Novel Developments to Enable Treatment of CNS Diseases with Targeted Drug Delivery.

The blood-brain barrier (BBB) is a major hurdle for the development of systemically delivered drugs against diseases of the central nervous system (CNS). Because of this barrier there is still a huge unmet need for the treatment of these diseases, despite years of research efforts across the pharmaceutical industry. Novel therapeutic entities, such as gene therapy and degradomers, have become increasingly popular in recent years, but have not been the focus for CNS indications so far. To unfold their full potential for the treatment of CNS diseases, these therapeutic entities will most likely have to rely on innovative delivery technologies. Here we will describe and assess approaches, both invasive and non-invasive, that can enable, or at least increase, the probability of a successful drug development of such novel therapeutics for CNS indications.

In vivo study of flow-rate accuracy of the MedStream Programmable Infusion System.

OBJECTIVE: Flow-rate accuracy and precision are important parameters to optimizing the efficacy of programmable intrathecal (IT) infusion pump delivery systems. Current programmable IT pumps are accurate within ±14.5% of their programmed infusion rate when assessed under ideal environmental conditions and specific flow-rate settings in vitro. We assessed the flow-rate accuracy of a novel programmable pump system across its entire flow-rate range under typical conditions in sheep (in vivo) and nominal conditions in vitro. MATERIALS AND METHODS: The flow-rate accuracy of the MedStream Programmable Pump was assessed in both the in vivo and in vitro settings. In vivo flow-rate accuracy was assessed in 16 sheep at various flow-rates (producing 90 flow intervals) more than 90 ± 3 days. Pumps were then explanted, re-sterilized and in vitro flow-rate accuracy was assessed at 37°C and 1013 mBar (80 flow intervals). RESULTS: In vivo (sheep body temperatures 38.1°C-39.8°C), mean ± SD flow-rate error was 9.32% ± 9.27% and mean ± SD leak-rate was 0.028 ± 0.08 mL/day. Following explantation, mean in vitro flow-rate error and leak-rate were -1.05% ± 2.55% and 0.003 ± 0.004 mL/day (37°C, 1013 mBar), respectively. CONCLUSIONS: The MedStream Programmable Pump demonstrated high flow-rate accuracy when tested in vivo and in vitro at normal body temperature and environmental pressure as well as when tested in vivo at variable sheep body temperature. The flow-rate accuracy of the MedStream Programmable Pump across its flow-rate range, compares favorably to the accuracy of current clinically utilized programmable IT infusion pumps reported at specific flow-rate settings and conditions.

Assessment of passive cardiovascular implant devices for MRI compatibility.

PURPOSE: The increasing popularity of both magnetic resonance angiography and minimally invasive cardiovascular interventional procedures has led to the requirement for the development of implant devices that not only provide for patient safety, but produce minimal artifacts in diagnostic images. The purpose of this paper is to assess and discuss physical principles and ASTM testing standards related to the MRI compatibility of implanted devices. ANALYSIS AND REVIEW OF IMAGING COMPATIBILITY AND SAFETY OF COMMON IMPLANTS AND DEVICES: Standard procedures are described to assess safety and ability to image near implanted stents and heart valves made from different materials and of varying geometry. MRI physical principles, material properties and MR simulations are discussed in the context of estimation of ferromagnetic force, displacement, torque, tissue heating, susceptibility artifacts, and radiofrequency shielding in cardiovascular stents and heart valves during MR imaging. CONCLUSION: MRI compatibility is a function of both material composition and device geometry. MR-safe devices are available that provide for reduced image artifacts over stainless-steel devices.

Comparison of rechargeable versus battery-operated insulin pumps: temperature fluctuations.

The role of continuous subcutaneous insulin infusion (insulin pumps) has become increasingly important in diabetes management, and many different types of these systems are currently available. This exploratory study focused on the reported heating issues that lithium-ion battery-powered pumps may have during charging compared with battery-operated pumps. It was found that pump temperature increased by 6.4°C during a long charging cycle of a lithiumion battery-operated pump under ambient temperatures. In an environmental-chamber kept at 35°C, the pump temperature increased by 4.4°C, which indicates that the pump temperature was above that of the recommended safety limit for insulin storage of 37°C. When designing new pumps, and when using currently available rechargeable pumps in warmer climates, the implications of these temperature increases should be taken into consideration. Future studies should also further examine insulin quality after charging.

