Background: Early cranioplasty after decompressive craniectomy (DC) for moderate-to-severe traumatic brain injury (TBI) improves functional recovery. However, patient candidacy is limited by persistent brain swelling, soft-tissue inflammation, and fibrotic wound remodeling. Zwitterion (ZI) hydrogels exhibit antifouling and anti-inflammatory properties that may improve the DC wound microenvironment. We hypothesize that ZI hydrogel application at the DC site attenuates TBI-associated biomarkers and improves motor recovery in rodents. Methods: Adult CD1 mice were randomized to sham, TBI, TBI/DC, or TBI/DC/ZI hydrogel (hereafter referred to as ZI hydrogel) groups to quantify serum GFAP, NfL, and UCH-L1 by ELISA at 24 hours. Adult Long Evans rats underwent the same interventions to assess ZI-dependent motor recovery using beam-walk time and limb slips normalized to baseline at days 7 and 14. Results: TBI significantly elevated serum GFAP and UCH-L1 versus sham ( P = .0014 and .0471). Both TBI/DC and ZI hydrogel normalized GFAP, NfL, and UCH-L1 to sham-comparable levels; however, only ZI hydrogel significantly reduced NfL ( P = .0256) and UCH-L1 ( P = .0200) versus TBI/DC. Beam-walk testing showed no significant post-TBI motor deterioration in ZI hydrogel rats, whereas TBI/DC rats exhibited persistent deficits in crossing time and limb slips at days 7 and 14. Conclusions: ZI hydrogel application at the time of DC reduced TBI-specific serum biomarkers and improved motor recovery in a rodent moderate-to-severe TBI model. These findings support further investigation of ZI hydrogels as adjunctive therapy to attenuate neuroinflammation and facilitate earlier, safer cranioplasty after DC.

Cochlear implants (CIs) have revolutionized the treatment of sensorineural hearing loss, yet patient outcomes remain highly variable due to biological responses within the cochlea. A critical challenge is the foreign body response (FBR) triggered by CI biomaterials, which can lead to inflammation, fibrosis, and increased electrode impedance, ultimately impairing auditory function. Zwitterionic hydrogels have been shown to provide a highly lubricious anti-fouling surface that minimizes protein and cell adsorption. This study evaluates a carboxybetaine methacrylate (CBMA) zwitterionic hydrogel coating to reduce the FBR to cochlear implants. Using a large animal (sheep) model, human CI electrode arrays were coated with a thin film CBMA hydrogel via one step UV photografting and photopolymerization with a custom mold. Electrophysiological measurements at the time of implantation demonstrate significantly reduced total impedance, polarization impedance, and access resistance in CBMA-coated CIs. Reductions in total impedance and access resistance were maintained after 4 weeks in vivo. High-resolution Xray Microscopy imaging confirmed intracochlear placement without translocation or tip fold-over and a trend to reduced neoossification in CBMA-coated implants. Histological analysis revealed significantly decreased cellular infiltration, macrophage infiltration, and fibrotic tissue deposition within the cochlea surrounding CBMA-coated implants compared to uncoated controls. This work highlights the potential of durable thin film zwitterionic coatings to enhance CI performance and preserve residual hearing by mitigating insertional trauma and attenuating chronic inflammation and fibrosis.

Light-induced NMP 2 initiators reversibly activate-deactivate carbon radicals, enabling pseudo-first order hexyl acrylate polymerization with up to 9-fold molecular weight enhancement.

Objective:To determine the effects of zwitterionic hydrogel films on mucus contact angles, flow, and stasis with respect to medical polymer surfaces, both flat and tubular. Methods:A zwitterionic hydrogel thin film was photografted onto medical rubber surfaces and compared against non-zwitterionic hydrogel thin films and untreated surfaces to determine its impact on mucus contact angles, mucus flow on sheets and tubes, and mucus plugging. Results:Zwitterionic and conventional hydrogel films significantly reduce the mucus contact angles and the tilt required to initiate mucus flow on sheets and in tubular systems. Preliminary experiments show that these films may also shorten the time required for a mucus-plugged tube to unplug when exposed to saline. Conclusion:Zwitterionic and conventional hydrogel films on typical medical surfaces reduce resistance to mucus flow, increase mucus discharge, and may facilitate faster unplugging of dried mucus. These effects are the most pronounced on tubes of larger inner diameter (greater than 2.6 mm) and tend to dissipate for tubes of smaller diameter. These results may help guide future improvements to medical tubes intended to discharge mucus and ventilate, resulting in fewer complications for patients. Level of Evidence:Level 2, randomized individual trial.

