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We demonstrate a novel application of the time-temperature superposition (TTS) principle to predict solute diffusivity

Nitinol exhibits unique (thermo)mechanical properties that make it central to the design of many medical devices. However, nitinol nominally contains 50 atomic percent nickel, which if released in sufficient quantities, can lead to adverse health effects. While nickel release from nitinol devices is typically characterized using in vitro immersion tests, these evaluations require lengthy time periods. We have explored elevated temperature as a potential method to expedite this testing. Nickel release was characterized in nitinol materials with surface oxide thickness ranging from 12 to 1564 nm at four different temperatures from 310 to 360 K. We found that for three of the materials with relatively thin oxide layers, ≤ 87 nm nickel release exhibited Arrhenius behavior over the entire temperature range with activation energies of 80 to 85 kJ/mol. Conversely, the fourth ''black-oxide'' material, with a much thicker, complex oxide layer, was not well characterized by an Arrhenius relationship. Power law release profiles were observed in all four materials; however, the exponent from the thin oxide materials was approximately 1/4 compared with 3/4 for the black-oxide material. To illustrate the potential benefit of using elevated temperature to abbreviate nickel release testing, we demonstrated that a > 50 day 310 K release profile could be accurately recovered by testing for less than 1 week at 340 K. However, because the materials explored in this study were limited, additional testing and mechanistic insight are needed to establish a protective temperature scaling that can be applied to all nitinol medical device components.

Various public health concerns can arise from the unintended leaching of additives and impurities from polymeric medical devices or food packaging, which is directly related to each solute's diffusivity D. Both experimental and simulation methods can be used to quantify D, but slow diffusion at physiologic temperature in glassy polymers can render these approaches impractical. Here, we investigate a simulation approach with the potential to more rapidly calculate D. Specifically, we examine links between dynamic localization, characterized by the Debye-Waller factor, ⟨u2⟩, and D in a variety of polymer/solute systems using atomistic molecular dynamics (MD) simulations. Using short, high-temperature MD simulations to estimate D at physiologic temperature, we find that the relation ln D ∝ 1/⟨u2⟩ quantitatively predicts D for small solutes and produces an upper-bound estimate of D for larger solutes. Upper-bound estimates are useful in certain contexts, and we compare our results with another approach for determining upper bounds, the Piringer model, to show where each method may be useful. Then, we examine a modified relation where the Debye-Waller factor is rescaled by the mode coupling temperature Tc, which can produce better estimates of D if Tc is carefully chosen. Last, we compare our approach with several other models that relate temperature or localized dynamics with diffusivity. Although each of these approaches can be used to model D across wide temperature ranges using one or more adjustable parameters, none of them are truly predictive in glassy polymers. Further developments are needed to predict the optimal values of the adjustable parameters a priori.

Toxicological risk assessment approaches are increasingly being used in lieu of animal testing to address toxicological concerns associated with release of chemical constituents from polymeric medical device components. These approaches currently rely on in vitro extraction testing in aggressive environments to estimate patient exposure to these constituents, but the clinical relevance of the test results is often ambiguous. Physics-based mass transport models can provide a framework to interpret extraction test results to provide more clinically relevant exposure estimates. However, the models require system-specific material properties, such as diffusion (D) and partition coefficients (K), to be established a priori for the extraction conditions. Using systems comprised high-density polyethylene and 4 different additives, we demonstrate that these properties can be quantified through standard extraction testing in hexane and isopropyl alcohol. The values of D and K derived in this manner were consistent with theoretical predictions for these quantities. Based on these results, we discuss both the challenges and benefits to leveraging extraction data to parameterize physics-based exposure models. Our observations suggest that clinically relevant, yet still conservative, exposure dose estimates provided by applying this approach to a single extraction measurement can be more than 100 times lower than would be measured under typical aggressive extraction conditions. However, to apply the framework on a routine basis, limiting values of D and K must be established for device-relevant systems either through the aggregation and analysis of more extensive extraction test data and/or advancements in theoretical and computational modeling efforts to predict these quantities.