Hemoglobin adsorption isotherm at the silica-water interface with evanescent wave cavity ring-down spectroscopy.

Evanescent wave cavity ring-down spectroscopy (EW-CRDS) is used to observe the adsorption isotherm for hemoglobin (Hb) from controlled urine samples to assess the potential for rapid diagnosis in hemoglobinuria. The absorbance of Hb at 425 nm is monitored using an alexandrite laser-pumped, room temperature, LiF:F2+** color-center pulsed laser. A minimum absorbance detection level of 2.57 x 10(-4) is achieved, corresponding to a minimum detectable concentration of Hb in urea of 5.8 nM. A multilayered Hb biofilm is formed, and a minimum of eight layers are required to model the adsorption isotherm, allowing for cooperative binding within the layers and extending 56 nm into the interface. A binding constant for Hb to silica 18.23+/-7.58 x 10(6) M is derived, and a binding constant for Hb to Hb in subsequent layers is determined to be 5.631+/-0.432 x 10(5) M. Stoichiometric binding coefficients of 1.530+/-0.981 for layer one and 1.792+/-0.162 for subsequent layers suggest that cooperative binding both to the silica surface and between the layers of the biofilm is important.

Middle infrared, quantum cascade laser optoelectronic absorption system for monitoring glucose in serum.

Advances in middle infrared technology are leading researchers beyond the Fourier transform infrared spectrometer and to the quantum cascade laser. While most research focuses on gas-phase detection, recent research explores its use for condensed-phase matter studies. This work investigates its use for monitoring biologically relevant samples of glucose in serum. Samples with physiological glucose concentrations were monitored with a laser at 1036 cm-1. A 0.992 R2 linearity value was observed. In addition, using another laser at 1194 cm-1 as a measure of the background spectroscopic characteristics, a linearity of 0.998 R2 was observed. The average predictive standard errors of the mean (SEM) were 32.5 and 24.7 mg/dL, respectively, for each method. Quantum cascade lasers could be used to develop middle infrared devices for uses beyond the confines of the laboratory.

The effect of a microcarrier suspension cell culture system on polarization measurements from Ni-Cr dental casting alloys.

OBJECTIVES: Recent research has demonstrated that cells/cellular components can influence the corrosion or degradation of the implant material in addition to being challenged by the cytotoxic by-products the implant material may release. The overall objective of this research was to modify a microcarrier suspension cell culture system to incorporate an active corrosion experimental capacity. METHODS: The ability to conduct polarization experiments on two Ni-Cr dental casting alloys under the following environmental conditions: media only, media plus serum, media plus serum and antibiotics (complete media), complete media with microcarriers, and complete media with cells grown on microcarriers; was evaluated during this initial study. RESULTS: Results obtained were reproducible within sample groups (95% confidence level) indicating the precision of the corrosion set-up under all environmental conditions. These studies also show that media with serum and antibiotics (complete media) induced a significantly higher corrosion rate (95% confidence level) for both materials compared to the other test conditions. SIGNIFICANCE: Future experiments will focus on cytotoxic effects caused by parametrically controlled corrosion experiments on the suspension cell cultures, including co-cultures.

Sensitivity of the Predictive Hypoglycemia Minimizer System to the Algorithm Aggressiveness Factor.

BACKGROUND: The Predictive Hypoglycemia Minimizer System ("Hypo Minimizer"), consisting of a zone model predictive controller (the "controller") and a safety supervision module (the "safety module"), aims to mitigate hypoglycemia by preemptively modulating insulin delivery based on continuous glucose monitor (CGM) measurements. The "aggressiveness factor," a pivotal variable in the system, governs the speed and magnitude of the controller's insulin dosing characteristics in response to changes in CGM levels. METHODS: Twelve adults with type 1 diabetes were studied in closed-loop in a clinical research center for approximately 24 hours. This analysis focused primarily on the effect of the aggressiveness factor on the automated insulin-delivery characteristics of the controller, and secondarily on the glucose control results. RESULTS: As aggressiveness increased from "conservative" to "medium" to "aggressive," the controller recommended less insulin (-3.3% vs -14.4% vs -19.5% relative to basal) with a higher frequency (5.3% vs 14.4% vs 20.3%) during the critical times when the CGM was reading 90-120 mg/dl and decreasing. Blood glucose analyses indicated that the most aggressive setting resulted in the most desirable combination of the least time spent <70 mg/dl and the most time spent 70-180 mg/dl, particularly in the overnight period. Hyperglycemia, diabetic ketoacidosis, or severe hypoglycemia did not occur with any of the aggressiveness values. CONCLUSION: The Hypo Minimizer's controller took preemptive action to prevent hypoglycemia based on predicted changes in CGM glucose levels. The most aggressive setting was quickest to take action to reduce insulin delivery below basal and achieved the best glucose metrics.

