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.

Small-molecule inhibitors of the cancer target, isoprenylcysteine carboxyl methyltransferase, from Hovea parvicalyx.

Isoprenylcysteine carboxyl methyltransferase (Icmt) is enzyme target in anticancer drug discovery. An Icmt natural product high-throughput screening campaign was conducted and a hit extract from the roots of Hovea parvicalyx was identified. 2'-Methoxy-3'-prenyl-licodione and 2'-methoxy-3',3''-diprenyl-licodione, two prenylated beta-hydroxychalcone compounds, together with the known flavanone (S)-glabrol, were isolated and identified as bioactive constituents. Their structures were determined largely by 1D and 2D NMR spectroscopy.

Aplysamine 6, an alkaloidal inhibitor of Isoprenylcysteine carboxyl methyltransferase from the sponge Pseudoceratina sp.

The anticancer target isoprenylcysteine carboxyl methyltransferase (Icmt) was the focus of a natural product high-throughput screening campaign. The Australian marine sponge Pseudoceratina sp. yielded aplysamine 6, a new bromotyrosine derivative with an alpha,beta-unsaturated amide linkage, as the bioactive constituent. Its structure was determined by 1D and 2D NMR spectroscopy.

Spermatinamine, the first natural product inhibitor of isoprenylcysteine carboxyl methyltransferase, a new cancer target.

Isoprenylcysteine methyltransferase (Icmt) catalyzes the carboxyl methylation of oncogenic proteins in the final step of a series of post-translational modifications. The inhibition of Icmt provides an attractive and novel anticancer target. A natural product high-throughput screening campaign was conducted to discover inhibitors of Icmt. The Australian marine sponge, Pseudoceratina sp., yielded spermatinamine, a novel alkaloid with a bromotyrosyl-spermine-bromotyrosyl sequence, as the bioactive constituent. Its structure was determined by 1D and 2D NMR spectroscopy. Spermatinamine is the first natural product inhibitor of Icmt.

Two-year performance study of porous, thermoset, shape memory polyurethanes intended for vascular medical devices.

The long-term shape-recovery behavior of shape memory polymers has often been shown to be dependent on the length of time the material has been stored in the secondary shape. Typically, recovery performance and shape fixity will decrease with increased time in the secondary shape. In medical materials, a shelf-life is crucial to establish as it sets the upper threshold for device performance in a clinical setting, and a reduction in shape recovery would limit the development of SMP medical devices. Here, we present a two-year study of strain recovery, strain fixity, and shape recovery kinetics for passively and actively actuated SMPs intended for vascular devices. While kinetic experiments using immersion DMA indicate slight material relaxation and a decrease in the time to recovery, these changes are not found for bulk recovery experiments. The results indicate that a two-year shelf-life for these SMPs is very reasonable, as there is no change in the recovery kinetics, strain recovery, or strain fixity associated with this aging time. Further, a thermal accelerated aging test is presented for more rapid testing of the shape memory behavior of these SMPs and is compared with the real time aging results, indicating that this test is a reasonable indicator of the two-year behavior.

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.

Shape memory polyurethanes with oxidation-induced degradation: In vivo and in vitro correlations for endovascular material applications.

The synthesis of thermoset shape memory polymer (SMP) polyurethanes from symmetric, aliphatic alcohols and diisocyanates has previously demonstrated excellent biocompatibility in short term in vitro and in vivo studies, although long term stability has not been investigated. Here we demonstrate that while rapid oxidation occurs in these thermoset SMPs, facilitated by the incorporation of multi-functional, branching amino groups, byproduct analysis does not indicate toxicological concern for these materials. Through complex multi-step chemical reactions, chain scission begins from the amines in the monomeric repeat units, and results, ultimately, in the formation of carboxylic acids, secondary and primary amines; the degradation rate and product concentrations were confirmed using liquid chromatography mass spectrometry, in model compound studies, yielding a previously unexamined degradation mechanism for these biomaterials. The rate of degradation is dependent on the hydrogen peroxide concentration, and comparison of explanted samples reveals a much slower rate in vivo compared to the widely accepted literature in vitro real-time equivalent of 3% H2O2. Cytotoxicity studies of the material surface, and examination of the degradation product accumulations, indicate that degradation has negligible impact on cytotoxicity of these materials. STATEMENT OF SIGNIFICANCE: This paper presents an in-depth analysis on the degradation of porous, shape memory polyurethanes (SMPs), including traditional surface characterization as well as model degradation compounds with absolute quantification. This combination of techniques allows for determination of rates of degradation as well as accumulation of individual degradation products. These behaviors are used for in vivo-in vitro comparisons for determination of real time degradation rates. Previous studies have primarily been limited to surface characterization without examination of degradation products and accumulation rates. To our knowledge, our work presents a unique example where a range of material scales (atomistic-scale model compounds along with macroscopic porous SMPs) are used in conjunction with ex planted samples for calculation of degradation rates and toxicological risk.

