Mechanical and Shape Memory Properties of Electrospun Polyurethane with Thiol-Ene Crosslinking.

The ability to treat complex medical issues often requires dynamic and versatile materials. Electrospinning is a fabrication technique which produces nano-/microfibers that can mimic the extracellular matrix of many biological tissues while shape memory polymers allow for geometric changes in devices upon implantation. Here, we present the fabrication of electrospun polyurethane which exhibits the shape memory effect. To improve the mechanical and shape memory properties of this system, we incorporate vinyl side chains in the polymer backbone which enable crosslinking via thiol-ene click chemistry post fabrication. We also discuss a novel technique to improve photoinitiated crosslinking for electrospun materials. A material with these properties is potentially beneficial for various medical applications, such as vascular anastomosis, and the characterization of this material will be valuable in directing those applications.

Macrophage activation in response to shape memory polymer foam-coated aneurysm occlusion devices.

Brain aneurysms can be treated with embolic coils using minimally invasive approaches. It is advantageous to modulate the biologic response of platinum embolic coils. Our previous studies demonstrated that shape memory polymer (SMP) foam coated embolization coils (FCC) devices demonstrate enhanced healing responses in animal models compared with standard bare platinum coil (BPC) devices. Macrophages are the most prevalent immune cell type that coordinate the greater immune response to implanted materials. Hence, we hypothesized that the highly porous SMP foam coatings on embolic coils activate a pro-regenerative healing phenotype. To test this hypothesis, we analyzed the number and type of infiltrating macrophages in FCC or BPC devices implanted in a rabbit elastase aneurysm model. FCC devices elicited a great number of infiltration macrophages, skewed significantly to a pro-regenerative M2-like phenotype 90 days following implantation. We devised an in vitro assay, where monocyte-derived macrophages were placed in close association with FCC or BPC devices for 6-72 h. Macrophages encountering SMP FCC-devices demonstrated highly mixed activation phenotypes at 6 h, heavily skewing toward an M2-like phenotype by 72 h, compared with macrophages encountering BPC devices. Macrophage activation was evaluated using gene expression analysis, and secreted cytokine evaluation. Together, our results demonstrate that FCC devices promoted a pro-regenerative macrophage activation phenotype, compared with BPC devices. Our in vitro findings corroborate with in vivo observations that SMP-based modification of embolic coils can promote better healing of the aneurysm site, by sustaining a pro-healing macrophage phenotype.

Chemical Modifications of Porous Shape Memory Polymers for Enhanced X-ray and MRI Visibility.

The goal of this work was to develop a shape memory polymer (SMP) foam with visibility under both X-ray and magnetic resonance imaging (MRI) modalities. A porous polymeric material with these properties is desirable in medical device development for applications requiring thermoresponsive tissue scaffolds with clinical imaging capabilities. Dual modality visibility was achieved by chemically incorporating monomers with X-ray visible iodine-motifs and MRI visible monomers with gadolinium content. Physical and thermomechanical characterization showed the effect of increased gadopentetic acid (GPA) on shape memory behavior. Multiple compositions showed brightening effects in pilot, T1-weighted MR imaging. There was a correlation between the polymeric density and X-ray visibility on expanded and compressed SMP foams. Additionally, extractions and indirect cytocompatibility studies were performed to address toxicity concerns of gadolinium-based contrast agents (GBCAs). This material platform has the potential to be used in a variety of medical devices.

Micro-CT and histopathology methods to assess host response of aneurysms treated with shape memory polymer foam-coated coils versus bare metal coil occlusion devices.

Recent studies utilizing shape memory polymer foams to coat embolizing coils have shown potential benefits over current aneurysm treatments. In the current study utilizing a rabbit-elastase aneurysm model, the performance of test article (foam-coated coil [FCC]) and control (bare platinum coils [BPCs]) devices were compared at 30, 90, and 180 days using micro-CT and histological assessments. The host response was measured by identifying the cells regionally present within the aneurysm, and assessing the degree of residual debris and connective tissue. The 3D reconstructions of aneurysms provided context for histologic findings, and aided in the overall aneurysm assessment. At all time points, >75% of the cells categorized in each aneurysm were associated with a bioactive yet biocompatible host response (vs. the remainder of cells that were associated with acute inflammation). The extracellular matrix exhibited a transition from residual fibrin at 30 days to a greater degree of connective tissue at 90 and 180 days. Although the control BPC-treated aneurysms exhibited a greater degree of connective tissue at the earliest time point examined (30 days), by 180 days, the FCC-treated aneurysms had more connective tissue and less debris overall than the control aneurysms. When considering cell types and extracellular matrix composition, the overall host response scores were significantly better in FCC-treated aneurysms at the later time point. Based on the results of these metrics, the FCC device may lead to an advanced tissue remodeling response over BPC occlusion devices.

Tissue-engineered aneurysm models for in vitro assessment of neurovascular devices.

