Tornado-inspired acoustic vortex tweezer for trapping and manipulating microbubbles.

Spatially concentrating and manipulating biotherapeutic agents within the circulatory system is a longstanding challenge in medical applications due to the high velocity of blood flow, which greatly limits drug leakage and retention of the drug in the targeted region. To circumvent the disadvantages of current methods for systemic drug delivery, we propose tornado-inspired acoustic vortex tweezer (AVT) that generates net forces for noninvasive intravascular trapping of lipid-shelled gaseous microbubbles (MBs). MBs are used in a diverse range of medical applications, including as ultrasound contrast agents, for permeabilizing vessels, and as drug/gene carriers. We demonstrate that AVT can be used to successfully trap MBs and increase their local concentration in both static and flow conditions. Furthermore, MBs signals within mouse capillaries could be locally improved 1.7-fold and the location of trapped MBs could still be manipulated during the initiation of AVT. The proposed AVT technique is a compact, easy-to-use, and biocompatible method that enables systemic drug administration with extremely low doses.

Ultrasonic technologies in imaging and drug delivery.

Ultrasonic technologies show great promise for diagnostic imaging and drug delivery in theranostic applications. The development of functional and molecular ultrasound imaging is based on the technical breakthrough of high frame-rate ultrasound. The evolution of shear wave elastography, high-frequency ultrasound imaging, ultrasound contrast imaging, and super-resolution blood flow imaging are described in this review. Recently, the therapeutic potential of the interaction of ultrasound with microbubble cavitation or droplet vaporization has become recognized. Microbubbles and phase-change droplets not only provide effective contrast media, but also show great therapeutic potential. Interaction with ultrasound induces unique and distinguishable biophysical features in microbubbles and droplets that promote drug loading and delivery. In particular, this approach demonstrates potential for central nervous system applications. Here, we systemically review the technological developments of theranostic ultrasound including novel ultrasound imaging techniques, the synergetic use of ultrasound with microbubbles and droplets, and microbubble/droplet drug-loading strategies for anticancer applications and disease modulation. These advancements have transformed ultrasound from a purely diagnostic utility into a promising theranostic tool.

Sonogenetic-Based Neuromodulation for the Amelioration of Parkinson's Disease.

Sonogenetics is a promising strategy allowing the noninvasive and selective activation of targeted neurons in deep brain regions; nevertheless, its therapeutic outcome for neurodegeneration diseases that need long-term treatment remains to be verified. We previously enhanced the ultrasound (US) sensitivity of targeted cells by genetic modification with an engineered auditory-sensing protein, mPrestin (N7T, N308S). In this study, we expressed mPrestin in the dopaminergic neurons of the substantia nigra in Parkinson's disease (PD) mice and used 0.5 MHz US for repeated and localized brain stimulation. The mPrestin expression in dopaminergic neurons persisted for at least 56 days after a single shot of adeno-associated virus, suggesting that the period of expression was long enough for US treatment in mice. Compared to untreated mice, US stimulation ameliorated the dopaminergic neurodegeneration 10-fold and mitigated the PD symptoms of the mice 4-fold, suggesting that this sonogenetic strategy has the clinical potential to treat neurodegenerative diseases.

Cataract surgery in patients with corneal opacities.

BACKGROUND: Investigating the efficacy and safety of phacoemulsification with intraocular lens (IOL) implantation in corneal opacities. METHODS: This retrospective study was conducted in a tertiary medical center. Twenty-three eyes of 19 patients with cataracts and corneal opacities obscuring the pupillary center having received phacoemulsification with IOL insertion without any ancillary techniques were enrolled. The primary study outcome measures were uncorrected and best corrected visual acuity (BCVA), and complications. Backscatters of corneal scar lesions were evaluated by slit lamp-based haze grading, Scheimpflug Pentacam and anterior segment optical coherence tomography (ASOCT). Visual outcomes after cataract surgeries and improvement range were used to determine the safety and efficacy of cataract surgery for our patients. RESULTS: All patients underwent uneventful capsulorhexis and phacoemulsification. The mean age was 72.22 ± 10.1 years, and the mean follow-up period was 18.57 ± 15.42 months. The mean BCVA significantly improved from 1.45 ± 0.65 preoperatively to 0.94 ± 0.55 logMAR postoperatively (p < 0.001), and the number of eyes with a BCVA of 20/100 or better increased from 4 to 14. Complications included corneal edema in two eyes and reactivation of the previous corneal pathology in five eyes. Four eyes did not achieve an improvement in visual acuity after surgery, which may have been due to co-existing ocular co-morbidities. Both Pentacam corneal densitometry and ASOCT demonstrated no significant correlations with final visual outcome. However, a statistically significant relationship between the severity of corneal opacity and improvement range in BCVA (r = - 0.782, P = 0.001) was found by our OCT grading method. CONCLUSIONS: Phacoemulsification and IOL implantation in selected cases of coexisting cataracts and corneal opacities is safe that can provide suboptimal but long-term vision when penetrating keratoplasty is not possible or at high-risk of graft failure. ASOCT is a simple tool to predict visual outcomes after cataract surgery in opacified corneas.

