Repeat and single dose administration of gadodiamide to rats to investigate concentration and location of gadolinium and the cell ultrastructure.

Gadolinium based contrast agents (GBCA) are used to image patients using magnetic resonance (MR) imaging. In recent years, there has been controversy around gadolinium retention after GBCA administration. We sought to evaluate the potential toxicity of gadolinium in the rat brain up to 1-year after repeated gadodiamide dosing and tissue retention kinetics after a single administration. Histopathological and ultrastructural transmission electron microscopy (TEM) analysis revealed no findings in rats administered a cumulative dose of 12 mmol/kg. TEM-energy dispersive X-ray spectroscopy (TEM-EDS) localization of gadolinium in the deep cerebellar nuclei showed ~ 100 nm electron-dense foci in the basal lamina of the vasculature. Laser ablation-ICP-MS (LA-ICP-MS) showed diffuse gadolinium throughout the brain but concentrated in perivascular foci of the DCN and globus pallidus with no observable tissue injury or ultrastructural changes. A single dose of gadodiamide (0.6 mmol/kg) resulted in rapid cerebrospinal fluid (CSF) and blood clearance. Twenty-weeks post administration gadolinium concentrations in brain regions was reduced by 16-72-fold and in the kidney (210-fold), testes (194-fold) skin (44-fold), liver (42-fold), femur (6-fold) and lung (64-fold). Our findings suggest that gadolinium does not lead to histopathological or ultrastructural changes in the brain and demonstrate in detail the kinetics of a human equivalent dose over time in a pre-clinical model.

Sonoporation for Augmenting Chemotherapy of Pancreatic Ductal Adenocarcinoma.

Pancreatic cancer is the third most common cancer diagnosed in the United States, with more than 53,000 new cases in 2017. It is the fourth leading cause of cancer-related death in both men and women. Nonetheless, there has been no significant improvement in survival for pancreatic ductal adenocarcinoma (PDAC) patients over the past 30+ years. For this reason, there is a considerable and urgent clinical need to develop innovative strategies for effective drug delivery and treatment monitoring, resulting in improved outcomes for patients with PDAC.This chapter describes the development of contrast-enhanced ultrasound image-guided drug delivery (CEUS-IGDD or sonoporation) to be that method and to translate it from the lab to the clinic. The initial clinical focus has been on a Phase I clinical trial for enhancing the effectiveness of standard chemotherapeutics for treatment of inoperable PDAC, which demonstrated a median survival increase from 8.9 months to 17.6 months in ten subjects augmented with sonoporation compared to 63 historical controls (p = 0.011). Recent efforts to optimize this platform and move forward to a larger Phase II clinical trial will be described.

Clearance of Gadolinium from the Brain with No Pathologic Effect after Repeated Administration of Gadodiamide in Healthy Rats: An Analytical and Histologic Study.

Purpose To measure the levels of gadolinium present in the rat brain 1 and 20 weeks after dosing with contrast agent and to determine if there are any histopathologic sequelae. Materials and Methods The study was approved by the GE Global Research Center Institutional Animal Care and Use Committee. Absolute gadolinium levels were quantified in the blood and brains of rats 1 week after dosing and 20 weeks after dosing with up to 20 repeat doses of gadodiamide (cumulative dose, 12 mmol per kilogram of body weight) by using inductively coupled plasma-mass spectrometry. Treatment groups (n = 6 rats per group) included low-dosage and high-dosage gadodiamide and osmolality-matched saline controls. Brain sections were submitted (blinded) for standard toxicology assessment per Registry of Industrial Toxicology Animal data guidelines. Analysis of variance and Mann-Whitney U tests with post hoc correction were used to assess differences in absolute gadolinium levels and percentage of injected dose, respectively. Results Dose-dependent low levels of gadolinium were detected in the brain, a mean ± standard deviation of 2.49 nmol per gram of brain tissue ± 0.30 or 0.00019% of the injected dose 1 week after dosing. This diminished by approximately 50% (to 1.38 nmol per gram of brain tissue ± 0.10 or 0.00011% of the injected dose) 20 weeks after dosing. As a percentage of injected dose, the levels of gadolinium measured were comparable between different doses, indicating that mechanisms of uptake and elimination were not saturated at the tested doses. There were no histopathologic findings associated with the levels of gadolinium measured. Conclusion Low levels of gadolinium are present in the brain after repeat dosing with gadodiamide, which is partially cleared over 20 weeks with no detectable neurotoxicity.

Drug and Gene Delivery using Sonoporation for Cardiovascular Disease.

Using the improvements made in diagnostic contrast enhanced ultrasound, researchers have made significant progress in the field of ultrasound-mediated sonoporation for drug delivery. Many programs take advantage of commercial products; both ultrasound imaging systems and contrast agents to better enable translation from preclinical to first-in-man studies (Kotopoulis et al., Med Phys 40:072902, 2013). Particularly well-suited targets for this novel therapy are diseases of the cardiovascular system. This chapter will highlight several recent studies addressing treatment of both acute and chronic conditions.

