A Predictive Toxicokinetic Model for Nickel Leaching from Vascular Stents.

In vitro testing methods offer valuable insights into the corrosion vulnerability of metal implants and enable prompt comparison between devices. However, they fall short in predicting the extent of leaching and the biodistribution of implant byproducts under in vivo conditions. Physiologically based toxicokinetic (PBTK) models are capable of quantitatively establishing such correlations and therefore provide a powerful tool in advancing nonclinical methods to test medical implants and assess patient exposure to implant debris. In this study, we present a multicompartment PBTK model and a simulation engine for toxicological risk assessment of vascular stents. The mathematical model consists of a detailed set of constitutive equations that describe the transfer of nickel ions from the device to peri-implant tissue and circulation and the nickel mass exchange between blood and the various tissues/organs and excreta. Model parameterization was performed using (1) in-house-produced data from immersion testing to compute the device-specific diffusion parameters and (2) full-scale animal in situ implantation studies to extract the mammalian-specific biokinetic functions that characterize the time-dependent biodistribution of the released ions. The PBTK model was put to the test using a simulation engine to estimate the concentration-time profiles, along with confidence intervals through probabilistic Monte Carlo, of nickel ions leaching from the implanted devices and determine if permissible exposure limits are exceeded. The model-derived output demonstrated prognostic conformity with reported experimental data, indicating that it may provide the basis for the broader use of modeling and simulation tools to guide the optimal design of implantable devices in compliance with exposure limits and other regulatory requirements.

Pirfenidone-Loaded Polymeric Micelles as an Effective Mechanotherapeutic to Potentiate Immunotherapy in Mouse Tumor Models.

Ongoing research is actively exploring the use of immune checkpoint inhibitors to treat solid tumors by inhibiting the PD-1/PD-L1 axis and reactivating the function of cytotoxic T effector cells. Many types of solid tumors, however, are characterized by a dense and stiff stroma and are difficult to treat. Mechanotherapeutics have formed a recent class of drugs that aim to restore biomechanical abnormalities of the tumor microenvironment, related to increased stiffness and hypo-perfusion. Here, we have developed a polymeric formulation containing pirfenidone, which has been successful in restoring the tumor microenvironment in breast tumors and sarcomas. We found that the micellar formulation can induce similar mechanotherapeutic effects to mouse models of 4T1 and E0771 triple negative breast tumors and MCA205 fibrosarcoma tumors but with a dose 100-fold lower than that of the free pirfenidone. Importantly, a combination of pirfenidone-loaded micelles with immune checkpoint inhibition significantly delayed primary tumor growth, leading to a significant improvement in overall survival and in a complete cure for the E0771 tumor model. Furthermore, the combination treatment increased CD4+ and CD8+ T cell infiltration and suppressed myeloid-derived suppressor cells, creating favorable immunostimulatory conditions, which led to immunological memory. Ultrasound shear wave elastography (SWE) was able to monitor changes in tumor stiffness during treatment, suggesting optimal treatment conditions. Micellar encapsulation is a promising strategy for mechanotherapeutics, and imaging methods, such as SWE, can assist their clinical translation.

Resveratrol loaded polymeric micelles for theranostic targeting of breast cancer cells.

Treatment of breast cancer underwent extensive progress in recent years with molecularly targeted therapies. However, non-specific pharmaceutical approaches (chemotherapy) persist, inducing severe side-effects. Phytochemicals provide a promising alternative for breast cancer prevention and treatment. Specifically, resveratrol (res) is a plant-derived polyphenolic phytoalexin with potent biological activity but displays poor water solubility, limiting its clinical use. Here we have developed a strategy for delivering res using a newly synthesized nano-carrier with the potential for both diagnosis and treatment. Methods: Res-loaded nanoparticles were synthesized by the emulsion method using Pluronic F127 block copolymer and Vitamin E-TPGS. Nanoparticle characterization was performed by SEM and tunable resistive pulse sensing. Encapsulation Efficiency (EE%) and Drug Loading (DL%) content were determined by analysis of the supernatant during synthesis. Nanoparticle uptake kinetics in breast cancer cell lines MCF-7 and MDA-MB-231 as well as in MCF-10A breast epithelial cells were evaluated by flow cytometry and the effects of res on cell viability via MTT assay. Results: Res-loaded nanoparticles with spherical shape and a dominant size of 179±22 nm were produced. Res was loaded with high EE of 73±0.9% and DL content of 6.2±0.1%. Flow cytometry revealed higher uptake efficiency in breast cancer cells compared to the control. An MTT assay showed that res-loaded nanoparticles reduced the viability of breast cancer cells with no effect on the control cells. Conclusions: These results demonstrate that the newly synthesized nanoparticle is a good model for the encapsulation of hydrophobic drugs. Additionally, the nanoparticle delivers a natural compound and is highly effective and selective against breast cancer cells rendering this type of nanoparticle an excellent candidate for diagnosis and therapy of difficult to treat mammary malignancies.