ExPRESS miniature glaucoma shunt for intractable secondary glaucoma in superior vena cava syndrome - a case report.

BACKGROUND: The aim of this study was to clarify the pathogenic mechanism and to evaluate an intervention for intractable secondary glaucoma in superior vena cava (SVC) syndrome. CASE PRESENTATION: A 66-year-old female with underlying hypertension, diabetes mellitus, ischaemic heart disease and end-stage renal disease complained of bilateral puffy eyelids for 3 months. Over three years, the patient experienced a progressive, marked face and neck swelling, which was accompanied by dyspnoea and nocturnal coughing. The patient has been under haemodialysis for the past 5 years; there were several occurrences of vascular access re-establishment for susceptibility to vascular thrombosis, and she was also diagnosed with SVC syndrome 2 years after haemodialysis. The patient's best-corrected visual acuity (BCVA) was 20/60 in the right eye and 20/400 in the left eye. Pneumatic tonometry revealed a gradual increase in the intraocular pressure (IOP), even with the use of three types of anti-glaucoma agents. The ratio was 0.7 and bilaterally symmetric; optical coherence tomography indicated a thinning of the superior and inferior retina nerve fibre layers, and standard automated perimetry showed partial to generalized depression in both eyes. Filtering surgery for the left eye was performed, but postoperatively, the IOP increased gradually over three months. The subsequent placement of the ExPRESS miniature glaucoma device p200 effectively lowered the IOP. Postoperatively, the IOP of the left eye remained under 20 mmHg without a further decrease in visual acuity, while the right eye, which was controlled with only medication, had an IOP of greater than 30 mmHg. Because this patient refused cardiovascular intervention, conventional trabeculectomy was used to redirect the aqueous humour to the subconjunctival space to form a bleb, but failed. Fortunately, the subsequent ExPRESS implant effectively facilitated aqueous outflow through the intrascleral space, resulting in the maintenance of a normal IOP at 6 months, postoperatively. CONCLUSION: Sustained high IOP may occur after conventional filtration surgery for secondary glaucoma in SVC syndrome. To facilitate aqueous outflow, an ExPRESS glaucoma implant can be used to effectively control the IOP.

Epithelial phenotype in total sclerocornea.

PURPOSE: To understand whether the epithelial phenotype in total sclerocornea is corneal or conjunctival in origin. METHODS: Four cases of total sclerocornea (male:female = 1:3; mean age = 5.4 ± 4.3; 1-11 years old) who received penetrating keratoplasty (PKP) at our hospital between 2008 and 2011 were included. Corneal buttons obtained during PKP were used for transmission electron microscopy (TEM) as well as immunoconfocal microscopy for cytokeratins 3, 12, and 13, goblet cell mucin MUC5AC, connexin 43, stem cell markers p63 and ABCG2, laminin-5, and fibronectin. RESULTS: After a mean follow-up period of 38.8 ± 14.0 (12-54) months, the grafts remained clear in half of the patients. TEM examination revealed a markedly attenuated Bowman's layer in the scleralized corneas, with irregular and variably thinned collagen lamellar layers, and disorganization and random distribution of collagen fibrils, which were much larger in diameter compared with a normal cornea. Immunoconfocal microscopy showed that keratin 3 was expressed in all four patients, while p63, ABCG2, and MUC5AC were all absent. Cornea-specific keratin 12 was universally expressed in Patients 1 to 3, while mucosa (including conjunctiva)-specific keratin 13 was negative in these patients. Interestingly, keratin 12 and 13 were expressed in Patient 4 in a mutually exclusive manner. Linear expression of laminin-5 in the basement membrane zone and similar expression of fibronectin were observed. CONCLUSIONS: The epithelia in total sclerocornea are essentially corneal in phenotype, but in the event of massive corneal angiogenesis, invasion by the conjunctival epithelium is possible.

