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Chemical equivalence testing can be used to assess the biocompatibility implications of a materials or manufacturing change for a medical device. This testing can provide a relatively facile means to evaluate whether the change may result in additional or different toxicological concerns. However, one of the major challenges in the interpretation of chemical equivalence data is the lack established criteria for determining if two sets of extractables data are effectively equivalent. To address this gap, we propose a two-part approach based upon a relatively simple statistical model. First, the probability of a false positive conclusion, wherein there is an incorrectly perceived increase for a given analyte in the comparator relative to the baseline device, can be reduced to a prescribed level by establishing an appropriate acceptance criterion for the ratio of the observed means. Second, the probability of a false negative conclusion, where an actual increase in a given analyte cannot be discerned from the test results, can be minimized by specifying a limiting value of applicability based on the margin of safety (MoS) of the analyte. This approach provides a quantitative, statistically motivated method to interpret chemical equivalence data, despite the relatively high intrinsic variability and small number of replicates typically associated with a chemical characterization evaluation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Extraction testing is critical for biocompatibility evaluation of medical devices, whether to generate samples for biological testing or form the basis for toxicological risk assessment. However, it is not always clear how to compare extraction testing between different extraction conditions and sample geometries. We employ a physics-based model to elucidate the theoretical impact of extraction conditions, sample geometry and material properties on extraction efficiency (M/M 0 ) and extract concentration (C/C 0 ) for single-step and iterative/exhaustive extraction test methods. The model is specified by three parameters: thermodynamic contributions (Ψ), kinetic contributions (τ), and number of extraction iterations (N). We find that over the range of typical parameters for single-step extractions, M/M 0 only approaches one (complete exhaustion) for relatively large values of Ψ (≥10) and τ(≥1). Further, the model suggests that test article geometry and solvent volume can have a dramatic and sometimes opposing effect on M/M 0 and C/C 0 . Our results imply that iterative extractions can be approximated as a single-step extraction with scaled parameters Ψ' = ΨN and τ' = τN. The model provides a framework to reduce the biocompatibility evaluation test burden by optimizing test article and extraction condition selection and guiding development of new test protocols., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Many cardiovascular device alloys contain nickel, which if released in sufficient quantities, can lead to adverse health effects. However, in-vivo nickel release from implanted devices and subsequent biodistribution of nickel ions to local tissues and systemic circulation are not well understood. To address this uncertainty, we have developed a multi-scale (material, tissue, and system) biokinetic model. The model links nickel release from an implanted cardiovascular device to concentrations in peri-implant tissue, as well as in serum and urine, which can be readily monitored. The model was parameterized for a specific cardiovascular implant, nitinol septal occluders, using in-vitro nickel release test results, studies of ex-vivo uptake into heart tissue, and in-vivo and clinical measurements from the literature. Our results show that the model accurately predicts nickel concentrations in peri-implant tissue in an animal model and in serum and urine of septal occluder patients. The congruity of the model with these data suggests it may provide useful insight to establish nickel exposure limits and interpret biomonitoring data. Finally, we use the model to predict local and systemic nickel exposure due to passive release from nitinol devices produced using a wide range of manufacturing processes, as well as general relationships between release rate and exposure. These relationships suggest that peri-implant tissue and serum levels of nickel will remain below 5 μg/g and 10 μg/l, respectively, in patients who have received implanted nitinol cardiovascular devices provided the rate of nickel release per device surface area does not exceed 0.074 μg/(cm 2  d) and is less than 32 μg/d in total., Statement of Significance: The uncertainty in whether in-vitro tests used to evaluate metal ion release from medical products are representative of clinical environments is one of the largest roadblocks to establishing the associated patient risk. We have developed and validated a multi-scale biokinetic model linking nickel release from cardiovascular devices in-vivo to both peri-implant and systemic levels. By providing clinically relevant exposure estimates, the model vastly improves the evaluation of risk posed to patients by the nickel contained within these devices. Our model is the first to address the potential for local and systemic metal ion exposure due to a medical device and can serve as a basis for future efforts aimed at other metal ions and biomedical products., (Published by Elsevier Ltd.)

