Investigating the Equivalent Plastic Strain in a Variable Ring Length and Strut Width Thin-Strut Bioresorbable Scaffold.

PURPOSE: The ArterioSorb[Formula: see text] bioresorbable scaffold (BRS) developed by Arterius Ltd is about to enter first in man clinical trials. Previous generations of BRS have been vulnerable to brittle fracture, when expanded via balloon inflation in-vivo, which can be extremely detrimental to patient outcome. Therefore, this study explores the effect of variable ring length and strut width (as facilitated by the ArterioSorb[Formula: see text] design) on fracture resistance via analysis of the distribution of equivalent plastic strain in the scaffold struts post expansion. Scaffold performance is also assessed with respect to side branch access, radial strength, final deployed diameter and percentage recoil. METHODS: Finite element analysis was conducted of the crimping, expansion and radial crushing of five scaffold designs comprising different variations in ring length and strut width. The Abaqus/Explicit (DS SIMULIA) solution method was used for all simulations. Direct comparison between in-silico predictions and in-vitro measurements of the performance of the open cell variant of the ArterioSorb[Formula: see text] were made. Paths across the width of the crown apex and around the scaffold rings were defined along which the plastic strain distribution was analysed. RESULTS: The in-silico results demonstrated good predictions of final shape for the baseline scaffold design. Percentage recoil and radial strength were predicted to be, respectively, 2.8 and 1.7 times higher than the experimentally measured values, predominantly due to the limitations of the anisotropic elasto-plastic material property model used for the scaffold. Average maximum values of equivalent plastic strain were up to 2.4 times higher in the wide strut designs relative to the narrow strut scaffolds. As well as the concomitant risk of strut fracture, the wide strut designs also exhibited twisting and splaying behaviour at the crowns located on the scaffold end rings. Not only are these phenomena detrimental to the radial strength and risk of strut fracture but they also increase the likelihood of damage to the vessel wall. However, the baseline scaffold design was observed to tolerate significant over expansion without inducing excessive plastic strains, a result which is particularly encouraging, due to post-dilatation being commonplace in clinical practice. CONCLUSION: Therefore, the narrow strut designs investigated herein, are likely to offer optimal performance and potentially better patient outcomes. Further work should address the material modelling of next generation polymeric BRS to more accurately capture their mechanical behaviour. Observation of the in-vitro testing indicates that the ArterioSorb[Formula: see text] BRS can tolerate greater levels of over expansion than anticipated.

Exploring a parallel rheological framework to capture the mechanical behaviour of a thin-strut polymeric bioresorbable coronary scaffold.

Computational modelling of bioresorbable scaffolds (BRS) has employed several different material property models, ranging from those based on simple elasto-plastic theory through to anisotropic parallel network models that capture the viscoelastic-plastic behaviour observed in poly-l-lactic acid (PLLA). The increased complexity of higher fidelity material models, particularly in terms of calibration to in-vitro data, can limit their use. Consequently, their suitability for predicting the mechanical response of next-generation BRS is not well understood. Therefore, we have used the Bergstrom-Boyce (BB) parallel network material model, implemented in Abaqus/Explicit (Dassault Systemes), to investigate the mechanical response of a scaffold based upon the ArterioSorbTM BRS (Arterius Ltd, Leeds, UK). In-silico crimping, balloon expansion and radial crushing were simulated and validated against an analogous in-vitro test. Calibration of the model to uniaxial tensile test data was considered given the model's strain rate dependency and the inability to maintain the natural time period of the simulation when using the explicit solution method in finite element analysis. The isotropic limitations of this model were also explored. The model was also compared to an elasto-plastic model developed by the authors in previous work. Relative to bench-top measurements, prediction of the final diameter and radial strength of the scaffold by the BB model was found to be significantly more accurate than other models, within 2% of the in-vitro result. Additionally, the effect of the crimping strategy and an elevated ambient temperature upon the in-silico prediction of the post-crimping scaffold diameter were investigated. A multi-step crimping process with holding to facilitate stress relaxation and the lower stresses induced by the increased temperature were found to improve the accuracy of the predicted post-crimping scaffold diameter.

Investigating the material modelling of a polymeric bioresorbable scaffold via in-silico and in-vitro testing.

The accurate material modelling of poly-l-lactic acid (PLLA) is vital in conducting finite element analysis of polymeric bioresorbable scaffolds (BRS) to investigate their mechanical performance and seek improved scaffold designs. To date, a large variety of material models have been utilised, ranging from simple elasto-plastic models to high fidelity parallel network models. However, no clear consensus has been reached on the appropriateness of these different models and whether simple, less computationally expensive models can serve as acceptable approximations. Therefore, we present a study which explored the use of different isotropic and anisotropic elasto-plastic models in simulating the balloon expansion and radial crushing of the thin-strut (sub-100 µm) ArterioSorbTM BRS using the Abaqus/Explicit (DS SIMULIA) solution method. Stress-strain data was obtained via tensile tests at two different displacement rates. The use of isotropic and transversely isotropic elastic theories was explored, as well as the implementation of stress relaxation in the plastic regime of the material. The scaffold performance was quantified via its post-expansion diameter, percentage recoil and radial strength. The in-silico results were validated via comparison with in-vitro data of an analogous bench test. Accurately predicting both the post-expansion scaffold shape and radial strength was found to be challenging using the in-built Abaqus models. Therefore, a novel user-defined material model was developed via the VUMAT subroutine which improved functionality by facilitating a variable yield ratio, dependent upon the plastic strain as well as stress relaxation in overly strained elements. This achieved prediction of the radial strength within 1.1% of the in-vitro results and the scaffold's post-expansion diameter within 6.7%. A realistic multi-balloon simulation strategy was also used which confirmed that a mechanism exists in the PLLA which facilitates the extremely low percentage recoil behaviour observed in the ArterioSorbTM BRS. This could not be captured by the aforementioned material property models.