Performance of Intra-arrest Echocardiography: A Systematic Review.

Introduction: Intra-arrest transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) have been introduced in adult patients with cardiac arrest (CA). Whether the diagnostic performance of TTE or TEE is superior during resuscitation is unclear. We conducted a systematic review following PRISMA guidelines. Methods: We searched databases from PubMed, Embase, and Google Scholar and evaluated articles with intra-arrest TTE and TEE in adult patients with non-traumatic CA. Two authors independently screened and selected articles for inclusion; they then dual-extracted study characteristics and target conditions (pericardial effusion, aortic dissection, pulmonary embolism, myocardial infarction, hypovolemia, left ventricular dysfunction, and sonographic cardiac activity). We performed quality assessment using the Quality Assessment of Diagnostic Accuracy Studies Version 2 criteria. Results: A total of 27 studies were included: 14 studies with 2,145 patients assessed TTE; and 16 with 556 patients assessed TEE. A high risk of bias or applicability concerns in at least one domain was present in 20 studies (74%). Both TTE and TEE found positive findings in nearly one-half of the patients. The etiology of CA was identified in 13% (271/2,145), and intervention was performed in 38% (102/271) of patients in the TTE group. In patients who received TEE, the etiology was identified in 43% (239/556), and intervention was performed in 28% (68/239). In the TEE group, a higher incidence regarding the etiology of CA was observed, particularly for those with aortic dissection. However, the outcome of those with aortic dissection in the TEE group was poor. Conclusion: While TEE could identify more causes of CA than TTE, sonographic cardiac activity was reported much more in the TTE group. The impact of TTE and TEE on the return of spontaneous circulation and further survival was still inconclusive in the current dataset.

Defective determination of synthetic cathinones in blood for forensic investigation.

Antemortem specimens are sometimes the sole sources available for forensic investigation, and samples collected in nonideal ways are inevitably employed to achieve toxicological analysis. It is essential to assess the effects of blood collection tubes on the recoveries of emerging synthetic cathinones (SC) to estimate actual drug concentrations, and no such systematic investigations have been previously carried out. Seventy-one SC with various LogP values were employed to examine commonly used blood collection tubes, including plasma tubes, serum tubes and gel-containing tubes in recoveries which determined by a reliable LC-MS/MS method. Significantly poor recoveries for hydrophobic SC were obtained using serum separating tubes (SST). Notably, the suppressed recoveries in SST can be reversed by adding anticoagulants. Adding a procoagulant to a plasma separating tube (PST) considerably reduced recoveries, which indicated that clotting processes in the presence of polymeric gels contributed to poor recoveries of these hydrophobic drugs. In this study, we find that clotting formation in the presence of polymeric gels could significantly affect the determination of hydrophobic drugs. However, in real-world scenarios, nonideal collection methods are inevitably employed for antemortem specimens. Thus, it is important to rigorously interpret forensic toxicological results, especially for susceptible species.

Oxygen-loaded microbubble-mediated sonoperfusion and oxygenation for neuroprotection after ischemic stroke reperfusion.

BACKGROUND: Ischemic stroke-reperfusion (S/R) injury is a crucial issue in the protection of brain function after thrombolysis. The vasodilation induced by ultrasound (US)-stimulated microbubble cavitation has been applied to reduce S/R injury through sonoperfusion. The present study uses oxygen-loaded microbubbles (OMBs) with US stimulation to provide sonoperfusion and local oxygen therapy for the reduction of brain infarct size and neuroprotection after S/R. METHODS: The murine S/R model was established by photodynamic thrombosis and thrombolysis at the remote branch of the anterior cerebral artery. In vivo blood flow, partial oxygen pressure (pO2), and brain infarct staining were examined to analyze the validity of the animal model and OMB treatment results. The animal behaviors and measurement of the brain infarct area were used to evaluate long-term recovery of brain function. RESULTS: The percentage of blood flow was 45 ± 3%, 70 ± 3%, and 86 ± 2% after 60 min stroke, 20 min reperfusion, and 10 min OMB treatment, respectively, demonstrating sonoperfusion, and the corresponding pO2 level was 60 ± 1%, 76 ± 2%, and 79 ± 4%, showing reoxygenation. After 14 days of treatment, a 87 ± 3% reduction in brain infarction and recovery of limb coordination were observed in S/R mice. The expression of NF-κB, HIF-1α, IL-1ß, and MMP-9 was inhibited and that of eNOS, BDNF, Bcl2, and IL-10 was enhanced, indicating activation of anti-inflammatory and anti-apoptosis responses and neuroprotection. Our study demonstrated that OMB treatment combines the beneficial effects of sonoperfusion and local oxygen therapy to reduce brain infarction and activate neuroprotection to prevent S/R injury.

