Devatha P. Nair

Relative reactivity and selectivity of vinyl sulfones and acrylates towards the thiol–Michael addition reaction and polymerization

The reactivity, selectivity and kinetics of vinyl sulfones and acrylates in base and nucleophile-catalyzed thiol–Michael addition reactions were examined in detail in this study. The vinyl sulfones react selectively and more rapidly with thiols in the presence of acrylates, which was clearly indicated from reactions of hexanethiol (HT), ethyl vinyl sulfone (EVS) and hexyl acrylate (HA) at a molar ratio of 2 : 1 : 1. EVS reaches 100% conversion with minimal consumption (<10%) of HA, which demonstrates the high selectivity of vinyl sulfones over acrylates. The reaction rate of EVS with HT was approximately 7 times higher than that of HA. A detailed study of the kinetics of the nucleophile-catalyzed thiol–Michael addition reaction was carried out, and it was shown that the delay observed in the initial stages of the nucleophile-catalyzed thiol–Michael addition reaction is due to the relatively slow attack of the nucleophiles on the vinyl. The presence of protic species other than thiols in the reaction mixture has also been shown to significantly impede the reaction rate, and in extreme cases, has been shown to inhibit the Michael addition reaction. These results provided a better understanding of the conditions under which the thiol–Michael addition reaction can or cannot be considered as a click reaction. Finally, the high reaction selectivity of vinyl sulfones over acrylates via thiol–Michael addition reaction in ternary systems is used to control gelation behavior in crosslinked polymer networks formed by thiol–Michael addition reactions.

Tailorable and programmable liquid-crystalline elastomers using a two-stage thiol–acrylate reaction

This study introduces an unexplored method to synthesize and program liquid-crystalline elastomers (LCEs) based on a two-stage thiol–acrylate Michael addition and photopolymerization (TAMAP) reaction. This methodology can be used to program permanently-aligned monodomain samples capable of “hands-free” shape switching as well as offer spatio-temporal control over liquid-crystalline behaviour. LCE networks were shown to have a cytocompatible response at both stages of the reaction.

Nucleus replacement device failure: a case report and biomechanical study.

Study Design. Case report and biomechanical study. Objective. The objectives of this study were to report on a single case of a failed nucleus replacement device and to test the biomechanical properties of the failed device. Summary of Background Data. The use of spine arthroplasty techniques in the treatment of degenerative disc disease is becoming a popular alternative to spinal fusion and discectomy. Nucleus replacement is an emerging surgical treatment that is in the early stages of development. Methods. A 36-year-old woman presented to our institution with excruciating low back pain 15 months after receiving a prosthetic disc nucleus (PDN; Raymedica, Inc.) at L5–S1 as part of an IDE clinical trial. A computed tomography scan showed subsidence of the PDN into the endplates and asymmetric collapse of the L5–S1 disc space. The patient underwent surgery for removal of the device and fusion of L5–S1. After removal, the nucleus replacement device underwent micro-computed tomography imaging and was tested in unconfined and confined compression. Results. The density of the inner core of the PDN was estimated to be 105 g/cm3. Compression testing revealed that the stiffness of the PDN was grossly elevated in comparison to previously published values for human lumbar nuclei and other candidate nucleus replacement hydrogels. The linear-region modulus values were 0.94 MPa for unconfined compression and 32.4 MPa for confined compression. Conclusion. The PDN device excised from this patient failed to reproduce the function of a healthy nucleus. Because preoperative mechanical values were not available for this device, it is difficult to know if the PDN was abnormally stiff at implantation or if it became increasingly stiff after implantation. Whether this was a result of manufacturing, the patients biologic response to the PDN, or some yet unknown contraindication to PDN placement in this specific patient is unclear.

Synthesis of Programmable Main-chain Liquid-crystalline Elastomers Using a Two-stage Thiol-acrylate Reaction.

