US FDA best practices for initiating early feasibility studies for neurological devices in the United States.

This article describes the efforts of the US Food and Drug Administration (FDA) Office of Neurological and Physical Medicine Devices to facilitate early clinical testing of potentially beneficial neurological devices in the US. Over the past 5 years, the FDA has made significant advances to this aim by developing early feasibility study best practices and encouraging developers and innovators to initiate their clinical studies in the US. The FDA uses several regulatory approaches to help start neurological device clinical studies, such as early engagement with sponsors and developers, in-depth interaction during the FDA review phase of a regulatory submission, and provision of an FDA toolkit that reviewers can apply to the most challenging submissions.

Mechanical performance of traditional distraction-based dual growing rod constructs.

BACKGROUND: Growing rod constructs are an important contribution in the treatment of children with early onset scoliosis even though these devices experience high rates of rod fracture. The mechanical performance of traditional, distraction-based dual growing rod constructs is not well understood, and mechanical models for predicting device performance are limited. PURPOSE: Two mechanical models were developed and used to determine the mechanical performance of various growing rod configurations by increasing construct complexity. STUDY DESIGN/SETTING: Mechanical bench testing and finite element (FE) analysis. METHODS: Static and dynamic compression bending tests were based on an ASTM F1717 method modified to accommodate dual growing rod constructs. Six construct configurations were tested, mechanical properties were recorded, and statistical analyses were performed to determine significant differences between groups: (1) no connectors (rods only), (2) side-by-side connectors, (3) side-by-side connectors plus 4 crosslinks, (4) (40-mm long tandem connectors, (5) 80-mm long tandem connectors, and (6) 80-mm long tandem connectors plus 4 crosslinks. FE analysis was used to predict the stress distribution within the constructs. RESULTS: The static results indicated greater stiffness, yield load, and peak load as the axial connector length increased (side-by-side to 40 mm tandem to 80 mm tandem). The dynamic results showed similar cycles to failure for side-by-side and tandem connector (40 and 80 mm) construct configurations without crosslinks. Crosslinks shifted the location of rod fracture observed experimentally and significantly reduced the fatigue life of the construct. The flexibility of the construct decreased significantly as the axial connector length increased. FE predictions were highly consistent with the experimentally measured values and provided information on stress distribution within the rod for comparison to experimental fracture locations. CONCLUSIONS: This is the first study to evaluate mechanical performance of various configurations of pediatric growing rod constructs using preclinical models. The current study is consistent with a previous retrieval study in that rigid constructs lacking flexibility (ie, higher stiffness and lower displacement), such as those with 80-mm tandem connectors and multiple crosslinks, demonstrated decreased mechanical performance as shown through both experimental and computational models. Additionally, the experimental and computational findings suggest that surgeons should strategically consider the number of interconnecting components and subsequent stress concentrations along the posterior side of the rod. For example, changing the placement of crosslinks to low stress regions of the construct or not using crosslinks in the construct are options.

Effects of tissue digestion solutions on surface properties of nitinol stents.

Analysis of explanted medical implants can provide a wealth of knowledge about device safety and performance. However, the quality of information may be compromised if the methods used to clean tissue from the device disturb the retrieved condition. Common solutions used to digest tissue may adversely affect the surface of the device and its severity can be material and processing dependent. In this study, two groups of stents made from the same material (Nitinol) were shape set in a salt pot (SP) or further processed by mechanical polishing (MP) and then immersed in one of three tissue digestion solutions (TDS): nitric acid (HNO3 ), sodium hydroxide (NaOH), or papain enzyme (papain). Nickel (Ni) ion concentrations were measured for each stent-TDS combination and post-immersion stent surface constituents, morphology and oxide depths were compared to baseline samples. Exposure to the HNO3 TDS resulted in relatively high Ni ion release and surface damage for both stent types. Papain TDS induced a greater Ni ion release than NaOH TDS, however, both were significantly lower than HNO3 . The NaOH TDS increased the oxide layer thickness on MP stents. In contrast, all other stent immersions resulted in thinner oxide layers. For the Nitinol finishes used in this study, HNO3 is not recommended while papain and NaOH solutions may be appropriate depending on the post-retrieval analysis performed. This study elucidates the importance of preliminary testing for TDS selection and how the surface finish can affect the sensitivity of a material to a TDS. 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 331-339, 2018.

