Epicardial delivery of therapies has the potential to prevent adverse remodeling and promote in situ regeneration after myocardial infarction (MI) but further optimization of bioagent dosing and transport to heart muscle is required to maximize their therapeutic potential. Replenishable reservoir systems have enabled localized bioagent delivery to the epicardial surface but therapy transport from these systems is constrained by semipermeable membranes and fibrous capsule formation. Our approach to improved therapy delivery from epicardial reservoir systems is multi-pronged. First, we introduce a membrane-free reservoir system by incorporating a gelatin scaffold into a flexible polymer implant to promote direct integration with the epicardial surface and act as a replenishable depot to encourage myocardial-directed transport. Next, we perform in vitro and ex vivo validations and multi-scale computational simulations to characterize biomaterial, tissue, and organ-level transport of therapy, considering both native tissue architecture, and the effect of blood vessel clearance. As an in vivo use case of our system, we investigated the functional effect of multi-dose regimens of human follistatin-like 1 protein (FSTL1) in a rat model of myocardial infarction (MI). Groups receiving multiple doses of FSTL1 show increased cardiac performance (ejection fraction and fractional shortening), and decreased chamber stiffness 28 days after MI. Multi-dosing increases ventricular wall thickness and reduces infarct size. We demonstrate a dose-dependent increase in blood vessel number and density in the infarct zone. Finally, we establish a computational and experimental framework for patient-specific modeling to optimize implant parameters such as reservoir size and shape, infarct location, and dosing regimens, with a vision for clinical-imaging guided bioagent delivery strategies that can be modified on a per-patient, therapy-specific basis to optimize dosing regimens of various bioagents. This study highlights the potential for integrating personalized computational models with replenishable delivery systems to improve bioagent transport from biomaterials and enhance post-MI therapeutic outcomes.

The integration of biomaterials and additive manufacturing (AM) has revolutionized the design, manufacturing, and clinical applications of permanent and bioresorbable implants. AM offers design flexibility and potential for mass customization but poses challenges for scalable manufacturing. Unlike other high-commodity implantable devices that are already clinically approved, stent AM is still in the early phases of research and development. Here, following the recent Food and Drug Administration approval of Abbott's Esprit stent for below-the-knee use, we examine the current prospects for AM of polymeric stents, specifically focusing on polymeric bioresorbable stent geometry, material composition and mechanical properties, and surface quality, predominantly intended for cardiovascular applications. The advancement of bioresorbable polymeric stents is shown through a comparison with metallic stents commonly used in clinical practice. The different AM techniques used for stent fabrication and the level of currently fabricated bioresorbable stents are reviewed. A road map for translating AM stents from the research laboratory to the clinic is proposed.

Bioabsorbable textile scaffolds are promising for bone tissue engineering applications. Their tuneable, porous, fibre-based architecture resembles that of native extracellular matrix, and they can sustain tissue growth while being gradually absorbed in the body. In this work, immortalized mouse calvaria preosteoblast MC3T3-E1 cells were culturedin vitroon two warp-knitted bioabsorbable spacer fabric scaffolds made of poly(lactic acid) (PLA) and poly-4-hydroxybutyrate (P4HB), to investigate their osteogenic properties. Scaffold structure and yarn properties were characterized after manufacturing. Cells were seeded on the two scaffolds and treated with osteogenic media for up to 35 days. Both scaffolds supported similar cell growth patterns, featuring a higher cell density on multifilament yarns, which could be beneficial to drive cell proliferation or related phenomena in localized area of the construct. The increase in alkaline phosphatase activity and the calcium deposition observed on some PLA and P4HB scaffolds after 28 and 35 days of culture, confirm their potential to support MC3T3-E1 cells differentiation, however inconsistent mineralization was observed on the scaffolds. Due to their structural and morphological features, ability to support cell attachment and growth, and their limited osteogenic potential, these PLA and P4HB bioabsorbable textile scaffolds are recommended for further investigation for bone tissue engineering applications.

