Permeation-Enhancing Strategies for Transdermal Delivery of Cannabinoids.

Introduction: This review aims to provide an overview of the advancements and status of clinical studies and potential permeation-enhancing strategies in the transdermal delivery of cannabinoids. Methods: A systematic and comprehensive literature search across academic databases, search engines, and online sources to identify relevant literature on the transdermal administration of cannabinoids. Results: Cannabinoids have proven beneficial in the treatment of wide-ranging physical and psychological disorders. A shift toward legalized cannabinoid products has increased both interests in cannabinoid research and the development of novel medicinal exploitations of cannabinoids in recent years. Oral and pulmonary delivery of cannabinoids has several limitations, including poor bioavailability, low solubility, and potential side effects. This has diverted scientific attention toward the transdermal route, successfully overcoming these hurdles by providing higher bioavailability, safety, and patient compliance. Yet, due to the barrier properties of the skin and the lipophilic nature of cannabinoids, there is a need to increase the permeation of the drugs to the underneath layers of skin to reach desired therapeutic plasma levels. Literature describing detailed clinical trials on cannabinoid transdermal delivery, either with or without permeation-enhancing strategies, is limited. Conclusion: The limited number of reports indicates that increased attention is needed on developing and examining efficient transdermal delivery systems for cannabinoids, including patch design and composition, drug-patch interaction, clinical effectiveness and safety in vivo, and permeation-enhancing strategies.

Scalable Synthetic Route to PDMS Ring Polymers in High Yields from Commercially Available Materials Using the Piers-Rubinsztajn Reaction.

While cyclic polymers have intrigued researchers for their novel set of architecture-driven rheological interactions, the possibility of incorporating them in topological systems has been limited by the availability of large ring polymers. Thus, the need for scalable methods to produce ring polymers has become apparent. Here, a facile method to prepare polysiloxane ring polymers by means of Piers-Rubinsztajn chemistry is presented. The one-pot nature and commercial availability of reagents additionally confirm the applicability of the method for large-scale production. Furthermore, a highly efficient yet simple purification method was developed for the isolation of pure ring polymers without linear side products.

Crosslinking Methodology for Imidazole-Grafted Silicone Elastomers Allowing for Dielectric Elastomers Operated at Low Electrical Fields with High Strains.

For improved actuation at low voltages of dielectric elastomers, a high dielectric permittivity has been targeted for several years but most successful methods then either increase the stiffness of the elastomer and/or introduce notable losses of both mechanical and dielectric nature. For polydimethylsiloxane (PDMS)-based elastomers, most high-permittivity moieties inhibit the sensitive platinum catalyst used in the addition curing scheme. In contrast to the classical addition curing pathway to prepare PDMS elastomers, here, an alternative strategy is reported to prepare PDMS elastomers via the crosslinking reaction between multifunctional imidazole-grafted PDMS with difunctional bis(1-ethylene-imidazole-3-ium) bromide ionic liquid (bis-IL). The prepared IL-elastomer entails uniformly dispersed IL and presents stable mechanical and dielectric properties due to the covalent nature of the crosslinking as opposed to previously reported physical mixing in of ILs. The relative permittivity was improved up to 200% by including the bis-IL in the elastomer, and Young's modulus was around 0.04 MPa. As a result of the excellent combination of properties, the dielectric actuator developed exhibits an area strain of 20% at 15 V/µm. The novel strategy to prepare PDMS elastomers provides a new paradigm for achieving high-performance dielectric elastomer actuators by a simple methodology.

A reliable quantitative method for determining CBD content and release from transdermal patches in Franz cells.