Three-dimensional (3D) printing has enabled benchtop fabrication of customized bioengineered constructs with intricate architectures. Various approaches are being explored to enable optimum integration of such constructs into the physiological environment including addition of bioactive fillers. In this work, we incorporated a corticosteroid drug, dexamethasone (Dex), in a low modulus polyester (SC5050) and examined the effect of Dex incorporation on solvent-, initiator-, and monomer-free pneumatic extrusion-based 3D printing of the polymer. Dex-SC5050 interactions were characterized by plotting thermodynamic binary phase diagrams based on the Flory-Huggins theory. The effect of Dex composition on the 3D printability of the SC5050 polyester was examined by rheological characterization and by image analysis of each layer of the 3D printed scaffolds. The drug release and the degradation of the polymer from the 3D printed scaffolds was used to analyze the effect of Dex composition on the performance of the 3D printed scaffolds. We found that Dex was insoluble in SC5050 polyester at relevant 3D printing temperatures and the insoluble drug particles physically reinforced the polymer, increasing the viscosity and the shear modulus of the base polymer. In addition, the reinforcing effect improved the shape fidelity of the printed filaments and the overall quality of the scaffolds. The Dex particles demonstrated a two-phase release, with an initial burst release and a slower sustained release of drug under in vitro conditions. To investigate preliminary host response of the 3D printed SC5050 scaffolds for tissue engineering applications, the printed scaffolds were implanted subcutaneously in Sprague-Dawley rats for 6 weeks and examined for fibrous tissue formation, infiltration of cells, and vascularization into the pores of the scaffolds.

Ethylene oxide (EO) gas is commonly used to sterilize medical devices. Bioavailable residual EO, however, presents a significant toxicity risk to patients. Residual EO is assessed using international standards describing extraction conditions for different medical device applications. We examine a series of polymers and explore different extraction conditions to determine residual EO. Materials were sterilized with EO and exhaustively extracted in water, in one of three organic solvents, or in air using thermal desorption. The EO exhaustively extracted varies significantly and is dictated by two factors: the EO that permeates the material during sterilization; and the effectiveness of the extraction protocol in flushing residual EO from the material. Extracted EO is maximized by a close matches between Hildebrand solubility parameters δpolymer , δEO , and δsolvent . There remain complexities to resolve, however, because maximized EO uptake and detection are accompanied by great variability. These observations may inform protocols for material selection, sterilization, and EO extraction. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2455-2463, 2018.

Liners used in orthopedic devices are often made from ultrahigh molecular weight polyethylene (UHMWPE). A general predictive capability for transport coefficients of small molecules in UHMWPE does not exist, making it difficult to assess properties associated with leaching or uptake of small molecules. To address this gap, we describe here how a form of the Vrentas-Duda free volume model can be used to predict upper-bound diffusion coefficients (D) of arbitrary molecules within UHMWPE on the basis of their size and shape. Within this framework, the free-volume microstructure of UHMWPE is defined by analysis of a curated set of model diffusants. We determined an upper limit on D for vitamin E, a common antioxidant added to UHMWPE, to be 7.1 × 10-12 cm2 s-1 . This means that a liner that contains 0.1 wt % or less Vitamin E and has

Many polymeric medical device materials contain color additives which could lead to adverse health effects. The potential health risk of color additives may be assessed by comparing the amount of color additive released over time to levels deemed to be safe based on available toxicity data. We propose a conservative model for exposure that requires only the diffusion coefficient of the additive in the polymer matrix, D, to be specified. The model is applied here using a model polymer (poly(ether-block-amide), PEBAX 2533) and color additive (quinizarin blue) system. Sorption experiments performed in an aqueous dispersion of quinizarin blue (QB) into neat PEBAX yielded a diffusivity D = 4.8 × 10−10 cm2 s−1, and solubility S = 0.32 wt %. On the basis of these measurements, we validated the model by comparing predictions to the leaching profile of QB from a PEBAX matrix into physiologically representative media. Toxicity data are not available to estimate a safe level of exposure to QB, as a result, we used a Threshold of Toxicological Concern (TTC) value for QB of 90 µg/adult/day. Because only 30% of the QB is released in the first day of leaching for our film thickness and calculated D, we demonstrate that a device may contain significantly more color additive than the TTC value without giving rise to a toxicological concern. The findings suggest that an initial screening-level risk assessment of color additives and other potentially toxic compounds found in device polymers can be improved. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2017.

Many polymeric medical devices contain color additives for differentiation or labeling. Although some additives can be toxic under certain conditions, the risk associated with the use of these additives in medical device applications is not well established, and evaluating their impact on device biocompatibility can be expensive and time consuming. Therefore, we have developed a framework to conduct screening-level risk assessments to aid in determining whether generating color additive exposure data and further risk evaluation are necessary. We first derive tolerable intake values that are protective for worst-case exposure to 8 commonly used color additives. Next, we establish a model to predict exposure limited only by the diffusive transport of the additive through the polymer matrix. The model is parameterized using a constitutive model for diffusion coefficient (D) as a function of molecular weight (Mw) of the color additive. After segmenting polymer matrices into 4 distinct categories, upper bounds on D(Mw) were determined based on available data for each category. The upper bounds and exposure predictions were validated independently to provide conservative estimates. Because both components (toxicity and exposure) are conservative, a ratio of tolerable intake to exposure in excess of one indicates acceptable risk. Application of this approach to typical colored polymeric materials used in medical devices suggests that additional color additive risk evaluation could be eliminated in a large percentage (≈90%) of scenarios.