Using two discrete frequencies within the middle infrared to quantitatively determine glucose in serum.

Tight glucose monitoring is essential for the reduction of diabetic complications. This research investigated the changes of absorption spectra observed in serum at three prominent glucose absorption peaks in the middle infrared using a demountable liquid, transmission cell. Two frequencies of light were used to determine the glucose absorption: one at 1193 cm(-1 ) to determine the background water absorption and the other at one of the characteristic peaks (1035, 1080, and 1109 cm(-1)). The peak at 1035 cm(-1) was best for quantitative determination with a standard of error of 20.6 mg/dl (1.1 mmol/L). While interference from other serum constituents could cause problems, urea and albumin-two constituents known to have close absorption peaks-were determined to have no effect on the ability to determine the glucose levels at 1035 cm( -1).

Nanostructured ceramics for biomedical implants.

Recent progress in the synthesis, characterization, and biological compatibility of nanostructured ceramics for biomedical implants is reviewed. A major goal is to develop ceramic coating technology that can reduce the friction and wear in mating total joint replacement components, thus contributing to their significantly improved function and longer life span. Particular attention is focused on the enhancement of mechanical properties such as hardness, toughness, and friction coefficient and on the bioactivity as they pertain to the nanostructure of the material. The development of three nanostructured implant coatings is discussed: diamond, hydroxyapatite, and functionally graded metalloceramics based on the Cr-Ti-N ternary system. Nanostructured diamond produced by chemical vapor deposition (CVD) techniques and composed of nano-size diamond grains have particular promise because of the combination of ultrahigh hardness, improved toughness over conventional microcrystalline diamond, low friction, and good adhesion to titanium alloys. Nanostructured processing applied to hydroxyapatite coatings is used to achieve the desired mechanical characteristics and enhanced surface reactivity and has been found to increase osteoblast adhesion, proliferation, and mineralization. Finally, nanostructured metalloceramic coatings provide continuous variation from a nanocrystalline metallic bond at the interface to the hard ceramic bond on the surface and have the ability to overcome adhesion problems associated with ceramic hard coatings on metallic substrates.

A flow visualization study of an anatomic coronary artery anastomosis model with an implant.

Flow Streamlining Devices is a new tool in Coronary Artery Bypass Grafting (CABG). They aim in: a) Performing a sutureless anastomosis to reduce thrombosis at the veno-arterial junction, and b) Providing a hemodynamically efficient scaffolding to reduce secondary flow disturbances. Thrombosis and flow disturbances are factors that have been reported as contributing factors to the development of intimal hyperplasia (IH) and failure of the graft. By reducing thrombosis and flow disturbances, it is expected that IH will be inhibited and the lifetime of the graft extended. To evaluate the hemodynamic benefits of such an implant, two models were designed and fabricated. One simulated the geometry of the conventional anastomosis without an implant, and the other simulated an anastomosis with a flow streamlining implant. Identical flow conditions relevant to a coronary anastomosis were imposed on both models and flow visualization was performed with dye injection and a digital camera. Results showed reduction of disturbances in the presence of the implant. This reduction seems to be favorable to hemodynamic streamlining which may create conditions that may inhibit the initialization of IH. However, the compliance and geometric mismatch between the anastomosis and the implant created a disturbance at the rigid compliant wall interface, which should be eliminated prior to clinical applications.

The hemodynamic effects of compliance, bulging, and curvature in a saphenous vein coronary artery bypass graft model.