Many alloys used in cardiovascular device applications contain high levels of nickel, which if released in sufficient quantities, can lead to adverse health effects. While nickel release from these devices is typically characterized through the use of in-vitro immersion tests, it is unclear if the rate at which nickel is released from a device during in-vitro testing is representative of the release rate following implantation in the body. To address this uncertainty, we have developed a novel biokinetic model that combines a traditional toxicokinetic compartment model with a physics-based model to estimate nickel release from an implanted device. This model links the rate of in-vitro nickel release from a cardiovascular device to serum nickel concentrations, an easily measured endpoint, to estimate the rate and extent of in-vivo nickel release from an implanted device. The model was initially parameterized using data in the literature on in-vitro nickel release from a nickel-containing alloy (nitinol) and baseline serum nickel levels in humans. The results of this first step were then used to validate specific components of the model. The remaining unknown quantities were fit using serum values reported in patients following implantation with nitinol atrial occluder devices. The model is not only consistent with levels of nickel in serum and urine of patients following treatment with the atrial occluders, but also the optimized parameters in the model were all physiologically plausible. The congruity of the model with available data suggests that it can provide a framework to interpret nickel biomonitoring data and use data from in-vitro nickel immersion tests to estimate in-vivo nickel release from implanted cardiovascular devices., (Published by Elsevier Inc.)

Drug-eluting stent (DES) implantation is a common treatment for atherosclerosis. The safety and efficacy of these devices will depend on the uptake and distribution of drug into the vessel wall. It is established that the composition of atherosclerotic vessels can vary dramatically with patients' age and gender. However, studies focused on elucidating and quantifying the impact of these variations on important drug transport properties, such as diffusion (D) and partition (k) coefficients, are limited. We have developed an improved tissue mimic or artificial plaque to probe the effect of varying concentrations of plaque constituents on drug transport in vitro. Based on these artificial plaques, we have quantified the impact of gelatin (hydrolyzed collagen) and lipid (cholesterol) concentration on D and k using two model drugs, tetracycline and fluvastatin. We found that for tetracycline, increasing the collagen concentration from 0.025 to 0.100 (w/w) resulted in a fivefold decrease in diffusivity, whereas there was no discernible impact on solubility. Increasing the lipid concentration up to 0.034 (w/w) resulted in only minor changes to transport properties of tetracycline. However, fluvastatin exhibited nearly a fivefold increase in k and 10-fold decrease in D with increased lipid concentration. These results were in reasonable agreement with existing models and exhibited behavior consistent with previous observations on drugs commonly used in DES applications. These observations suggest that variations in the chemical characteristics of atherosclerotic plaque can significantly alter the release rate and distribution of drug following DES implantation., (Copyright © 2013 Wiley Periodicals, Inc.)

We have devised a novel diffuse interface formulation to model the development of chemical and physical inhomogeneities, i.e. microstructure, during the process of casting drug-eluting coatings. These inhomogeneities, which depend on the coating constituents and manufacturing conditions, can have a profound affect on the rate and extent of drug release, and therefore the ability of coated medical devices to function successfully. By deriving the model equations in a time-dependent reference frame, we find that it is computationally viable to probe a wide, physically relevant range of material and process quantities. To illustrate the application of the model, we have evaluated the impact of manufacturing solvent, coating thickness and evaporation rate on microstructure development. Our results suggest that modifying these process conditions can have a strong and nearly discontinuous effect on coating microstructure, and therefore on drug release. Further, we demonstrate that the model can be applied to processes that involve the incremental application of the coating in layers or passes. This new model formulation, which can also be used to predict the kinetics of drug release, provides a tool to elucidate and quantify the relationships between process variables, microstructure and performance. Establishing these relationships can reduce empiricism in materials selection and process design, providing a facile and efficient means to tailor the underlying microstructure and achieve a desired drug-release behavior., (Published by Elsevier Ltd.)

A critical metrology issue for pharmaceutical industries is the application of analytical techniques for the characterization of drug delivery systems to address interrelationships between processing, structure, and drug release. In this study, cast coatings were formed from solutions of poly(styrene-b-isobutylene-b-styrene) (SIBS) and tetracycline in tetrahydrofuran (THF). These coatings were characterized by several imaging modalities, including time-of-flight secondary ion mass spectrometry (TOF-SIMS) for chemical imaging and analysis, atomic force microscopy (AFM) for determination of surface structure and morphology, and laser scanning confocal microscopy (LSCM), which was used to characterize the three-dimensional structure beneath the surface. The results showed phase separation between the drug and copolymer regions. The size of the tetracycline phase in the polymer matrix ranged from hundreds of nanometers to tens of microns, depending on coating composition. The mass of drug released was not found to be proportional to drug loading, because the size and spatial distribution of the drug phase varied with drug loading and solvent evaporation rate, which in turn affected the amount of drug released., ((c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association)

