Correlating Ionic Conductivity and Microstructure in Polyelectrolyte Hydrogels for Bioelectronic Devices.

Hydrogels have become the material of choice in bioelectronic devices because their high-water content leads to efficient ion transport and a conformal interface with biological tissue. While the morphology of hydrogels has been thoroughly studied, systematical studies on their ionic conductivity are less common. Here, an easy-to-implement strategy is presented to characterize the ionic conductivity of a series of polyelectrolyte hydrogels with different amounts of monomer and crosslinker and correlate their ionic conductivity with microstructure. Higher monomer increases the ionic conductivity of the polyelectrolyte hydrogel due to the increased charge carrier density, but also leads to excessive swelling that may cause device failure upon integration with bioelectronic devices. Increasing the amount of crosslinker can reduce the swelling ratio by increasing the crosslinking density and reducing the mesh size of the hydrogel, which cuts down the ionic conductivity. Further investigation on the porosity and tortuosity of the swollen hydrogels correlates the microstructure with the ionic conductivity. These results are generalizable for various polyelectrolyte hydrogel systems with other ions as the charge carrier and provide facile guidance to design polyelectrolyte hydrogel with desired ionic conductivity and microstructure for applications in bioelectronic devices.

Diverse Proton-Conducting Nanotubes via a Tandem Macrocyclization and Assembly Strategy.

Macrocycles that assemble into nanotubes exhibit emergent properties stemming from their low dimensionality, structural regularity, and distinct interior environments. We report a versatile strategy to synthesize diverse nanotube structures in a single, efficient reaction by using a conserved building block bearing a pyridine ring. Imine condensation of a 2,4,6-triphenylpyridine-based diamine with various aromatic dialdehydes yields chemically distinct pentagonal [5 + 5], hexagonal [3 + 3], and diamond-shaped [2 + 2] macrocycles depending on the substitution pattern of the aromatic dialdehyde monomer. Atomic force microscopy and in solvo X-ray diffraction demonstrate that protonation of the macrocycles under the mild conditions used for their synthesis drives assembly into high-aspect ratio nanotubes. Each of the pyridine-containing nanotube assemblies exhibited measurable proton conductivity by electrochemical impedance spectroscopy, with values as high as 10-3 S m-1 (90% R.H., 25 °C) that we attribute to differences in their internal pore sizes. This synthetic strategy represents a general method to access robust nanotube assemblies from a universal pyridine-containing monomer, which will enable systematic investigations of their emergent properties.

Natural biopolymers as proton conductors in bioelectronics.

Bioelectronic devices sense or deliver information at the interface between living systems and electronics by converting biological signals into electronic signals and vice-versa. Biological signals are typically carried by ions and small molecules. As such, ion conducting materials are ideal candidates in bioelectronics for an optimal interface. Among these materials, ion conducting polymers that are able to uptake water are particularly interesting because, in addition to ionic conductivity, their mechanical properties can closely match the ones of living tissue. In this review, we focus on a specific subset of ion-conducting polymers: proton (H+ ) conductors that are naturally derived. We first provide a brief introduction of the proton conduction mechanism, and then outline the chemical structure and properties of representative proton-conducting natural biopolymers: polysaccharides (chitosan and glycosaminoglycans), peptides and proteins, and melanin. We then highlight examples of using these biopolymers in bioelectronic devices. We conclude with current challenges and future prospects for broader use of natural biopolymers as proton conductors in bioelectronics and potential translational applications.

Single-Crystal Polycationic Polymers Obtained by Single-Crystal-to-Single-Crystal Photopolymerization.

The efficient preparation of single-crystalline ionic polymers and fundamental understanding of their structure-property relationships at the molecular level remains a challenge in chemistry and materials science. Here, we describe the single-crystal structure of a highly ordered polycationic polymer (polyelectrolyte) and its proton conductivity. The polyelectrolyte single crystals can be prepared on a gram-scale in quantitative yield, by taking advantage of an ultraviolet/sunlight-induced topochemical polymerization, from a tricationic monomer-a self-complementary building block possessing a preorganized conformation. A single-crystal-to-single-crystal photopolymerization was revealed unambiguously by in situ single-crystal X-ray diffraction analysis, which was also employed to follow the progression of molecular structure from the monomer, to a partially polymerized intermediate, and, finally, to the polymer itself. Collinear polymer chains are held together tightly by multiple Coulombic interactions involving counterions to form two-dimensional lamellar sheets (1 nm in height) with sub-nanometer pores (5 Å). The polymer is extremely stable under 254 nm light irradiation and high temperature (above 500 K). The extraordinary mechanical strength and environmental stability-in combination with its impressive proton conductivity (∼3 × 10-4 S cm-1)-endow the polymer with potential applications as a robust proton-conducting material. By marrying supramolecular chemistry with macromolecular science, the outcome represents a major step toward the controlled synthesis of single-crystalline polyelectrolyte materials with perfect tacticity.