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.

Poly (lactic-co-glycolic acid) (PLGA) copolymers have been broadly used in controlled drug release applications. Because these polymers are biodegradable, they provide an attractive option for drug delivery vehicles. There are a variety of material, processing, and physiological factors that impact the degradation rates of PLGA polymers and concurrent drug release kinetics. This work is intended to provide a comprehensive and collective review of the physicochemical and physiological factors that dictate the degradation behavior of PLGA polymers and drug release from contemporary PLGA-based drug-polymer products. In conjunction with the existing experimental results, analytical and numerical theories developed to predict drug release from PLGA-based polymers are summarized and correlated with the experimental observations. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1692-1716, 2017.

Potential connections between release profiles and solvent evaporation rates alongside polymer chemistry were elucidated for the release of tetracycline hydrochloride from two different poly (d, l-lactide-co-glycolide) (PLGA) film matrices containing high drug fractions (50%, 30%, and 15%), and prepared at two distinct solvent evaporation rates. At highest tetracycline concentrations (50%), (i) the early release rates were ≤0.5 μg/min in all cases; (ii) release was linear from systems fabricated with lower lactic content and slower solvent evaporation rate and bimodal from systems fabricated with higher lactic content and faster evaporation rate; (iii) surface fractions covered by the drug were similar at both evaporation rates for 85:15 PLGA but very different for 50:50 PLGA, leading to unexpectedly reduced early release from 50:50 PLGA than from 85:15 PLGA when both the matrices were fabricated using a slower evaporation rate. These features remained unaffected in case of low drug concentration. Results suggested that during the formation of the drug-polymer microstructure, the combined effect of polymer chemistry and solvent evaporation rate sets apart the surface characteristics and the initial release profiles of systems containing high drug fraction, and an appropriate combination of these parameters may be utilized to control the early stage of drug release.

In an effort to better understand current test practices and improve nonclinical testing of cardiovascular metallic implants, the Food and Drug Administration (FDA) held a public workshop on Cardiovascular Metallic Implants: corrosion, surface characterization, and nickel leaching. The following topics were discussed: (1) methods used for corrosion assessments, surface characterization techniques, and nickel leach testing of metallic cardiovascular implant devices, (2) the limitations of each of these in vitro tests in predicting in vivo performance, (3) the need, utility, and circumstances when each test should be considered, and (4) the potential testing paradigms, including acceptance criteria for each test. In addition to the above topics, best practices for these various tests were discussed, and knowledge gaps were identified. Prior to the workshop, discussants had the option to provide feedback and information on issues relating to each of the topics via a voluntary preworkshop assignment. During the workshop, the pooled responses were presented and a panel of experts discussed the results. This article summarizes the proceedings of this workshop and background information provided by workshop participants. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. J Biomed Mater Res Part B: Appl Biomater, 105B: 1330-1341, 2017.

Blood passage through medical devices can cause hemolysis and increased levels of plasma free hemoglobin (pfH) that may lead to adverse effects such as vasoconstriction and renal tubule injury. Although the hemolytic potential of devices is typically characterized in vitro using animal blood, the results can be impacted by various blood parameters, such as donor species. Moreover, it is unclear how to relate measured in vitro hemolysis levels to clinical performance because pfH accumulation in vivo depends on both hemolysis rate and availability of plasma haptoglobin (Hpt) that can bind and safely eliminate pfH. To help to address these uncertainties, we developed a biokinetic model linking in vivo hemolysis rates to time-dependent pfH and Hpt concentrations. The model was initially parameterized using studies that characterized baseline levels and evolution of pfH and Hpt after introduction of excess pfH in humans. With the biokinetic parameters specified, the model was applied to predict hemolysis rates in three patient groups undergoing cardiopulmonary bypass surgery. The congruity of the model with these clinical data suggests that it can infer in vivo hemolysis rates and provide insight into pfH levels that may cause concern. The model was subsequently used to evaluate acceptance threshold hemolysis values proposed in the literature for chronic circulatory assist blood pumps and to assess the impact of patient weight on pfH accumulation using simple scaling arguments, which suggested that identical hemolysis index values may increase pfH levels nearly threefold in 10 kg pediatric patients compared with 80 kg adults.