Chondrogenic differentiation of mesenchymal stem cells (MSCs) within a three-dimensional (3D) environment can be guided to form cartilage-like tissue in vitro to generate cartilage grafts for implantation. 3D bioprinted, MSC-populated cartilage grafts have the potential to replace autologous cartilage in reconstructive airway surgery. Here, bone marrow-derived ferret MSCs (fMSCs) capable of directed musculoskeletal differentiation were generated for the first time. A multi-material, 3D bioprinted fMSC-laden scaffold was then engineered that was capable of in vitro cartilage regeneration, as evidenced by glycosaminoglycan (GAG) production and collagen II immunohistochemical staining. In vivo implantation of these 3D bioprinted scaffolds in a ferret model of laryngotracheal reconstruction (LTR) demonstrated healing of the defect site, epithelial mucosalization of the inner lumen, and expansion of the airway volume. While the implanted scaffold allowed for reconstruction of the created airway defect, minimal chondrocytes were identified at the implant site. Nevertheless, we have established the ferret as a biomedical research model for airway reconstruction and, although further evaluation is warranted, the generation of fMSCs provides an opportunity for realizing the potential for 3D bioprinted regenerative stem cell platforms in the ferret.

Cochlear implants (CIs) provide auditory perception to those with profound sensorineural hearing loss: however, the quality of sound perceived by a CI user does not approximate natural hearing. This limitation is due in part to the large physical gap between the stimulating electrodes and their target neurons. Therefore, directing the controlled outgrowth of processes from spiral ganglion neurons (SGNs) into close proximity to the electrode array could provide significantly increased hearing function. For this objective to be properly designed and implemented, the ability and limits of SGN neurites to be guided must first be determined. In this work, we engineered precise topographical microfeatures with angle turn challenges of various geometries to study SGN pathfinding. Additionally, we analyze sensory neurite growth in response to topographically patterned substrates and use live imaging to better understand how neurite growth is guided by these cues. In assessing the ability of neurites to sense and turn in response to topographical cues, we find that the geometry of the angled microfeatures determines the ability of neurites to navigate the angled microfeature turns. SGN neurite pathfinding fidelity can be increased by 20-70% through minor increases in microfeature amplitude (depth) and by 25% if the angle of the patterned turn is made more obtuse. Further, by using engineered topographies and live imaging of dorsal root ganglion neurons (DRGNs), we see that DRGN growth cones change their morphology and migration to become more elongated within microfeatures. However, our observations also indicate complexities in studying neurite turning. First, as the growth cone pathfinds in response to the various cues, the associated neurite often reorients across the angle topographical microfeatures. This reorientation is likely related to the tension the neurite shaft experiences when the growth cone elongates in the microfeature around a turn. Additionally, neurite branching is observed in response to topographical guidance cues, most frequently when turning decisions are most uncertain. Overall, the multi-angle channel micropatterned substrate is a versatile and efficient system to assess SGN neurite turning and pathfinding in response to topographical cues. These findings represent fundamental principles of neurite pathfinding that will be essential to consider for the design of 3D systems aiming to guide neurite growth in vivo.

Utilizing self-assembled lyotropic liquid crystal (LLC) templates with radical photopolymerization shows promise in controlling polymer structure on the nanometer scale This control of nanostructure allows tailoring and enhancement of material properties not attainable in traditional polymerization in applications including hydrogels and stimuli-responsive systems. However, thermodynamically driven phase separation between the polymer and LLC templates often hinders the control of local polymer order and resultant polymer properties. This study investigates an alternative method to control the hydrogel nanostructure and avoid phase separation using imidazolium ionic liquids (ILs) in the LLC template while modulating the light intensity used in photopolymerization. The addition of the IL improves the thermodynamic stability and enhances the polymerization rate in the LLC system. The degree of LLC nanostructure retention is increased by increasing light intensities during polymerization. In addition, intermediate concentrations of cross-linker allow a balance between phase stability and cross-linking to lock in LLC morphology. With enhanced retention, the maximum water uptake is significantly higher compared with isotropic controls. These results demonstrate a method to increase the structure on the nanometer scale of a polymer by combining the addition of ILs with the proper selection of light intensity and cross-link density that allows access to unique hydrogel properties. These templated polymers demonstrate enhanced swelling and a stimuli response that show promise in applications ranging from drug delivery to water remediation.

