Public Regulatory Databases as a Source of Insight for Neuromodulation Devices Stimulation Parameters.

OBJECTIVE: The Shannon model is often used to define an expected boundary between non-damaging and damaging modes of electrical neurostimulation. Numerous preclinical studies have been performed by manufacturers of neuromodulation devices using different animal models and a broad range of stimulation parameters while developing devices for clinical use. These studies are mostly absent from peer-reviewed literature, which may lead to this information being overlooked by the scientific community. We aimed to locate summaries of these studies accessible via public regulatory databases and to add them to a body of knowledge available to a broad scientific community. METHODS: We employed web search terms describing device type, intended use, neural target, therapeutic application, company name, and submission number to identify summaries for premarket approval (PMA) devices and 510(k) devices. We filtered these records to a subset of entries that have sufficient technical information relevant to safety of neurostimulation. RESULTS: We identified 13 product codes for 8 types of neuromodulation devices. These led us to devices that have 22 PMAs and 154 510(k)s and six transcripts of public panel meetings. We found one PMA for a brain, peripheral nerve, and spinal cord stimulator and five 510(k) spinal cord stimulators with enough information to plot in Shannon coordinates of charge and charge density per phase. CONCLUSIONS: Analysis of relevant entries from public regulatory databases reveals use of pig, sheep, monkey, dog, and goat animal models with deep brain, peripheral nerve, muscle and spinal cord electrode placement with a variety of stimulation durations (hours to years); frequencies (10-10,000 Hz) and magnitudes (Shannon k from below zero to 4.47). Data from located entries indicate that a feline cortical model that employs acute stimulation might have limitations for assessing tissue damage in diverse anatomical locations, particularly for peripheral nerve and spinal cord simulation.

Engagement of the medical-technology sector with society.

The medical-technology sector must educate society in an unbiased rational way about the successes and benefits of biotechnology innovation.

Electrical neurostimulation with imbalanced waveform mitigates dissolution of platinum electrodes.

OBJECTIVE: Electrical neurostimulation has traditionally been limited to the use of charge-balanced waveforms. Charge-imbalanced and monophasic waveforms are not used to deliver clinical therapy, because it is believed that these stimulation paradigms may generate noxious electrochemical species that cause tissue damage. APPROACH: In this study, we investigated the dissolution of platinum as one of such irreversible reactions over a range of charge densities up to 160 µC cm-2 with current-controlled first phase, capacitive discharge second phase waveforms of both cathodic-first and anodic-first polarity. We monitored the concentration of platinum in solution under different stimulation delivery conditions including charge-balanced, charge-imbalanced, and monophasic pulses. MAIN RESULTS: We observed that platinum dissolution decreased during charge-imbalanced and monophasic stimulation when compared to charge-balanced waveforms. SIGNIFICANCE: This observation provides an opportunity to re-evaluate the charge-balanced waveform as the primary option for sustainable neural stimulation.

High-throughput in vitro assay to evaluate the cytotoxicity of liberated platinum compounds for stimulating neural electrodes.

BACKGROUND: It is currently unclear how the platinum (Pt) species released from platinum-containing stimulating electrodes may affect the health of the surrounding tissue. This study develops an effective system to assess the cytotoxicity of any electrode-liberated Pt over a short duration, to screen systems before future in vivo testing. NEW METHOD: A platinum electrode was stimulated for two hours under physiologically relevant conditions to induce the liberation of Pt species. The total concentration of liberated Pt species was quantified and the concentration found was used to develop a range of Pt species for our model system comprised of microglia and neuron-like cells. RESULTS: Under our stimulation conditions (k=2.3, charge density of 57.7µC/cm2), Pt was liberated to a concentration of 1ppm. Interestingly, after 24h of Pt exposure, the dose-dependent cytotoxicity plots revealed that cell death became statistically significant at 10ppm for microglia and 20ppm for neuronal cells. However, in neuron-like cell cultures, concentrations above 1ppm resulted in significant neurite loss after 24h. COMPARISON WITH EXISTING METHODS: To our knowledge, there does not exist a simple, in vitro assay system for assessing the cytotoxicity of Pt liberated from stimulating neural electrodes. CONCLUSIONS: This work describes a simple model assay that is designed to be applicable to almost any electrode and stimulation system where the electrode is directly juxtaposed to the neural target. Based on the application, the duration of stimulation and Pt exposure may be varied.

Electron transfer processes occurring on platinum neural stimulating electrodes: a tutorial on the i(V e) profile.

The aim of this tutorial is to encourage members of the neuroprosthesis community to incorporate electron transfer processes into their thinking and provide them with the tools to do so when they design and work with neurostimulating devices. The focus of this article is on platinum because it is the most used electrode metal for devices in commercial use. The i(V e) profile or cyclic voltammogram contains information about electron transfer processes that can occur when the electrode-electrolyte interface, V e, is at a specific potential, and assumed to be near steady-state conditions. For the engineer/designer this means that if the potential is not in the range of a specific electron transfer process, that process cannot occur. An i(V e) profile, recorded at sweep rates greater than 0.1 mVs(-1), approximates steady-state conditions. Rapid transient potential excursions, like that seen with neural stimulation pulses, may be too fast for the reaction to occur, however, this means that if the potential is in the range of a specific electron transfer process it may occur and should be considered. The approach described here can be used to describe the thermodynamic electron transfer processes on other candidate electrode metals, e.g. stainless steel, iridium, carbon-based, etc.