The effects of surface processing on in-vivo corrosion of Nitinol stents in a porcine model.

A major limitation with current assessments of corrosion in metallic medical devices is the lack of correlation between in-vitro and in-vivo corrosion performance. Therefore, the objective of this study was to elucidate the relationship between pitting corrosion measured by breakdown potentials (Eb) in ASTM F2129 testing and corrosion resistance in-vivo. Four groups of Nitinol stents were manufactured using different processing methods to create unique surface properties. The stents were implanted into iliac arteries of minipigs for six months and explanted for corrosion analysis. Scanning electron microscopy and energy dispersive X-ray spectrometry analyses indicated that stents with a thick complex thermal oxide (420nm) and high corrosion resistance in-vitro (Eb=975±94mV) were free from detectable corrosion in-vivo and exhibited no changes in Ni/Ti ratio when compared to non-implanted controls. This result was also found in mechanically polished stents with a thin native oxide (4nm; Eb=767±226mV). In contrast, stents with a moderately thick thermal oxide (130nm) and low corrosion resistance in-vitro (Eb=111±63mV) possessed corrosion with associated surface microcracks in-vivo. In addition, Ni/Ti ratios in corroded regions were significantly lower compared to non-corroded adjacent areas on explanted stents. When stents were minimally processed (i.e. retained native tube oxide from the drawing process), a thick thermal oxide was present (399nm) with low in-vitro corrosion resistance (Eb=68±29mV) resulting in extensive in-vivo pitting. These findings demonstrate that functional corrosion testing combined with a detailed understanding of the surface characteristics of a Nitinol medical device can provide insight into in-vivo corrosion resistance. STATEMENT OF SIGNIFICANCE: Nitinol is a commonly used material in the medical device industry. However, correlations between surface processing of nitinol and in-vivo corrosion has yet to be established. Elucidating the link between in-vivo corrosion and pre-clinical characterization can aid in improved prediction of clinical safety and performance of nitinol devices. We addressed this knowledge gap by fabricating nitinol stents to possess distinct surface properties and evaluating their corrosion susceptibility both in-vitro and after six months of in-vivo exposure. Relationships between stent processing, surface characterization, corrosion bench testing, and outcomes from explanted devices are discussed. These findings highlight the importance of surface characterization in nitinol devices and provide in-vitro pitting corrosion levels that can induce in-vivo corrosion in nitinol stents.

Relationships among ultrasonic and mechanical properties of cancellous bone in human calcaneus in vitro.

Clinical bone sonometers applied at the calcaneus measure broadband ultrasound attenuation and speed of sound. However, the relation of ultrasound measurements to bone strength is not well-characterized. Addressing this issue, we assessed the extent to which ultrasonic measurements convey in vitro mechanical properties in 25 human calcaneal cancellous bone specimens (approximately 2×4×2cm). Normalized broadband ultrasound attenuation, speed of sound, and broadband ultrasound backscatter were measured with 500kHz transducers. To assess mechanical properties, non-linear finite element analysis, based on micro-computed tomography images (34-micron cubic voxel), was used to estimate apparent elastic modulus, overall specimen stiffness, and apparent yield stress, with models typically having approximately 25-30 million elements. We found that ultrasound parameters were correlated with mechanical properties with R=0.70-0.82 (p<0.001). Multiple regression analysis indicated that ultrasound measurements provide additional information regarding mechanical properties beyond that provided by bone quantity alone (p≤0.05). Adding ultrasound variables to linear regression models based on bone quantity improved adjusted squared correlation coefficients from 0.65 to 0.77 (stiffness), 0.76 to 0.81 (apparent modulus), and 0.67 to 0.73 (yield stress). These results indicate that ultrasound can provide complementary (to bone quantity) information regarding mechanical behavior of cancellous bone.

