Nanocellulose materials have undergone rapid development in recent years as promising biomedical materials because of their excellent physical and biological properties, in particular their biocompatibility, biodegradability, and low cytotoxicity. Recently, a significant amount of research has been directed toward the fabrication of advanced cellulose nanofibers with different morphologies and functional properties. These nanocellulose fibers are widely applied in medical implants, tissue engineering, drug delivery, wound-healing, cardiovascular applications, and other medical applications. In this review, we reflect on recent advancements in the design and fabrication of advanced nanocellulose-based biomaterials (cellulose nanocrystals, bacterial nanocellulose, and cellulose nanofibrils) that are promising for biomedical applications and discuss material requirements for each application, along with the challenges that the materials might face. Finally, we give an overview on future directions of nanocellulose-based materials in the biomedical field. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 41719.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/app.41719

Recent advances in nanocellulose for biomedical applications

The use of implants that can electrically stimulate or record electrophysiological or neurochemical activity in nervous tissue is rapidly expanding. Despite remarkable results in clinical studies and increasing market approvals, the mechanisms underlying the therapeutic effects of neuroprosthetic and neuromodulation devices, as well as their side effects and reasons for their failure, remain poorly understood. A major assumption has been that the signal-generating neurons are the only important target cells of neural-interface technologies. However, recent evidence indicates that the supporting glial cells remodel the structure and function of neuronal networks and are an effector of stimulation-based therapy. Here, we reframe the traditional view of glia as a passive barrier, and discuss their role as an active determinant of the outcomes of device implantation. We also discuss the implications that this has on the development of bioelectronic medical devices.

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Glial responses to implanted electrodes in the brain.

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.

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Progress towards biocompatible intracortical microelectrodes for neural interfacing applications

The loss of a limb or paralysis resulting from spinal cord injury has devastating consequences on quality of life. One approach to restoring lost sensory and motor abilities in amputees and patients with tetraplegia is to supply them with implants that provide a direct interface with the CNS. Such brain-machine interfaces might enable a patient to exert voluntary control over a prosthetic or robotic limb or over the electrically induced contractions of paralysed muscles. A parallel interface could convey sensory information about the consequences of these movements back to the patient. Recent developments in the algorithms that decode motor intention from neuronal activity and in approaches to convey sensory feedback by electrically stimulating neurons, using biomimetic and adaptation-based approaches, have shown the promise of invasive interfaces with sensorimotor cortices, although substantial challenges remain.

Restoring sensorimotor function through intracortical interfaces: progress and looming challenges

New biomimetic, stimuli-responsive mechanically adaptive nanocomposites, which change their mechanical properties upon exposure to water and display a water-activated shape-memory effect, were investigated. These materials were produced by introducing rigid cotton cellulose nanowhiskers (CNWs) into a rubbery polyurethane (PU) matrix. A series of materials with CNW concentrations of 2–20% v/v was produced by solution blending CNWs and the PU. Films were subsequently prepared by compression molding. The introduction of CNWs led to an increase of the tensile storage moduli (E′) in the dry nanocomposites. The level of reinforcement scaled with the CNW content and followed the Halpin–Kardos model below and the percolation model above the percolation limit of ∼7% v/v. Upon exposure to water, the materials with a CNW content above the percolation limit swelled slightly and showed a decrease of E′, for example from 1 GPa to 144 MPa in the case of the material with 20% v/v CNWs. This effect is the result of compet...

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Bioinspired Mechanically Adaptive Polymer Nanocomposites with Water-Activated Shape-Memory Effect

We recently introduced a series of stimuli-responsive, mechanically adaptive polymer nanocomposites. Here, we report the first application of these bio-inspired materials as substrates for intracortical microelectrodes. Our hypothesis is that the ideal electrode should be initially stiff to facilitate minimal trauma during insertion into the cortex, yet become mechanically compliant to match the stiffness of the brain tissue and minimize forces exerted on the tissue, attenuating inflammation. Microprobes created from mechanically reinforced nanocomposites demonstrated a significant advantage compared to model microprobes composed of neat polymer only. The nanocomposite microprobes exhibit a higher storage modulus (E' = ~5 GPa) than the neat polymer microprobes (E' = ~2 GPa) and can sustain higher loads (~12 mN), facilitating penetration through the pia mater and insertion into the cerebral cortex of a rat. In contrast, the neat polymer microprobes mechanically failed under lower loads (~7 mN) before they were capable of insertion into cortical tissue. Further, we demonstrated the material's ability to morph while in the rat cortex to more closely match the mechanical properties of the cortical tissue. Nanocomposite microprobes that were implanted into the rat cortex for up to eight weeks demonstrated increased cell density at the microelectrode-tissue interface and a lack of tissue necrosis or excessive gliosis. This body of work introduces our nanocomposite-based microprobes as adaptive substrates for intracortical microelectrodes and potentially for other biomedical applications.

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In vivo deployment of mechanically adaptive nanocomposites for intracortical microelectrodes

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 Young's 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 Young's 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.

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Andreas E. Hess

Papers

In vivo deployment of mechanically adaptive nanocomposites for intracortical microelectrodes

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