This study presents a novel two-stage thiol-acrylate Michael addition-photopolymerization (TAMAP) reaction to prepare main-chain liquid-crystalline elastomers (LCEs) with facile control over network structure and programming of an aligned monodomain. Tailored LCE networks were synthesized using routine mixing of commercially available starting materials and pouring monomer solutions into molds to cure. An initial polydomain LCE network is formed via a self-limiting thiol-acrylate Michael-addition reaction. Strain-to-failure and glass transition behavior were investigated as a function of crosslinking monomer, pentaerythritol tetrakis(3-mercaptopropionate) (PETMP). An example non-stoichiometric system of 15 mol% PETMP thiol groups and an excess of 15 mol% acrylate groups was used to demonstrate the robust nature of the material. The LCE formed an aligned and transparent monodomain when stretched, with a maximum failure strain over 600%. Stretched LCE samples were able to demonstrate both stress-driven thermal actuation when held under a constant bias stress or the shape-memory effect when stretched and unloaded. A permanently programmed monodomain was achieved via a second-stage photopolymerization reaction of the excess acrylate groups when the sample was in the stretched state. LCE samples were photo-cured and programmed at 100%, 200%, 300%, and 400% strain, with all samples demonstrating over 90% shape fixity when unloaded. The magnitude of total stress-free actuation increased from 35% to 115% with increased programming strain. Overall, the two-stage TAMAP methodology is presented as a powerful tool to prepare main-chain LCE systems and explore structure-property-performance relationships in these fascinating stimuli-sensitive materials.

Combined, independent small molecule release and shape memory via nanogel-coated thiourethane polymer networks

Drug releasing shape memory polymers (SMPs) were prepared from poly(thiourethane) networks that were coated with drug loaded nanogels through a UV initiated, surface mediated crosslinking reaction. Multifunctional thiol and isocyanate monomers were crosslinked through a step-growth mechanism to produce polymers with a homogeneous network structure that exhibited a sharp glass transition with 97% strain recovery and 96% shape fixity. Incorporating a small stoichiometric excess of thiol groups left pendant functionality for a surface coating reaction. Nanogels with diameter of approximately 10 nm bearing allyl and methacrylate groups were prepared separately via solution free radical polymerization. Coatings with thickness of 10-30 μm were formed via dip-coating and subsequent UV-initiated thiol-ene crosslinking between the SMP surface and the nanogel, and through inter-nanogel methacrylate homopolymerization. No significant change in mechanical properties or shape memory behavior was observed after the coating process, indicating that functional coatings can be integrated into an SMP without altering its original performance. Drug bioactivity was confirmed via in vitro culturing of human mesenchymal stem cells with SMPs coated with dexamethasone-loaded nanogels. This article offers a new strategy to independently tune multiple functions on a single polymeric device, and has broad application toward implantable, minimally invasive medical devices such as vascular stents and ocular shunts, where local drug release can greatly prolong device function.

Cell-penetrating peptide CGKRK mediates efficient and widespread targeting of bladder mucosa following focal injury

The bladder presents an attractive target for topical drug delivery. The barrier function of the bladder mucosa (urothelium) presents a penetration challenge for small molecules and nanoparticles. We found that focal mechanical injury of the urothelium greatly enhances the binding and penetration of intravesically-administered cell-penetrating peptide CGKRK (Cys-Gly-Lys-Arg-Lys). Notably, the CGKRK bound to the entire urothelium, and the peptide was able to penetrate into the muscular layer. This phenomenon was not dependent on intravesical bleeding and was not caused by an inflammatory response. CGKRK also efficiently penetrated the urothelium after disruption of the mucosa with ethanol, suggesting that loss of barrier function is a prerequisite for widespread binding and penetration. We further demonstrate that the ability of CGKRK to efficiently bind and penetrate the urothelium can be applied toward mucosal targeting of CGKRK-conjugated nanogels to enable efficient and widespread delivery of a model payload (rhodamine) to the bladder mucosa.

Thiol-functionalized nanogels as reactive plasticizers for crosslinked polymer networks