Development of a Flow Evolution Network Model for the Stress-Strain Behavior of Poly(L-lactide).

Computational modeling is critical to medical device development and has grown in its utility for predicting device performance. Additionally, there is an increasing trend to use absorbable polymers for the manufacturing of medical devices. However, computational modeling of absorbable devices is hampered by a lack of appropriate constitutive models that capture their viscoelasticity and postyield behavior. The objective of this study was to develop a constitutive model that incorporated viscoplasticity for a common medical absorbable polymer. Microtensile bars of poly(L-lactide) (PLLA) were studied experimentally to evaluate their monotonic, cyclic, unloading, and relaxation behavior as well as rate dependencies under physiological conditions. The data were then fit to a viscoplastic flow evolution network (FEN) constitutive model. PLLA exhibited rate-dependent stress-strain behavior with significant postyield softening and stress relaxation. The FEN model was able to capture these relevant mechanical behaviors well with high accuracy. In addition, the suitability of the FEN model for predicting the stress-strain behavior of PLLA medical devices was investigated using finite element (FE) simulations of nonstandard geometries. The nonstandard geometries chosen were representative of generic PLLA cardiovascular stent subunits. These finite element simulations demonstrated that modeling PLLA using the FEN constitutive relationship accurately reproduced the specimen's force-displacement curve, and therefore, is a suitable relationship to use when simulating stress distribution in PLLA medical devices. This study demonstrates the utility of an advanced constitutive model that incorporates viscoplasticity for simulating PLLA mechanical behavior.

Retrieval and clinical analysis of distraction-based dual growing rod constructs for early-onset scoliosis.

BACKGROUND CONTEXT: Growing rod constructs are an important contribution for treating patients with early-onset scoliosis. These devices experience high failure rates, including rod fractures. PURPOSE: The objective of this study was to identify the failure mechanism of retrieved growing rods, and to identify differences between patients with failed and intact constructs. STUDY DESIGN/SETTING: Growing rod patients who had implant removal and were previously enrolled in a multicenter registry were eligible for this study. PATIENT SAMPLE: Forty dual-rod constructs were retrieved from 36 patients across four centers, and 34 of those constructs met the inclusion criteria. Eighteen constructs failed due to rod fracture. Sixteen intact constructs were removed due to final fusion (n=7), implant exchange (n=5), infection (n=2), or implant prominence (n=2). OUTCOME MEASURES: Analyses of clinical registry data, radiographs, and retrievals were the outcome measures. METHODS: Retrievals were analyzed with microscopic imaging (optical and scanning electron microscopy) for areas of mechanical failure, damage, and corrosion. Failure analyses were conducted on the fracture surfaces to identify failure mechanism(s). Statistical analyses were performed to determine significant differences between the failed and intact groups. RESULTS: The failed rods fractured due to bending fatigue under flexion motion. Construct configuration and loading dictate high bending stresses at three distinct locations along the construct: (1) mid-construct, (2) adjacent to the tandem connector, or (3) adjacent to the distal anchor foundation. In addition, high torques used to insert set screws may create an initiation point for fatigue. Syndromic scoliosis, prior rod fractures, increase in patient weight, and rigid constructs consisting of tandem connectors and multiple crosslinks were associated with failure. CONCLUSION: This is the first study to examine retrieved, failed growing rod implants across multiple centers. Our analysis found that rod fractures are due to bending fatigue, and that stress concentrations play an important role in rod fractures. Recommendations are made on surgical techniques, such as the use of torque-limiting wrenches or not exceeding the prescribed torques. Additional recommendations include frequent rod replacement in select patients during scheduled surgeries.

The Role of Computational Modeling and Simulation in the Total Product Life Cycle of Peripheral Vascular Devices.

