Facilitating drug delivery in the central nervous system by opening the blood-cerebrospinal fluid barrier with a single low energy shockwave pulse.

BACKGROUND: The blood-cerebrospinal fluid (CSF) barrier (BCSFB) is critically important to the pathophysiology of the central nervous system (CNS). However, this barrier prevents the safe transmission of beneficial drugs from the blood to the CSF and thus the spinal cord and brain, limiting their effectiveness in treating a variety of CNS diseases. METHODS: This study demonstrates a method on SD rats for reversible and site-specific opening of the BCSFB via a noninvasive, low-energy focused shockwave (FSW) pulse (energy flux density 0.03 mJ/mm2) with SonoVue microbubbles (2 × 106 MBs/kg), posing a low risk of injury. RESULTS: By opening the BCSFB, the concentrations of certain CNS-impermeable indicators (70 kDa Evans blue and 500 kDa FITC-dextran) and drugs (penicillin G, doxorubicin, and bevacizumab) could be significantly elevated in the CSF around both the brain and the spinal cord. Moreover, glioblastoma model rats treated by doxorubicin with this FSW-induced BCSFB (FSW-BCSFB) opening technique also survived significantly longer than untreated controls. CONCLUSION: This is the first study to demonstrate and validate a method for noninvasively and selectively opening the BCSFB to enhance drug delivery into CSF circulation. Potential applications may include treatments for neurodegenerative diseases, CNS infections, brain tumors, and leptomeningeal carcinomatosis.

Pathogenic Hydrogel? A Novel-Entrapment Neuropathy Model Induced by Ultrasound-Guided Perineural Injections.

Entrapment neuropathy (EN) is a prevalent and debilitative condition caused by a complex pathogenesis that involves a chronic compression-edema-ischemia cascade and perineural adhesion that results in excessive shear stress during motion. Despite decades of research, an easily accessible and surgery-free animal model mimicking the mixed etiology is currently lacking, thus limiting our understanding of the disease and the development of effective therapies. In this proof-of-concept study, we used ultrasound-guided perineural injection of a methoxy poly(ethylene glycol)-b-Poly(lactide-co-glycoilide) carboxylic acid (mPEG-PLGA-BOX) hydrogel near the rat's sciatic nerve to induce EN, as confirmed sonographically, electrophysiologically, and histologically. The nerve that was injected with hydrogel appeared unevenly contoured and swollen proximally with slowed nerve conduction velocities across the injected segments, thus showing the compressive features of EN. Histology showed perineural cellular infiltration, deposition of irregular collagen fibers, and a possible early demyelination process, thus indicating the existence of adhesions. The novel method provides a surgery-free and cost-effective way to establish a small-animal model of EN that has mixed compression and adhesion features, thus facilitating the additional elucidation of the pathophysiology of EN and the search for promising treatments.

A Single High-Intensity Shock Wave Pulse With Microbubbles Opens the Blood-Brain Barrier in Rats.

Focused extracorporeal shockwave (FSW), one kind of focused high-intensity pulsed ultrasound, has been shown to induce blood-brain barrier (BBB) opening in targeted brain areas in rat animal models with minimal detrimental effects below threshold intensity levels or iterations. In the current study, we found that the thresholds could be further reduced by the addition of microbubbles (ultrasound contrast agents or UCA; SonoVue). FSW with 2 × 106 MBs/kg of UCA (20% of clinical dosage) at an intensity level of 0.1 (peak positive pressure 5.4 MPa; peak negative pressure -4.2 MPa; energy flux density 0.03 mJ/mm2) resulting in a 100% BBB opening rate without detectable hemorrhage or apoptosis in the brain. Significantly reduced free radical production was found compared with 0.5 MHz focused ultrasound at a peak negative pressure of 0.44 MPa (1% duty cycle and 4 × 107 MBs/kg of UCA). FSW devices offer advantages of commercial availability and high safety, and thus may facilitate future research and applications of focal BBB opening for oncological and pharmacological purposes.