Therapeutic ultrasound: Increased HDL-Cholesterol following infusions of acoustic microspheres and apolipoprotein A-I plasmids.

BACKGROUND: Low levels of HDL-C are an independent cardiovascular risk factor associated with increased premature cardiovascular death. However, HDL-C therapies historically have been limited by issues relating to immunogenicity, hepatotoxicity and scalability, and have been ineffective in clinical trials. OBJECTIVE: We examined the feasibility of using injectable acoustic microspheres to locally deliver human ApoA-I DNA plasmids in a pre-clinical model and quantify increased production of HDL-C in vivo. METHODS: Our novel site-specific gene delivery system was examined in naïve rat model and comprised the following steps: (1) intravenous co-administration of a solution containing acoustically active microspheres (Optison™, GE Healthcare, Princeton, New Jersey) and human ApoA-I plasmids; (2) ultrasound verification of the presence of the microspheres within the liver vasculature; (3) External application of locally-directed acoustic energy, (4) induction of microsphere disruption and in situ sonoporation; (4) ApoA-I plasmid hepatic uptake; (5) transcription and expression of human ApoA-I protein; and (6) elevation of serum HDL-C. RESULTS: Co-administration of ApoA-I plasmids and acoustic microspheres, activated by external ultrasound energy, resulted in transcription and production of human ApoA-I protein and elevated serum HDL-C in rats (up to 61%; p-value < 0.05). CONCLUSIONS: HDL-C was increased in rats following ultrasound directed delivery of human ApoA-I plasmids by microsphere sonoporation. The present method provides a novel approach to promote ApoA-I synthesis and nascent HDL-C elevation, potentially permitting the use of a minimally-invasive ultrasound-based, gene delivery system for treating individuals with low HDL-C.

Ultrasound-directed, site-specific gene delivery.

With the implementation of gene therapy looming in the near term, an effective delivery system using noninvasive, nonviral-mediated methods appears as an attractive option. This novel platform technology uses gas-filled, ultrasound-directed acoustic microspheres for both diagnostic imaging and therapy and yet may provide a key component for future success in the pursuit of single-gene replacement therapy.

Ultrasound-mediated targeted drug delivery: recent success and remaining challenges.

The potential clinical value of developing a novel, nonviral, ultrasound-directed gene and drug delivery system is immense. Investigators soon will initiate clinical trials with the goal of treating a wide variety of maladies using noninvasive, ultrasound-based technology. The ongoing, scientific validation associated with promising preclinical success portents a novel range of therapeutics. The clinical utility and eventual clinical successes await vigorous testing. This review highlights the recent successes and challenges within the field of ultrasound-mediated drug delivery.

A hydromechanical biomimetic cochlea: experiments and models.

The construction, measurement, and modeling of an artificial cochlea (ACochlea) are presented in this paper. An artificial basilar membrane (ABM) was made by depositing discrete Cu beams on a piezomembrane substrate. Rather than two fluid channels, as in the mammalian cochlea, a single fluid channel was implemented on one side of the ABM, facilitating the use of a laser to detect the ABM vibration on the other side. Measurements were performed on both the ABM and the ACochlea. The measurement results on the ABM show that the longitudinal coupling on the ABM is very strong. Reduced longitudinal coupling was achieved by cutting the membrane between adjacent beams using a laser. The measured results from the ACochlea with a laser-cut ABM demonstrate cochlear-like features, including traveling waves, sharp high-frequency rolloffs, and place-specific frequency selectivity. Companion computational models of the mechanical devices were formulated and implemented using a circuit simulator. Experimental data were compared with simulation results. The simulation results from the computational models of the ABM and the ACochlea are similar to their experimental counterparts.

Management of peripheral nerve defects: external fixator-assisted primary neurorrhaphy.