INTRODUCTION: There are several cannabidiol (CBD) transdermal patches available on the market. However, none are FDA-approved. Furthermore, not much evidence has been published about CBD release and skin permeation from such patches, so the effectiveness and reliability remain unclear. OBJECTIVES: We aimed to develop a method to determine the in vitro release and skin permeation of CBD from transdermal patches using Franz cell diffusion in combination with quantitative 1 H-NMR (qNMR). MATERIALS AND METHODS: The study was conducted on CBD patches with known CBD content and six different commercially available or market-ready CBD patches using a Franz cell with a Strat-M™ membrane and with samples taken directly from the transdermal patch for qNMR analysis. RESULTS: The use of qNMR yielded an average recovery of 100% ± 7% when samples with known CBD content were tested. Results from the testing of six commercially available patches indicated that five out of six patches did not contain the CBD amount stated by the manufacturer according to a ± 10% variance margin, of which four patches were under-labeled and one was over-labeled. The release rate of patches was determined, and significant differences between the patches were shown. Maximum release of CBD was calculated to occur after 39 to 70 h. CONCLUSION: The established method was proven to be a reliable means of determining the quantity and release of CBD from transdermal patches and can be used to verify CBD content and release rate in transdermal patches.

Recycling of dielectric electroactive materials enabled through thermoplastic PDMS.

In the green transition, actuators and generators play an essential role in the development of sustainable solutions across a broad range of applications. In this context, dielectric transducers are advocated as one of the most promising solutions in terms of effectiveness, lifetime and running costs. However, they are classically produced as sandwich structures, whereby a cross-linked dielectric material is placed between two compliant electrodes. From a materials consumption viewpoint, this is problematic, since it will inherently result in a loss of material during production as well as inhibit the recycling of expended systems when their life comes to an end. Herein, we present a cleaning method employing surfactants and sonication to remove electrodes from the surface of the dielectric material. By applying a thermoplastic silicone elastomer as the dielectric material, it is possible to reprocess the material by hot-pressing, and to prepare new actuators after the rinsing process. This effectively shows that recycling production scrap, for example, is possible. By comparing the cleaned material with a directly recycled material, it is clear that cleaning removes a critical amount of metals from the material and enables recycling for at least five cycles. Comparatively, a directly recycled material is prone to a high leakage current and premature electronic breakdown after only two cycles. This simple cleaning process, in combination with use of a thermoplastic dielectric material, enables less waste from production as well as the possibility of reclaiming and recycling materials in general.

Characterization of a Radiofluorogenic Polymer for Low-Energy Electron Beam Penetration Depth Visualization.

Low-energy (80-300 keV) electron beam accelerators are gaining in importance in the radiation processing industry due to their ease of use and wide range of applications (e.g. product surface sterilizations or polymer curing and cross-linking). Due to their very low penetration depth (tens to hundreds of microns), currently used film dosimeters exhibit dose gradients over their thickness and do not resolve the dose response in the first microns of the irradiated material. Hence, the surface dose, defined as the dose in the first micron Dµ, cannot be measured directly. This study presents a polymer material as a dosimeter candidate for high-dose low-energy electron beam irradiations. The readout of the dose-dependent fluorescence intensity, originating from a pararosaniline dye reaction when irradiated, is measured using fluorescence microscopy. So far, no in-depth characterization of the material has been performed, leaving the stability and fluorescence properties of the material not fully optimized. We describe the improvements in polymer composition and the fabrication method, and characterize the material properties in terms of the thermal stability, glass transition temperature, refractive index, hardness, rheological behavior, and water affinity. All of these create a complex set of requirements a polymer needs to fulfill to become an effective dosimeter when measuring using confocal microscopy. The fluorescence readout procedure will be addressed in further studies.

One reaction to make highly stretchable or extremely soft silicone elastomers from easily available materials.