Risk stratification of patients with chest pain who have an unscheduled revisit to the emergency department.

AIMS: Acute cardiovascular (CV) emergencies are critical conditions that require urgent attention in the emergency department (ED). Failure to make a timely diagnosis may result in unscheduled ED revisits and severe outcomes. Therefore, this study aimed to investigate the risk factors associated with potentially missed acute CV emergencies. METHODS AND RESULTS: This retrospective study enrolled adult patients who presented with chest pain and returned to the ED within 72 h. Demographic information, pre-existing medical conditions, chief complaints, triage level and vital signs, electrocardiography (ECG) reports, and laboratory data were collected from medical charts by independent physicians. The primary outcome was the diagnosis of acute CV diseases, including ACS, pulmonary embolism, unstable arrhythmia, acute decompensated heart failure, and aortic dissection. Multivariable logistic regression was used to analyze the association between variables and acute CV emergencies. A total of 453 eligible patients were included, with 60 (13.2%) patients diagnosed as acute CV emergencies at the ED revisit. Risk factors for acute CV emergencies included male gender (adjusted odds ratio [aOR] = 2.71, 95% confidence interval [CI] = 1.17-6.25), abnormal ECG rhythm (aOR = 10.33, 95% CI = 4.68-22.83), and abnormal changes in high sensitivity Troponin-T (hs-cTnT) during sequential follow-up (aOR = 6.52, 95% CI = 2.19-19.45). CONCLUSIONS: Male gender, abnormal ECG rhythm, and a significant increase in sequential follow-up hs-cTnT levels were identified as significant risk factors for acute CV emergencies. ED physicians should recognize these high-risk patients with chest pain to prevent misdiagnosis and potential severe complications.

Preventing ischemia-reperfusion injury by acousto-mechanical local oxygen delivery.

Ischemia-reperfusion (I/R) injury is a pathological process that causes vascular damage and dysfunction which increases recurrence and/or mortality in myocardial infarction, ischemic stroke, and organ transplantation. We hypothesized that ultrasound-stimulated oxygen-loaded microbubble (O2-MB) cavitation would enhance mechanical force on endothelium and simultaneously release oxygen locally at the targeted vessels. This cooperation between biomechanical and biochemical stimuli might modulate endothelial metabolism, providing a potential clinical approach to the prevention of I/R injury. Murine hindlimb and cardiac I/R models were used to demonstrate the feasibility of injury prevention by O2-MB cavitation. Increased mechanical force on endothelium induced eNOS-activated vasodilation and angiogenesis to prevent re-occlusion at the I/R vessels. Local oxygen therapy increased endothelial oxygenation that inhibited HIF-1α expression, increased ATP generation, and activated cyclin D1 for cell repair. Moreover, a decrease in interstitial H2O2 level reduced the expression of caspase3, NFκB, TNFα, and IL6, thus ameliorating inflammatory responses. O2-MB cavitation showed efficacy in maintaining cardiac function and preventing myocardial fibrosis after I/R. Finally, we present a potential pathway for the modulation of endothelial metabolism by O2-MB cavitation in relation to I/R injury, wound healing, and vascular bioeffects.

Selective Activation of Cells by Piezoelectric Molybdenum Disulfide Nanosheets with Focused Ultrasound.