A Microfluidic Ion Sensor Array.

A balanced concentration of ions is essential for biological processes to occur. For example, [H+ ] gradients power adenosine triphosphate synthesis, dynamic changes in [K+ ] and [Na+ ] create action potentials in neuronal communication, and [Cl- ] contributes to maintaining appropriate cell membrane voltage. Sensing ionic concentration is thus important for monitoring and regulating many biological processes. This work demonstrates an ion-selective microelectrode array that simultaneously and independently senses [K+ ], [Na+ ], and [Cl- ] in electrolyte solutions. To obtain ion specificity, the required ion-selective membranes are patterned using microfluidics. As a proof of concept, the change in ionic concentration is monitored during cell proliferation in a cell culture medium. This microelectrode array can easily be integrated in lab-on-a-chip approaches to physiology and biological research and applications.

Influence of Backbone Regioregularity on the Optoelectronic and Mechanical Response of Conjugated Polyelectrolyte-Based Hydrogels.

The ability to form robust, optoelectronically responsive, and mechanically tunable hydrogels using facile processing is desirable for sensing, biomedical, and light-harvesting applications. We demonstrate that such a hydrogel can be formed using aqueous complexation between one conjugated and one nonconjugated polyelectrolyte. We show that the rheological properties of the hydrogel can be tuned using the regioregularity of the conjugated polyelectrolyte (CPE) backbone, leading to significantly different mesoscale gel morphologies. We also find that the exciton dynamics in the long-time limit reflect differences in the underlying electronic connectivity of the hydrogels as a function CPE regioregularity. The influence of excess small ions on the hydrogel structure and the exciton dynamics similarly depends on the regioregularity in a significant way. Finally, electrical impedance measurements lead us to infer that these hydrogels can act as mixed ionic/electronic conductors. We believe that such gels possess an attractive combination of physical-chemical properties that can be leveraged in multiple applications.

Colloidal structure and proton conductivity of the gel within the electrosensory organs of cartilaginous fishes.

Cartilaginous fishes possess gel-filled tubular sensory organs called Ampullae of Lorenzini (AoL) that are used to detect electric fields. Although recent studies have identified various components of AoL gel, it has remained unclear how the molecules are structurally arranged and how their structure influences the function of the organs. Here we describe the structure of AoL gel by microscopy and small-angle X-ray scattering and infer that the material is colloidal in nature. To assess the relative function of the gel's protein constituents, we compared the microscopic structure, X-ray scattering, and proton conductivity properties of the gel before and after enzymatic digestion with a protease. We discovered that while proteins were largely responsible for conferring the viscous nature of the gel, their removal did not diminish proton conductivity. The findings lay the groundwork for more detailed studies into the specific interactions of molecules inside AoL gel at the nanoscale.

A feedback control architecture for bioelectronic devices with applications to wound healing.

Bioelectronic devices can provide an interface for feedback control of biological processes in real-time based on sensor information tracking biological response. The main control challenges are guaranteeing system convergence in the presence of saturating inputs into the bioelectronic device and complexities from indirect control of biological systems. In this paper, we first derive a saturated-based robust sliding mode control design for a partially unknown nonlinear system with disturbance. Next, we develop a data informed model of a bioelectronic device for in silico simulations. Our controller is then applied to the model to demonstrate controlled pH of a target area. A modular control architecture is chosen to interface the bioelectronic device and controller with a bistable phenomenological model of wound healing to demonstrate closed-loop biological treatment. External pH is regulated by the bioelectronic device to accelerate wound healing, while avoiding chronic inflammation. Our novel control algorithm for bioelectronic devices is robust and requires minimum information about the device for broad applicability. The control architecture makes it adaptable to any biological system and can be used to enhance automation in bioengineering to improve treatments and patient outcomes.

The multi-channel potentiostat: Development and evaluation of a scalable mini-potentiostat array for investigating electrochemical reaction mechanisms.

