created offline to quantitatively evaluate SHI parameters (fractional tumor perfusion, peak contrast intensity, time to peak contrast enhancement, and area under the time-intensity curve), which were compared to pathologic characterizations of the lesions. RESULTS—: Of the 12 masses, 8 were benign, and 4 were malignant. A qualitative analysis of the SHI images by an experienced radiologist resulted in diagnostic accuracy of 70%, compared to 56% without contrast, whereas an inexperienced radiologist improved from 50% to 58% accuracy, demonstrating the benefit of SHI. A quantitative analysis of SHI parameters produced diagnostic accuracy as high as 81%. Peak contrast intensity was significantly greater in malignant than benign masses (mean ± SD, 0.109 ± 0.088 versus 0.046 ± 0.030 arbitrary units; P = .046). Malignant masses also showed significantly greater perfusion than benign masses (24.79% ± 25.34% versus 7.62% ± 6.50%; P = .045). When the radiologist reads were combined with the most predictive quantitative SHI parameter (percent perfusion), diagnostic accuracy improved to 84% for the experienced radiologist and 96% for the novice radiologist. CONCLUSIONS—: Results indicate that SHI for presurgical characterization of adnexal masses may improve the determination of malignancy and diagnostic accuracy, albeit based on a small sample size.

PURPOSE—: Left ventricular assist device (LVAD) support is associated with peripheral vascular abnormalities beyond those associated with heart failure (HF). These abnormalities are associated with persistent functional impairments that adversely impact quality of life (QoL). Methods for measuring peripheral vascular function in this population are needed. METHODS—: This pilot study investigated the use of contrast-enhanced ultrasound (CEUS) using standardized protocols to estimate changes in peripheral (quadriceps) muscle perfusion among patients with HF (INTERMACS profile 3) undergoing LVAD implantation (n = 7). Patients were then stratified by those who did (“responders”, n = 4) and did not (“nonresponders”, n = 3) report QoL improvement with LVAD support. RESULTS—: Serial measurements obtained preoperatively and 3 months following LVAD implantation showed no significant change (P > .23) in muscle perfusion by all CEUS-based measures at rest or with an exercise stimulus for the overall population. Responders exhibited improved muscle perfusion at rest (P = .043) and decreased time to peak contrast enhancement (P = .010) at 3 months compared with baseline, suggesting improved delivery of blood to the extremities post-LVAD. Nonresponders showed unchanged resting muscle perfusion (P > .99), time to peak contrast enhancement (P = .59), and response to exercise stimulus (P > .99) following LVAD therapy. CONCLUSION—: Our findings suggest that CEUS evaluation is a promising noninvasive, quantitative modality for real-time assessment of peripheral vasculature and muscle perfusion as an indication of treatment response in LVAD recipients and that this modality may capture perfusion measures important to QoL following LVAD implantation.

Ultrasound imaging presents many positive attributes, including safety, real-time imaging, universal accessibility, and cost. However, inherent difficulties in discrimination between soft tissues and tumors prompted development of stabilized microbubble contrast agents. This presents the opportunity to develop agents in which drug is entrapped in the microbubble shell. We describe preparation and characterization of theranostic poly(lactide) (PLA) and pegylated PLA (PEG-PLA) shelled microbubbles that entrap gemcitabine, a commonly used drug for pancreatic cancer (PDAC). Entrapping 6 wt% gemcitabine did not significantly affect drug activity, microbubble morphology, or ultrasound contrast activity compared with unmodified microbubbles. In vitro microbubble concentrations yielding ≥ 500nM entrapped gemcitabine were needed for complete cell death in MIA PaCa-2 PDAC drug sensitivity assays, compared with 62.5 nM free gemcitabine. In vivo administration of gemcitabine-loaded microbubbles to xenograft MIA PaCa-2 PDAC tumors in athymic mice was well tolerated and provided substantial tumoral image enhancement before and after destructive ultrasound pulses. However, no significant differences in tumor growth were observed among treatment groups, in keeping with the in vitro observation that much higher doses of gemcitabine are required to mirror free gemcitabine activity. Statement of significance The preliminary results shown here are encouraging and support further investigation into increased gemcitabine loading. Encapsulation of gemcitabine within polylactic acid (PLA) microbubbles does not damage its activity towards pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) cells. Excellent imaging and evidence of penetration into the highly desmoplastic PDAC tumors is demonstrated. Microbubble destruction was confirmed in vivo, showing that elevated mechanical index shatters the microbubbles for enhanced delivery. The potential to slow PDAC growth in vivo is shown, but higher gemcitabine concentrations are required. Current efforts are directed at increasing drug loading by inclusion of drug-carrying nanoparticles for effective in vivo treatment.