The total product life cycle (TPLC) of medical devices has been defined by four stages: discovery and ideation, regulatory decision, product launch, and postmarket monitoring. Manufacturers of medical devices intended for use in the peripheral vasculature, such as stents, inferior vena cava (IVC) filters, and stent-grafts, mainly use computational modeling and simulation (CM&S) to aid device development and design optimization, supplement bench testing for regulatory decisions, and assess postmarket changes or failures. For example, computational solid mechanics and fluid dynamics enable the investigation of design limitations in the ideation stage. To supplement bench data in regulatory submissions, manufactures can evaluate the effects of anatomical characteristics and expected in vivo loading environment on device performance. Manufacturers might also harness CM&S to aid root-cause analyses that are necessary when failures occur postmarket, when the device is exposed to broad clinical use. Once identified, CM&S tools can then be used for redesign to address the failure mode and re-establish the performance profile with the appropriate models. The Center for Devices and Radiological Health (CDRH) wants to advance the use of CM&S for medical devices and supports the development of virtual physiological patients, clinical trial simulations, and personalized medicine. Thus, the purpose of this paper is to describe specific examples of how CM&S is currently used to support regulatory submissions at different phases of the TPLC and to present some of the stakeholder-led initiatives for advancing CM&S for regulatory decision-making.

Effects of fatigue on the chemical and mechanical degradation of model stent sub-units.

Understanding the fatigue and durability performance of implantable cardiovascular stents is critical for assessing their performance. When the stent is manufactured from an absorbable material, however, this durability assessment is complicated by the transient nature of the device. Methodologies for evaluating the fatigue performance of absorbable stents while accurately simulating the degradation are limited and little is known about the interaction between fatigue and degradation. In this study, we investigated the fatigue behavior and effect of fatigue on the degradation rate for a model absorbable cardiovascular stent. Custom v-shaped stent sub-units manufactured from poly(L-lactide), i.e., PLLA, were subjected to a simultaneous fatigue and degradation study with cycle counts representative of one year of expected in vivo use. Fatigue loading was carried out such that the polymer degraded at a rate that was aligned with a modest degree of fatigue acceleration. Control, un-loaded specimens were also degraded under static immersion conditions representative of simulated degradation without fatigue. The study identified that fatigue loading during degradation significantly increased specimen stiffness and lowered the force at break. Fatigue loading also significantly increased the degree of molecular weight decline highlighting an interaction between mechanical loading and chemical degradation. This study demonstrates that fatigue loading during degradation can affect both the mechanical properties and the chemical degradation rate. The results are important for defining appropriate in vitro degradation conditions for absorbable stent preclinical evaluation.

Evaluating changes in structure and cytotoxicity during in vitro degradation of three-dimensional printed scaffolds.

This study evaluated the structural, mechanical, and cytocompatibility changes of three-dimensional (3D) printed porous polymer scaffolds during degradation. Three porous scaffold designs were fabricated from a poly(propylene fumarate) (PPF) resin. PPF is a hydrolytically degradable polymer that has been well characterized for applications in bone tissue engineering. Over a 224 day period, scaffolds were hydrolytically degraded and changes in scaffold parameters, such as porosity and pore size, were measured nondestructively using micro-computed tomography. In addition, changes in scaffold mechanical properties were also measured during degradation. Scaffold degradation was verified through decreasing pH and increasing mass loss as well as the formation of micropores and surface channels. Current methods to evaluate polymer cytotoxicity have been well established; however, the ability to evaluate toxicity of an absorbable polymer as it degrades has not been well explored. This study, therefore, also proposes a novel method to evaluate the cytotoxicity of the absorbable scaffolds using a combination of degradation extract, phosphate-buffered saline, and cell culture media. Fibroblasts were incubated with this combination media, and cytotoxicity was evaluated using XTT assay and fluorescence imaging. Cell culture testing demonstrated that the 3D-printed scaffold extracts did not induce significant cell death. In addition, results showed that over a 224 day time period, porous PPF scaffolds provided mechanical stability while degrading. Overall, these results show that degradable, 3D-printed PPF scaffolds are suitable for bone tissue engineering through the use of a novel toxicity during degradation assay.

