Hysteresis-free and high sensitivity strain sensing of ionically conductive hydrogels.

Hydrogels are promising materials for soft and implantable strain sensors owing to their large compliance (E<100 kPa) and significant extensibility (εmax >500%) compared to other polymer networks. Further, hydrogels can be functionalized to seamlessly integrate with many types of tissues. However, most current methods attempt to imbue additional electronic functionality to structural hydrogel materials by incorporating fillers with orthogonal properties such as electronic or mixed ionic conduction. Although composite strategies may improve performance or facilitate heterogeneous integration with downstream hardware, composites complicate the path for regulatory approval and may compromise the otherwise compelling properties of the underlying structural material. Here we report hydrogel strain sensors composed of genipin-crosslinked gelatin and dopamine-functionalized poly(ethylene glycol) for in vivo monitoring of cardiac function. By measuring their impedance only in their resistive regime (>10 kHz), hysteresis is reduced and the resulting gauge factor is increased by ~50x to 1.02±0.05 and 1.46±0.05 from approximately 0.03-0.05 for PEG-Dopa and genipin-crosslinked gelatin respectively. Adhesion and in vivo biocompatibility are studied to support implementation of strain sensors for monitoring cardiac output in porcine models. Impedance-based strain sensing in the kilohertz regime simplifies the piezoresistive behavior of these materials and expands the range of hydrogel-based strain sensors.

Recent Progress in Materials Chemistry to Advance Flexible Bioelectronics in Medicine.

Designing bioelectronic devices that seamlessly integrate with the human body is a technological pursuit of great importance. Bioelectronic medical devices that reliably and chronically interface with the body can advance neuroscience, health monitoring, diagnostics, and therapeutics. Recent major efforts focus on investigating strategies to fabricate flexible, stretchable, and soft electronic devices, and advances in materials chemistry have emerged as fundamental to the creation of the next generation of bioelectronics. This review summarizes contemporary advances and forthcoming technical challenges related to three principal components of bioelectronic devices: i) substrates and structural materials, ii) barrier and encapsulation materials, and iii) conductive materials. Through notable illustrations from the literature, integration and device fabrication strategies and associated challenges for each material class are highlighted.

Control Release and Diffusion-Reaction Kinetics of Genipin-Eluting Fibers Using an in Vitro Aneurysm Flow Model.

The minimally invasive treatment of intracranial aneurysms by endovascular coiling is attractive yet faces challenges related to the degradation of fibrin clots in the aneurysm sac over time. Fibrin gels cross-linked with genipin exhibit enhanced mechanical and chemical stability, but there are many unknowns related to best practices for delivery from endovascular devices and subsequent integration of cross-linkers with the nascent clot. Here, we describe the in vitro characterization of genipin-eluting polymer fibers prepared by coextrusion with poly(ethylene-co-vinyl acetate). Genipin incorporation and release from these fibers are characterized by various gravimetric and spectroscopic techniques. Genipin release adheres to Higuchi kinetics with Higuchi constants varying between (2.44 ± 0.83) × 10-7 and (8.41 ± 0.82) × 10-7 mol·h-0.5 depending on genipin loading and vinyl acetate concentration in the polymer matrix. The diffusion-reaction kinetics of genipin released from polymeric fibers within fibrin hydrogels was investigated using an in vitro aneurysm flow model. Spatiotemporal maps of genipin cross-linking density in fibrin gels produced by absorbance measurements suggest that genipin cross-link concentrations up to 9,993.87 ± 909.01 µM can be achieved. This work describes relevant diffusion-reaction parameters of genipin in fibrin gels and establishes the viability of genipin-eluting fibers as a platform for improving endovascular embolization of intracranial aneurysms.

Hydrogel-based electrodes for selective cervical vagus nerve stimulation.

Objective.Electrical vagus nerve stimulation (VNS) has the potential to treat a wide variety of diseases by modulating afferent and efferent communication to the heart, lungs, esophagus, stomach, and intestines. Although distal vagal nerve branches, close to end organs, could provide a selective therapeutic approach, these locations are often surgically inaccessible. In contrast, the cervical vagus nerve has been targeted for decades using surgically implantable helix electrodes to treat epileptic seizures and depression; however, to date, clinical implementation of VNS has relied on an electrode with contacts that fully wrap around the nerve, producing non-selective activation of the entire nerve. Here we demonstrate selective cervical VNS using cuff electrodes with multiple contacts around the nerve circumference to target different functional pathways.Approach.These flexible probes were adjusted to the diameter of the nerve using an adhesive hydrogel wrap to create a robust electrode interface. Our approach was verified in a rat model by demonstrating that cervical VNS produces neural activity in the abdominal vagus nerve while limiting effects on the cardiovascular system (i.e. changes in heart rate or blood pressure).Main results.This study demonstrates the potential for selective cervical VNS as a therapeutic approach for modulating distal nerve branches while reducing off target effects.Significance.This methodology could potentially be refined to treat gastrointestinal, metabolic, inflammatory, cardiovascular, and respiratory diseases amenable to vagal neuromodulatory control.

Electrochemical-Mediated Gelation Of Catechol-Bearing Hydrogels Based On Multimodal Crosslinking.