Abrasion and fatigue resistance of PDMS containing multiblock polyurethanes after accelerated water exposure at elevated temperature.

Segmented polyurethane multiblock polymers containing polydimethylsiloxane and polyether soft segments form tough and easily processed thermoplastic elastomers (PDMS-urethanes). Two commercially available examples, PurSil 35 (denoted as P35) and Elast-Eon E2A (denoted as E2A), were evaluated for abrasion and fatigue resistance after immersion in 85 °C buffered water for up to 80 weeks. We previously reported that water exposure in these experiments resulted in a molar mass reduction, where the kinetics of the hydrolysis reaction is supported by a straight forward Arrhenius analysis over a range of accelerated temperatures (37-85 °C). We also showed that the ultimate tensile properties of P35 and E2A were significantly compromised when the molar mass was reduced. Here, we show that the reduction in molar mass also correlated with a reduction in both the abrasion and fatigue resistance. The instantaneous wear rate of both P35 and E2A, when exposed to the reciprocating motion of an ethylene tetrafluoroethylene (ETFE) jacketed cable, increased with the inverse of the number averaged molar mass (1/Mn). Both materials showed a change in the wear surface when the number-averaged molar mass was reduced to ≈ 16 kg/mole, where a smooth wear surface transitioned to a 'spalling-like' pattern, leaving the wear surface with ≈ 0.3 mm cracks that propagated beyond the contact surface. The fatigue crack growth rate for P35 and E2A also increased in proportion to 1/Mn, after the molar mass was reduced below a critical value of ≈30 kg/mole. Interestingly, this critical molar mass coincided with that at which the single cycle stress-strain response changed from strain hardening to strain softening. The changes in both abrasion and fatigue resistance, key predictors for long term reliability of cardiac leads, after exposure of this class of PDMS-urethanes to water suggests that these materials are susceptible to mechanical compromise in vivo.

Degradability of polymers for implantable biomedical devices.

Many key components of implantable medical devices are made from polymeric materials. The functions of these materials include structural support, electrical insulation, protection of other materials from the environment of the body, and biocompatibility, as well as other things such as delivery of a therapeutic drug. In such roles, the stability and integrity of the polymer, over what can be a very long period of time, is very important. For most of these functions, stability over time is desired, but in other cases, the opposite-the degradation and disappearance of the polymer over time is required. In either case, it is important to understand both the chemistry that can lead to the degradation of polymers as well as the kinetics that controls these reactions. Hydrolysis and oxidation are the two classes of reactions that lead to the breaking down of polymers. Both are discussed in detail in the context of the environmental factors that impact the utility of various polymers for medical device applications. Understanding the chemistry and kinetics allows prediction of stability as well as explanations for observations such as porosity and the unexpected behavior of polymeric composite materials in some situations. In the last part, physical degradation such interfacial delamination in composites is discussed.

Maximum conductivity of packed nanoparticles and their polymer composites.

Adding conductive fillers to nonconductive polymers is a common way to make soft conductive materials such as conductive adhesives. An important issue is how to achieve high volume conductivity with acceptable mechanical performance. Two questions pertaining to this issue were studied in this paper. One question was whether the maximum conductivity benefits from larger or smaller particle sizes. The second was what is the maximum achievable conductivity. One incentive for this work is the recent availability of nanomaterials that provide opportunities to make conductive composites using much smaller particles than in the past. We found that the conductivity of platinum, carbon black, and silver particles in their polyurethane composites did not vary greatly with particle size (from micrometer to nanometer range). What was unexpected was that in all the composite examples, the highest conductivity achieved was only on the order of 1% of that of the pure bulk conductive materials. Further experiments to emulate these conductive composites with platinum, carbon black, copper, and nickel particles without polymer matrix showed similar results, indicating the issue is not simply dispersion homogeneity, nano versus macro particles, particle connectivity/percolation, or the presence of the matrix materials. We interpret this to mean that the composite systems are intrinsically limited by the contact between filler particles.

In vitro biostability evaluation of polyurethane composites in acidic, basic, oxidative, and neutral solutions.

New and improved properties can often be achieved by compounding two or more different but compatible materials. But, can failure possibility also be increased by such a compounding strategy? In this article, we compared the in vitro biostability of composites with that of the pure polymer. We tested three model composites in oxidative, acidic, basic, and neutral solutions. We found that oxidation degradation was much more profound in the composites than in the corresponding pure polymer. This degradation seemed to be an intrinsic property of composite materials. We also observed the well documented interfacial debonding between filler and matrix and its effects on the mechanical reinforcement of the hydrated composites. The improvements in acid and base resistance were also observed.

Kinetics and time-temperature equivalence of polymer degradation.

We studied the hydrolysis kinetics of amorphous polylactide. It was found the hydrolysis rate had a slow-to-fast transition at a certain molecular weight (Mn). This transition was not correlated with the mass loss and water uptake of samples, nor the pH values of testing media. We speculated that this transition was due to the slow diffusion of polymer chain ends. The chain ends did not significantly promote the hydrolysis of samples until their concentrations (approximately 1/Mn) reached a critical value. The degradation tests were also conducted over a temperature range from 37 to 90 degrees C. A time-temperature equivalent relationship of degradation processes was established and a master curve spanning a time range equivalent to 3-5 years at 37 degrees C was constructed. This master curve can be used to predict polymer degradation processes based on accelerated tests. The functional time and disappearance time of degradable polymers were also discussed.