4D Printable Salicylic Acid Photopolymers for Sustained Drug Releasing, Shape Memory, Soft Tissue Scaffolds.

3D printing of pharmaceuticals offers a unique opportunity for long-term, sustained drug release profiles for an array of treatment options. Unfortunately, this approach is often limited by physical compounding or processing limitations. Modification of the active drug into a prodrug compound allows for seamless incorporation with advanced manufacturing methods that open the door to production of complex tissue scaffold drug depots. Here we demonstrate this concept using salicylic acids with varied prodrug structures for control of physical and chemical properties. The role of different salicylic acid derivatives (salicylic acid, bromosalicylic allyl ester, iodosalicylic allyl ester) and linker species (allyl salicylate, allyl 2-(allyloxy)benzoate, allyl 2-(((allyloxy)carbonyl)oxy)benzoate) were investigated using thiol-ene cross-linking in digital light processing (DLP) 3D printing to produce porous prodrug tissue scaffolds containing more than 50% salicylic acid by mass. Salicylic acid photopolymer resins were all found to be highly reactive (solidification within 5 s of irradiation at λ = 405 nm), while the cross-linked solids display tunable thermomechanical behaviors with low glass transition temperatures (Tgs) and elastomeric behaviors, with the carbonate species displaying an elastic modulus matching that of adipose tissue (approximately 65 kPa). Drug release profiles were found to be zero order, sustained release based upon hydrolytic degradation of multilayered scaffolds incorporating fluorescent modeling compounds, with release rates tuned through selection of the linker species. Cytocompatibility in 2D and 3D was further demonstrated for all species compared to polycarbonate controls, as well as salicylic acid-containing composites (physical incorporation), over a 2-week period using murine fibroblasts. The use of drugs as the matrix material for solid prodrug tissue scaffolds opens the door to novel therapeutic strategies, longer sustained release profiles, and even reduced complications for advanced medicine.

Bioderived 4D Printable Terpene Photopolymers from Limonene and ß-Myrcene.

Green manufacturing and reducing our cultural dependency on petrochemicals have been topics of growing interest in the past decade, particularly for three-dimensional (3D) printable photopolymers where often toxic solvents and reagents have been required. Here, a simple solvent-free, free-radical polymerization is utilized to homo- and copolymerize limonene and ß-myrcene monomers to produce oligomeric photopolymers (Mn < 11 kDa) displaying Newtonian, low viscosities (∼10 Pa × s) suitable for thiol-ene photo-cross-linking, yielding photoset materials in a digital light processing (DLP)-type 3D printer. The resulting photosets display tunable thermomechanical properties (poly(limonene) displays elastic moduli exceeding 1 GPa) compared with previous works focusing on monomeric terpenes as well as four-dimensional (4D) shape memory behavior. The utility of such photopolymers for biomedical applications is briefly considered on the premise of the hydrophilic nature (measured by contact angle) as well as their cytocompatibility upon seeding films with macrophages. These terpene-derived, green 4D photopolymers are shown to have promising physical behaviors suitable for an array of manufacturing and 3D printing applications.

Selective Reactivity of Myrcene for Vat Photopolymerization 3D Printing and Postfabrication Surface Modification.

Biosourced materials are gaining interest industrially, but there are still limitations on the library of available materials suitable for advanced manufacturing, especially using photopolymerization-based processing techniques. Terpenes, such as myrcene, are naturally produced materials possessing structural features, specifically alkenes, that avail themselves for such techniques. Free-radical and anionic polymerization techniques were used to explore molecular architecture, such as branching, as well as molecular weight and dispersity on physical properties prior to the production of 3D printing photopolymer resins. The polymyrcene resins were printed into dogbones and mold templates for soft materials. Model reactions with monofunctional thiols were used to demonstrate the potential for postpolymerization and fabrication functionalization, accompanying a physical demonstration where the surface hydrophobicity of polymyrcene could be tuned from superhydrophobic when using an alkyl chain monothiol (greater than 100° water contact angle) to a hydrophilic surface displaying a water contact angle of less than 45° compared with that of the unmodified surface (∼60°). Tunable bulk and surface properties are a unique feature for 3D printing materials and demonstrate the potential of polymyrcene and other biosourced photopolymers to a wide range of research applications.