Bioabsorbable stents offer a significant advantage over metallic stents by providing temporary mechanical support to blood vessels and gradually degrading, thereby reducing the risk of long-term complications and restenosis. Polymeric stents, particularly those made from poly(l-lactic acid), have attracted attention for below-the-knee artery interventions because of their biocompatibility and potential for customized geometries and mechanical properties. However, challenges remain in the development of efficient and scalable fabrication techniques for such devices. This study aimed to develop and evaluate a rotational-axis fused filament fabrication method for the fabrication of bioabsorbable polymeric stents with improved mechanical and biological performance. A rotating-mandrel-based multiaxis system was used to print stents with a conventional closed-cell design while exploring variations in seam line overlaps and ring joint formations. Box-Behnken method was employed to systematically study the influence of key printing parameters─extrusion temperature, printing speed, and extrusion flow rate─on critical stent performance metrics: strut width, radial force, and flexural force. Microscopic analysis, radial compression, and three-point bending tests were performed for performance evaluation. Regression models and analysis of variance (ANOVA) revealed that the extrusion temperature and flow rate significantly influenced the mechanical properties. A multiobjective optimization approach was used to minimize the strut width while maximizing the radial and flexural strengths, resulting in a strut width of 205 μm and radial and flexural forces of 2.5 and 0.19 N, respectively, with an extrusion temperature, speed, and value of 200 °C, 90 mm/min, and 120%, respectively. Further characterization using microtomography and surface profilometry confirmed the structural integrity, consistent strut morphology, and surface quality. Accelerated degradation tests and in vitro biocompatibility assessments demonstrated favorable degradation profiles and cytotoxicity. A 95% mass change was observed in the printed stent after 10 d of accelerated degradation. This study presents a robust rotational-axis FFF method for scalable, bioabsorbable, and patient-specific stent fabrication.

Purpose Altered hemodynamics caused by the presence of an endovascular device may undermine the success of peripheral stenting procedures. Flow-enhanced stent designs are under investigation to recover physiological blood flow patterns in the treated artery and reduce long-term complications. However, flow-enhanced designs require the development of customised manufacturing processes that consider the complex behaviour of Nickel-Titanium (Ni-Ti). While the manufacturing routes of traditional self-expanding Ni–Ti stents are well-established, the process to introduce alternative stent designs is rarely reported in the literature, with much of this information (especially related to shape-setting step) being commercially sensitive and not reaching the public domain, as yet. Methods A reliable manufacturing method was developed and improved to induce a helical ridge onto laser-cut and wire-braided Nickel–Titanium self-expanding stents. The process consisted of fastening the stent into a custom-built fixture that provided the helical shape, which was followed by a shape-setting in air furnace and rapid quenching in cold water. The parameters employed for the shape-setting in air furnace were thoroughly explored, and their effects assessed in terms of the mechanical performance of the device, material transformation temperatures and surface finishing. Results Both stents were successfully imparted with a helical ridge and the optimal heat treatment parameters combination was found. The settings of 500 °C/30 min provided mechanical properties comparable with the original design, and transformation temperatures suitable for stenting applications ( A f = 23.5 °C). Microscopy analysis confirmed that the manufacturing process did not alter the surface finishing. Deliverability testing showed the helical device could be loaded onto a catheter delivery system and deployed with full recovery of the expanded helical configuration. Conclusion This demonstrates the feasibility of an additional heat treatment regime to allow for helical shape-setting of laser-cut and wire-braided devices that may be applied to further designs.

Swellable microneedles (MNs) expand to mechanically interlock with wet biological tissue, offering improved adhesion and enhanced drug delivery over non-swellable counterparts. This study numerically evaluates how the material and geometric parameters of swellable MN arrays influence shape change. Using finite element simulation, MNs were subjected to unconstrained swelling, approximated via a thermal-strain analogy. Optimal MN design must support mechanical interlocking to prevent dislodgement. We observed that wet in vivo environments induce unwanted swelling-mediated curvature, hindering contact and interlocking. We quantified this bending and calibrated gel material swellability using experimental data. To counteract curling, we introduced a design approach to shift the direction of the unwanted curling and improve MN array conformability.

An experimentally informed device model capturing reduced factor transport resulting from the fibrous capsule (FC) and recovered using fluid flow.