Sonoelastographic evaluation of plantar fascia after shock wave therapy for recalcitrant plantar fasciitis: A 12-month longitudinal follow-up study.

Extracorporeal shockwave therapy (ESWT) is proposed to be effective in reducing pain and improving functional outcome in chronic plantar fasciitis. However, no long-term reports exist on the changes in plantar fascia (PF) elasticity after ESWT. We aimed to evaluate the changes in PF stiffness in patients with plantar fasciitis undergoing ESWT. The visual analogue scale (VAS, 0-100) was used for evaluating heel pain severity. B-mode sonography and strain sonoelastography were used for evaluating the PF thickness and stiffness. The sonoelastogram was analyzed using hue histogram analysis (value: 0-255, from stiffer to softer). All evaluations were recorded before ESWT, and 1 week, 1 month, 3 months, 6 months, and 12 months after ESWT. Repeated measures ANOVA was used to compare pain VAS, PF thickness, and PF hue value at different follow-up time-points. Twenty-two participants (8 men, 14 women) completed all measurements for 12 months. The VAS of heel pain, PF thickness, and PF hue values at pre-ESWT, and 1-week, 1-month, 3-month, 6-month, and 12-month evaluations after ESWT were 62.4 ± 4.2, 49.3 ± 5.8, 38.3 ± 5.7, 27.9 ± 5.3, 18.9 ± 4.7, and 13.2 ± 3.0 (p < 0.01 in all measurements post ESWT versus pre-ESWT); 5.57 ± 0.22 mm, 5.64 ± 0.18 mm, 5.45 ± 0.24 mm, 5.37 ± 0.20 mm, 5.08 ± 0.20 mm, and 4.62 ± 0.15 mm (p < 0.01 at 6-month; otherwise p > 0.05); and 24.5 ± 2.4, 35.2 ± 3.1, 31.0 ± 4.1, 30.5 ± 3.9, 21.4 ± 2.1, and 15.9 ± 1.6 (p < 0.01 at 1-week and 6-month; otherwise p > 0.05), respectively. In conclusion, the heel pain intensity and PF thickness reduced gradually over 12 months after ESWT. The PF stiffness decreased during the first week and increased thereafter; at the 12-month follow-up, stiffness was more than at pre-ESWT.

Volume Matters in Ultrasound-Guided Perineural Dextrose Injection for Carpal Tunnel Syndrome: A Randomized, Double-Blinded, Three-Arm Trial.

Ultrasound-guided perineural dextrose injection (PDI) has been reported effective for carpal tunnel syndrome (CTS). Higher volume of injectate may reduce adhesion of median nerve from other tissues, but volume-dependent effects of PDI in CTS remain unknown. We aimed to investigate whether PDI with different injectate volumes had different effects for CTS participants. In this randomized, double-blinded, three-arm trial, 63 wrists diagnosed with CTS were randomized into three groups that received ultrasound-guided PDI with either 1, 2 or 4 ml of 5% dextrose water. All participants finished this study. Primary outcome as visual analog scale (VAS) and secondary outcomes including Boston Carpal Tunnel Questionnaire (BCTQ), Disability of the Arm, Shoulder and Hand score (QuickDASH), electrophysiological studies and cross-sectional area (CSA) of the median nerve at carpal tunnel inlet were assessed before and after PDI at the 1st, 4th, 12th and 24th weeks. For within-group analysis, all three groups (21 participants, each) revealed significant improvement from baseline in VAS, BCTQ and QuickDASH at the 1st, 4th, 12th and 24th weeks. For between-group analysis, 4 ml-group yielded better VAS reduction at the 4th and 12th weeks as well as improvement of BCTQ and QuickDASH at the 1st, 4th, and 12th weeks, compared to other groups. No significant between-group differences were observed in electrophysiological studies or median nerve CSA at any follow-up time points. There were no severe complications in this trial, and transient minor adverse effects occurred equally in the three groups. In conclusion, ultrasound-guided PDI with 4 ml of 5% dextrose provided better efficacy than with 1 and 2 ml based on symptom relief and functional improvement for CTS at the 1st, 4th, and 12th week post-injection, with no reports of severe adverse effects. There was no significant difference between the three groups at the 24th-week post-injection follow-up. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03598322.