To formalize our understanding of indiscriminate grafting chemistries as they pertain to cross-linkable polymers and emerging patterning technologies, we designed a new polymer, poly(styrene sulfonyl azide-alt-maleic anhydride) (PSSMA). By modulating its solubility, it can be deposited into smooth, ultrathin films atop polar and nonpolar polymers. Upon heating above 120 °C or exposure to UV light, highly reactive nitrene intermediates are generated from the azide groups which form covalent adducts and cross-link the PSSMA. Azide photolysis and polymer gelation were studied in the context of a statistical model to gain insight into the network outcomes of nitrenes in a polymer film. For every azide group converted to a nitrene in ambient atmosphere, it has an 11% likelihood of grafting to another chain and a 5% chance of causing a scission. These values can be increased over 3-fold by reducing the O2 content by 85%. Alternatively, the effects of quenching by ground-state O2 can be mitigated by adding Michl...

An overview of diffuse interface models specific to drug-eluting stent coatings is presented. Microscale heterogeneities, both in the coating and use environment, dictate the performance of these coatings. Using diffuse interface methods, these heterogeneities can be explicitly incorporated into the model equations with relative ease. This enables one to predict the complex microstructures that evolve during coating fabrication and subsequent impact on drug release. Examples are provided that illustrate the wide range of phenomena that can be addressed with diffuse interface models including: crystallization, constrained phase separation, hydrolytic degradation, and heterogeneous binding. Challenges associated with the lack of material property data and numerical solution of the model equations are also highlighted. Finally, in light of these potential drawbacks, the potential to utilize diffuse interface models to help guide product and process development is discussed.

The successful function of drug-eluting devices used in the treatment of atherosclerosis relies on the concentration and retention of the drug in the vessel wall. While drug deposition necessarily depends on the underlying tissue structure, conventional models do not account for the intrinsic structural complexity of arterial tissue and its impact on deposition. By employing only average bulk material properties, the capability to predict the potential for local toxicity or therapeutic failure is limited. To address these limitations, we have developed a model that accounts explicitly for variations in the tissue structure. The approach uses a laminate approximation of the underlying microscopic structure to specify an expression for the continuous spatial dependence of the effective macroscopic material properties. Based on this continuum description, we derive an analytic expression for drug uptake into arterial tissue under typical ex vivo experimental conditions. This expression is used to extract relevant material properties for paclitaxel in bovine arteries based on available literature data. The best fit parameters are then used as the basis for numerical simulations of long-term deposition behavior from a stent with a pure paclitaxel coating. The results of these simulations are quantitatively consistent with previously reported in vivo observations. We also demonstrate that significant errors can arise in both the interpretation of experimental data and the prediction of drug deposition when structural heterogeneities are ignored. Establishing a robust deposition model can ultimately reduce empiricism in the design of drug-eluting devices, providing a facile means to guide the development and refinement of these technologies.

The drug coating process for coated drug-eluting stents (DES) has been identified as a key source of inter- and intra-batch variability in drug elution rates. Quality-by-design (QbD) principles were applied to gain an understanding of the ultrasonic spray coating process of DES. Statistically based design of experiments (DOE) were used to understand the relationship between ultrasonic atomization spray coating parameters and dependent variables such as coating mass ratio, roughness, drug solid state composite microstructure, and elution kinetics. Defect-free DES coatings composed of 70% 85:15 poly(DL-lactide-co-glycolide) and 30% everolimus were fabricated with a constant coating mass. The drug elution profile was characterized by a mathematical model describing biphasic release kinetics. Model coefficients were analyzed as a DOE response. Changes in ultrasonic coating processing conditions resulted in substantial changes in roughness and elution kinetics. Based on the outcome from the DOE study, a design space was defined in terms of the critical coating process parameters resulting in optimum coating roughness and drug elution. This QbD methodology can be useful to enhance the quality of coated DES.

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/(cm2 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.