3D Printing for the Clinic: Examining Contemporary Polymeric Biomaterials and Their Clinical Utility.

The advent of additive manufacturing offered the potential to revolutionize clinical medicine, particularly with patient-specific implants across a range of tissue types. However, to date, there are very few examples of polymers being used for additive processes in clinical settings. The state of the art with regards to 3D printable polymeric materials being exploited to produce novel clinically relevant implants is discussed here. We focus on the recent advances in the development of implantable, polymeric medical devices and tissue scaffolds without diverging extensively into bioprinting. By introducing the major 3D printing techniques along with current advancements in biomaterials, we hope to provide insight into how these fields may continue to advance while simultaneously reviewing the ongoing work in the field.

Harnessing the Chemical Diversity of the Natural Product Magnolol for the Synthesis of Renewable, Degradable Neolignan Thermosets with Tunable Thermomechanical Characteristics and Antioxidant Activity.

Magnolol, a neolignan natural product with antioxidant properties, contains inherent, orthogonal, phenolic, and alkenyl reactive groups that were used in both direct thermoset synthesis, as well as the stepwise synthesis of a small library of monomers, followed by transformation into thermoset materials. Each monomer from the small library was prepared via a single step functionalization reaction of the phenolic groups of magnolol. Thermoset materials were realized through solvent-free, thiol-ene reactions, and the resulting cross-linked materials were each comprised of thioether and ester linkages, with one retaining the hydrophilic phenols from magnolol, another having the phenols protected as an acetonide, and two others incorporating the phenols into additional cross-linking sites via hydrolytically labile carbonates or stable ether linkages. With this diversity of chemical compositions and structures, the thermosets displayed a range of thermomechanical properties including glass transition temperatures, Tg, 29-52 °C, onset of thermal degradation, Td, from about 290-360 °C, and ultimate strength up to 50 MPa. These tunable materials were studied in their degradation and biological properties with the aim of exploiting the antioxidant properties of the natural product. Hydrolytic degradation occurred under basic conditions (pH = 11) in all thermosets, but with kinetics that were dependent upon their chemical structures and mechanical properties: 20% mass loss was observed at 5, 7, 27, and 40 weeks for the thermosets produced from magnolol directly, acetonide-protected magnolol, bis(allyl carbonate)-functionalized magnolol, and bis(allyl ether)-functionalized magnolol, respectively. Isolated degradation products and model compounds displayed antioxidant properties similar to magnolol, as determined by both UV-vis and in vitro reactive oxygen species (ROS) assays. As these magnolol-based thermosets were found to also allow for extended cell culture, these materials may serve as promising degradable biomaterials.

Shape Memory Poly(ß-hydroxythioether) Foams for Oil Remediation in Aquatic Environments.

Shape memory poly(ß-hydroxythioether) foams were produced using organobase catalyzed reactions between epoxide and thiol monomers, allowing for the rapid formation of porous media within approximately 5 min, confirmed using both rheology and physical foam blowing. The porous materials possess ultralow densities (0.022 g × cm-3) and gel fractions of approximately 93%. Thermomechanical characterizations of the materials revealed glass transition temperatures tunable from approximately 50 to 100 °C, elastic moduli of approximately 2 kPa, and complete strain recovery upon heating of the sample above its glass transition temperature. The foams were characterized for their ability to take up oil from an aqueous multilayered ideal environment, revealing more than 2000% mass of oil (relative to the foam mass) could be collected. Importantly, while post-fabrication functionalization was possible with isocyanate chemistry followed by addition of hexadecanethiol or 3,3-bis(hexadecylthio)propan-1-ol, the oil collection efficiency of the system was not significantly enhanced, indicating that these materials, as porous media, possess unique attributes that make them appealing for environmental remediation without the need for costly modifications or manipulations.

4D polycarbonates via stereolithography as scaffolds for soft tissue repair.