The development of Intimal Hyperplasia (IH) in saphenous vein coronary artery bypass grafts (SV-CABG) is responsible for the short-term patency of these grafts. Previous studies of SV-CABG models were performed on rigid anastomotic vessels. However, the effects of compliance, bulging and curvature at the anastomosis on the general hemodynamic field, due to compliance and geometric mismatch between the vein and the artery have not been evaluated. We studied axial and transverse velocities by Laser Doppler Velocimetry on a compliant, in vitro, anatomical model of an end-to-side saphenous vein graft (SVG) to left anterior descending (LAD). The model incorporated a bulge at the sinus and curvature at the graft-host junction. Physiologic pressure and flow conditions pertaining to SV-CABG were applied. The presence of the bulge and curvature showed differences in the velocity profiles in comparison with previous rigid model studies. Dynamic separation zones were temporally augmented at the flow divider. The moving stagnation point at the floor of the host vessel was observed to move past the toe of the model during the accelerating portion of the cycle. These findings suggest that the presence of the bulge curvature and compliance may further favor conditions for the development of intimal hyperplasia (IH) at the floor of a CABG.

Closed-Loop Control Performance of the Hypoglycemia-Hyperglycemia Minimizer (HHM) System in a Feasibility Study.

BACKGROUND: This feasibility study investigated the insulin-delivery characteristics of the Hypoglycemia-Hyperglycemia Minimizer (HHM) System-an automated insulin delivery device-in participants with type 1 diabetes. METHODS: Thirteen adults with type 1 diabetes were enrolled in this nonrandomized, uncontrolled, clinical-research-center-based feasibility study. The HHM System comprised a continuous subcutaneous insulin infusion pump, a continuous glucose monitor (CGM), and a model predictive control algorithm with a safety module, run on a laptop platform. Closed-loop control lasted approximately 20 hours, including an overnight period and two meals. RESULTS: When attempting to minimize glucose excursions outside of a prespecified target zone, the predictive HHM System decreased insulin infusion rates below the participants' preset basal rates in advance of below-zone excursions (CGM < 90 mg/dl), and delivered 80.4% less insulin than basal during those excursions. Similarly, the HHM System increased infusion rates above basal during above-zone excursions (CGM > 140 mg/dl), delivering 39.9% more insulin than basal during those excursions. Based on YSI, participants spent a mean ± standard deviation (SD) of 0.2 ± 0.5% of the closed-loop control time at glucose levels < 70 mg/dl, including 0.3 ± 0.9% for the overnight period. The mean ± SD glucose based on YSI for all participants was 164.5 ± 23.5 mg/dl. There were nine instances of algorithm-recommended supplemental carbohydrate administrations, and there was no severe hypoglycemia or diabetic ketoacidosis. CONCLUSIONS: Results of this study indicate that the current HHM System is a feasible foundation for development of a closed-loop insulin delivery device.

Effect of algorithm aggressiveness on the performance of the Hypoglycemia-Hyperglycemia Minimizer (HHM) System.

The Hypoglycemia-Hyperglycemia Minimizer (HHM) System aims to mitigate glucose excursions by preemptively modulating insulin delivery based on continuous glucose monitor (CGM) measurements. The "aggressiveness factor" is a key parameter in the HHM System algorithm, affecting how readily the system adjusts insulin infusion in response to changing CGM levels. Twenty adults with type 1 diabetes were studied in closed-loop in a clinical research center for approximately 26 hours. This analysis focused on the effect of the aggressiveness factor on the insulin dosing characteristics of the algorithm and, to a lesser extent, on the glucose control results observed. As the aggressiveness factor increased from conservative to medium to aggressive: the maximum observed insulin dose delivered by the algorithm­which is designed to give doses that are corrective in nature every 5 minutes­increased (1.00 vs 1.15 vs 2.20 U, respectively); tendency to adhere to the subject's nominal basal dose decreased (61.9% vs 56.6% vs 53.4%); and readiness to decrease insulin below basal also increased (18.4% vs 19.4% vs 25.2%). Glucose analyses by both CGM and Yellow Springs Instruments (YSI) indicated that the aggressive setting of the algorithm resulted in the least time spent at levels >180 mg/dL, and the most time spent between 70-180 mg/dL. There was no severe hyperglycemia, diabetic ketoacidosis, or severe hypoglycemia for any of the aggressiveness values investigated. These analyses underscore the importance of investigating the sensitivity of the HHM System to its key parameters, such as the aggressiveness factor, to guide future development decisions.

