Jeffrey R. Capadona

Stimuli-Responsive Polymer Nanocomposites Inspired by the Sea Cucumber Dermis

Sea cucumbers, like other echinoderms, have the ability to rapidly and reversibly alter the stiffness of their inner dermis. It has been proposed that the modulus of this tissue is controlled by regulating the interactions among collagen fibrils, which reinforce a low-modulus matrix. We report on a family of polymer nanocomposites, which mimic this architecture and display similar chemoresponsive mechanic adaptability. Materials based on a rubbery host polymer and rigid cellulose nanofibers exhibit a reversible reduction by a factor of 40 of the tensile modulus, for example, from 800 to 20 megapascals (MPa), upon exposure to a chemical regulator that mediates nanofiber interactions. Using a host polymer with a thermal transition in the regime of interest, we demonstrated even larger modulus changes (4200 to 1.6 MPa) upon exposure to emulated physiological conditions.

A versatile approach for the processing of polymer nanocomposites with self-assembled nanofibre templates

The incorporation of nanoparticles into polymers is a design approach that is used in many areas of materials science. The concept is attractive because it enables the creation of materials with new or improved properties by mixing multiple constituents and exploiting synergistic effects. One important technological thrust is the development of structural materials with improved mechanical and thermal characteristics. Equally intriguing is the possibility to design functional materials with unique optical or electronic properties, catalytic activity or selective permeation. The broad technological exploitation of polymer nanocomposites is, however, stifled by the lack of effective methods to control nanoparticle dispersion. We report a simple and versatile process for the formation of homogeneous polymer/nanofibre composites. The approach is based on the formation of a three-dimensional template of well-individualized nanofibres, which is filled with any polymer of choice. We demonstrate that this template approach is broadly applicable and allows for the fabrication of otherwise inaccessible nanocomposites of immiscible components.

Polymer Nanocomposites with Nanowhiskers Isolated from Microcrystalline Cellulose

The ability to produce polymer nanocomposites, which comprise a percolating, three-dimensional network of well-individualized nanofibers, is important to maximize the reinforcing effect of the nanofibers. While microcrystalline cellulose (MCC) has been previously shown to improve the mechanical properties of polymer composites, the formation of fibrous percolating networks within the nanocomposites has been stifled. Through the utilization of a template approach, nanocomposites based on an ethylene oxide/epichlorohydrin copolymer and nanowhiskers isolated from MCC were produced that display the maximum mechanical reinforcement predicted by the percolation model.

Progress towards biocompatible intracortical microelectrodes for neural interfacing applications

To ensure long-term consistent neural recordings, next-generation intracortical microelectrodes are being developed with an increased emphasis on reducing the neuro-inflammatory response. The increased emphasis stems from the improved understanding of the multifaceted role that inflammation may play in disrupting both biologic and abiologic components of the overall neural interface circuit. To combat neuro-inflammation and improve recording quality, the field is actively progressing from traditional inorganic materials towards approaches that either minimizes the microelectrode footprint or that incorporate compliant materials, bioactive molecules, conducting polymers or nanomaterials. However, the immune-privileged cortical tissue introduces an added complexity compared to other biomedical applications that remains to be fully understood. This review provides a comprehensive reflection on the current understanding of the key failure modes that may impact intracortical microelectrode performance. In addition, a detailed overview of the current status of various materials-based approaches that have gained interest for neural interfacing applications is presented, and key challenges that remain to be overcome are discussed. Finally, we present our vision on the future directions of materials-based treatments to improve intracortical microelectrodes for neural interfacing.

Bio-inspired mechanically-adaptive nanocomposites derived from cotton cellulose whiskers

A new series of biomimetic, stimuli-responsive nanocomposites, which change their mechanical properties upon exposure to physiological conditions, was investigated. The materials were produced by introducing percolating networks of cellulose whiskers isolated from cotton into poly(vinyl acetate). Below the glass-transition temperature (Tg ∼ 63 °C), the tensile storage moduli (E′) of the dry nanocomposites increased two fold, from 2 GPa for the neat polymer to 4 GPa for a nanocomposite with 16.5% v/v whiskers. The relative reinforcement was more significant above Tg, where E′ was increased nearly 40 fold, from ∼1.2 MPa to ∼45 MPa. Upon exposure to emulated physiological conditions (immersion in artificial cerebrospinal fluid at 37 °C) all nanocomposites showed a pronounced decrease in E′, for example to 5 MPa for the 16.5% v/v whisker nanocomposites with only about 28% w/w swelling. This is a significant reduction in the amount of swelling required to decrease the E′, compared to earlier material versions based on cellulose whiskers with higher surface charge density; the decreased swelling may be a considerable advantage for the intended use of these materials as adaptive substrates for intracortical electrodes and other biomedical applications.

Stab injury and device implantation within the brain results in inversely multiphasic neuroinflammatory and neurodegenerative responses

An estimated 25 million people in the US alone rely on implanted medical devices, ∼2.5 million implanted within the nervous system. Even though many devices perform adequately for years, the host response to medical devices often severely limits tissue integration and long-term performance. This host response is believed to be particularly limiting in the case of intracortical microelectrodes, where it has been shown that glial cell encapsulation and localized neuronal cell loss accompany intracortical microelectrode implantation. Since neuronal ensembles must be within ∼50 µm of the electrode to obtain neuronal spikes and local field potentials, developing a better understanding of the molecular and cellular environment at the device-tissue interface has been the subject of significant research. Unfortunately, immunohistochemical studies of scar maturation in correlation to device function have been inconclusive. Therefore, here we present a detailed quantitative study of the cellular events and the stability of the blood-brain barrier (BBB) following intracortical microelectrode implantation and cortical stab injury in a chronic survival model. We found two distinctly inverse multiphasic profiles for neuronal survival in device-implanted tissue compared to stab-injured animals. For chronically implanted animals, we observed a biphasic paradigm between blood-derived/trauma-induced and CNS-derived inflammatory markers driving neurodegeneration at the interface. In contrast, stab injured animals demonstrated a CNS-mediated neurodegenerative environment. Collectively these data provide valuable insight to the possibility of multiple roles of chronic neuroinflammatory events on BBB disruption and localized neurodegeneration, while also suggesting the importance to consider multiphasic neuroinflammatory kinetics in the design of therapeutic strategies for stabilizing neural interfaces.