Degradation tests are a key step in the development of a bioresorbable stent. The present study focused on the degradation of bioresorbable stents made from PLLA filaments, and examined the variation of the physical, thermal, and mechanical properties of the material and the devices under both real-time and accelerated degradation conditions. Results showed that the undegraded filaments were highly crystalline and composed by both alpha and alpha ' crystalline phases, induced by both the melt spinning and heat treatment processes. The latter was shown to have an important influence on the further formation of alpha crystalline phase and therefore crystalline structure perfectioning. Real-time degradation tests showed that the devices maintained structural stability for up to a year, meeting the required 6-month degradation period for vascular stents. Degradation was shown to primarily affect the crystalline regions, and to cause a gradual loss of material ductility before any mass loss or decrease in crystallinity. In turn, a constant decrease of molecular weight was observed, with stent failure occurring around day 389 due to a drop in molecular weight below 10,000 g/mol. Accelerated degradation tests mirrored real-time results until mass loss began. Subsequently a slower molecular weight decrease was observed, with an increase and subsequent decrease of material crystallinity. The consistency of the data obtained between real-time and accelerated degradation before mass loss confirmed the possibility to gain insights into real-time degradation through an accelerated protocol. However, attention must be paid to the initial molecular weight of the material, which has been shown to highly influence the acceleration rate. This study provides a wide range of experimental data both on the real-time and thermally accelerated degradation behaviour of PLLA braided stents that can be used as benchmark for further studies in the field.

Prior to degradation, biocompatible polymers exhibit ductile behaviour and yield stress offers a suitable design approach. However, as degradation proceeds the material transitions to a brittle failure mode, suggesting a more conservative design approach is necessary. Here, we predict the evolving ductility of biodegrading polymers, concentrating on the relationship between molecular weight and failure strain, εf, in poly (lactic acid). Several datasets are chosen from literature to explore the relationship, with an overview of the experimental techniques provided. Failure criteria are proposed and examined alongside these datasets: the first assumes εf is related to the finite chain extensibility of an average chain; the second introduces an exponential empirical trend; the third proposes a modified extensibility criterion (based on the first criterion) that considers the entire molecular weight distribution; and the fourth offers an alternative to the third by considering the effect of chain scissions. Combining the failure criteria with a previously introduced time-dependent kinetic scission model provides results as a function of degradation duration. The predictions obtained can offer insight into material failure, particularly at advanced stages of degradation.

The objective of this study is to present a credibility assessment of finite element modelling of self-expanding nickel-titanium (Ni-Ti) stents through verification and validation (VV) activities, as set out in the ASME VV-40 standard. As part of the study, the role of calculation verification, model input sensitivity, and model validation is examined across three different application contexts (radial compression, stent deployment in a vessel, fatigue estimation). A commercially available self-expanding Ni-Ti stent was modelled, and calculation verification activities addressed the effects of mesh density, element integration and stable time increment on different quantities of interests, for each context of use considered. Sensitivity analysis of the geometrical and material input parameters and validation of deployment configuration with in vitro comparators were investigated. Results showed similar trends for global and local outputs across the contexts of use in response to the selection of discretization parameters, although with varying sensitivities. Mesh discretisation showed substantial variability for less than 4 × 4 element density across the strut cross-section in radial compression and deployment cases, while a finer grid was deemed necessary in fatigue estimation for reliable predictions of strain/stress. Element formulation also led to substantial variation depending on the chosen integration options. Furthermore, for explicit analyses, model results were highly sensitive to the chosen target time increment (e.g., mass scaling parameters), irrespective of whether quasistatic conditions were ensured (ratios of kinetic and internal energies below 5%). The higher variability was found for fatigue life simulation, with the estimation of fatigue safety factor varying up to an order of magnitude depending on the selection of discretization parameters. Model input sensitivity analysis highlighted that the predictions of outputs such as radial force and stresses showed relatively low sensitivity to Ni-Ti material parameters, which suggests that the calibration approaches used in the literature to date appear reasonable, but a higher sensitivity to stent geometry, namely strut thickness and width, was found. In contrast, the prediction of vessel diameter following deployment was least sensitive to numerical parameters, and its validation with in vitro comparators offered a simple and accurate (error ~ 1-2%) method when predicting diameter gain, and lumen area, provided that the material of the vessel is appropriately characterized and modelled.