BACKGROUND: Controlled joint extension followed by gradual distraction with use of an external fixator may facilitate primary repair of peripheral nerve defects by permitting end-to-end repair without tension. The hypothesis of the present study was that gradual lengthening of nerve repairs with use of incremental distraction would provide superior results compared with grafting or repair under tension. METHODS: A median nerve segment measuring four times the diameter of the nerve was resected in thirty-six rabbits to create a 7-mm gap in the nerve. Neurorrhaphy was performed with use of one of three techniques. In Group 1 (cable graft), a tension-free medial antebrachial cutaneous graft was placed to allow full range of motion of the elbow postoperatively. In Group 2 (end-to-end repair without distraction), the elbow was externally fixed in hyperflexion and the nerve was repaired end-to-end. At fourteen days, the fixator was removed and unprotected elbow motion was permitted. In Group 3 (end-to-end repair with gradual distraction), the elbow was externally fixed in hyperflexion and primary neurorrhaphy was performed. At fourteen days, the elbow was extended 10 degrees every other day with use of the articulated external fixator until full extension was achieved. Median nerve amplitude, latency, and nerve-conduction velocity; flexor digitorum superficialis single-twitch force generation and maximum tetanic force generation; muscle mass; and elbow range of motion were measured at three or six months. In addition, histologic analysis of the median nerve distal to the repair site and the morphometry of the neuromuscular junction in the flexor digitorum superficialis were performed at six months. RESULTS: All rabbits regained full active and passive range of motion. At three months, the nerve-conduction velocities in Groups 2 and 3 were significantly greater than that in Group 1. At six months, the nerve-conduction velocities and amplitudes in Group 3 were significantly greater than those in Groups 1 and 2. At six months, the tetanic force in Group 3 was significantly greater than those in Groups 1 and 2. There were no significant differences in muscle mass among the groups. There were no significant differences in histological findings among the three groups, although there was a trend toward larger fiber size in Group 3 as compared with the other two groups. The neuromuscular junctions in Group 3 had a significantly larger surface area than did those in Group 1 (p = 0.002) and Group 2 (p = 0.034). CONCLUSION: The use of an articulated external fixator and controlled gradual distraction appears to facilitate the treatment of peripheral nerve defects.

Arthroscopic resection of the common extensor origin: anatomic considerations.

This study examines the intra-articular anatomy and safe zones for arthroscopic resection of the common extensor origin for the treatment of lateral epicondylitis. The extensor complex was arthroscopically debrided in 7 cadaveric elbows to determine the percentage of each tendinous origin that was resectable. Elbow stability was assessed, and safe zones of resection were determined. The extensor carpi radialis brevis and extensor digitorum communis origin was resected a mean of 100% and 90%, respectively. Elbow stability was maintained when resection did not extend posteriorly to an intra-articular line bisecting the radial head. Posterolateral rotatory instability occurred when debridement was continued posteriorly to the axis of the radial head. In conclusion, complete resection of the extensor carpi radialis brevis-extensor digitorum communis common origin is achievable via standard arthroscopic techniques. The lateral ulnar collateral ligament remains intact and elbow stability is maintained when debridement of the extensor origin does not extend posteriorly to a line bisecting the radial head.

Radius pull test: predictor of longitudinal forearm instability.

BACKGROUND: Longitudinal instability of the forearm (the Essex-Lopresti lesion) following radial head excision may be difficult to detect. This cadaveric study examines a stress test that can be performed in the operating room to identify injury to the ligamentous structures of the forearm. METHODS: Twelve cadaveric upper extremities were randomized into two groups and underwent radial head resection. Group 1 underwent sequential transection of the triangular fibrocartilage complex and the interosseous membrane. Group 2 underwent sequential transection of the interosseous membrane and the triangular fibrocartilage complex. Ulnar variance and radial migration were examined with use of fluoroscopy of the wrist before, during, and after the application of a 9.1-kg load via longitudinal traction on the proximal part of the radius. RESULTS: Group 1 demonstrated no significant changes in proximal radial migration with load (compared with the findings after radial head resection alone) after transection of the triangular fibrocartilage complex. However, Group 2 demonstrated significant changes in proximal radial migration with load after transection of the interosseous membrane (p = 0.03; median, 3.5 mm). In both groups, transection of both the triangular fibrocartilage complex and the interosseous membrane resulted in significant changes in proximal radial migration with load (p = 0.001; median, 9.5 mm). When the load was removed, specimens were ulnar positive (median, 3.0 mm), with no specimen returning to the preload position of ulnar variance (p = 0.001). CONCLUSION: After radial head resection, 3 mm of proximal radial migration with longitudinal traction indicated disruption of the interosseous membrane. In all specimens, proximal radial migration of > or =6 mm with load indicated gross longitudinal instability with disruption of all ligamentous structures of the forearm.

Technique for iliopsoas ultrasound-guided active electromyography-directed botulinum a toxin injection in cerebral palsy.

Symptomatic hip flexion deformity secondary to iliopsoas spasticity may interfere with gait, impair sitting balance, or contribute to hip subluxation or dislocation. A nonsurgical, minimally invasive technique to ameliorate iliopsoas spasticity is presented. The technique uses intramuscular injections of botulinum A toxin to provide selective neuromuscular blockade of the iliacus or psoas muscles or both. Because of the anatomic location of the target muscles, this technique uses ultrasound guidance for needle placement. Active electromyographic stimulation is used to verify the needle position adjacent to active myoneural interfaces. The authors' experience to date includes the treatment of 28 patients (53 hips). Use of this technique has resulted in improved hip range of motion. No intraoperative or postoperative adverse events or complications have been observed.