Highly stretchable, soft silicone elastomers are of great interest for the fabrication of stretchable, soft devices. However, there is a lack of available chemistries capable of efficiently preparing silicone elastomers with superior stretchability and softness. Here we show an easy curing reaction to prepare silicone elastomers, in which a platinum-catalyzed reaction of telechelic/multi-hydrosilane (Si-H) functional polydimethylsiloxane (PDMS) in the presence of oxygen and water leads to slow crosslinking. This curing chemistry allows versatile tailoring of elastomer properties, which exceed their intrinsic limitations. Specifically, both highly stretchable silicone elastomers (maximum strain of 2800%) and extremely soft silicone elastomers (lowest shear modulus of 1.2 kPa) are prepared by creating highly entangled elastomers and bottle-brush elastomers from commercial precursor polymers, respectively.

Highly Stretchable Silicone Elastomer Applied in Soft Actuators.

In this work, a highly stretchable silicone elastomer is incorporated into dielectric elastomer actuators (DEAs) in order to decrease operation voltages by applying high prestretches. Results show that the fabricated DEAs (5 mm diameter circle active region) can be actuated to a lateral strain of 30% at 4.3 kV for a 122 µm thick prestretched film, and to a lateral strain of 2.5% at only 250 V for a 6.9 µm thick prestretched film. Due to the significant viscous component of the silicone elastomer, the DEAs respond more slowly (2-14 s to reach 90% of full strain) and show greater strain changes over time compared to conventional silicone-based DEAs. While this inherent viscosity is not universally favorable, it can be advantageous in applications where actuator damping is desirable. The studied DEAs' mean lifetimes under DC actuation range significantly-from 0.9 h to more than 123.0 h-depending mainly on initial electrical fields (17.8-36.3 V µm-1 ). For instance, DEAs with a 150 µm initial thickness and a prestretch ratio of 3 show 1.4-2.6% lateral strains for the mean lifetime (123.0 h) at only 300 V. Given the strains achieved at low voltage, such DEAs show promise for applications that do not require fast response speeds.

Highly Sensitive Flexible Pressure Sensors Enabled by Mixing of Silicone Elastomer With Ionic Liquid-Grafted Silicone Oil.

Developing highly sensitive flexible pressure sensors has become crucially urgent due to the increased societal demand for wearable electronic devices capable of monitoring various human motions. The sensitivity of such sensors has been shown to be significantly enhanced by increasing the relative dielectric permittivity of the dielectric layers used in device construction via compositing with immiscible ionic conductors. Unfortunately, however, the elastomers employed for this purpose possess inhomogeneous morphologies, and thus suffer from poor long-term durability and unstable electrical response. In this study, we developed a novel, flexible, and highly sensitive pressure sensor using an elastomeric dielectric layer with particularly high permittivity and homogeneity due to the addition of synthesized ionic liquid-grafted silicone oil (denoted LMS-EIL). LMS-EIL possesses both a very high relative dielectric permittivity (9.6 × 105 at 10-1 Hz) and excellent compatibility with silicone elastomers due to the covalently connected structure of conductive ionic liquid (IL) and chloropropyl silicone oil. A silicone elastomer with a relative permittivity of 22 at 10-1 Hz, Young's modulus of 0.78 MPa, and excellent homogeneity was prepared by incorporating 10 phr (parts per hundreds rubber) of LMS-EIL into an elastomer matrix. The sensitivity of the pressure sensor produced using this optimized silicone elastomer was 0.51 kPa-1, which is 100 times higher than that of the pristine elastomer. In addition, a high durability illustrated by 100 loading-unloading cycles and a rapid response and recovery time of approximately 60 ms were achieved. The excellent performance of this novel pressure sensor suggests significant potential for use in human interfaces, soft robotics, and electronic skin applications.

Silicone-Ionic Liquid Elastomer Composite with Keratin as Reinforcing Agent Utilized as Pressure Sensor.