An accurate method for neural stimulation within the brain could be very useful for treating brain circuit dysfunctions and neurological disorders. With the aim of developing such a method, this study investigated the use of piezoelectric molybdenum disulfide nanosheets (MoS2 NS) to remotely convert ultrasound energy into localized electrical stimulation in vitro and in vivo. The application of ultrasound to cells surrounding MoS2 NS required only a single pulse of 2 MHz ultrasound (400 kPa, 1,000,000 cycles, and 500 ms pulse duration) to elicit significant responses in 37.9 ± 7.4% of cells in terms of fluxes of calcium ions without detectable cellular damage. The proportion of responsive cells was mainly influenced by the acoustic pressure, number of ultrasound cycles, and concentration of MoS2 NS. Tests using appropriate blockers revealed that voltage-gated membrane channels were activated. In vivo data suggested that, with ultrasound stimulation, neurons closest to the MoS2 NS were 3-fold more likely to present c-Fos expression than cells far from the NS. The successful activation of neurons surrounding MoS2 NS suggests that this represents a method with high spatial precision for selectively modulating one or several targeted brain circuits.

A simplified scoring model for predicting bacteremia in the unscheduled emergency department revisits: The SADFUL score.

BACKGROUND: Bacteremia is a severe complication of infectious disease. Patients with a high bacteremia risk in the emergency department (ED) but misidentified would lead to the unscheduled revisits. This study aimed to develop a simplified scoring model to predict bacteremia in patients with unscheduled ED revisits. METHODS: Adult patients with unscheduled ED revisits within 72 h with a final diagnosis of infectious disease were retrospectively included. The development cohort included patients visiting the ED from January 1, 2019 to December 31, 2021. Internal validation was performed in patients visiting the ED from January 1, 2022 to March 31, 2022. Variables including demographics, pre-comorbidities, triage levels, vital signs, chief complaints, and laboratory data in the index visit were analyzed. Bacteremia was the primary outcome determined by blood culture in either index visits or revisits. RESULTS: The SADFUL score for predicting bacteremia comprised the following predictors: "S"egmented neutrophil percentage (+3 points), "A"ge > 55 years (+1 point), "D"iabetes mellitus (+1 point), "F"ever (+2 points), "U"pper respiratory tract symptoms (-2 points), and "L"eukopenia (2 points). The area under receiver operating characteristic curve with 95% confidence interval in the development (1802 patients, 190 [11%] with bacteremia) and the validation cohort (134 patients, 17 [13%] with bacteremia) were 0.78 (0.74-0.81) and 0.79 (0.71-0.88), respectively. CONCLUSIONS: The SADFUL score is a simplified useful tool for predicting bacteremia in patients with unscheduled ED revisits. The scoring model could help ED physicians decrease misidentification of patients at a high risk for bacteremia and potential complications.

Up-regulation of heat shock protein 70-1 (Hsp70-1) in human limbo-corneal epithelial cells cultivated on amniotic membrane: A proteomic study.

Transplantation of cultivated human limbo-corneal epithelial (HLE) cells has been recognized as an effective stem cell (SC) therapy for treating corneal epithelial SC deficiency caused by burn or other diseases. With this technique, cryo-preserved human intact amniotic membrane (IAM) has been successfully used as a cell culture substrate and carrier, and is reported to preferentially preserve HLE stem/progenitor cells in vitro. However, little is known about what factors released by HLE cells are involved in the progenitor cell-preserving mechanism. Using proteomic method, we identified 13 proteins over-expressed by HLE cells cultured on IAM, which included heat shock protein 70-1 (Hsp70-1), Hsp-27, glutathione (GSH) S-transferase, annexin A2, galectin-7, and protein S100-A9. Increased Hsp70-1 expression was confirmed by Western blot and real-time PCR. The role of Hsp70-1 in promoting HLE cell survival was demonstrated by increased apoptosis index and increased cleaved poly ADP-ribose polymerase (CPARP) formation in hsp70-1-silenced, but not normal HLE cells after exposure to sublethal UVB irradiation or hydrogen peroxide. To understand the regulatory mechanism of Hsp70-1 expression in HLE cells, the role of transcription factor deltaNp63 (a well-recognized HLE stem cell; SC marker) was studied. We found that over-expression of deltaNp63α by plasmid vector induced a corresponding increase in Hsp70-1 protein production. Likewise, Hsp70-1 expression decreased in HLE cells after addition of deltaNp63α SiRNA. Immunoconfocal microscopy also revealed a paralleled expression of both proteins in corneal specimens. Thus, deltaNp63α-associated Hsp70-1 over-expression may promote HLE progenitor cell survival on IAM, possibly through the cytoprotective and anti-apoptotic effect of Hsp70-1.