In recent years, traditional rigid materials have been replaced with softer elastomers in intraocular lenses to minimize the size of the required surgical incision, thereby reducing patient recuperation time. However, water-filled cavities that may impact visual acuity are found in many of these new implants. We demonstrate that the cavitation observed in vivo can occur due to an osmotic pressure difference between the aqueous solution within the cavity and the external media in which the lens is immersed. By reducing the osmolarity of the external solution from 300 to 0mM, we observe an increase in cavity volume of almost a factor of 30. Further, we have developed a model for cavity growth assuming the controlling factor is diffusion of hydrophilic molecules from the polymer matrix into the cavity. We find that the experimental observations are consistent with the model and suggest that oligomeric species generated during polymerization are responsible for the observed cavitation., (Published by Elsevier Ltd.)

In recent years, controlled release coatings, comprised of drug-polymer composites, have been integrated with medical devices, improving device functionality and performance. However, relationships between material properties, manufacturing environment, composite (micro)structure, and subsequent release kinetics are not well established. We apply a thermodynamically consistent model to probe the influence of drug-polymer chemistry (phobicity), drug loading, and evaporation rate on microstructure development during fabrication. For these structures, we compute release profiles for exposure to polymer-insoluble media and media in which the polymer readily dissolves. We find that with increasing drug-polymer phobicity, structural heterogeneities form at lower loadings and more rapid rates. The heterogeneities remain isolated and compact at low loadings and become interconnected as the drug to polymer ratio approaches 1.0. Release into polymer-insoluble media was dramatically enhanced by heterogeneities, resulting in up to a fourfold increase in drug release. In polymer-soluble media, however, heterogeneities diminished release. Although reductions of only 30% were typically observed, the absolute changes were much larger than observed in polymer-insoluble media. Our results suggest that improved comprehension and quantification of the physico-chemical properties in controlled release systems will enable the microstructure to be tailored to achieve desired responses that are insensitive to manufacturing variations., ((c) 2008 Wiley-Liss, Inc. and the American Pharmacists Association)

A common method of controlling drug release has been to incorporate the drug into a polymer matrix, thereby creating a diffusion barrier that slows the rate of drug release. It has been demonstrated that the internal microstructure of these drug-polymer composites can significantly impact the drug release rate. However, the effect of processing conditions during manufacture on the composite structure and the subsequent effects on release behavior are not well understood. We have developed a diffuse-interface theory for microstructure evolution that is based on interactions between drug, polymer and solvent species, all of which may be present in either crystalline or amorphous states. Because the theory can be applied to almost any specific combination of material species and over a wide range of environmental conditions, it can be used to elucidate and quantify the relationships between processing, microstructure and release response in controlled drug release systems. Calculations based on the theory have now demonstrated that, for a characteristic delivery system, variations in microstructure arising due to changes in either drug loading or processing time, i.e. evaporation rate, could have a significant impact on both the bulk release kinetics and the uniformity of release across the system. In fact, we observed that changes in process time alone can induce differences in bulk release of almost a factor of two and typical non-uniformities of +/-30% during the initial periods of release. Because these substantial variations may have deleterious clinical ramifications, it is critical that both the system microstructure and the control of that microstructure are considered to ensure the device will be both safe and effective in clinical use.

Hematopoietic stem cell (HSC) therapy can significantly lower instances of infection in chemotherapy patients by accelerating the recovery of white blood cells in the body. However, therapy requires that HSCs be stored at cryogenic temperatures to retain the cells' ability to proliferate. Currently, cells are stored in polymeric blood bags that are subject to fracture at the extremely low storage temperatures, which leads to cell contamination, thereby reducing their effectiveness. Therefore, we have developed an analytical model to predict the accumulation of stresses that ultimately lead to crack initiation and bag fracture during cryogenic storage. Our model gives explicit relationships between stress state in the container and thermoelastic properties of the container material, container geometry, and environmental factors that include temperature of the system and pressure induced by excess gas evolving from the stored medium. Predictions based on the model are consistent with experimental observations of bag failures that occurred during cryogenic storage applications. Finally, the model can provide guidance in material selection and bag design to fabricate bags that will be less susceptible to fracture.