Increased X-ray Visualization of Shape Memory Polymer Foams by Chemical Incorporation of Iodine Motifs.

Shape memory polymers can be programmed into a secondary geometry and recovered to their primary geometry with the application of a controlled stimulus. Porous shape memory polymer foam scaffolds that respond to body temperature show particular promise for embolic medical applications. A limitation for the minimally invasive delivery of these materials is an inherent lack of X-ray contrast. In this work, a triiodobenzene containing a monomer was incorporated into a shape memory polymer foam material system to chemically impart X-ray visibility and increase material toughness. Composition and process changes enabled further control over material density and thermomechanical properties. The proposed material system demonstrates a wide range of tailorable functional properties for the design of embolic medical devices, including X-ray visibility, expansion rate, and porosity. Enhanced visualization of these materials can improve the acute performance of medical devices used to treat vascular malformations, and the material porosity provides a healing scaffold for durable occlusion.

In vitro and in vivo evaluation of a shape memory polymer foam-over-wire embolization device delivered in saccular aneurysm models.

Current endovascular therapies for intracranial saccular aneurysms result in high recurrence rates due to poor tissue healing, coil compaction, and aneurysm growth. We propose treatment of saccular aneurysms using shape memory polymer (SMP) foam to improve clinical outcomes. SMP foam-over-wire (FOW) embolization devices were delivered to in vitro and in vivo porcine saccular aneurysm models to evaluate device efficacy, aneurysm occlusion, and acute clotting. FOW devices demonstrated effective delivery and stable implantation in vitro. In vivo porcine aneurysms were successfully occluded using FOW devices with theoretical volume occlusion values greater than 72% and rapid, stable thrombus formation. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1407-1415, 2016.

Design and biocompatibility of endovascular aneurysm filling devices.

The rupture of an intracranial aneurysm, which can result in severe mental disabilities or death, affects approximately 30,000 people in the United States annually. The traditional surgical method of treating these arterial malformations involves a full craniotomy procedure, wherein a clip is placed around the aneurysm neck. In recent decades, research and device development have focused on new endovascular treatment methods to occlude the aneurysm void space. These methods, some of which are currently in clinical use, utilize metal, polymeric, or hybrid devices delivered via catheter to the aneurysm site. In this review, we present several such devices, including those that have been approved for clinical use, and some that are currently in development. We present several design requirements for a successful aneurysm filling device and discuss the success or failure of current and past technologies. We also present novel polymeric-based aneurysm filling methods that are currently being tested in animal models that could result in superior healing.

Reticulation of low density shape memory polymer foam with an in vivo demonstration of vascular occlusion.

Predominantly closed-cell low density shape memory polymer (SMP) foam was recently reported to be an effective aneurysm filling device in a porcine model (Rodriguez et al., Journal of Biomedical Materials Research Part A 2013: (http://dx.doi.org/10.1002/jbm.a.34782)). Because healing involves blood clotting and cell migration throughout the foam volume, a more open-cell structure may further enhance the healing response. This research sought to develop a non-destructive reticulation process for this SMP foam to disrupt the membranes between pore cells. Non-destructive mechanical reticulation was achieved using a gravity-driven floating nitinol pin array coupled with vibratory agitation of the foam and supplemental chemical etching. Reticulation resulted in a reduced elastic modulus and increased permeability, but did not impede the shape memory behavior. Reticulated foams were capable of achieving rapid vascular occlusion in an in vivo porcine model.

Controlling the Actuation Rate of Low-Density Shape-Memory Polymer Foams in Water.

SMPs have been shown to actuate below their dry glass transition temperatures in the presence of moisture due to plasticization. This behavior has been proposed as a self-actuating mechanism of SMPs in water/physiological media. However, control over the SMP actuation rate, a critical factor for in vivo transcatheter device delivery applications, has not been previously reported. Here, a series of polyurethane SMPs with systematically varied hydrophobicity is described that permits control of the time for their complete shape recovery in water from under 2 min to more than 24 h. This control over the SMP actuation rate can potentially provide significant improvement in their delivery under conditions, which may expose them to high-moisture environments prior to actuation.