Catechol-bearing polymers form hydrogel networks through cooperative oxidative crosslinking and coordination chemistry. Here we describe the kinetics of cation-dependent electrochemical-mediated gelation of precursor solutions composed of catechol functionalized four-arm poly(ethylene glycol) combined with select metal cations. The gelation kinetics, mechanical properties, crosslink composition, and self-healing capacity is a strong function of the valency and redox potential of metal ions in the precursor solution. Catechol-bearing hydrogels exhibit highly compliant mechanical properties with storage moduli ranging from G' = 0.1-5 kPa depending on the choice of redox active metal ions in the precursor solution. The gelation kinetics is informed by the net cell potential of redox active components in the precursor solution. Finally, redox potential of the metal ion precursor can differentially alter the effective density of crosslinks in networks and confer properties to hydrogels such as self-healing capacity. Taken together, this parametric study generates new insight to inform the design of catechol-bearing hydrogel networks formed by electrochemical-mediated multimodal crosslinking.

Controlled release of collagen-binding SDF-1α from the collagen scaffold promoted tendon regeneration in a rat Achilles tendon defect model.

It had been demonstrated that stromal cell-derived factor-1α (SDF-1α) could promote in situ tendon regeneration by recruiting endogenous cells. However, native SDF-1α diffuses too fast in vivo, reducing its local concentration and efficacy. In this study, we prepared a recombinant SDF-1α containing a collagen-binding domain (CBD-SDF-1α) and developed a functional collagen scaffold by tethering CBD-SDF-1α on the collagen scaffold for in situ tendon regeneration. CBD-SDF-1α could induce the migration of mesenchymal stem cells, dermal fibroblasts and Achilles tendon fibroblasts in vitro, and achieve controlled release from the collagen scaffold. In a rat Achilles tendon defect model, the functional scaffold could increase the recruitment of CXCR4 positive fibroblast-like cells and the deposition of Tenascin-C at 7 days after implantation. After 4 and 12 weeks, the functional collagen scaffold could promote the expression of type I collagen, increase the diameters of collagen fibrils and improve the mechanical properties of regenerated tendons. Hence, the functional scaffold increased the efficacy of tendon regeneration by controlling release of SDF-1α, enhancing the recruitment of fibroblast-like cells and providing instructive microenvironment and mechanical support for tendon regeneration. Therefore, CBD-SDF-1α-modified collagen scaffold could serve as a practical application for tendon regeneration.

Ultrasound-Mediated Self-Healing Hydrogels Based on Tunable Metal-Organic Bonding.

Stimulus-responsive hydrogels make up an important class of programmable materials for a wide range of biomedical applications. Ultrasound (US) is a stimulus that offers utility because of its ability to permeate tissue and rapidly induce chemical alterations in aqueous media. Here we report on the synthesis and US-mediated disintegration of stimulus-responsive telechelic Dopa-modified polyethylene glycol-based hydrogels. Fe3+-[PEG-Dopa]4 hydrogels are formed through Fe3+-induced cross-linking of four-arm polyethylene glycol-dopamine precursors to produce networks. The relative amounts of H-bonds, coordination bonds, and covalent bonds can be controlled by the [Fe3+]:[Dopa] molar ratio in precursor solutions. Networks formed from precursors with high [Fe3+]:[Dopa] ratios create mechanically robust networks (G' = 6880 ± 240 Pa) that are largely impervious to US-mediated disintegration at intensities of ≤43 W/cm2. Conversely, lightly cross-linked networks formed through [Fe3+]:[Dopa] molar ratios of <0.73 are susceptible to rapid disintegration upon exposure to US. Pulsatile US exposure allows temporal control over hydrogel disintegration and programmable self-healing. Sustained US energy can also stabilize hydrogels through the formation of additional cross-links via free radical-mediated coupling of pendant catechols. Taken together, the diverse ranges of mechanical behavior, self-healing capability, and differential susceptibility to ultrasonic disintegration suggest that Fe3+-[PEG-Dopa]4 hydrogels yield a class of application-specific stimulus-responsive polymers as smart materials for applications ranging from transient medical implants to matrices for smart drug delivery.

Regulation of human mesenchymal stem cells differentiation into chondrocytes in extracellular matrix-based hydrogel scaffolds.

To induce human mesenchymal stem cells (hMSCs) to differentiate into chondrocytes in three-dimensional (3D) microenvironments, we developed porous hydrogel scaffolds using the cartilage extracellular matrix (ECM) components of chondroitin sulfate (CS) and collagen (COL). The turbidity and viscosity experiments indicated hydrogel could form through pH-triggered co-precipitation when pH=2-3. Enzyme-linked immunosorbent assay (ELISA) confirmed the hydrogel scaffolds could controllably release growth factors as envisaged. Transforming growth factor-ß (TGF-ß) was released to stimulate hMSCs differentiation into chondrocytes; and then collagen binding domain-basic fibroblast growth factor (CBD-bFGF) was released to improve the differentiation and preserve the chondrocyte phenotype. In in vitro cell culture experiments, the differentiation processes were compared in different microenvironments: 2D culture in culture plate as control, 3D culture in the fabricated scaffolds without growth factors (CC), the samples with CBD-bFGF (CC-C), the samples with TGF-ß (CC-T), the samples with CBD-bFGF/TGF-ß (CC-CT). Real-time polymerase chain reaction (RT-PCR) revealed the hMSC marker genes of CD44 and CD105 decreased; at the same time the chondrocyte marker genes of collagen type II and aggrecan increased, especially in the CC-CT sample. Immunostaining results further confirmed the hMSC marker protein of CD 44 disappeared and the chondrocyte marker protein of collagen type II emerged over time in the CC-CT sample. These results imply the ECM-based hydrogel scaffolds with growth factors can supply suitable 3D cell niches for hMSCs differentiation into chondrocytes and the differentiation process can be regulated by the controllably released growth factors.