Ultrasonographic Imaging for Sural Nerve Injury after Achilles Tendon Repair.

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Meta-analysis Comparing Autologous Blood-Derived Products (Including Platelet-Rich Plasma) Injection Versus Placebo in Patients With Achilles Tendinopathy.

PURPOSE: To compare the effectiveness of autologous blood-derived products (ABP) injection with that of placebo (sham injection, no injection, or physiotherapy alone) in patients with Achilles tendinopathy. METHODS: Electronic databases, including PubMed, Scopus, EMBASE, and Cochrane Library were searched up to June 2017. All published or unpublished randomized controlled trials (RCTs) were included. Two independent raters assessed the risk of bias of RCTs with the Cochrane Risk of Bias Tool. The primary outcome was Victorian Institute of Sports Assessment-Achilles (VISA-A) score. Weighted mean differences (WMDs) were used for random effect meta-analysis. RESULTS: Seven RCTs were enrolled in meta-analysis. The ABP injection and placebo revealed equal effectiveness in VISA-A score improvement at 4 to 6 weeks (short term, WMD 2.29, 95% confidence interval [CI]: -1.69, 6.27), 12 weeks (medium term, WMD 2.63, 95% CI: -1.72, 6.98), 24 weeks (long term, WMD 4.61, 95% CI: -1.25, 10.47), and 48 weeks (very long term, WMD 4.16, 95% CI: -6.82, 15.14). In meta-regression, there was no association between change in VISA-A score and duration of symptoms at 4 to 6 weeks (short term), 12 weeks (medium term), and 24 weeks (long term). CONCLUSIONS: This meta-analysis revealed that ABP injection was not more effective than placebo (sham injection, no injection, or physiotherapy alone) in Achilles tendinopathy and that no association was found between therapeutic effects and duration of symptoms. LEVEL OF EVIDENCE: Level I, meta-analysis of Level I studies.

Synergistic Effect of PEI and PDMAEMA on Transgene Expression in Vitro.

Polyethylenimine (PEI) and poly(2-(dimethylamino) ethyl methacrylate) (PDMAEMA) have both been used for DNA delivery. PDMAEMA has been shown to exhibit better gene transfection efficiency but lower expression ability than PEI. We mixed the two polymers at different ratios to investigate whether the resulting "dual" polyplex (PEI/PDMAEMA/DNA) could enhance both gene transfection efficiency and DNA expression ability. Experimental results showed a significant increase in DNA internalization and DNA expression for the PDMAEMA/PEI/DNA polyplexes at a ratio of 1:3 or 1:9 (PDMAEMA: PEI), depending on cell type, in comparison with PEI/DNA, PDMAEMA/DNA, and PDMAEMA/PEI/DNA at other ratios. PDMAEMA/PEI/DNA polyplexes did not reduce cell viability. In contrast to with the conventional approach using covalently modified PEI, the proposed "combination" approach provided a more convenient and effective way to improve transgene expression efficiency.

Sonographic appearance of nontraumatic tear of flexor carpi radialis muscle-a case report.

We present an unusual case of a man with a nontraumatic tear of the flexor carpi radialis muscle after a regular swimming exercise, without known precipitation factors. The muscle tear was diagnosed by ultrasonography, which showed a cystic mass with increased peripheral vascularity, and was confirmed by magnetic resonance imaging. After conservative treatment, follow-up ultrasonography showed resolution of the hematoma. The patient was able to continue swimming without pain or limitation of function.