A novel approach for rapid risk assessment of targeted leachables in medical device polymers is proposed and validated. Risk evaluation involves understanding the potential of these additives to migrate out of the polymer, and comparing their exposure to a toxicological threshold value. In this study, we propose that a simple diffusive transport model can be used to provide conservative exposure estimates for phase separated color additives in device polymers. This model has been illustrated using a representative phthalocyanine color additive (manganese phthalocyanine, MnPC) and polymer (PEBAX 2533) system. Sorption experiments of MnPC into PEBAX were conducted in order to experimentally determine the diffusion coefficient, D = (1.6 ± 0.5) × 10−11 cm2/s, and matrix solubility limit, C s = 0.089 wt.%, and model predicted exposure values were validated by extraction experiments. Exposure values for the color additive were compared to a toxicological threshold for a sample risk assessment. Results from this study indicate that a diffusion model-based approach to predict exposure has considerable potential for use as a rapid, screening-level tool to assess the risk of color additives and other small molecule additives in medical device polymers.

Liners used in orthopedic devices are often made from ultrahigh molecular weight polyethylene (UHMWPE). A general predictive capability for transport coefficients of small molecules in UHMWPE does not exist, making it difficult to assess properties associated with leaching or uptake of small molecules. To address this gap, we describe here how a form of the Vrentas-Duda free volume model can be used to predict upper-bound diffusion coefficients (D) of arbitrary molecules within UHMWPE on the basis of their size and shape. Within this framework, the free-volume microstructure of UHMWPE is defined by analysis of a curated set of model diffusants. We determined an upper limit on D for vitamin E, a common antioxidant added to UHMWPE, to be 7.1 × 10

An aqueous hyaluronic acid (HA(aq)) pericellular coat, when mediating the tactile aspect of cellular contact inhibition, has three tasks: interface formation, mechanical signal transmission and interface separation. To quantify the interfacial adhesive behavior of HA(aq), we induce simultaneous interface formation and separation between HA(aq) and a model hydrophobic, hysteretic Si-SAM surface. While surface tension γ remains essentially constant, interface formation and separation depend greatly on concentration (5 ≤ C ≤ 30 mg mL(-1)), molecular weight (6 ≤ MW ≤ 2000 kDa) and interfacial velocity (0 ≤ V ≤ 3 mm s(-1)), each of which affect shear elastic and loss moduli G′ and G′′, respectively. Viscoelasticity dictates the mode of interfacial motion: wetting-dewetting, capillary necking, or rolling. Wetting-dewetting is quantified using advancing and receding contact angles θ(A) and θ(R), and the hysteresis between them, yielding data landscapes for each C above the [MW, V] plane. The landscape sizes, shapes, and curvatures disclose the interplay, between surface tension and viscoelasticity, which governs interfacial dynamics. Gel point coordinates modulus G and angular frequency ω appear to predict wetting-dewetting (G75 ω0.2), capillary necking (75 ω0.2G200 ω0.075) or rolling (G200ω0.075). Dominantly dissipative HA(aq) sticks to itself and distorts irreversibly before separating, while dominantly elastic HA(aq) makes contact and separates with only minor, reversible distortion. We propose the dimensionless number (G′V)/(ω(r)γ), varying from 10(-5) to 10(3) in this work, as a tool to predict the mode of interface formation-separation by relating interfacial kinetics with bulk viscoelasticity. Cellular contact inhibition may be thus aided or compromised by physiological or interventional shifts in [C, MW, V], and thus in (G′V)/(ω(r)γ), which affect both mechanotransduction and interfacial dynamics. These observations, understood in terms of physical properties, may be broadened to probe interfacial dynamics of other viscoelastic aqueous biopolymers.

Diffusion of small to medium sized molecules in polymeric medical device materials underlies a broad range of public health concerns related to unintended leaching from or uptake into implantable medical devices. However, obtaining accurate diffusion coefficients for such systems at physiological temperature represents a formidable challenge, both experimentally and computationally. While molecular dynamics simulation has been used to accurately predict the diffusion coefficients, D, of a handful of gases in various polymers, this success has not been extended to molecules larger than gases, e.g., condensable vapours, liquids, and drugs. We present atomistic molecular dynamics simulation predictions of diffusion in a model drug eluting system that represent a dramatic improvement in accuracy compared to previous simulation predictions for comparable systems. We find that, for simulations of insufficient duration, sub-diffusive dynamics can lead to dramatic over-prediction of D. We present useful metrics for monitoring the extent of sub-diffusive dynamics and explore how these metrics correlate to error in D. We also identify a relationship between diffusion and fast dynamics in our system, which may serve as a means to more rapidly predict diffusion in slowly diffusing systems. Our work provides important precedent and essential insights for utilizing atomistic molecular dynamics simulations to predict diffusion coefficients of small to medium sized molecules in condensed soft matter systems.