Bioinspired microfibrillar surfaces adhere by exploiting the presence of intermolecular forces at the contact interface. Experimental work has shown that compliant mushroom shaped fibrils can facilitate optimal adhesion across a range of substrates. This work evaluates numerically how fibril contact tip shape and the degree of elastic mismatch at the fibril-substrate interface influence adhesion. In a finite element simulation of fibrils subject to a remote stress, the interfacial stress distributions that define the detachment behaviour are computed for a range of fibril cap diameters, thicknesses, and substrate stiffnesses. Depending on the substrate stiffness, there is a singular stress field present at the edge of contact for smaller mushroom cap and straight punch fibrils while the stress at the corner for larger mushroom fibrils tends to zero. This variation in fibril-substrate interfacial stress has implications for the most probable defect type to initiate detachment and the stability of this crack growth. For fibrils within this corner singularity regime, the adhesion strength of a patch of fibrils is determined using interfacial fracture mechanics. The simulations are compared with experimental data of pull-off strengths and the biomedical applications of adhesive microfibrillar patches are considered.

Guidewires are critically important components in medical implant and device delivery systems and their desired clinical performance or "steerability" requires a good torque response, i.e., the rotation of the (distal) guidewire tip should follow exactly the (proximal) applied input rotation. However, guidewires can suffer from phenomena known as lag (tip rotation is significantly less than the input rotation) and whip (the lag is suddenly recovered). Nitinol is a common guidewire material that can give superior performance but has been known to exhibit lag and whip depending on the specific material formulation and processing route. In this study, the torsional response of Nitinol guidewires is investigated using computational modelling (the finite element method) and analytical approaches, with a view to gaining a fundamental understanding of the mechanisms behind the lag and whip phenomena and how these relate to the specific material properties of a range of Nitinol variants and the geometrical configuration of the wire during torsion. An idealised vascular geometry is considered; this consists of a curved section and a straight section of varying length where the curved section is representative of geometries that are encountered in tortuous path navigation in the vasculature.The results capture the experimentally observed phenomena and reveal the relationship between material properties and guidewire performance. The stress state in the wire, which is dictated by the stress plateaus in the Nitinol material response, leads to the generation of a net moment within the wire which requires net work to be done during rotation of the wire. Analysis of idealised hypothetical materials show that the transformation strain is also an important parameter. The analysis reduced the performance of the guidewire material to a single metric that is given in terms of the energy dissipated during transformation, i.e., the area of the hysteresis loop. The results show that the combination of torsion and the bending of the wire in the curved path are critically important in the generation of lag and whip, and that both are accentuated by increasing the length of the straight section once the phenomena are active.

Cell transplantation aims to regenerate damaged tissues and cure currently incurable diseases, such as Type 1 diabetes. Post-transplantation cell survival is highly limited by the lack of suitable support matrix (anoikis) and insufficient oxygen supply (hypoxia), which is aggravated when using macroencapsulation devices. Graft failure can be overcome by encapsulation in extracellular matrix (ECM)-based hydrogels with high oxygen capacity. Estimation of the oxygen durability in these systems is critical for the design of hydrogel loaded macroencapsulation devices aimed to increase graft survival. In this study, a novel hyaluronic acid/perfluorocarbon biomaterial (Oxygel) is formulated, oxygenated, and characterized. Oxygel exhibits shear thinning and self-healing properties while it can carry high oxygen payloads and slowly release them for 90 h, exhibiting a 14.5 times smaller oxygen diffusivity than PBS. In parallel, a model able to predict the oxygen durability within Oxygel upon cell encapsulation is developed and experimentally validated in vitro. Correlations between model estimations and experimental results are found, demonstrating the validity of the model to analyze oxygen durability. The application of this mathematical model to oxygenated cell scaffolds (such as Oxygel) holds great promise to improve cell transplantation success.