Evaluating 3D-printed biomaterials as scaffolds for vascularized bone tissue engineering.

There is an unmet need for a consistent set of tools for the evaluation of 3D-printed constructs. A toolbox developed to design, characterize, and evaluate 3D-printed poly(propylene fumarate) scaffolds is proposed for vascularized engineered tissues. This toolbox combines modular design and non-destructive fabricated design evaluation, evaluates biocompatibility and mechanical properties, and models angiogenesis.

Effects of vertebroplasty on endplate subsidence in elderly female spines.

OBJECT: The aim in this study was to quantify the effects of vertebroplasty on endplate subsidence in treated and adjacent vertebrae and their relationship to endplate thickness and underlying trabecular bone in elderly female spines. METHODS: Vertebral compression fractures were created in female cadaveric (age range 51-88 years) thoracolumbar spine segments. Specimens were placed into either the control or vertebroplasty group (n = 9/group) such that bone mineral density, trabecular microarchitecture, and age were statistically similar between groups. For the vertebroplasty group, polymethylmethacrylate bone cement was injected into the fractured vertebral body under fluoroscopy. Cyclic compression (685-1370 N sinusoid) was performed on all spine segments for 115,000 cycles. Micro-CT scans were obtained before and after cyclic loading to quantify endplate subsidence. Maximum subsidence was compared between groups in the caudal endplate of the superior adjacent vertebra (SVcau); cranial (TVcra) and caudal (TVcau) endplates of the treated vertebra; and the cranial endplate of the inferior adjacent vertebra (IVcra). In addition, micro-CT images were used to quantify average endplate thickness and trabecular bone volume fraction. These parameters were then correlated with maximum endplate subsidence for each endplate. RESULTS: The maximum subsidence in SVcau endplate for the vertebroplasty group (0.34 ± 0.58 mm) was significantly (p < 0.05) greater than for the control group (-0.13 ± 0.27 mm). Maximum subsidence in the TVcra, TVcau, and IVcra endplates were greater in the vertebroplasty group, but these differences were not significant (p > 0.16). Increased subsidence in the vertebroplasty group manifested locally in the anterior region of the SVcau endplate and in the posterior region of the TVcra and TVcau endplates (p < 0.10). Increased subsidence was observed in thinner endplates with lower trabecular bone volume fraction for both vertebroplasty and control groups (R(2) correlation up to 62%). In the SVcau endplate specifically, these 2 covariates aided in understanding subsidence differences between vertebroplasty and control groups. CONCLUSIONS: Bone cement injected during vertebroplasty alters local biomechanics in elderly female spines, resulting in increased endplate disruption in treated and superior adjacent vertebrae. More specifically, bone cement increases subsidence in the posterior regions of the treated endplates and the anterior region of the superior caudal endplate. This increased subsidence may be the initial mechanism leading to subsequent compression fractures after vertebroplasty, particularly in vertebrae superior to the treated level.

Creep loading during degradation attenuates mechanical property loss in PLGA.

While absorbable materials and medical devices primarily degrade through hydrolysis, their degradation kinetics are sensitive to environmental conditions, including temperature, pH, and mechanical loading. While there is some consistent information in the literature suggesting that strain controlled loading accelerates strength loss, there is much more limited information on the interaction between degradation and mechanical load applied under force control. Force control conditions impose a different stress state on the material and therefore, may exhibit different effects on degradation. In this study, the interaction between loading and degradation rate for an exemplary absorbable polymer, poly(l-lactide-co-glycolide), was investigated. The results indicated that load during degradation results in significant polymer creep, which is associated with increased force loss, but decreased strength loss (i.e., stress based parameters such as ultimate stress). This study further identified that changes to the degradation kinetics from exposure to loading were not associated with alterations to polymer crystallinity but were associated with delayed loss of molecular weight. Overall, these results demonstrate the importance of investigating the interaction between loading and degradation and that physical changes, such as those induced by creep, rather than chemical changes offer the strongest explanation for alteration of degradation kinetics.