Preclinical evaluation of a thin-strut bioresorbable scaffold (ArterioSorb): acute-phase invasive imaging assessment and hemodynamic implication.

AIMS: The aim of this study was to assess the acute performance of the 95 µm ArterioSorb oriented poly L-lactic acid (PLLA) scaffold in comparison with the XIENCE metallic drug-eluting stent (DES) in porcine coronary arteries. METHODS AND RESULTS: In 15 non-atherosclerotic Yucatan mini pigs, the ArterioSorb (3.0/14 mm) and XIENCE (3.0/15 mm) were implanted in 25 and 15 vessels, respectively. Acute performance was evaluated by using quantitative coronary angiography (QCA) and optical coherence tomography (OCT). Following three-dimensional reconstruction of the coronary arteries, endothelial shear stress (ESS) was quantified using non-Newtonian steady-flow simulation. Acute recoil measured by QCA was comparable in the two arms. Post-procedural flow and scaffold/stent area by OCT did not differ between the two devices. ESS post procedure was comparable between ArterioSorb and XIENCE (2.21±1.97 vs 2.25±1.71 Pa, p=0.314). CONCLUSIONS: Acute recoil, luminal dimensions and ESS in the ArterioSorb oriented PLLA scaffold with thin struts of 95 µm were comparable to those in the XIENCE metallic DES.

Establishing a transport protocol for the delivery of melanocytes and keratinocytes for the treatment of vitiligo.

We have previously developed a cell delivery and transfer technology for delivering autologous keratinocytes and melanocytes to patients with vitiligo. However, for this technology to benefit many patients geographically distant from the cell culture facility transportation issues need to be overcome. In this study we begin to investigate this by looking at what role surface chemistry and medium supplements, including fetal calf serum, CO2 gassing, and temperature, play in influencing cell viability. Cells were maintained on carriers for up to 48 h outside of a CO2 incubator at 37 °C and their subsequent ability to adhere and become organized into a new epithelium with appropriately located melanocytes was assessed. Consistently good viability and performance on an in vitro wound bed model was achieved by maintaining cells for 48 h adherent to a 20% acrylic acid coated carrier at lower (around 23 °C rather than 37 °C) temperatures in the medium preperfused with CO2 before transport. Under these circumstances fetal calf serum was not required. In summary, the surface chemistry of the transport substrate and an appropriately CO2 buffered medium at near room temperature can extend the effective performance life of these cultured cells to at least 48 h from when they leave standard incubator conditions.

Development of a surface-modified contact lens for the transfer of cultured limbal epithelial cells to the cornea for ocular surface diseases.

Our aim was to develop an improved cell transfer system for delivering laboratory-cultured human limbal epithelial cells to the cornea, which would be low risk for the patient and convenient to use for the surgeon. We took a standard contact lens and developed a plasma polymer layer for coating this for attachment of cells to the lens and subsequent transfer of cells to the cornea. A range of plasma polymer surfaces were examined for initial cell attachment using three different combinations of human and rabbit epithelial and stromal cells, initially expanding cells both with and without bovine serum. The most promising surfaces, based on acrylic acid, were then coated onto contact lenses. Cell transfer from the lenses to the denuded surface of a 3D rabbit organ culture model was then used to make a second selection of substrates, which permitted reliable cell transfer. Primary rabbit and human corneal cells attached and proliferated well on acrylic acid-coated surfaces. Reliable transfer of primary epithelial cells from the coated contact lenses to a rabbit cornea was achieved by coating lenses with acrylic acid at 5 W/10 cm(3)/min and using cell densities of 1 x 10(5)/lens and above.

Simplifying the delivery of melanocytes and keratinocytes for the treatment of vitiligo using a chemically defined carrier dressing.

Obtaining pigmentary function in autologous skin grafts is a current challenge for burn surgeons as is developing reliable robust grafting strategies for patients with vitiligo and piebaldism. In this paper, we present the development of a simple methodology for delivering cultured keratinocytes and melanocytes to the patient that is of low risk for the patient but also user friendly for the surgeon. In this study, we examined the ability of keratinocytes and melanocytes to transfer from potential cell carriers under different media conditions to an in vitro human wound bed model. The number of melanocytes transferred, their location within the neoepidermis, and their ability to pigment were evaluated as preclinical end points. Two inert substrates (polyvinyl chloride and silicone sheets) and three candidate plasma-polymerized coatings with controlled surface chemistry deposited on these substrates were explored. Two media for expansion of cells, Greens, currently used clinically (but which contains fetal calf serum), and a serum-free alternative, M2 (melanocyte medium), were explored. Reproducible transfer of physiologically relevant numbers of melanocytes capable of pigmentation from the coculture of melanocytes and keratinocytes was obtained using either Greens medium or M2 medium, and a silicone carrier pretreated with 20% carboxylic acid deposited by plasma polymerization.