Bioresorbable stents have the potential to restore patency to blood vessels while minimising the risk of long-term complications. Bioresorbable stents can dissolve after restoring flow to a blocked artery, leaving behind a blood vessel with restored vascular tone. This can provide increased lumen gain, long-term vascular rehabilitation, and long-term healing. Additive manufacturing (AM) could offer new design freedom and patient-specific solutions; however, AM fabrication of bioresorbable stents, especially for specific patients, is challenging. In recent times, AM-based Fused Filament Fabrication (FFF) has gained popularity for printing stents by employing a rotating mandrel as a printing bed. However, using standard slicing methodology is challenging when generating extrusion profiles with strut dimensions at this size scale. By eliminating the requirement for a CAD model and instead slicing based on direct extrusion path generation from parametric curves, a method has been proposed for the FFF printing of bioresorbable stents on rotating mandrels. A Grasshopper (plugin in Rhinoceros) -based visual programming method was adopted for the generation of the required shapes of curves for the stent. The extrusion profile (gCode) was generated by Grasshopper for 3D printing on an FFF multi-axis machine. Poly (l-lactic) acid (PLLA) polymer material was chosen along with a standard zigzag stent shape for testing the proposed methodology. The extrusion temperature, nozzle speed, and extrusion values were varied as per the design of the experiment (Taguchi L9) approach to study their effect on the stent strut width and flexural strength. The optimisation was carried out to obtain a feasible relationship between parameters to print minimum strut width and maximum flexural strength. The proposed methodology successfully demonstrates printing complex stent shapes without a CAD model and slicing.

Three-dimensional bioabsorbable textiles represent a novel technology for the manufacturing of tissue engineering scaffolds. In the present study, 3D bioabsorbable poly(lactic acid) (PLA) spacer fabric scaffolds are fabricated by warp-knitting and their potential for tissue engineering is explored in vitro. Changes in physical properties and mechanical performance with different heat setting treatments are assessed. To characterize the microenvironment experienced by cells in the scaffolds, yarn properties are investigated prior to, and during, hydrolytic degradation. The differences in yarn morphology, thermal properties, infrared spectra, and mechanical properties are investigated and monitored during temperature accelerated in vitro degradation tests in phosphate buffered saline (PBS) solution at 58 °C and pH 7.4 for 55 days. Yarn and textile cytocompatibility are tested to assess the effect of materials employed, manufacturing conditions, post processing and sterilization on cell viability, together with the cytocompatibility of the textile degradation products. Results show that the heat setting process can be used to modify scaffold properties, such as thickness, porosity, pore size and stiffness within the range useful for tissue regeneration. Scaffold degradation rate in physiological conditions is estimated by comparing yarn degradation data with PLA degradation data from literature. This will potentially allow the prediction of scaffold mechanical stability in the long term and thus its suitability for the remodelling of different tissues. Mouse calvaria preosteoblast MC3T3-E1 cells attachment and proliferation are observed on the scaffold over 12 days of in vitro culture by 4',6-diamidino-2-phenylindole (DAPI) fluorescent staining and DNA quantification. The present work shows the potential of spacer fabric scaffolds as a versatile and scalable scaffold fabrication technique, having the ability to create a microenvironment with appropriate physical, mechanical, and degradation properties for 3D tissue engineering. The high control and tunability of spacer fabric properties makes it a promising candidate for the regeneration of different tissues in patient-specific applications.

Further development of bioresorbable devices for use in clinical applications, where they can reduce long term risks, has been hindered by the complex degradation mechanisms that bioresorbable polymers exhibit and the difficulty this causes in designing suitable devices. Furthermore, experimental degradation studies often take years to complete, and small changes to the design of the test sample may significantly alter the degradation behavior. Motivated by existing degradation models, we present a kinetic scission model to predict how the molecular weight distribution evolves as a function of degradation time for bioresorbable polymers. Here, a refined kinetic model has been developed to capture the autocatalytic effect of carboxylic acid ends created via chain scissions, and our framework accounts for reduction in molecular weight via the cleavage of monomers from chain ends and from scissions in the middle of the polymer chain. These developments allow for a more complete representation of the molecular weight distribution during degradation. Young's modulus is estimated by approximating the changes in entropy for the molecular weight distributions following previous so-called "entropy spring" models. The results obtained are quantitatively compared to and calibrated with existing experimental data for PLGA films. Finally, the effect of the initial carboxylic acid end on the degradation behavior is explored.