Nanotribological response of a-C:H coated metallic biomaterials: the cases of stainless steel, titanium, and niobium.

Background Wear and corrosion have been identified as two of the major forms of medical implant failures. This study aims to improve the surface, protective and tribological characteristics of bare metals used for medical implants, so as to improve scratch resistance and increase lifetime. Methods Hydrogenated amorphous carbon (a-C:H) films were deposited, using plasma enhanced chemical vapor deposition (PECVD), on stainless steel (SS), titanium (Ti) and niobium (Nb) metal plates. Nanomechanical and nanotribological responses were investigated before and after a-C:H deposition. Film thickness and density were quantified through X-ray reflectivity, and surface morphology before and after deposition were measured using atomic force microscopy, whereas the tribomechanical characteristics were probed using instrumented indentation. Results and conclusions Films of approximately 40 nm in thickness and density of 1.7 g/cm3 were deposited. The a-C:H films reduce the roughness and coefficient of friction while improving the tribomechanical response compared with bare metals for Ti, SS and Nb plates. The very good tribomechanical properties of a-C:H make it a promising candidate material for protective coating on metallic implants.

Multi-scale mechanical investigation of stainless steel and cobalt-chromium stents.

In-stent restenosis (ISR) remains a significant limitation despite the considerable previous clinical and investigative emphasis on the problem. Complications arising from the interaction of stent materials with the surrounding vessel wall as well as from the mechanical forces developing after implantation, play an important role in the development of ISR. To investigate the relation between mechanical factors and stent structural integrity, and to identify any structural weakness points on the geometry of commercially available Stainless Steel and Cobalt-Chromium stents, accelerated pulsatile durability tests were carried out in a simulated physiological environment. Potential spatial variations in the mechanical properties on stent struts and their role in the observed premature failures of the stent devices during operation were also examined. Fretting wear and fatigue-induced fractures were found on stent surfaces after exposure to cyclic loading similar to that arising in vivo. Nanoindentation studies performed on various locations along the stent struts have shown that the hardness of specific stent locations significantly increases after mechanical expansion. The increase in hardness was associated with a reduction of the material's ability to dissipate energy in plastic deformations, therefore an increased vulnerability to fracture and fatigue. We conclude that the locations of fatigue fractures in stent struts are controlled not only by the geometrically-driven stress concentrations developing during cyclic loading but also by the local material mechanical changes that are imparted on various parts of the stent during the deployment process.

The role of vascular calcification in inducing fatigue and fracture of coronary stents.

Traditional approaches for in-vitro pulsatile and fatigue testing of endovascular stents do not take into consideration the pathologies of the stented vessel and their associated biomechanical effects. One important pathology is calcification, which may be capable of inducing changes in the vessel wall leading to inhomogeneous distribution of stresses combined with wall motion during the cardiac cycle. These local property changes in the region adjacent to stents could directly influence in-vivo stent performance. Seven cases containing a total of 18 stents were obtained from autopsy. Radiographs were evaluated and vessels were sectioned for histology and stent topographical analysis. Stents were retrieved by chemical removal of surrounding tissue and surfaces were evaluated using 3D digital optical and scanning electron microscopy for biomechanical abrasion and fracture features. Pathologic complications such as restenosis and thrombus formation were assessed from histological sections. Direct evidence of fracture was found in 6 of the 7 cases (in 12 out of 18 stents; 9 drug eluting and 3 bare metal). The degree of stent alterations was variable, where separation of segments due to fracture occurred mostly in drug-eluting stents. All fracture surfaces were representative of a high cycle fatigue mechanism. These fractures occurred in complex lesions involving the presence of diffuse calcification alone, or in combination with vessel angulations and multiple overlapping stents. Morphologic analysis of tissue at or near some fracture sites showed evidence of thrombus formation and/or neointimal tissue growth.