Characterization of load dependent creep behavior in medically relevant absorbable polymers.

While synthetic absorbable polymers have a substantial history of use in medical devices, their use is expanding and becoming more prevalent for devices where long term loading and structural support is required. In addition, there is evidence that current absorbable medical devices may experience permanent deformations, warping (out of plane twisting), and geometric changes in vivo. For clinical indications with long term loading or structural support requirements, understanding the material's viscoelastic properties becomes increasingly important whereas these properties have not been used historically as preclinical indications of performance or design considerations. In this study we measured the static creep, creep recovery and cyclic creep responses of common medically relevant absorbable materials (i.e., poly(l-lactide, PLLA) and poly(l-co-glycolide, PLGA) over a range of physiologically relevant loading magnitudes. The results indicate that both PLLA and PLGA exhibit creep behavior and failure at loads significantly less than the yield or ultimate properties of the material and that significant material specific responses to loading exist. In addition, we identified a strong correlation between the extent of creep in the material and its crystallinity. Results of the study provide new information on the creep behavior of PLLA and PLGA and support the use of viscoelastic properties of absorbable polymers as part of the material selection process.

Vertebroplasty increases compression of adjacent IVDs and vertebrae in osteoporotic spines.

BACKGROUND CONTEXT: Approximately 25% of vertebroplasty patients experience subsequent fractures within 1 year of treatment, and vertebrae adjacent to the cemented level are up to three times more likely to fracture than those further away. The increased risk of adjacent fractures postaugmentation raises concerns that treatment of osteoporotic compression fractures with vertebroplasty may negatively impact spine biomechanics. PURPOSE: To quantify the biomechanical effects of vertebroplasty on adjacent intervertebral discs (IVDs) and vertebral bodies (VBs). STUDY DESIGN: A biomechanics study was conducted using cadaveric thoracolumbar spinal columns from elderly women (age range, 51-98 years). METHODS: Five level motion segments (T11-L3) were assigned to a vertebroplasty treated or untreated control group (n=10/group) such that bone mineral density (BMD), trabecular architecture, and age were similar between groups. Compression fractures were created in the L1 vertebra of all specimens, and polymethylmethacrylate bone cement was injected into the fractured vertebra of vertebroplasty specimens. All spine segments underwent cyclic axial compression for 115,000 cycles. Microcomputed tomography imaging was performed before and after cyclic loading to quantify compression in adjacent VBs and IVDs. RESULTS: Cyclic loading increased strains 3% on average in the vertebroplasty group when compared with controls after 115,000 cycles. This global strain manifested locally as approximately fourfold more compression in the superior VB (T12) and two- to fourfold higher axial and circumferential deformations in the superior IVD (T12-L1) of vertebroplasty-treated specimens when compared with untreated controls. Low BMD and high cement fill were significant factors that explained the increased strain in the vertebroplasty-treated group. CONCLUSIONS: These data indicate that vertebroplasty alters spine biomechanics resulting in increased compression of adjacent VB and IVD in severely osteoporotic women and may be the basis for clinical reports of adjacent fractures after vertebroplasty.

Relationships of quantitative ultrasound parameters with cancellous bone microstructure in human calcaneus in vitro.

Ultrasound parameters (attenuation, phase velocity, and backscatter), bone mineral density (BMD), and microarchitectural features were measured on 29 human cancellous calcaneus samples in vitro. Regression analysis was performed to predict ultrasound parameters from BMD and microarchitectural features. The best univariate predictors of the ultrasound parameters were the indexes of bone quantity: BMD and bone volume fraction (BV/TV). The most predictive univariate models for attenuation, phase velocity, and backscatter coefficient yielded adjusted squared correlation coefficients of 0.69-0.73. Multiple regression models yielded adjusted correlation coefficients of 0.74-0.83. Therefore attenuation, phase velocity, and backscatter are primarily determined by bone quantity, but multiple regression models based on bone quantity plus microarchitectural features achieve slightly better predictive performance than models based on bone quantity alone.