Many polymeric medical device materials contain color additives which could lead to adverse health effects. The potential health risk of color additives may be assessed by comparing the amount of color additive released over time to levels deemed to be safe based on available toxicity data. We propose a conservative model for exposure that requires only the diffusion coefficient of the additive in the polymer matrix, D, to be specified. The model is applied here using a model polymer (poly(ether-block-amide), PEBAX 2533) and color additive (quinizarin blue) system. Sorption experiments performed in an aqueous dispersion of quinizarin blue (QB) into neat PEBAX yielded a diffusivity D = 4.8 × 10

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.

With the advent of nanotechnology, silver nanoparticles increasingly are being used in coatings, especially in medical device applications, to capitalize on their antimicrobial properties. The attractiveness of nanoparticulate silver systems is the expected increased antimicrobial efficacy relative to their bulk counterparts, which may be attributed to an increased silver ion (Ag+) solubility, and hence availability, that arises from capillarity effects in small, nanometer-sized particles. However, a change of the material upon which the antimicrobial nanoparticulate silver is deposited (herein called "substrate") may affect the availability of Ag+ ions and the intended efficacy of the device. We utilize both theory and experiment to determine the effect of substrate on ion release from silver particles in electrochemical environments and find that substrate surface charge, chemical reactivity or affinity of the surface for Ag+ ions, and wettability of the surface all affect availability of Ag+ ions, and hence antimicrobial efficacy. It is also observed that with time of exposure to deionized water, Ag+ ion release increases to a maximum value at 5 min before decreasing to undetectable levels, which is attributed to coarsening of the nanoparticles, and which subsequently reduces the solubility and availability of Ag+ ions. This coarsening phenomenon is also predicted by the theoretical considerations and has been confirmed experimentally by transmission electron microscopy.

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.

Quantitative homology metrics are proposed for characterizing the thermal–elastic response of polycrystalline materials. Simulations for a calcite-based polycrystal, marble, are used as an illustrative example. The homology metrics are based on topological measurements, such as the number of components and the number of handles of the thermal–elastic response fields for a complex microstructure. These homology metrics are applied to characterize not only the elastic energy density and maximum principal stress response fields in a polycrystal but also the correlated grain-boundary misorientation distributions that influenced the formation of these response fields. It is demonstrated that the topological analysis can quantitatively distinguish between different types of grain-boundary misorientations, as well as between differences in the resulting response fields.

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.

Two-dimensional, microstructure-based finite element simulations were used to elucidate the influence of grain orientation configuration on the thermal-elastic response of polycrystalline ceramic materials. The two main constituent minerals of marbles, calcite and dolomite, were considered. The crystallographic configuration of the grains is described in terms of the distribution of grain orientations and grain-boundary misorientations. To probe the influence of grain orientation configuration, we first generated the geometry of a hypothetical microstructure. Next, crystallographic orientations were assigned to each grain in the microstructure such that the grain orientations and grain-boundary misorientations matched predefined distributions. By varying the predefined distributions, we generated 45 unique microstructures covering a wide range of crystallographic configurations. After assigning thermal-elastic properties to each structure, corresponding to either calcite or dolomite, finite-element simulations were performed. The simulations demonstrated that both the orientation and misorientation distributions have a substantial impact on the thermal-elastic response of microstructures with the same material properties: varying the crystallographic configuration results in variations of stored elastic strain energy density from 10 kJ m−3 to 39 kJ m−3 for a 100 °C temperature change. Further, the ratio of the bulk coefficient of thermal expansion in the two principal directions varies from − 0.17 to 1.46. Surprisingly, the grain-boundary misorientations alone had a substantial impact on the thermal-elastic response of the system. By simply rearranging a fixed set of crystallographic orientations to obtain different nearest-neighbor misorientation configurations, we observed variations in strain energy density from 10 kJ m−3 to 39 kJ m−3 and variations in thermal expansion ratio from 0.06 to 0.90. The results suggest that to predict accurately the thermal-elastic response of polycrystalline ceramics, it is critical to consider both the distribution of grain-boundary misorientations as well as the distribution of grain orientations.

Poly (lactic-co-glycolic acid) (PLGA) copolymers have been broadly used in controlled drug release applications. Because these polymers are biodegradable, they provide an attractive option for drug delivery vehicles. There are a variety of material, processing, and physiological factors that impact the degradation rates of PLGA polymers and concurrent drug release kinetics. This work is intended to provide a comprehensive and collective review of the physicochemical and physiological factors that dictate the degradation behavior of PLGA polymers and drug release from contemporary PLGA-based drug-polymer products. In conjunction with the existing experimental results, analytical and numerical theories developed to predict drug release from PLGA-based polymers are summarized and correlated with the experimental observations. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1692-1716, 2017.