The implantation of penile protheses for the surgical treatment of erectile dysfunction has risen in popularity over the past several decades. Considerable advances have been made in surgical protocol and device design, specifically targeting infection prevention. Despite these efforts, device infection remains a critical problem, which causes significant physical and emotional burden to the patient. The aim of this review is to broaden the discussion of best practices by not only examining practices in urology, but additionally delving into the field of orthopaedic surgery to identify techniques and approaches that may be applied to penile prothesis surgery.

Post-operative infection is a catastrophic complication of spinal fusion surgery, with up to 10% occurrence, and existing preventative measures (i.e., peri-operative antibiotics) are only partially successful. To combat this clinical problem, we have designed a drug delivery system around polyetheretherketone (PEEK) clips to be used for prophylactic post-surgical release of antibiotics upon application of ultrasound. The overall hypothesis is that antimicrobial release from this system will aggressively combat post-surgical bacterial survival. This study investigated a set of acoustic parameters optimized for in vitro ultrasound-triggered coating rupture and subsequent release of encapsulated prophylactic antibiotics. We determined that a transducer frequency of 1.7 MHz produced the most consistent burst release, and that at this frequency a pulse repetition frequency of 6.4 kHz and acoustic output power of 100% (3.41 MPa) produced the greatest release, representing an important proof of principle and the basis for continued development of this novel drug delivery system.

This study evaluated whether quantitative contrast-enhanced ultrasound (CEUS) can predict long term response of hepatocellular carcinoma (HCC) to Yttrium-90 (Y-90) radioembolization therapy. Twelve patients scheduled for Y-90 radioembolization therapy of a previously untreated HCC underwent CEUS at 3 time points: immediately following treatment, and 7 and 14 days post-treatment. Ultrasound imaging was performed using a Siemens S3000 Helx scanner with a C6-1 probe in dual 2D B-mode/contrast mode. Treatment response was evaluated with MRI 3-4 months post-treatment using modified response evaluation criteria in solid tumors (mRECIST) by two experienced radiologists in consensus. CEUS data was analyzed by quantifying tumor perfusion and residual fractional vascularity, using contrast time intensity curves that were created off-line. At 7 days post-treatment, the patient with stable disease exhibited significantly greater tumor vascularity (70.96 ± 7.63%) than patients with partial response (30.88 ± 20.56%, p < 0.0001) and complete response (13.64 ± 10.97%, p < 0.0001). Additionally, patients with stable disease exhibited significantly greater tumor perfusion 14 days post-treatment (2.33 ± 0.22 ml/s*mg) than both partial response (0.05 ± 0.05 ml/s*mg, p < 0.0001) and complete response patients (0.47 ± 0.46 ml/s*mg, p < 0.0001). Although larger sample sizes and longer follow up are needed to fully evaluate the clinical impact of CEUS, it appears to provide an earlier indicator of Y-90 treatment response than MRI.