Directing self-assembly of photopolymerizable systems is advantageous for controlling polymer nanostructure and material properties, but developing techniques for inducing ordered structure remains challenging. In this work, well-defined diblock or random copolymers were incorporated into cationic photopolymerizable epoxy systems to investigate the impact of copolymer architecture on self-assembly and phase separated nanostructures. Copolymers consisting of poly(hydroxyethyl acrylate)-x-(butyl acrylate) were prepared using photoiniferter polymerization to control functional group placement and molecular weight/polydispersity. Prepolymer configuration and concentration induced distinctly different effects on the resin flow and photopolymerization kinetics. The diblock copolymer self-assembled into nanostructured phases within the resin matrix, whereas the random copolymer formed an isotropic mixture. Rapid photopolymerization and ambient temperature conditions during cure facilitated retention of the self-assembled phases, leading to considerably different composite morphology and thermomechanical behavior. Increased loading of the diblock copolymer induced long-range ordered cocontinuous structures. Even with nearly identical prepolymer composition, controlled nanophase separation resulted in significantly enhanced tensile properties relative to those of the isotropic system. This work demonstrates that controlling phase separation with a block copolymer architecture allows access to nanostructured photopolymers with unique and enhanced properties.

Micro and nanoscale patterning of surface features and biochemical cues have emerged as tools to precisely direct neurite growth into close proximity with next generation neural prosthesis electrodes. Biophysical cues can exert greater influence on neurite pathfinding compared to the more well studied biochemical cues; yet the signaling events underlying the ability of growth cones to respond to these microfeatures remain obscure. Intracellular Ca2+ signaling plays a critical role in how a growth cone senses and grows in response to various cues (biophysical features, repulsive peptides, chemo-attractive gradients). Here, we investigate the role of inositol triphosphate (IP3) and ryanodine-sensitive receptor (RyR) signaling as sensory neurons (spiral ganglion neurons, SGNs, and dorsal root ganglion neurons, DRGNs) pathfind in response to micropatterned substrates of varied geometries. We find that IP3 and RyR signaling act in the growth cone as they navigate biophysical cues and enable proper guidance to biophysical, chemo-permissive, and chemo-repulsive micropatterns. In response to complex micropatterned geometries, RyR signaling appears to halt growth in response to both topographical features and chemo-repulsive cues. IP3 signaling appears to play a more complex role, as growth cones appear to sense the microfeatures in the presence of xestospongin C but are unable to coordinate turning in response to them. Overall, key Ca2+ signaling elements, IP3 and RyR, are found to be essential for SGNs to pathfind in response to engineered biophysical and biochemical cues. These findings inform efforts to precisely guide neurite regeneration for improved neural prosthesis function, including cochlear implants.

Hybrid formulation chemistry was used to internally control the reaction rate differences between radical and cationic photopolymerizations leading to a tailorable array of polymer morphologies and mechanical properties.

Due to mild conditions and straightforward synthetic routes, photoiniferter polymerization has received increasing use as a facile method for preparation of polymers with highly controlled structure. However, low quantum yields inherent to thiocarbonylthio species result in polymerization speeds that are considerably slower than traditional controlled radical polymerization techniques. To improve polymerization speed while maintaining high level control, it is critical to understand relationships between reaction parameters and ultimate polymer structure. In this work, initiating light intensity, reactant concentration, and monomer pendant groups were manipulated in the photoiniferter polymerization of acrylate monomers to explore the effect of these conditions on reaction kinetics and molecular weight control. Polymerization rate of n-butyl acrylate was significantly enhanced by increasing light intensity rivaling speeds of conventional thermally initiated RAFT polymerization while enabling more precise control over molecular weight. Interestingly, photoiniferter rate asymptotically approached saturation at relatively high light intensities. Moreover, degradation of trithiocarbonate species occurred at greater intensities, ultimately resulting in moderate increases in molecular weight. Increased reactant concentration enabled faster rates with bulk polymerization, possibly due to reduced macro radical mobility and termination. Additionally, comparing photoiniferter polymerization of methyl acrylate and hydroxyethyl acrylate showed that greater polarity considerably enhanced polymerization speeds. Finally, the utility of precisely controlling polymer structure was demonstrated by synthesizing and incorporating a series of amphiphilic block copolymers with increasing molecular weight into a photocurable epoxy resin. The well-defined block copolymer structures enabled controllable phase separation and thermomechanical properties in epoxy composites. This work showed that photoiniferter polymerization speeds could be significantly enhanced using elementary reaction conditions, and that these conditions enable facile production of well-defined copolymers allowing tailored composite morphology and properties.