Extrinsic toughening, such as fibre bridging, acts behind the crack tip to increase toughness in composite laminates. Computational studies have captured this phenomenon; however, the uniqueness of fit between computational results (which vary based on the interface traction-separation relationship) and experimental results has not been explored in detail. Here, detailed exploration of the parameter space for various traction-separation laws (TSL) using finite elements is presented to investigate the role of fibre bridging. In the absence of extrinsic toughening, a linear softening TSL is sufficient to capture the key R-curve features, the total input fracture energy is of primary importance. Where extrinsic toughening is present, the ratio between intrinsic and extrinsic energy dictates the shape of the crack growth resistance curve (where fracture toughness (energy) increases with increasing crack growth). The influence of fibre bridging length on the crack growth required to reach a plateau in toughness is examined. A strategy for determining key cohesive properties from a double cantilever beam test is presented and applied to experimental results.

Despite being commonly employed to treat peripheral artery disease, self-expanding Nitinol stents are still associated with relatively high incidence of failure in the mid- and long-term due to in-stent restenosis or fatigue fracture. The practice of stent oversizing is necessary to obtain suitable lumen gain and apposition to the vessel wall, though it is regarded as a potential cause of negative clinical outcomes when mis-sizing occurs. The objective of this study was to develop a computational model to provide a better understanding of the structural effects of stent sizing in a patient-specific scenario, considering oversizing ratio OS, defined as the stent nominal diameter to the average vessel diameter, between 1.0 and 1.8. It was found that OS < 1.2 resulted in problematic short-term outcomes, with poor lumen gain and significant strut malapposition. Oversizing ratios that were in the range 1.2 ≤ OS ≤ 1.4 provided the optimum biomechanical performance following implantation, with improved lumen gain, reduced incomplete stent apposition and favourable predicted long-term fatigue performance. Excessive oversizing, OS > 1.4, did not provide any further benefit in outcomes, showing limited increases in lumen gain and unfavourable long-term performance, with higher mean strain values predicted from the fatigue analysis. Therefore, our findings predict that the optimal oversizing ratio for self-expanding Nitinol stents is in the range of 1.2 ≤ OS ≤ 1.4, which is similar to clinical observations, with this study providing detailed insight into the biomechanical basis for this.

Medical guidewires are typically subjected to combined bending and torsion and undergo large deformations past the point of initial yielding. Experimental and clinical use of guidewires report two undesirable phenomena: lag, where output rotation of the wire is less than the input rotation; and whip, where the output rotation rate suddenly increases. In the current study, we present a finite element model of a guidewire in an idealised tortuous path. This model is used to elucidate the relationship between material properties, in particular, the onset of yield and hardening behaviour, and these phenomena. Combined bending and torsion lead to cyclic strains locally in the wire. For yielding materials, plastic dissipation during cyclic loading means external work is necessary and a reaction moment develops. This moment resists rotation leading to the lag phenomenon. Subsequent strain hardening leads to whip, which increases with tangent modulus. Straight sections of wire ahead of the curved region are shown to increase the amount of whip observed. A simplified theoretical treatment explains the key trends and provides strategies to reduce the unwanted phenomena.

This study presents a systematic evaluation of the physical, thermal and mechanical performance of medical-grade semi-crystalline PLLA undergoing thermally-accelerated degradation. Samples were immersed in phosphate-buffered saline solution at 50 °C for 112 days and mass loss, molecular weight, thermal properties, degree of crystallinity, FTIR and Raman spectra, tensile elastic modulus, yield stress and failure stress/strain were evaluated at consecutive time points. Samples showed a consistent reduction in molecular weight and melting temperature, a consistent increase in percent crystallinity and limited changes in glass transition temperature and mass loss. At day 49, a drastic reduction in tensile failure strain was observed, despite the fact that elastic modulus, yield and tensile strength of samples were maintained. Brittleness increase was followed by rapid increase in degradation rate. Beyond day 70, samples became too brittle to test indicating substantial deterioration of their load-bearing capacity. This study also presents a computational micromechanics framework that demonstrates that the elastic modulus of a semi-crystalline polymer undergoing degradation can be maintained, despite a reducing molecular weight through compensatory increases in percent crystallinity. This study presents novel insight into the relationship between physical properties and mechanical performance of medical-grade PLLA during degradation and could have important implications for design and development of bioresorbable stents for vascular applications.