Development of a flexible pressure sensor is crucial for the future improvement of the wearable electronic devices designed to detect dynamic human motion. In this study, a novel pressure sensor with remarkably improved force sensing characteristics is obtained through combined usage of polydimethylsiloxane (PDMS) and ionic liquid (IL). Keratin is dispersed homogeneously in the PDMS matrix to serve as a reinforcing filler. High conductivity IL is employed as sensitivity-enhancing constituent in the elastomer, and the effect of the amount of IL on elastomers' pressure-sensing performance is investigated. The elastomer with 70 parts per hundred rubber (phr) IL shows excellent pressure-sensing performance. This novel pressure sensor demonstrates high linear sensitivity (0.037 kPa-1 ) in the large pressure region of 0-10 kPa. Response and recovery times are 8 and 11 ms, respectively, which are much shorter than previously reported. Moreover, the pressure sensor could distinguish different pressures via stable sensing signals in the pressure range of 0 to 50 kPa. The excellent performance of the novel pressure sensor has application potential in various fields, such as health monitoring and soft robotics.

Novel polyrotaxane cross-linkers as a versatile platform for slide-ring silicone.

Slide-ring elastomers have garnered a lot of interest for their potential use in dielectric elastomer actuators due to their intrinsically soft nature and high elasticity. However, the use of sliding cross-linkers has been constrained by their low miscibility with commonly used elastomer precursors and the specialized curing chemistries that are necessary for incorporating them into networks. Here, we have presented a method to produce vinyl functional polyrotaxane cross-linkers that are compatible with polysiloxanes and can be processed by industrially scalable methods. The sliding silicone films that were fabricated with these novel cross-linkers were highly extensible (>350%) and did not exhibit strain hardening even at high elongation. The composite films also retained the favorable dielectric properties of silicone elastomers such as the characteristic low dielectric loss. The modified polyrotaxanes present a robust platform for producing a new class of sliding silicone elastomers with well-defined networks structures.

Synergistic effect of carotenoid and silicone-based additives for photooxidatively stable organic solar cells with enhanced elasticity.

Photochemical and mechanical stability are critical in the production and application of organic solar cells. While these factors can individually be improved using different additives, there is no example of studies on the combined effects of such additive-assisted stabilization. In this study, the properties of PTB7:[70]PCBM organic solar cells are studied upon implementation of two additives: the carotenoid astaxanthin (AX) for photochemical stability and the silicone polydimethylsiloxane (PDMS) for improved mechanical properties. A newly designed additive, AXcPDMS, based on astaxanthin covalently bonded to PDMS was also examined. Lifetime tests, produced in ISOS-L-2 conditions, reveal an improvement in the accumulated power generation (APG) of 10% with pure AX, of 90% when AX is paired with PDMS, and of 140% when AXcPDMS is added in the active layer blend, as compared to the control devices. Singlet oxygen phosphorescence measurements are utilized to study the ability of AX and AXcPDMS to quench singlet oxygen and its precursors in the films. The data are consistent with the strong stabilization effect of the carotenoids. While AX and AXcPDMS are both efficient photochemical stabilizers, the improvement in device stability observed in the presence of AXcPDMS is likely due to a more favorable localization of the stabilizer within the blend. The mechanical properties of the active layers were investigated by tensile testing and cohesive fracture measurements, showing a joint improvement of the photooxidative stability and the mechanical properties, thus yielding organic solar cell devices that are promising for flexible photovoltaic applications.

Reliable Condensation Curing Silicone Elastomers with Tailorable Properties.

The long-term stability of condensation curing silicone elastomers can be affected by many factors such as curing environment, cross-linker type and concentration, and catalyst concentration. Mechanically unstable silicone elastomers may lead to undesirable application failure or reduced lifetime. This study investigates the stability of different condensation curing silicone elastomer compositions. Elastomers are prepared via the reaction of telechelic silanol-terminated polydimethylsiloxane (HO-PDMS-OH) with trimethoxysilane-terminated polysiloxane ((MeO)3Si-PDMS-Si(OMe)3) and ethoxy-terminated octakis(dimethylsiloxy)-T8-silsesquioxane ((QMOEt)8), respectively. Two post-curing reactions are found to significantly affect both the stability of mechanical properties over time and final properties of the resulting elastomers: Namely, the condensation of dangling and/or unreacted polymer chains, and the reaction between cross-linker molecules. Findings from the stability study are then used to prepare reliable silicone elastomer coatings. Coating properties are tailored by varying the cross-linker molecular weight, type, and concentration. Finally, it is shown that, by proper choice of all three parameters, a coating with excellent scratch resistance and electrical breakdown strength can be produced even without an addition of fillers.