The durability of photografted zwitterionic hydrogel coatings on cochlear implant biomaterials was examined to determine the viability of these antifouling surfaces during insertion and long-term implant usage. Tribometry was used to determine the effect of zwitterionic coatings on the lubricity of surfaces with varying hydration levels, applied normal force, and time frame. Additionally, flexural resistance was investigated using mandrel bending. Ex vivo durability was assessed by determining the coefficient of friction between tissues and treated surfaces. Furthermore, cochlear implantation force was measured using cadaveric human cochleae. Hydrated zwitterionic hydrogel coatings reduced frictional resistance approximately 20-fold compared to uncoated PDMS, which led to significantly lower mean force experienced by coated cochlear implants during insertion compared to uncoated systems. Under flexural force, zwitterionic films resisted failure for up to 60 min of desiccation. The large increase in lubricity was maintained for 20 h under continual force while hydrated. For loosely cross-linked systems, films remained stable and lubricious even after rehydration following complete drying. All coatings remained hydrated and functional under frictional force for at least 30 min in ambient conditions allowing drying, with lower cross-link densities showing the greatest longevity. Moreover, photografted zwitterionic hydrogel samples showed no evidence of degradation and nearly identical lubricity before and after implantation. This work demonstrates that photografted zwitterionic hydrogel coatings are sufficiently durable to maintain viability before, during, and after implantation. Mechanical properties, including greatly increased lubricity, are preserved after complete drying and rehydration for various applied forces. Additionally, this significantly enhanced lubricity translates to significantly decreased force during insertion of implants which should result in less trauma and scarring.

Correction for ‘Controlling phase separated domains in UV-curable formulations with OH-functionalized prepolymers’ by Erion Hasa et al., Polym. Chem., 2022, 13, 3102–3115, https://doi.org/10.1039/D2PY00159D.

Dentin biomodification is a promising approach to enhance dental tissue biomechanics and biostability for restorative and reparative therapies. One of the most active dentin tissue biomodifiers is proanthocyanidin (PAC)-rich natural extracts, which are used in the dental bonding procedure in combination with resin-based adhesives (RBAs). This study aimed to investigate the use of mesoporous silica nanoparticles (MSNs) for the sustained delivery of PACs for dentin biomodification as a novel drug-delivery system for dental applications. The effects of the incorporation of MSN functionalized with 3-aminopropyltriethoxysilane (APTES) and loaded with PAC into an experimental RBA were assessed by characterizing the material mechanical properties. In addition, the immediate and long-term bonding performance of an experimental resin-based primer (RBP) containing MSN-APTES loaded with PAC was also evaluated. For that, different formulations of RBA and RBP were prepared containing 20% w/v MSN-APTES loaded with PAC before or after functionalization (MSN-PAC-APTES and MSN-APTES-PAC, respectively). The incorporation of MSN-APTES-PAC did not negatively impact the degree of conversion or the overall mechanical properties of the RBA. However, adding MSN-PAC-APTES resulted in inferior mechanical properties of the experimental RBA. In the adhesion studies, APTES-functionalized MSN was successfully added to an experimental RBP for drug-delivery purposes without compromising the bond strength to the dentin or the failure mode. Interestingly, the sequence of surface functionalization with APTES resulted in differences in the bonding performance, with better long-term results for RBP containing MSN loaded with PAC after functionalization.

Reversible addition-fragmentation chain transfer (RAFT) processes in polymer systems have shown great utility in controlling radical polymerizations. Due to the reversible chain transfer mechanism, RAFT agents have been extensively used to synthesize monodisperse linear polymers and block copolymers in solution or emulsion polymerization. On the other hand, little is known about the effects of RAFT agents on the polymerization kinetics and thermo-mechanical properties of cross-linked materials. This work investigates the effect of RAFT agents on photopolymerization behavior and ultimate polymer properties in urethane acrylate systems. Our results indicate that RAFT agent addition has a significantly different impact on network development depending on inherent system characteristics, i.e., systems with glass transition temperature (Tg) below room temperature (LT) or those with Tg above room temperature (HT). When polymerizing with RAFT agents, photopolymerization rate decreases and can be tuned using different concentrations of RAFT agent. The final materials also show increased elongation at break with decreased Young's modulus. However, ultimate thermo-mechanical behavior and mechanical properties are different based on Tg. With RAFT addition decreased Tg is observed from HT polyurethane networks. Tensile toughness is also doubled in comparison to neat HT films. On the other hand, although the Tg of RAFT modified LT polyurethane networks does not change significantly, toughness of the final polymer films varies significantly with RAFT agent concentration. Enhanced toughness is only observed from films with low RAFT agent concentration while toughness decreases with higher loading of RAFT agent. These results demonstrate that the polymer network and thermo-mechanical properties can be modified by introducing RAFT agent which enables dynamic polymer chain rearrangements in both LT- and HT-acrylate network systems.