Significant efforts have been expended to mitigate plasticizer migration from crosslinked methacrylic and poly(vinyl chloride) polymer networks by synthesizing reactive plasticizers that can blend homogenously within the networks to reduce polymer property change, acute toxicity and downstream environmental effects of plasticizer migration with limited and varying amount of success. We hypothesized that appropriate thiol-functionalized nanogels synthesized using the same monomers as the parent network to generate highly compact, crosslinked structures will form thermally stable, homogenous networks and perform as optimal reactive plasticizers. Nanogels were synthesized via a thiol-Michael addition solution polymerization and incorporated at different mass ratios within a polyethylene glycol 400 urethane dimethacrylic monomer to form photo-crosslinked networks. While maintaining the inherent hydrolytic stability, thermal stability and biocompatibility of the parent matrix at ~99% acrylic group conversion, the PEG400 urethane dimethacrylic -nanogel networks retained optical clarity with >90% visible light transmission at 20wt% nanogel concentration within the matrix. The addition of the nanogels also enhanced the elongation of the parent matrix by up to 320%, while a 37°C reduction in glass transition temperature (∆Tg) and ≥50% reduction in modulus was observed. A 52% reduction in the shrinkage stress of the material was also noted. The results indicate that the application of thiol-functionalized nanogels as plasticizers to alter the bulk properties of the parent matrix while mitigating plasticizer migration by covalently crosslinking the nanogels within the polymer matrix provides a simple yet efficient technique to generate network-specific plasticizers with the ability to alter targeted properties within polymers.

Photopolymerization kinetics of methyl methacrylate with reactive and inert nanogels

The enhanced in situ photopolymerization kinetics of methyl methacrylate (MMA) to poly(methyl methacrylate) (PMMA) through the incorporation of both inert and reactive nanogel (NG) fillers under ambient conditions has been demonstrated. In addition to the polymerization kinetics, the physical and chemical properties of the prepolymeric NG were also utilized to tune the thermoplasticity and mechanical properties of the PMMA polymer network. The protocol followed in this study imparts superior MMA photopolymerization kinetics (≥ 60% double-bond conversion within 15 min for > 35 wt% nanogel loadings and ≥ 95% double-bond conversion in < 60 min for all NG concentrations) when compared with traditional polymerization mechanisms. PMMA remained a glassy material following the incorporation of both inert and reactive NG as demonstrated by the glass transition temperature (Tg) of the ultimate networks. Network linearity is uncompromised following incorporation of inert NG additives, thereby preserving the thermoplasticity of the PMMA network. As the non-functionalized, inert NG content increases, the maintenance of thermoplasticity occurs at the expense of mechanical properties (10× reduction of maximum strength at 25 wt% loading). These effects are less pronounced when reactive nanogels are employed (no significant reduction of maximum strength at 25 wt% loading with minimal crosslinking). The incorporation of NGs enable high chemical tunability within linear polymer networks. Given the wide range of monomers available for the synthesis of NGs, the methodology detailed in this study offers a scheme for the optimization of linear networks for specific targeted applications, hitherto deemed unrealistic under established polymerization protocols.

Holographic recording in two-stage networks

We demonstrate holography in a traditional two-component holographic photopolymer in which the solid polymer host matrix has three distinct sets of material properties: 1) an initially liquid state appropriate for formulation and casting into the desired final shape, 2) a rubbery state with low glass transition temperature appropriate for holographic recording, and 3) a final higher modulus state with improved mechanical robustness. The general chemical scheme is to form the second stage rubbery polymer network via a thiol-acrylate Michael addition with an excess of one functional group. Holographic recording then takes place via radically initiated photopolymerization of a mobile high refractive index monomer, per the common two-chemistry process. During final flood illumination of the material, the remaining monomer and excess functional groups are polymerized to increase crosslink density and improve the mechanical properties of the matrix. We described three such material schemes and report general trends. We demonstrate high (96%) efficiency holographic recording, low (1.1%) shrinkage, no oxygen sensitivity and stage 2 glass transition temperatures at or above room temperature, sufficient to enable self-supporting films.

Use of Cardiac Phase-Contrast MRI to Examine Hemodynamics and Wall Deformation Within the Aortic Root for Patients With Bicuspid Aortic Valves

As the most common congenital heart defect, bicuspid aortic valve (BAV) occurs in 1–2 % of the population and has been associated with serious complications such as aortic valve dysfunction, infective endocarditis, aortic dilatation, aortic aneurysm, and aortic dissection [1, 2]. While the pathogenesis of this valve malformation has been postulated to be genetic, the resulting vascular environment and abnormal hemodynamics are hypothesized to contribute to the progression of the disease and its subsequently high morbidity and mortality (greater than 33% of patients with BAV develop serious complications from the disease) [1]. However, clinical details supporting the causality between altered local blood flow dynamics and development of structural abnormality at the aortic root are still lacking.Copyright