Mechanically adaptive intracortical implants improve the proximity of neuronal cell bodies

The hypothesis is that the mechanical mismatch between brain tissue and microelectrodes influences the inflammatory response. Our unique, mechanically adaptive polymer nanocomposite enabled this study within the cerebral cortex of rats. The initial tensile storage modulus of 5 GPa decreases to 12 MPa within 15 min under physiological conditions. The response to the nanocomposite was compared to surface-matched, stiffer implants of traditional wires (411 GPa) coated with the identical polymer substrate and implanted on the contralateral side. Both implants were tethered. Fluorescent immunohistochemistry labeling examined neurons, intermediate filaments, macrophages, microglia and proteoglycans. We demonstrate, for the first time, a system that decouples the mechanical and surface chemistry components of the neural response. The neuronal nuclei density within 100 µm of the device at four weeks post-implantation was greater for the compliant nanocomposite compared to the stiff wire. At eight weeks post-implantation, the neuronal nuclei density around the nanocomposite was maintained, but the density around the wire recovered to match that of the nanocomposite. The glial scar response to the compliant nanocomposite was less vigorous than it was to the stiffer wire. The results suggest that mechanically associated factors such as proteoglycans and intermediate filaments are important modulators of the response of the compliant nanocomposite.

Nanocomposites based on cellulose whiskers and (semi)conducting conjugated polymers

Two examples of a new class of functional nanocomposites derived from cellulose nanofibers (referred to as “whiskers”) and (semi)conducting π-conjugated polymers were prepared and studied. The conjugated polymers used were polyaniline (PANI) and a poly(p-phenylene ethynylene) (PPE) derivative with quaternary ammonium side chains. Cellulose whiskers with a typical diameter of around 20 nm, a length of around 1–2 µm, and anionic surface charges were combined with the positively charged π-conjugated polymers to form stable dispersions in polar solvents such as formic acid. Thin films were produced by solution-casting. Their composition was systematically varied to comprise between 65 and 99.4% w/w of the whiskers. Measurements of electrical conductivity, photoluminescence, and mechanical properties reveal that the nanocomposites synergistically combine the electronic characteristics of the conjugated polymers with the outstanding mechanical characteristics of the cellulose scaffold.

Mechanically-compliant intracortical implants reduce the neuroinflammatory response

OBJECTIVE The mechanisms underlying intracortical microelectrode encapsulation and failure are not well understood. A leading hypothesis implicates the role of the mechanical mismatch between rigid implant materials and the much softer brain tissue. Previous work has established the benefits of compliant materials on reducing early neuroinflammatory events. However, recent studies established late onset of a disease-like neurodegenerative state. APPROACH In this study, we implanted mechanically-adaptive materials, which are initially rigid but become compliant after implantation, to investigate the long-term chronic neuroinflammatory response to compliant intracortical microelectrodes. MAIN RESULTS Three days after implantation, during the acute healing phase of the response, the tissue response to the compliant implants was statistically similar to that of chemically matched stiff implants with much higher rigidity. However, at two, eight, and sixteen weeks post-implantation in the rat cortex, the compliant implants demonstrated a significantly reduced neuroinflammatory response when compared to stiff reference materials. Chronically implanted compliant materials also exhibited a more stable blood-brain barrier than the stiff reference materials. SIGNIFICANCE Overall, the data show strikingly that mechanically-compliant intracortical implants can reduce the neuroinflammatory response in comparison to stiffer systems.

Development of a stimuli-responsive polymer nanocomposite toward biologically optimized, MEMS-based neural probes

This paper reports the development of micromachining processes and mechanical evaluation of a stimuli-responsive, mechanically dynamic polymer nanocomposite for biomedical microsystems. This nanocomposite consists of a cellulose nanofiber network encased in a polyvinyl acetate matrix. Micromachined tensile testing structures fabricated from the nanocomposite displayed a reversible and switchable stiffness comparable to bulk samples, with a Youngs modulus of 3420 MPa when dry, reducing to ~20 MPa when wet, and a stiff-to-flexible transition time of ~300 s. This mechanically dynamic behavior is particularly attractive for the development of adaptive intracortical probes that are sufficiently stiff to insert into the brain without buckling, but become highly compliant upon insertion. Along these lines, a micromachined neural probe incorporating parylene insulating/moisture barrier layers and Ti/Au electrodes was fabricated from the nanocomposite using a fabrication process designed specifically for this chemical- and temperature-sensitive material. It was found that the parylene layers only slightly increased the stiffness of the probe in the wet state in spite of its much higher Youngs modulus. Furthermore, the Ti/Au electrodes exhibited impedance comparable to Au electrodes on conventional substrates. Swelling of the nanocomposite was highly anisotropic favoring the thickness dimension by a factor of 8 to 12, leading to excellent adhesion between the nanocomposite and parylene layers and no discernable deformation of the probes when deployed in deionized water.