Modification of photocurable radical systems with high molecular weight prepolymers enables access to a wide array of polymer structures and properties.

Free radical polymerizations have been widely used for a variety of applications, including coating, packaging, adhesives, inks and dental materials. However, shrinkage stress in network systems due to volumetric shrinkage during polymerization often results in poor mechanical performance of final materials, often limiting end use. Delaying gelation during polymerization while incorporating functional structure or functionalized groups into the polymer networks may lead to significantly reduced shrinkage stress and, consequently, enhanced thermomechanical properties. In this review, we summarize several practical methods, including thiol-ene radical polymerization, addition-fragmentation chain transfer, controlled radical polymerization, covalent adaptable networks, ring-opening polymerization and cyclopolymerization, that have shown promise in reducing volumetric shrinkage and associated stress in network-forming systems. The resulting enhanced (thermo)mechanical material properties of these modified polymers are also introduced. These methods have proven to be powerful tools for fabricating polymers with novel functionality and properties and thereby show potential to expand application of free radical thermoset materials. (c) 2021 Society of Industrial Chemistry.

Correction for 'Controlling phase separated domains in UV-curable formulations with OH-functionalized prepolymers' by Erion Hasa et al., Polym. Chem., 2022, 13, 3102-3115, https://doi.org/10.1039/D2PY00159D.

Zwitterionic polymer networks have shown promise in reducing the short- and long-term inflammatory foreign body response to implanted biomaterials by combining the antifouling properties of zwitterionic polymers with the mechanical stability provided by cross-linking. Cross-link density directly modulates mechanical properties (i.e., swelling behavior, resistance to stress and strain, and lubricity) but theoretically could reduce desirable biological properties (i.e., antifouling) of zwitterionic materials. This work examined the effect of varying poly(ethylene glycol) dimethacrylate cross-linker concentration on protein adsorption, cell adhesion, equilibrium swelling, compressive modulus, and lubricity of zwitterionic thin films. Furthermore, this work aimed to determine the appropriate balance among each of these mechanical and biologic properties to produce thin films that are strong, durable, and lubricious, yet also able to resist biofouling. The results demonstrated nearly a 20-fold reduction in fibrinogen adsorption on zwitterionic thin films photografted on polydimethylsiloxane (PDMS) across a wide range of cross-link densities. Interestingly, either at high or low cross-link densities, increased levels of protein adsorption were observed. In addition to fibrinogen, macrophage and fibroblast cell adhesion was reduced significantly on zwitterionic thin films, with a large range of cross-link densities, resulting in low cell counts. The macrophage count was reduced by 30-fold, while the fibroblast count was reduced nearly 10-fold on grafted zwitterionic films relative to uncoated films. Increasing degrees of cell adhesion were noted as the cross-linker concentration exceeded 50%. As expected, increased cross-link density resulted in a reduced swelling but greater compressive modulus. Notably, the coefficient of friction was dramatically reduced for zwitterionic thin films compared to uncoated PDMS across a broad range of cross-link densities, an attractive property for insertional implants. This work identified a broad range of cross-link densities that provide desirable antifouling effects while also maintaining the mechanical functionality of the thin films.

Due to its attractive mechanical properties and biocompatibility, poly(dimethyl)siloxane (PDMS) is widely used in the fabrication of biomedical materials. On the other hand, PDMS is also prone to adsorption of both proteins and bacteria, making PDMS implants susceptible to infection. Herein, we examine the use of durably cross-linked zwitterionic coatings for PDMS surfaces to mitigate bacterial adhesion. Using a single-step photografting technique, poly(sulfobetaine methacrylate) (pSBMA) and poly(carboxybetaine methacrylate) (pCBMA) thin films were covalently attached to PDMS substrates. The abilities of these coatings to resist the adhesion of Staphylococcus aureus and Staphylococcus epidermidis were tested in vitro under both wet and droplet conditions, as well as in subcutaneous and transcutaneous implantation models using Sprague-Dawley rats. Zwitterionic thin films effectively reduced bacterial adhesion in both in vitro and in vivo conditions. This was particularly true for pCBMA-coated materials, which exhibited significant reduction in bacterial adhesion and growth with respect to S. aureus and S. epidermidis for all in vitro conditions as well as the ability to resist bacterial growth on PDMS implants. The results of this study suggest that a simple and durable photografting process can be used to produce polymer thin films capable of preventing infection of implantable medical devices.