PURPOSE: Preclinical testing of neurovascular devices is crucial for successful device design and is commonly performed using in vivo organisms such as the rabbit elastase-induced aneurysm model; however, simple in vitro models may help further refine this testing paradigm. The purpose of the current work was to evaluate, and further develop, tissue-engineered blood vessel mimics (BVMs) as simple, early-stage models to assess neurovascular devices in vitro prior to animal or clinical use. METHODS: The first part of this work used standard straight-vessel BVMs to evaluate flow diverters at 1, 3, and 5 days post-deployment. The second part developed custom aneurysm-shaped scaffolds to create aneurysm BVMs. Aneurysm scaffolds were characterized based on overall dimensions and microstructural features and then used for cell deposition and vessel cultivation. RESULTS: It was feasible to deploy flow diverters within standard BVMs and cellular linings could withstand and respond to implanted devices, with increasing cell coverage over time. This provided the motivation and foundation for the second phase of work, where methods were successfully developed to create saccular, fusiform, and blister aneurysm scaffolds using a wax molding process. Results demonstrated appropriate fiber morphology within different aneurysm shapes, consistent cell deposition, and successful cultivation of aneurysm BVMs. CONCLUSION: It is feasible to use tissue-engineered BVMs for assessing cellular responses to flow diverters, and to create custom aneurysm BVMs. This supports future use of these models for simple, early-stage in vitro testing of flow diverters and other neurovascular devices.

In vivo comparison of shape memory polymer foam-coated and bare metal coils for aneurysm occlusion in the rabbit elastase model.

Shape memory polymer (SMP) foam-coated coils (FCCs) are new embolic coils coated with porous SMP designed to expand for increased volume filling and enhanced healing after implantation. The purpose of this study was to compare chronic aneurysm healing after treatment with SMP FCCs to bare platinum coil (BPC) controls in the rabbit elastase aneurysm model. BPCs or SMP FCCs were implanted in rabbit elastase-induced aneurysms for follow-up at 30 days (n = 10), 90 days (n = 5), and 180 days (n = 12 for BPCs; n = 14 for SMP FCCs). Aneurysm occlusion and histologic healing, including a qualitative healing score, neointima thickness, collagen deposition, and inflammation were compared between the two groups. The mean neointima thickness was significantly greater in groups treated with SMP FCCs for all three time points. Histologic healing scores and collagen deposition quantification suggested that aneurysms treated with SMP FCCs experience more complete healing of the dome by 90 days, but the differences were not statistically significant. More progressive occlusion and recanalization were observed in aneurysms treated with SMP FCCs, but neither difference was statistically significant. Additionally, the SMP foam used in the FCCs was found to degrade faster in the rabbit elastase model than expected based on previous studies in a porcine sidewall aneurysm model. This study suggests that SMP FCCs can promote neointima formation along the aneurysm neck, and may lead to more complete healing of the dome and neck. These findings indicate potential benefits of this device for aneurysm occlusion procedures. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B:2466-2475, 2019.

In vitro performance of a shape memory polymer foam-coated coil embolization device.

Intracranial saccular aneurysm treatment using endovascular embolization devices are limited by aneurysm recurrence that can lead to aneurysm rupture. A shape memory polymer (SMP) foam-coated coil (FCC) embolization device was designed to increase packing density and improve tissue healing compared to current commercial devices. FCC devices were fabricated and tested using in vitro models to assess feasibility for clinical treatment of intracranial saccular aneurysms. FCC devices demonstrated smooth delivery through tortuous pathways similar to control devices as well as greater than 10 min working time for clinical repositioning during deployment. Furthermore, the devices passed pilot verification tests for particulates, chemical leachables, and cytocompatibility. Finally, devices were successfully implanted in an in vitro saccular aneurysm model with large packing density. Though improvements and future studies evaluating device stiffness were identified as a necessity, the FCC device demonstrates effective delivery and packing performance that provides great promise for clinical application of the device in treatment of intracranial saccular aneurysms.

Particulate Release From Nanoparticle-Loaded Shape Memory Polymer Foams.

Highly porous, open-celled shape memory polymer (SMP) foams are being developed for a number of vascular occlusion devices. Applications include abdominal aortic and neurovascular aneurysm or peripheral vascular occlusion. A major concern with implanting these high surface area materials in the vasculature is the potential to generate unacceptable particulate burden, in terms of number, size, and composition. This study demonstrates that particulate numbers and sizes in SMP foams are in compliance with limits stated by the most relevant standard and guidance documents. Particulates were quantified in SMP foams as made, postreticulation, and after incorporating nanoparticles intended to increase material toughness and improve radiopacity. When concentrated particulate treatments were administered to fibroblasts, they exhibited high cell viability (100%). These results demonstrate that the SMP foams do not induce an unacceptable level of risk to potential vascular occlusion devices due to particulate generation.