In-vivo corrosion and local release of metallic ions from vascular stents into surrounding tissue.

OBJECTIVES: To evaluate retrieved bare metal vascular stents and surrounding tissue. BACKGROUND: Limited information is available regarding the condition of stent surfaces and their interaction with vascular tissue following implantation. Corrosion of stents presents two main risks: release of metallic ions into tissue and deterioration of the mechanical properties of stents which may contribute to fracture. Release of heavy metal ions could alter the local tissue environment leading to up-regulation of inflammatory mediators and promote in-stent restenosis. METHODS: Nineteen cases were collected from autopsy, heart explants for transplant, and vascular surgery (23 vessels containing 33 bare metal stents). A method was developed for optimal tissue dissolution and separation of the stent/tissue components without inducing stent corrosion. When available, chemical analysis was performed to assess metallic content in both the control and dissolved tissue solutions. Electron microscopy and digital optical microscopy imaging were used to evaluate stents. RESULTS: Twelve of the 33 stents showed varying degrees of corrosion. Metallic levels in the tissue surrounding the corroded stents were significantly higher (0.5-3.0 mcg/cm² stent) than in control solutions (0-0.30 mcg/cm² stent) and in tissue surrounding stents that did not undergo corrosion (0- 0.20 mcg/cm² stent). CONCLUSIONS: Corrosion of some retrieved stents is described which leads to transfer of heavy metal ions into surrounding tissue. The contribution of this metallic ion release to the mechanisms of in-stent restenosis as well as its effect on the mechanical properties of stents is unknown and requires further investigation.

Evaluation of in-stent stenosis by magnetic resonance phase-velocity mapping in nickel-titanium stents.

PURPOSE: To evaluate different grades of in-stent stenosis in a nickel-titanium stent with MRI. MATERIALS AND METHODS: Magnetic resonance phase velocity mapping (MR-PVM) was used to measure flow velocity through a 9-mm NiTi stent with three different degrees of stenosis in a phantom study. The tested stenotic geometries were 1) axisymmetric 75%, 2) axisymmetric 90%, and 3) asymmetric 50%. The MR-PVM data were subsequently compared with the velocities from computational fluid dynamic (CFD) simulations of identical conditions. RESULTS: Good quantitative agreement in velocity distribution for the 50% and 75% stenoses was observed. The agreement was poor for the 90% stenosis, most likely due to turbulence and the high-velocity gradients found in the small luminal area relative to the pixel resolution in our imaging settings. CONCLUSION: The accuracy of the MRI velocities inside the stented area renders MRI a modality that may be used to assess moderate to severe in-stent restenosis (ISR) in medium-sized vascular stents in peripheral vessels, such as the iliac, carotid, and femoral arteries. Advances in MR instrumentation may provide sufficient resolution to obtain adequate velocity information from smaller vessels, such as the coronary arteries, and allow MRI to substitute for invasive and expensive catheterization procedures currently in clinical use.

A flow visualization study of an anatomic coronary artery anastomosis model with an implant.

Flow Streamlining Devices is a new tool in Coronary Artery Bypass Grafting (CABG). They aim in: a) Performing a sutureless anastomosis to reduce thrombosis at the veno-arterial junction, and b) Providing a hemodynamically efficient scaffolding to reduce secondary flow disturbances. Thrombosis and flow disturbances are factors that have been reported as contributing factors to the development of intimal hyperplasia (IH) and failure of the graft. By reducing thrombosis and flow disturbances, it is expected that IH will be inhibited and the lifetime of the graft extended. To evaluate the hemodynamic benefits of such an implant, two models were designed and fabricated. One simulated the geometry of the conventional anastomosis without an implant, and the other simulated an anastomosis with a flow streamlining implant. Identical flow conditions relevant to a coronary anastomosis were imposed on both models and flow visualization was performed with dye injection and a digital camera. Results showed reduction of disturbances in the presence of the implant. This reduction seems to be favorable to hemodynamic streamlining which may create conditions that may inhibit the initialization of IH. However, the compliance and geometric mismatch between the anastomosis and the implant created a disturbance at the rigid compliant wall interface, which should be eliminated prior to clinical applications.