Overcoming Hypoxia-Induced Drug Resistance via Promotion of Drug Uptake and Reoxygenation by Acousto-Mechanical Oxygen Delivery.

Hypoxia-induced drug resistance (HDR) is a critical issue in cancer therapy. The presence of hypoxic tumor cells impedes drug uptake and reduces the cytotoxicity of chemotherapeutic drugs, leading to HDR and increasing the probability of tumor recurrence and metastasis. Microbubbles, which are used as an ultrasound contrast agent and drug/gas carrier, can locally deliver drugs/gas and produce an acousto-mechanical effect to enhance cell permeability under ultrasound sonication. The present study applied oxygen-loaded microbubbles (OMBs) to evaluate the mechanisms of overcoming HDR via promotion of drug uptake and reoxygenation. A hypoxic mouse prostate tumor cell model was established by hypoxic incubation for 4 h. After OMB treatment, the permeability of HDR cells was enhanced by 23 ± 5% and doxorubicin uptake was increased by 11 ± 7%. The 61 ± 14% reoxygenation of HDR cells increased the cytotoxicity of doxorubicin from 18 ± 4% to 58 ± 6%. In combination treatment with OMB and doxorubicin, the relative contributions of uptake promotion and reoxygenation towards overcoming HDR were 11 ± 7% and 28 ± 10%, respectively. Our study demonstrated that reoxygenation of hypoxic conditions is a critical mechanism in the inhibition of HDR and enhancing the outcome of OMB treatment.

State-of-the-art of ultrasound-triggered drug delivery from ultrasound-responsive drug carriers.

INTRODUCTION: Delivering sufficient therapeutics at the target site without off-target effects is a major goal of drug delivery technology innovation. Among the established methods, ultrasound (US) with US-responsible carriers holds great promise and demonstrates on-demand delivery of a variety of functional substances with spatial precision of several millimeters in deep-seated tissues in animal models and humans. These properties have motivated several explorations of US with US responsible-responsible carriers as a modality for neuromodulation and the treatment of various diseases, such as stroke and cancer. AREAS COVERED: We briefly discuss three specific mechanisms that enhance in vivo drug delivery via US with US-responsible carriers: 1) permeabilizing cellular membrane, 2) increasing the permeability of vessels, and 3) promoting cellular endocytotic uptake. We then reviewed the state-of-the-art materials for US-triggered drug delivery, including conventional US contrast agents, and nanocarrier formulations, such as inorganic nanoparticles and gas vesicles. EXPERT OPINION: In this article, we summarized recent progress for each of US-responsible drug carrier, focusing on the routes of enhancing delivery and applications. The mechanisms of interaction between US-responsible carriers and US waves, such as cavitation, streaming, hyperthermia, and ROS, as well as how those interactions can improve drug release and cell/tissue uptake.

Exploring the Acoustic and Dynamic Characteristics of Phase-Change Droplets.

Acoustic droplet vaporization (ADV) provides the on-demand production of bubbles for use in ultrasound (US)-based diagnostic and therapeutic applications. The droplet-to-bubble transition process has been shown to involve localized internal gas nucleation, followed by a volume expansion of threefold to fivefold and inertial bubble oscillation, all of which take place within a few microseconds. Monitoring these ADV processes is important in gauging the mechanical effects of phase-change droplets in a biological environment, but this is difficult to achieve using regular optical observations. In this study, we utilized acoustic characterization [i.e., simultaneous passive cavitation detection (PCD) and active cavitation detection (ACD)] to investigate the acoustic signatures emitted from phase-change droplets ADV and determined their correlations with the physical behaviors observed using high-speed optical imaging. The experimental results showed that activation with three-cycle 5-MHz US pulse resulted in the droplets (diameter: 3.0- [Formula: see text]) overexpanding and undergoing damped oscillation before settling to bubbles with a final diameter. Meanwhile, a broadband shock wave was observed at the beginning of the PCD signal. The intense fluctuations of the ACD signal revealed that the shock wave arose from the inertial cavitation of nucleated small gas pockets in the droplets. It was particularly interesting that another shock-wave signal with a much lower acoustic frequency (< 2 MHz) was observed at about [Formula: see text] after the first half signal. This signal coincided with the reduction of the ACD signal amplitude that indicated the rebound of the transforming bubble. Since internal gas nucleation is a crucial process of ADV, the first half signal may indicate the occurrence of an ADV event, and the second half signal may further reveal the degrees of expansion and oscillation of the bubble. These acoustic signatures provide opportunities for monitoring ADV dynamics based on the detection of acoustic signals.