This paper describes some aspects of reconstruction of microstructures in three dimensions. A distinction is drawn between tomographic approaches that seek to characterize specific volumes of material, either with or without diffraction, and statistical approaches that focus on particular aspects of microstructure. A specific example of the application of the statistical approach is given for an aerospace aluminum alloy in which the distributions of coarse constituent particles are modeled. Such distributions are useful for modeling fatigue crack initiation and propagation.

An experimental technique has been developed to determine the surface energy anisotropy of crystalline solids. The technique is based on atomic force microscopy measurements, which are used to quantify the geometry of thermal grooves, and electron backscattered diffraction pattern measurements, which are used to specify crystallographic orientations. Observations are made at circumferential thermal grooves, where it is assumed that Herring's local equilibrium condition for a triple junction holds and that the grain-boundary energy is independent of its boundary plane. A truncated double Fourier series is used to approximate the surface energy, and the unknown coefficients of the series are determined by fitting the observations to the local equilibrium condition. The method, which should be applicable to most polycrystalline materials, has been tested on magnesia that has been thermally grooved at 1400°C in air. The maximum of the best-fit surface energy function is at (111) and the minimum is at (100). The relative surface energies of the low-index planes are γ 110 /γ 100 = 1.040 ± 0.008 and γ 111 /γ 100 = 1.072 ± 0.010.

We have used electron backscattered diffraction patterns to determine the misorientation of 201 adjacent pairs of grains in a magnesia polycrystal. The width and depth of the thermal grooves formed by these same grain boundaries were also measured by atomic force microscopy (AFM). By simulating the errors associated with the AFM observations and comparing our observations to existing data for magnesia and alumina, we show that, under appropriate experimental conditions, surface dihedral angles, relative grain-boundary energies, and surface diffusivities determined from AFM measurements are consistent with data acquired by more laborious techniques. Correlation of the grain-boundary misorientation and thermal groove geometry leads to the observation that grain boundaries with small misorientations, regardless of the rotation axis, have shallow thermal grooves and relatively low grain-boundary energies. Furthermore, numerous boundaries with relatively large misorientations but shallow thermal grooves correspond to special boundaries near coincident-site-lattice (CSL) misorientations. Finally, the data set indicates that factors other than the boundary misorientation, such as anisotropy of the surface energy and the grain-boundary tangent plane, play a role in determining the groove geometry.

A stereological method is described for estimating the distribution of grain-boundary types in polycrystalline materials on the basis of observations from a single planar section. The grain-boundary distribution is expressed in terms of five macroscopically observable parameters that include: three parameters that describe the lattice misorientation across the boundary and two parameters that describe the orientation of the grain-boundary plane normal. The grain-boundary distribution is derived from measurements of grain orientations and the orientations of the lines formed where grain boundaries intersect the plane of observation. Tests of the method on simulated observations illustrate that the distribution of boundaries in a material with cubic symmetry can be reliably determined with about 10° of resolution from the analysis of 5×104 or more line segments. Furthermore, grain-boundary distributions directly observed from serial sections of a SrTiO3 polycrystal are compared to those resulting from the stereological analysis of a single plane. The comparison shows that the stereological method provides a reasonable estimate of the measured distribution. The differences between the directly observed grain-boundary distribution and that derived from the stereological analysis are consistent with the results from the simulation.

Techniques are described that have been used to create a statistically representative three-dimensional model microstructure for input into computer simulations using the geometric and crystallographic observations from two orthogonal sections through an aluminum polycrystal. Orientation maps collected on the observation planes are used to characterize the sizes, shapes, and orientations of grains. Using a voxel-based tessellation technique, a microstructure is generated with grains whose size and shape are constructed to conform to those measured experimentally. Orientations are then overlaid on the grain structure such that distribution of grain orientations and the nearest-neighbor relationships, specified by the distribution of relative misorientations across grain boundaries, match the experimentally measured distributions. The techniques are applicable to polycrystalline materials with sufficiently compact grain shapes and can also be used to controllably generate a wide variety of hypothetical microstructures for initial states in computer simulations.

Measurements of the grain boundary population as a function of misorientation and boundary plane orientation show that the distribution is inversely correlated to the sum of the energies of the surfaces comprising each boundary. The observed correlation suggests that the difference between the energy of a high-angle grain boundary and the two component surfaces is relatively constant as a function of misorientation. Two exceptions to this correlation were identified: low-misorientation-angle boundaries and the coherent twin boundary, where the (111) planes in the adjoining crystals are parallel to each other, but rotated by 60° around the [111] axis. In these cases, the high degree of coincidence across this interface probably lowers the boundary energy with respect to that of the component surfaces. For all other boundaries, the anisotropy of the population is accurately predicted by the surface energy anisotropy, and in general, boundaries display a preference for {100} orientations, the planes of minimum surface energy.