This study evaluated the efficacy of ultrasound-triggered drug delivery devices against bacterial infection in an ex vivo cadaveric rabbit spine model. Polylactic acid (PLA)-coated, vancomycin (VAN)-loaded polyether ether ketone (PEEK) devices (1 cm3) with a drug-loading reservoir (0.785 cm3) were 3D printed. Two device designs were evaluated: 1 large hole for drug release vs 2 smaller holes. Clips were implanted medial to the spinal midline in mature (~6 months, 3 kg) female White New Zealand cadaveric rabbits (n=4) under an IACUC-approved protocol. To simulate infection, 104 CFU of Staphylococcus aureus were added to 2 of the 4 sites; the other 2 sites were left clean. Two of the 4 sites (1 inoculated, 1 clean) were insonated for 20 minutes with a Logiq E9 ultrasound scanner (GE Healthcare, Waukesha, WI, USA) equipped with a C1-6 curvilinear probe, using power Doppler imaging (1.7 MHz frequency, 6.4 kHz PRF, 100% acoustic output power) to induce rupture of the PLA coating for VAN release. Infected sites showed marked reduction in bacterial colonization following ultrasound-triggered VAN release, while uninsonated sites exhibited little reduction in bacterial colonization. At 48 hours, there was significantly greater VAN release from the insonated clips compared to the uninsonated clips (p < 0.04). There was significantly greater ultrasound-triggered total VAN release from the 1-hole device design than from the 2-hole design (7420 ± 2992 µg vs. 3500 ± 954 µg, p < 0.0001). These levels are sufficient to prevent adhesion of S. aureus to implant materials. This study demonstrated the feasibility of an ultrasound-mediated antibiotic delivery device, which could become a potent weapon against spinal surgical site infections.

This clinical pilot study evaluated whether contrast-enhanced ultrasound subharmonic imaging (CEUS SHI) could be used to characterize indeterminate ovarian masses prior to surgical intervention. Ten women (with twelve lesions) scheduled for surgery of an ovarian mass underwent CEUS SHI examination of their pelvis using a modified Logiq E9 scanner (GE Healthcare, Waukesha, WI, USA) with an endocavitary transducer. Patients first received a bolus injection of ultrasound contrast agent Definity (Lantheus Medical Imaging, N Billerica, MA, USA), while ultrasound imaging was continuously performed up to 5 minutes after contrast injection. Following a 10 minute wait to ensure contrast agent clearance from the circulation, patients received an infusion of 1.5 ml of Definity diluted in 25 ml of saline over 5 minutes. During this time, destruction/ replenishment CEUS SHI imaging was performed in multiple planes across the lesion. The contrast time intensity curves were created off-line to quantitatively evaluate CEUS SHI kinetic parameters, which were compared to the tissue histology of the lesion after surgery. Of the 12 lesions, 8 were benign and 4 were malignant. Qualitative analysis of CEUS SHI images by a radiologist with 15 years of CEUS experience demonstrated diagnostic accuracy (determined as the area under the ROC curve) of 70%, compared to 56% without contrast, while analysis by a radiologist with 6 months of experience only improved from 50% to 57%. Diagnostic accuracy of quantitative CEUS SHI kinetic parameters was as high as 81%. Malignant masses showed significantly higher peak contrast intensity (p = 0.046) and overall perfusion (p = 0.045) than benign lesions. These results suggest that CEUS SHI for pre-surgical characterization of ovarian lesions may improve determination of malignancy, albeit based on a small sample size.

OBJECTIVES—: Hypoxic cancer cells have been shown to be more resistant to radiation therapy than normoxic cells. Hence, this study investigated whether ultrasound (US)-induced rupture of oxygen-carrying microbubbles (MBs) would enhance the response of breast cancer metastases to radiation. METHODS—: Nude mice (n = 15) received stereotactic injections of brain-seeking MDA-MB-231 breast cancer cells into the right hemisphere. Animals were randomly assigned into 1 of 5 treatment groups: no intervention, 10 Gy radiation using a small-animal radiation research platform, nitrogen-carrying MBs combined with US-mediated MB rupture immediately before 10 Gy radiation, oxygen-carrying MBs immediately before 10 Gy radiation, and oxygen-carrying MBs with US-mediated MB rupture immediately before 10 Gy radiation. Tumor progression was monitored with 3-dimensional US, and overall survival was noted. RESULTS—: All groups except those treated with oxygen-carrying MB rupture and radiation had continued rapid tumor growth after treatment. Tumors treated with radiation alone showed a mean increase in volume ± SD of 337% ± 214% during the week after treatment. Tumors treated with oxygen-carrying MBs and radiation without MB rupture showed an increase in volume of 383% ± 226%. Tumors treated with radiation immediately after rupture of oxygen-carrying MBs showed an increase in volume of only 41% ± 1% (P = 0.045), and this group also showed a 1 week increase in survival time. CONCLUSIONS—: Adding US-ruptured oxygen-carrying MBs to radiation therapy appears to delay tumor progression and improve survival in a murine model of metastatic breast cancer.