Oscillatory behavior of microbubbles impacts efficacy of cellular drug delivery.

Drug-loaded microbubbles have been proven to be an effective strategy for non-invasive and local drug delivery when combined with ultrasound excitation for targeted drug release. Inertial cavitation is speculated to be a major mechanism for releasing drugs from drug-loaded microbubbles, but it results in lethal cellular pore damage that greatly limits its application. Thus, we investigated the cellular vesicle attachment and uptake to evaluate the efficiency of drug delivery by modulating the behaviors of targeted microbubble oscillation. The efficiency of vesicle attachment on the targeted cell membrane was 36.5 ± 15.9% and 3.8 ± 2.3% under stable and inertial cavitation, respectively. Further, stable cavitation enhanced cell permeability (26.8 ± 3.2%), maintained cell viability (90.8 ± 2.1%), and showed 7.9 ± 1.9-fold enhancement of in vivo vesicle release on tumor vessels. Therefore, our results reveal the ability to improve drug delivery via stable cavitation induced by targeted microbubbles. We propose that this strategy might be suitable for tissue repair or neuromodulation.

Dual-Frequency Chirp Excitation for Passive Cavitation Imaging in the Brain.

One of the main challenges that impede cavitation-mediated imaging in the brain is restricted opening of the blood-brain barrier (BBB) making it difficult to locate cavitating microbubbles (MBs). Passive cavitation imaging (PCI) has received attention due to the possibility of performing real-time monitoring by listening to acoustic cavitation. However, the long excitation pulses associated with PCI degrade its axial resolution. The present study combined a coded excitation technique with a dual-frequency chirp (DFC) excitation method to prevent interference from the nonlinear components of MBs' cavitation. The use of DFC excitation generates a low-frequency (0.4, 0.5, or 0.6 MHz) chirp component as the envelope of the signal-driving MBs' cavitation with a dual-frequency pulse ( ω1 = 1.35 MHz and ω2 = 1.65 MHz, ω1 = 1.3 MHz and ω2 = 1.7 MHz, and ω1 = 1.25 MHz and ω2 = 1.75 MHz). The cavitation of MBs was passively imaged utilizing a chirp component with pulse compression to maintain abundant insonation energy without any reduction in the axial imaging resolution. In vitro experiments showed that the DFC method improved the signal-to-noise ratio by 42.2% and the axial resolution by 4.1-fold compared with using a conventional long-pulse waveform. Furthermore, the cavitating MBs driven by different ultrasound (US) energy (0, 0.3, 0.6, and 0.9 MPa, N = 3 for each group) in the rat brain with an intact skull still could be mapped by DFC. Our successful demonstration of using the DFC method to image cavitation-induced BBB opening affords an alternative tool for assessing cavitation-dependent drug delivery to the brain, with the benefit of real-time and high convenient integration with current US imaging devices.

Ultrasonic Transdermal Delivery System with Acid-Base Neutralization-Generated CO2 Microbubble Cavitation.

Transdermal delivery systems provide a convenient noninvasive approach for drug administration through the skin, and they have been widely developed for in-home health care. The stratum corneum of the skin surface limits drug penetration, but ultrasound (US)-stimulated microbubble (MB) cavitation can enhance skin permeability to promote transdermal drug penetration. However, the specific materials and complex fabrication of MBs influence the scope of application in transdermal delivery systems. Hence, we studied the mixture of citric acid and NaHCO3 agents to generate shell-free CO2-MBs by acid-base neutralization effect. The generation rate of CO2-MBs was 36.3 ± 10 MBs/s and the mean size was 110 ± 14 µm under US sonication (3.1 MHz, 0.5 W/cm2, 50% duty cycle, 1 min). The penetration of Evans blue and FITC-conjugated hyaluronic acid in rat abdominal skin by CO2-MB cavitation improved 2.4 ± 0.3 and 2.1 ± 0.1 fold, respectively. The penetration depth of Evans blue (27.1 ± 5.1 µm) reached the epidermal layer, providing the potential for inducing transcutaneous immunization. Therefore, we proposed a simple and self-operating ultrasonic transdermal delivery system with CO2-MB cavitation to improve drug penetration for in-home health care development.