Insights into the Complex Prebreakdown Actuation of Silicone Elastomers and its Influence on Breakdown Behavior.

Dielectric elastomer transducers can be applied in many different applications, but their current use is limited by either their electrical breakdown strength or by electromechanical instabilities in the case of soft elastomers. The breakdown process is never a single, simple process but rather-most likely-an ensemble of thermoelectric processes taking place in both elastomer and electrode materials, coupled with mechanical and potentially also chemical degradation. In this work, by using a high-speed camera, we follow silicone-based dielectric elastomers undergoing a ramp-up in voltage close to electrical breakdown strength, with differently constructed elastomers and electrodes. As such, we present experimental insights into the electromechanical processes immediately before the dielectric breakdown of elastomers and identify three different actuation mechanisms taking place prior to electrical breakdown, denoted prebreakdown actuation in the following. The prebreakdown actuation mechanisms observed herein include film thinning and stretching, as well as the formation of bubble- and ring-shaped structures from the elastomer surface, respectively. We furthermore present a theoretical explanation for the observed actuation mechanisms.

Compatibilization of porphyrins for use as high permittivity fillers in low voltage actuating silicone dielectric elastomers.

Polysiloxanes represent, because of their unusual properties, a material with great potential for use in dielectric elastomers (DEs), a promising class of electroactive polymers. Currently, their application as actuators is limited by the need for high driving voltages, as a result of the low relative permittivity possessed by polysiloxanes (∼2-3). Reducing these voltages can be achieved to some degree by using high permittivity additives to improve the permittivity of the polysiloxane. However, modifying such additives so that they are compatible with, and can be dispersed within, polysiloxane elastomers remains challenging. For reliable actuation, full miscibility is key. In this work the porphyrin 5,10,15,20-(tetra-3-methoxyphenyl)porphyrin (TPMP) was investigated as a high permittivity additive. Its behaviour was compared to the analogue that was derivatized with bis(trimethylsiloxy)methylsilane groups using the Piers-Rubinsztajn reaction to improve compatability with silicone formulations. The derivatized porphyrin was dispersed in elastomers and their dielectric and mechanical properties were evaluated. It was discovered that only low levels of incorporation (1-10%) of the siliconized TPMP - much lower than the parent TPMP - were needed to elicit improvements in the permittivity and electromechanical actuation of the elastomers; actuation strains of up to 43% could be achieved using this method.

Elastomers without Covalent Cross-Linking: Concatenated Rings Giving Rise to Elasticity.

There is intense interest in making mechanically stable elastomers with properties resembling those of human muscles for use in soft robotics. Recently, a polydimethylsiloxane (PDMS) elastomer prepared without the use of cross-linking moieties from heterobifunctional PDMS macromonomers of intermediate molecular weight has been shown to exhibit surprising inherent softness and excellent stability upon both large deformation and swelling, in clear contradiction of classical rubber elasticity theories. In this work, this unexpected elasticity is shown to originate from concatenated rings.

How to tailor flexible silicone elastomers with mechanical integrity: a tutorial review.