Recent advances both in experimental instrumentation and computing power have made it possible to interrogate the distribution of internal interfaces in polycrystals and the three dimensional structure of the grain boundary network with an unprecedented level of detail. The purpose of this paper is to review techniques that can be used to study the mesoscopic crystallographic structure of grain boundary networks and to summarize current findings. Recent studies have shown that grain surfaces within dense polycrystals favor the same low energy planes that are found on equilibrium crystal shapes and growth forms of crystals in contact with another phase. In the materials for which comprehensive data exists, the distribution of grain boundaries is inversely correlated to the sum of the energies of the surfaces of the grains on either side of the boundary.

Using measurements of the geometric and crystallographic characteristics of approximately 104 triple junctions in a MgO polycrystal, the relative grain boundary energy has been determined as a function of five macroscopic parameters. The relative energy of a particular grain boundary is inversely correlated with its frequency of occurrence. At all misorientations, grain boundaries with {1 0 0} interface planes have relatively low energies. For low misorientation angle grain boundaries, the results are consistent with the predictions of dislocation models. At high misorientation angles, the population and energy are correlated to the sum of the energies of the free surfaces that comprise the boundary.

A semi-automated method has been used to measure all five macroscopically observable parameters of 4.1×10 6 boundary plane segments making up 5.4 mm 2 of boundary area in a hot-pressed magnesia polycrystal. The observations allow a complete description of the distribution of crystal orientations, grain boundary misorientations, and the crystallographic orientations of grain boundary planes. Among the low misorientation angle grain boundaries, there is a preference for tilt boundaries, especially those with boundary plane normals in the direction. At all fixed misorientations, there is a preference for boundaries with a boundary plane normal in the direction. These boundaries are generally asymmetric and occur at least twice as frequently as the average boundary for each fixed misorientation.

We have developed a technique that allows all five macroscopically observable grain boundary degrees of freedom to be characterized for a statistically significant number of interfaces. Using this technique, we have characterized 5 x 10 μm of grain boundary plane area in a 0.15 mm volume of MgO. The observations demonstrate that there is significant texture in the distribution of boundary planes. Here we compare the observed distribution of grain boundary planes at low misorientation angles (~ 5 °) to the calculated geometrically necessary dislocation content of the same interfaces. Based on the inverse correlation between these two quantities, we conclude that relatively low energy configurations are adopted with the highest frequency.

Wheels are important safety components in the vehicle driving system. Automobile lightweight is the direction of the modern automobile development. In this article, steel wheel lightweight was studied. The equal strength design of rim was used to reduce the weight of the wheel. Stress analysis of the wheel was studied using UG/Nastran. A professional software WheelStrength was used to predict the radial and cornering fatigue lives of the wheel. Sheet stamping process was set up to analyze the interference fit between the disk and the rim. The assembly was simulated by axisymmetric finite element method. After calculation and analysis, the stress distributions and fatigue lives for rim under different load cases have been found. The thicknesses of wheel rim bead and the interface between rim and disk cannot be reduced. Stress and fatigue simulation results were compared using different thicknesses of the optimized region. It was found that the best thickness of the optimized region was 1.5 mm. Spinning was used to form the flared preform. The thickness of the rim after spinning and rolling forming agreed well with the simulation. The results of fatigue tests indicated that the lightweight wheel met the design requirement. The weight of the rim was reduced by about 14%.

Microstructure-level residual stresses arise in polycrystalline ceramics during processing as a result of thermal expansion anisotropy and crystallographic disorientation across the grain boundaries. Depending upon the grain size, the magnitude of these stresses can be sufficiently high to cause spontaneous microcracking during the processing of these materials. They are also likely to affect where cracks initiate and propagate under macroscopic loading. The magnitudes of residual stresses in untextured and textured alumina samples were predicted using object oriented finite (OOF) element analysis and experimentally determined grain orientations. The crystallographic orientations were obtained by electron-backscattered diffraction (EBSD). The residual stresses were lower and the stress distributions were narrower in the textured samples compared to those in the untextured samples. Crack initiation and propagation were also simulated using the Griffith fracture criterion. The grain boundary to surface energy ratios required for computations were estimated using AFM groove measurements.