Convection enhanced delivery of different molecular weight tracers of gadolinium-tagged polylysine.

Convection enhanced delivery (CED) is a powerful method of circumventing the blood-brain barrier (BBB) to deliver therapeutic compounds directly to the CNS. While inferring the CED distribution of a therapeutic compound by imaging a magnetic resonance (MR)-sensitive tracer has many advantages, however how the compound distribution is affected by the features of the delivery system, its target tissue, and its molecular properties, such as its binding characteristics, charge, and molecular weight (MW) are not fully understood. We used MR imaging of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA)-tagged polylysine compounds of various MW, in vitro and in vivo, to measure the dependence of compounds MW on CED distribution. For the in vitro studies, the correlation between volume of distribution (Vd) as a function of MW was determined by measuring the T1 of the infused tracers, into 0.6% agarose gels through a multiport catheter. The compounds distributed in the gels inversely proportional to their MW, consistent with convection and unobstructed diffusion through a porous media. For the in vivo studies, Gd-DTPA tagged compounds were infused into the non-human primate putamen, via an implanted multiport catheter connected to a MedStream™ pump, programmed to deliver a predetermined volume with alternating on-off periods to take advantage of the convective and diffusive contributions to Vd. Unlike the gel studies, the higher MW polylysine-tracer infusions did not freely distribute from the multiport catheter in the putamen, suggesting that distribution was impeded by other properties that should also be considered in future tracer design and CED infusion protocols.

Programmable infusion pump and catheter: evaluation using 3-tesla magnetic resonance imaging.

Objective. This study assessed 3-Tesla magnetic resonance imaging (MRI) issues for a programmable infusion pump and associated catheters. Methods. A programmable infusion pump and associated catheters (MedStream Programmable Infusion Pump, 40 mL; SureStream TI Coil-Reinforced Intraspinal Catheter; SureStream TI Connector; and SureStream Silicone Catheter; Codman and Shurtleff Inc., a Johnson & Johnson Company, Raynham, MA, USA) underwent evaluation for magnetic field interactions (deflection angle and torque), heating (transmit/receive body radiofrequency coil; whole-body averaged specific absorption rate, 3 W/kg for 15 min), functional changes (before and after MRI using eight different MRI conditions), and artifacts (T1-weighted spin-echo and gradient-echo pulse sequences) at 3-Tesla. Results. The programmable infusion pump and associated catheters exhibited minor magnetic field interactions. Heating was not excessive (≤ 1.9°), especially considering the experimental conditions used for this evaluation (ie, relatively high radiofrequency power/specific absorption rate level and use of a nonperfused phantom). The function of three out of six pumps was temporarily altered by exposures to 3-Tesla MRI conditions. Reset was achieved in each case. Artifacts were relatively large for the pump and minor for the catheter. Conclusions. The programmable infusion pump and catheters will not pose increased risk to a patient examined using 3-Tesla MRI as long as specific safety guidelines are followed, which includes interrogation of the pump post-MRI to ensure proper settings. Artifacts for the programmable infusion pump may impact the diagnostic use of MRI if the area of interest is in the same area or near the device.

Corrosion on spinal implants.

OBJECTIVE: Modular spine implants are used as an aid to obtaining fusion, but fretting and corrosion occur between modular components in a biologic environment. METHODS: Forty-eight spinal implant constructs manufactured by a variety of companies were retrieved from 47 patients and were subjected to surface analysis stereomicroscopy. RESULTS: Stainless-steel implants (n = 23) had either semirigid constructs with mild or no surface alteration (n = 7) or rigid constructs with moderate or severe alteration (n = 16). Surface damage was consistent with previously observed mechanically assisted crevice corrosion phenomena. Titanium alloy implants (n = 25) showed no significant corrosion but had three constructs with fatigue failure of anchoring screws. One cobalt alloy construct showed no evidence of corrosion. CONCLUSIONS: Long-term effects of fretting and corrosion are unclear, and minimization of these phenomena seems justified. Selection of modular components with similar materials and surface finish may help the surgeon minimize localized changes over time. Stainless-steel implants with rigid interconnections and those with different surface finishes between rods and connectors are most susceptible to corrosion.