3D printing has emerged as one of the most promising tools to overcome the processing and morphological limitations of traditional tissue engineering scaffold design. However, there is a need for improved minimally invasive, void-filling materials to provide mechanical support, biocompatibility, and surface erosion characteristics to ensure consistent tissue support during the healing process. Herein, soft, elastomeric aliphatic polycarbonate-based materials were designed to undergo photopolymerization into supportive soft tissue engineering scaffolds. The 4D nature of the printed scaffolds is manifested in their shape memory properties, which allows them to fill model soft tissue voids without deforming the surrounding material. In vivo, adipocyte lobules were found to infiltrate the surface-eroding scaffold within 2 months, and neovascularization was observed over the same time. Notably, reduced collagen capsule thickness indicates that these scaffolds are highly promising for adipose tissue engineering and repair.

Exploiting the role of nanoparticle shape in enhancing hydrogel adhesive and mechanical properties.

The ability to control nanostructure shape and dimensions presents opportunities to design materials in which their macroscopic properties are dependent upon the nature of the nanoparticle. Although particle morphology has been recognized as a crucial parameter, the exploitation of the potential shape-dependent properties has, to date, been limited. Herein, we demonstrate that nanoparticle shape is a critical consideration in the determination of nanocomposite hydrogel properties. Using translationally relevant calcium-alginate hydrogels, we show that the use of poly(L-lactide)-based nanoparticles with platelet morphology as an adhesive results in a significant enhancement of adhesion over nanoparticle glues comprised of spherical or cylindrical micelles. Furthermore, gel nanocomposites containing platelets showed an enhanced resistance to breaking under strain compared to their spherical and cylindrical counterparts. This study opens the doors to a change in direction in the field of gel nanocomposites, where nanoparticle shape plays an important role in tuning mechanical properties.

Elastomeric polyamide biomaterials with stereochemically tuneable mechanical properties and shape memory.

Biocompatible polymers are widely used in tissue engineering and biomedical device applications. However, few biomaterials are suitable for use as long-term implants and these examples usually possess limited property scope, can be difficult to process, and are non-responsive to external stimuli. Here, we report a class of easily processable polyamides with stereocontrolled mechanical properties and high-fidelity shape memory behaviour. We synthesise these materials using the efficient nucleophilic thiol-yne reaction between a dipropiolamide and dithiol to yield an α,ß - unsaturated carbonyl moiety along the polymer backbone. By rationally exploiting reaction conditions, the alkene stereochemistry is modulated between 35-82% cis content and the stereochemistry dictates the bulk material properties such as tensile strength, modulus, and glass transition. Further access to materials possessing a broader range of thermal and mechanical properties is accomplished by polymerising a variety of commercially available dithiols with the dipropiolamide monomer.

Improved Oxidative Biostability of Porous Shape Memory Polymers by Substituting Triethanolamine for Glycerol.

While many aromatic polyurethane systems suffer from poor hydrolytic stability, more recently proposed aliphatic systems are oxidatively-labile. The use of the renewable monomer glycerol as a more oxidatively-resistant moiety for inclusion in shape memory polymers (SMPs) is demonstrated here. Glycerol-containing SMPs and the amino alcohol control compositions are compared, with accelerated degradation testing displaying increased stability (time to complete mass loss) as a result of the inclusion of glycerol without sacrificing the shape memory, thermal transitions, or the ultralow density achieved with the control compositions. Gravimetric analysis in accelerated oxidative solution indicates that the control will undergo complete mass loss by approximately 18 days, while lower concentrations of glycerol will degrade fully by 30 days and higher concentrations will possess approximately 40% mass at the same time. In real time degradation analysis, high concentrations of glycerol SMPs have 96% mass remaining at 8 months with 88% gel fraction remaining that that time, compared to less than 50% mass for the control samples with 5% gelation. Mechanically, low glycerol-containing SMPs were not robust enough for testing at three months, while high glycerol concentrations displayed increased elastic moduli (133% of virgin materials) and 18% decreased strain to failure. The role of the secondary alcohol, as well as isocyanates, is presented as being a crucial component in controlling degradation; a free secondary alcohol can more rapidly undergo oxidation or dehydration to ultimately yield carboxylic acids, aldehydes, carbon dioxide, and alkenes. Understanding these pathways will improve the utility of medical devices through more precise control of property loss and patient risk management through reduced degradation.