A potentiostat is an essential piece of analytical equipment for studying electrochemical devices and reactions. As the design of electrochemical devices evolve, applications for systems with multiple working electrodes have become more common. These applications drive a need for low-cost multi-channel potentiostat systems. We have developed a portable, low-cost and scalable system with a modular design that can support 8 to 64 channels at a cost as low as $8 per channel. This design can replace the functionality of commercial potentiostats which cost upwards of $10k for certain applications. Each channel in the multi-channel potentiostat has an independent adjustable voltage source with a built-in ammeter and switch, making the device flexible for various configurations. The multi-channel potentiostat is designed for low current applications (nA range), but its purpose can change by varying its shunt resistor value. The system can either function as a standalone device or remotely controlled. We demonstrate the functionality of this system for the control of a 24-channel bioelectronic ion pump for open- and closed- loop control of pH.

Soft and Ion-Conducting Materials in Bioelectronics: From Conducting Polymers to Hydrogels.

Bioelectronics devices that directly interface with cells and tissue have applications in neural and cardiac stimulation and recording, electroceuticals, and brain machine interfaces for prostheses. The interface between bioelectronic devices and biological tissue is inherently challenging due to the mismatch in both mechanical properties (hard vs soft) and charge carriers (electrons vs ions). In addition to conventional metals and silicon, new materials have bridged this interface, including conducting polymers, carbon-based nanomaterials, as well as ion-conducting polymers and hydrogels. This review provides an update on advances in soft bioelectronic materials for current and future therapeutic applications. Specifically, this review focuses on soft materials that can conduct both electrons and ions, and also deliver drugs and small molecules. The future opportunities and emerging challenges in the field are also highlighted.

Proton conductivity of glycosaminoglycans.

Proton conductivity is important in many natural phenomena including oxidative phosphorylation in mitochondria and archaea, uncoupling membrane potentials by the antibiotic Gramicidin, and proton actuated bioluminescence in dinoflagellate. In all of these phenomena, the conduction of protons occurs along chains of hydrogen bonds between water and hydrophilic residues. These chains of hydrogen bonds are also present in many hydrated biopolymers and macromolecule including collagen, keratin, chitosan, and various proteins such as reflectin. All of these materials are also proton conductors. Recently, our group has discovered that the jelly found in the Ampullae of Lorenzini- shark's electro-sensing organs- is the highest naturally occurring proton conducting substance. The jelly has a complex composition, but we proposed that the conductivity is due to the glycosaminoglycan keratan sulfate (KS). Here we measure the proton conductivity of hydrated keratan sulfate purified from Bovine Cornea. PdHx contacts at 0.50 ± 0.11 mS cm -1, which is consistent to that of Ampullae of Lorenzini jelly at 2 ± 1 mS cm -1. Proton conductivity, albeit with lower values, is also shared by other glycosaminoglycans with similar chemical structures including dermatan sulfate, chondroitin sulfate A, heparan sulfate, and hyaluronic acid. This observation supports the relationship between proton conductivity and the chemical structure of biopolymers.

Trapping and Characterization of Nontoxic Aß42 Aggregation Intermediates.

Amyloid ß (Aß) 42 is an aggregation-prone peptide and the believed seminal etiological agent of Alzheimer's disease (AD). Intermediates of Aß42 aggregation, commonly referred to as diffusible oligomers, are considered to be among the most toxic forms of the peptide. Here, we studied the effect of the age-related epimerization of Ser26 (i.e., S26s chiral edit) in Aß42 and discovered that this subtle molecular change led to reduced fibril formation propensity. Surprisingly, the resultant soluble aggregates were nontoxic. To gain insight into the structural changes that occurred in the peptide upon S26s substitution, the system was probed using an array of biophysical and biochemical methods. These experiments consistently pointed to the stabilization of aggregation intermediates in the Aß42-S26s system. To better understand the changes arising as a consequence of the S26s substitution, molecular level structural studies were performed. Using a combined nuclear magnetic resonance (NMR)- and density functional theory (DFT)-computational approach, we found that the S26s chiral edit induced only local structural changes in the Gly25-Ser26-Asn27 region. Interestingly, these subtle changes enabled the formation of an intramolecular Ser26-Asn27 H-bond, which disrupted the ability of Asn27 to engage in the fibrillogenic side chain-to-side chain H-bonding pattern. This reveals that intermolecular stabilizing interactions between Asn27 side chains are a key element controlling Aß42 aggregation and toxicity.