The hemodynamic effects of compliance, bulging, and curvature in a saphenous vein coronary artery bypass graft model.

The development of Intimal Hyperplasia (IH) in saphenous vein coronary artery bypass grafts (SV-CABG) is responsible for the short-term patency of these grafts. Previous studies of SV-CABG models were performed on rigid anastomotic vessels. However, the effects of compliance, bulging and curvature at the anastomosis on the general hemodynamic field, due to compliance and geometric mismatch between the vein and the artery have not been evaluated. We studied axial and transverse velocities by Laser Doppler Velocimetry on a compliant, in vitro, anatomical model of an end-to-side saphenous vein graft (SVG) to left anterior descending (LAD). The model incorporated a bulge at the sinus and curvature at the graft-host junction. Physiologic pressure and flow conditions pertaining to SV-CABG were applied. The presence of the bulge and curvature showed differences in the velocity profiles in comparison with previous rigid model studies. Dynamic separation zones were temporally augmented at the flow divider. The moving stagnation point at the floor of the host vessel was observed to move past the toe of the model during the accelerating portion of the cycle. These findings suggest that the presence of the bulge curvature and compliance may further favor conditions for the development of intimal hyperplasia (IH) at the floor of a CABG.

Effect of a flow-streamlining implant at the distal anastomosis of a coronary artery bypass graft.

Intimal thickening in the coronary artery bypass graft (CABG) distal anastomosis has been implicated as the major cause of restenosis and long-term graft failure. Several studies point to the interplay between nonuniform hemodynamics including disturbed flows and recirculation zones, wall shear stress, and long particle residence time as possible etiologies. The hemodynamic features of two anatomic models of saphenous-vein CABGs were studied and compared. One simulated an anastomosis with both diameter and compliance mismatch and a curvature at the connection, analogous to the geometry observed in a conventional cardiothoracic procedure. The other, simulated an anastomosis with a flow stabilizing anastomotic implant connector which improves current cardiothoracic procedures by eliminating the distal vein bulging and curvature. Physiologic flow conditions were imposed on both models and qualitative analysis of the flow was performed with dye injection and a digital camera. Quantitative analysis was performed with laser Doppler velocimetry. Results showed that the presence of the bulge at the veno-arterial junction, contributed to the formation of accentuated secondary structures (helices), which progress into the flow divider and significantly affect radial velocity components at the host vessel up to four diameters downstream of the junction. The model with the implant, achieved more hemodynamically efficient conditions on the host vessel with higher mean and maximum axial velocities and lower radial velocities than the conventional model. The presence of the sinus may also affect the magnitude and shape of the shear stress at locations where intimal thickening occurs. Thus, the presence of the implant creates a more streamlined environment with more primary and less secondary flow components which may then inhibit the development of intimal thickening, restenosis, and ultimate failure of the saphenous vein graft.

Comparative MRI compatibility of 316 L stainless steel alloy and nickel-titanium alloy stents.

The initial success of coronary stenting is leading to a proliferation in peripheral stenting. A significant portion of the stents used in a clinical setting are made of 316 low carbon stainless steel (SS). Other alloys that have been used for stent manufacture include tantalum, MP35N, and nickel-titanium (NiTi). The ferromagnetic properties of SS cause the production of artifacts in magnetic resonance imaging (MRI). The NiTi alloys, in addition to being known for their shape memory or superelastic properties, have been shown to exhibit reduced interference in MRI. Thus, the objective of this study was to determine the comparative MRI compatibility of SS and NiTi stents. Both gradient echo and spin-echo images were obtained at 1.5 and 4.1 T field strengths. The imaging of stents of identical geometry but differing compositions permitted the quantification of artifacts produced due to device composition by normalizing the radio frequency shielding effects. These images were analyzed for magnitude and spatial extent of signal loss within the lumen and outside the stent. B1 mapping was used to quantify the attenuation throughout the image. The SS stent caused significant signal loss and did not allow for visibility of the lumen. However, the NiTi stent caused only minor artifacting and even allowed for visualization of the signal from within the lumen. In addition, adjustments to the flip angle of standard imaging protocols were shown to improve the quality of signal from within the lumen.