Highly Cross-Linked Shape Memory Polymers with Tunable Oxidative and Hydrolytic Degradation Rates and Selected Products Based on Succinic Acid.

Minimally invasive medical devices are of great interest, with shape memory polymers (SMPs) representing one such possibility for producing these devices. Previous work with low density, highly porous SMPs has demonstrated oxidative degradation, while attempts to incorporate hydrolytic degradation have resulted in rapidly decreasing glass transition temperature (T g ), ultimately preventing strain fixity of the materials at clinically relevant temperatures. Through esterification of the amino alcohol triethanolamine, an alcohol containing network was synthesized and incorporated into SMPs. These ester networks were used to control the bulk morphology of the SMP, with the T g remaining above 37 °C when 50% of the alcohol was contributed by the ester network. This methodology also yielded SMPs that could degrade through both hydrolysis and oxidation; by oxidation, the SMPs degrade at a similar rate as the control materials (0.2%/day mass) for the first 30 days, at which point the rate changes to 3.5%/day until the samples become too fragile to examine at 80 days. By comparison, control materials have lost approximately 30% of mass by 140 days, at a constant rate of degradation, demonstrating that the ester SMPs are a promising material system for producing more rapidly degradable, soft, porous biomaterials.

Shape memory polyurethane-urea foams with improved toughness.

Current vascular aneurysm treatments often require either highly invasive strategy to surgically occlude an aneurysm or endovascular occlusion via metal coils. While endovascular coils are safer, they have limited efficacy. Endovascular coils that are integrated with shape memory polymer (SMP) foams have the potential to improve occlusion and reduce coil risks; however, the mechanical performance and limited homogeneity of SMP foams can hinder their effective use. To address this issue, SMP foams are synthesized using the monomer diethanolamine (DEA) in place of triethanolamine (TEA) to provide improved mechanical properties for medical device applications. Mechanical testing and micro-fracture analysis were performed on DEA and TEA foams. DEA foams show improved toughness and reduced micro-fractures compared to the control. This work presents the utility of DEA in SMP synthesis to enable the potential production of safer aneurysm treatment.

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.

Revealing the glass transition in shape memory polymers using Brillouin spectroscopy.

Emerging medical devices which employ shape memory polymers (SMPs) require precise measurements of the glass transition temperature (Tg) to ensure highly controlled shape recovery kinetics. Conventional techniques like differential scanning calorimetry (DSC) and dynamic mechanical analysis (DMA) have limitations that prevent utilization for certain devices, including limited accuracy and the need for sacrificial samples. In this report, we employ an approach based on Brillouin spectroscopy to probe the glass transition of SMPs rapidly, remotely, and nondestructively. Further, we compare the Tg obtained from Brillouin scattering with DMA- and DSC-measured Tg to demonstrate the accuracy of Brillouin scattering for this application. We conclude that Brillouin spectroscopy is an accurate technique for obtaining the glass transition temperature of SMPs, aligning closely with the most common laboratory standards while providing a rapid, remote, and nondestructive method for the analysis of unique polymeric medical devices.

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.

Examination of radio-opacity enhancing additives in shape memory polyurethane foams.

Three microparticle additives, tungsten (W), zirconium oxide (ZrO2), and barium sulfate (BaSO4) were selected to enhance the radio-opacity in shape memory polymer (SMP) foam biomaterials. The addition of filler causes no significant alterations of glass transition temperatures, density of the materials increases, pore diameter decreases, and total volume recovery decreases from approximately 70 times in unfilled foams to 20 times (4% W and 10% ZrO2). The addition of W increases time to recovery; ZrO2 causes little variation in time to shape recovery; BaSO4 increases the time to recovery. On a 2.00 mean X-ray density (mean X.D.) scale, a GDC coil standard has a mean X.D. of 0.62; 4% W enhances the mean X.D. to 1.89, 10% ZrO2 to 1.39 and 4% BaSO4 to 0.74. Radio-opacity enhancing additives could be used to produce SMP foams with controlled shape memory kinetics, low density, and enhanced X-ray opacity for medical materials.