The tutorial aims to equip the beginners in silicone research with the knowledge to formulate recipes and process elastomer networks, targeting specific properties related to soft applications such as stretchable electronics without compromising the mechanical integrity of the elastomer. In doing so, we hope to stimulate further research in the area of tailor-made soft silicone elastomers for novel applications and allow researchers to bypass the limitations imposed by the use of commercially available silicone elastomer formulations. Silicone elastomers are widely used due to the favourable properties, such as flexibility, durable dielectric insulation, barrier properties against environmental contaminants and stress-absorbing properties over a wide range of temperatures ≈-100 °C to 250 °C. For research on flexible electronics and other emerging technologies, the most commonly utilised silicone elastomer formulation is Sylgard 184 which is easier to process than most other commercially available silicone elastomers, due to the fact that the premixes have low viscosity. Furthermore, curing is robust and not as sensitive to poisoning as other silicone elastomer formulations. However, Sylgard 184 is not suitable for all fields of research that require flexible and stretchable silicones. When much softer networks are needed, the Sylgard 184 premixes are either mixed in non-stoichiometric ratios, or they are blended with softer types of commercially available elastomers, which compromise the mechanical integrity of the elastomer. Therefore, it is advantageous for researchers to formulate their own custom-made silicone elastomers and not depend on premade formulations which often harbour a few unknown components.

Enhancing the electro-mechanical properties of polydimethylsiloxane elastomers through blending with poly(dimethylsiloxane-co-methylphenylsiloxane) copolymers.

In this work, improved electro-mechanical properties of silicone-based dielectric elastomers are achieved by means of adding so-called "voltage-stabilisers" prepared from phenyl-functional copolymers prepared using oxyanionic ring-opening polymerisation of octamethylcyclotetrasiloxane (D4) and either tetramethyltetraphenylcyclotetrasiloxane (T4) or octaphenylcyclotetrasiloxane (O4). The concentration of the voltage stabiliser was varied both by changing the molar ratio between methyl and phenyl groups in the copolymer and also by varying the amount of copolymer mixed into a PDMS-based elastomer. The phenyl-functional copolymers were generally found to disperse homogeneously in the PDMS matrix and this resulted in networks with improved mechanical and electrical properties. The developed elastomers were inherently extensible with enhanced tensile and tear strengths, due to phenyl-rich microphases acting as reinforcing domains. Furthermore, addition of phenyl-functional copolymers resulted in elastomers with increased relative permittivity and electrical breakdown strength compared to control elastomers while retaining a low dielectric loss. This demonstrates their efficiency as voltage stabilisers.

Self-Healing, High-Permittivity Silicone Dielectric Elastomer.

Currently used dielectric elastomers do not have the ability to self-heal after detrimental events such as tearing or electrical breakdown, which are critical issues in relation to product reliability and lifetime. In this paper, we present a self-healing dielectric elastomer that additionally possesses high dielectric permittivity and consists of an interpenetrating polymer network of silicone elastomer and ionic silicone species that are cross-linked through proton exchange between amines and acids. The ionically cross-linked silicone provides self-healing properties after electrical breakdown or cuts made directly to the material due to the reassembly of the ionic bonds that are broken during damage. The dielectric elastomers presented in this paper pave the way to increased lifetimes and the ability of dielectric elastomers to survive millions of cycles in high-voltage conditions.

Constitutive equation for polymer networks with phonon fluctuations.

Recent research by Xing [Phys. Rev. Lett. 98, 075502 (2007)] has provided an expression for the Helmholtz free energy related to phonon fluctuations in polymer networks. We extend this result by constructing the corresponding nonlinear constitutive equation, usable for entirely general, volume conserving deformation fields. Constitutive equations for the sliplink model and the tube model are derived and the three models are examined by comparison with each other and with data from Xu and Mark [Rubber Chem. Technol. 63, 276 (1990)] and Wang and Mark [J. Polym. Sci., Part B: Polym. Phys. 30, 801 (1992)]. Elastic moduli are derived for the three models and compared with the moduli determined from the chemical stoichiometry. We conclude that the sliplink model and the phonon fluctuation model are relatively consistent with each other and with the data. The tube model seems consistent neither with the other models nor with the data.