Magnetic resonance phase velocity mapping through NiTi stents in a flow phantom model.

PURPOSE: To assess constant and pulsatile flow velocity within the lumen of a peripheral NiTi stent using phase velocity mapping for comparison with independent assessments of flow velocity in a phantom model. MATERIALS AND METHODS: A 9 x 20-mm stent installed in flexible tubing was placed in a phantom filled with stationary fluid. Constant and pulsatile flow (produced by a pump programmed to produce a simulation of the carotid artery flow) was assessed using phase velocity mapping at 4.1 T (for constant flow) and at 1.5 T (for pulsatile flow). In all cases 256 x 256 gradient echo phase velocity maps were acquired. For the pulsatile flow condition, cine images with acquisition gated to the pump cycle were acquired with 40 msec temporal resolution across the simulated cardiac cycle. Computed flow volume rates were compared with fluid volume collection for the constant flow model, and with ultrasonic Doppler flow meter measurements for the pulsatile model. RESULTS: The data showed that volume flow rate assessments by phase velocity mapping agreed with independent measurements within 10% to 15%. CONCLUSION: Phase velocity mapping of the lumen of peripheral size NiTi stents is possible in an in vitro model.

Evaluation of in-stent stenosis by magnetic resonance phase-velocity mapping in nickel-titanium stents.

PURPOSE: To evaluate different grades of in-stent stenosis in a nickel-titanium stent with MRI. MATERIALS AND METHODS: Magnetic resonance phase velocity mapping (MR-PVM) was used to measure flow velocity through a 9-mm NiTi stent with three different degrees of stenosis in a phantom study. The tested stenotic geometries were 1) axisymmetric 75%, 2) axisymmetric 90%, and 3) asymmetric 50%. The MR-PVM data were subsequently compared with the velocities from computational fluid dynamic (CFD) simulations of identical conditions. RESULTS: Good quantitative agreement in velocity distribution for the 50% and 75% stenoses was observed. The agreement was poor for the 90% stenosis, most likely due to turbulence and the high-velocity gradients found in the small luminal area relative to the pixel resolution in our imaging settings. CONCLUSION: The accuracy of the MRI velocities inside the stented area renders MRI a modality that may be used to assess moderate to severe in-stent restenosis (ISR) in medium-sized vascular stents in peripheral vessels, such as the iliac, carotid, and femoral arteries. Advances in MR instrumentation may provide sufficient resolution to obtain adequate velocity information from smaller vessels, such as the coronary arteries, and allow MRI to substitute for invasive and expensive catheterization procedures currently in clinical use.

Effect of a flow-streamlining implant at the distal anastomosis of a coronary artery bypass graft.

Intimal thickening in the coronary artery bypass graft (CABG) distal anastomosis has been implicated as the major cause of restenosis and long-term graft failure. Several studies point to the interplay between nonuniform hemodynamics including disturbed flows and recirculation zones, wall shear stress, and long particle residence time as possible etiologies. The hemodynamic features of two anatomic models of saphenous-vein CABGs were studied and compared. One simulated an anastomosis with both diameter and compliance mismatch and a curvature at the connection, analogous to the geometry observed in a conventional cardiothoracic procedure. The other, simulated an anastomosis with a flow stabilizing anastomotic implant connector which improves current cardiothoracic procedures by eliminating the distal vein bulging and curvature. Physiologic flow conditions were imposed on both models and qualitative analysis of the flow was performed with dye injection and a digital camera. Quantitative analysis was performed with laser Doppler velocimetry. Results showed that the presence of the bulge at the veno-arterial junction, contributed to the formation of accentuated secondary structures (helices), which progress into the flow divider and significantly affect radial velocity components at the host vessel up to four diameters downstream of the junction. The model with the implant, achieved more hemodynamically efficient conditions on the host vessel with higher mean and maximum axial velocities and lower radial velocities than the conventional model. The presence of the sinus may also affect the magnitude and shape of the shear stress at locations where intimal thickening occurs. Thus, the presence of the implant creates a more streamlined environment with more primary and less secondary flow components which may then inhibit the development of intimal thickening, restenosis, and ultimate failure of the saphenous vein graft.