Bioelectronic medicine is a treatment modality that uses electricity to treat disease by altering the body's electrical communication systems. All cells are electrically active, in that they possess bioelectric circuitry generating a resting membrane potential and endogenous electric fields that influence cell functions and communication. There is now an accepted paradigm that cancer is characterized by malfunctions in cells' bioelectrical circuitry. This yields opportunities for bioelectronic medicine as novel treatments for cancer by manipulating its bioelectrical properties. To highlight the possibilities a bioelectrical approach can offer cancer therapy, the relevance of bioelectrical activity in cancer is reviewed and also how such activity can be hijacked in novel treatments. This includes sensing or measuring the electrical activity of cells for diagnostic and prognostic applications, controlling or altering bioelectricity including both ionic and faradaic current processes, and eliciting morphological changes using electric fields. Importantly, key links between cellular ionic and faradaic processes that contribute to cancer phenotypes are presented, which if considered and understood as a whole, can bring broad-reaching improvements to cancer therapy.

Cellular homeostasis is in part controlled by biological generated electrical activity. By interfacing biology with electronic devices this electrical activity can be modulated to actuate cellular behaviour. There are current limitations in merging electronics with biology sufficiently well to target and sense specific electrically active components of cells. By addressing this limitation, researchers give rise to new capabilities for facilitating the two-way transduction signalling mechanisms between the electronic and cellular components. This is required to allow significant advancement of bioelectronic technology which offers new ways of treating and diagnosing diseases. Most of the progress that has been achieved to date in developing bioelectronic therapeutics stimulate neural communication, which ultimately orchestrates organ function back to a healthy state. Some devices used in therapeutics include cochlear and retinal implants and vagus nerve stimulators. However, all cells can be impacted by electrical inputs which gives rise to the opportunity to broaden the use of bioelectronic medicine for treating disease. Electronic actuation of non-excitable cells has been shown to lead to 'programmed' cell behaviour via application of electronic input which alter key biological processes. A neglected form of cellular electrical communication which has not yet been considered when developing bioelectronic therapeutics is faradaic currents. These are generated during redox reactions. A precedent of electrochemical technology being used to modulate these reactions, thereby controlling cell behaviour, has already been set. In this mini review we highlight the current state of the art of electronic routes to modulating cell behaviour and identify new ways in which electrochemistry could be used to contribute to the new field of bioelectronic medicine.

In order for the field of bioelectronics to make an impact on healthcare, there is an urgent requirement for the development of "wireless" electronic systems to both sense and actuate cell behaviour. Herein we report the first example of an innovative intracellular wireless electronic communication system. We demonstrate that chemistry can be electrically modulated in a "wireless" manner on the nanoscale at the surface of conductive nanoparticles uptaken by cells at unreported low potentials. The system is made functional by modifying gold nanoparticles incorporating a Zn-porphyrin, which are taken up by cells and are shown to be biocompatible. It is demonstrated the redox state of Zn-porphyrin modified gold nanoparticles is modulated and reported on fluorescently when applying an external electrical potential. This provides an attractive new "wireless" approach to develop novel bioelectronic devices for modulating and sensing cellular behaviour using intracellular monitoring. The field of bioelectronic medicine offers a new paradigm in therapeutic intervention 1, 2. The technology is in its infancy, but relies on the ability to merge electronic devices with biology to then be used to sense and actuate cell/tissue and organ behaviour 3. The key challenge in advancing the field further is to develop new non-invasive methods to both electrically sense and actuate cell 3 behaviour. Our group 4-6 and others 7-10 have pioneered new methods for electrically communicating with the internal environment of a cell via use of nanowire electrodes. However, these methods tend to be invasive in nature as they necessarily have to pierce the plasma membrane which can lead to cell perturbations 11, 12. In addition, these electrodes require physical electrical connectivity from inside of the cells to the outside, thus hindering their use in more complex biological environments. Therefore, an approach to addressing these issues is to develop novel wireless electronic systems for the development of intracellular sensors and actuators. The development of novel bioelectronics using such a wireless-electronic approach may subsequently enable significant advancements in the ability to use intracellular electronics to facilitate cell communication and actuation. Therefore, the aim of this work was to develop a new bioelectronic approach for sensing electrical changes in response to the application of an externally applied voltage inside biological cells, thereby offering the first example of a wireless electronic tool to modulate redox inside of cells 13-14. The work undertaken was inspired by the fields of bipolar electrochemistry and drug delivery. Bipolar electrochemistry (also known as wireless electrochemistry) relies on placing a conductive particle between feeder electrodes which have potential difference placed across them. This causes the conductive particle to polarise and in doing so, causes a potential difference between the electrolyte and poles of the particle, consequently providing the thermodyamic driving force required ...

Biological structures control cell behavior via physical, chemical, electrical, and mechanical cues. Approaches that allow us to build devices that mimic these cues in a combinatorial way are lacking due to there being no suitable instructive materials and limited manufacturing procedures. This challenge is addressed by developing a new conductive composite material, allowing for the fabrication of 3D biomimetic structures in a single manufacturing method based on two‐photon polymerization. The approach induces a combinatorial biostimulative input that can be tailored to a specific application. Development of the 3D architecture is performed with a chemically actuating photocurable acrylate previously identified for cardiomyocyte attachment. The material is made conductive by impregnation with multiwalled carbon nanotubes. The bioinstructive effect of 3D nano‐ and microtopography is combined with electrical stimulation, incorporating biochemical, and electromechanical cues to stimulate cells in serum‐free media. The manufactured architecture is combined with cardiomyocytes derived from human pluripotent stem cells. It is demonstrated that by mimicking biological occurring cues, cardiomyocyte behavior can be modulated. This represents a step change in the ability to manufacture 3D multifunctional biomimetic modulatory architectures. This platform technology has implications in areas spanning regenerative medicine, tissue engineering to biosensing, and may lead to more accurate models for predicting toxicity.

There is a pressing need to advance our ability to construct three-dimensional (3D) functional bioelectronic interfaces. Additionally, to ease the transition to building cellular electronic systems, a remote approach to merge electrical components with biology is desirable. By combining 3D digital inkjet printing with bipolar electrochemistry, we remotely control and fabricate conductive wires, forming a first of its kind contactless bionic manufacturing procedure. It enables controlled fabrication of conductive wires in a three-dimensional configuration. Moreover, we demonstrate that this technology could be used to grow and interface conductive conduits in situ with mammalian cells, offering a new strategy to engineering bioelectronic interfaces. This represents a step change in the production of functional complex circuitry and considerably increases the manufacturing capabilities of merging cells with electronics. This approach provides a platform to construct bioelectronics in situ offering a potential paradigm shift in the methods for building bioelectronics with potential applications in biosensing and bioelectronic medicine.

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Bioelectronic medicine aims to interface electronic technology with biological components and design more effective therapeutic and diagnostic tools. Advances in nanotechnology have moved the field forward improving the seamless interaction between biological and electronic components. In the lab many of these nanobioelectronic devices have the potential to improve current treatment approaches, including those for cancer, cardiovascular disorders, and disease underpinned by malfunctions in neuronal electrical communication. While promising, many of these devices and technologies require further development before they can be successfully applied in a clinical setting. Here, we highlight recent work which is close to achieving this goal, including discussion of nanoparticles, carbon nanotubes, and nanowires for medical applications. We also look forward toward the next decade to determine how current developments in nanotechnology could shape the growing field of bioelectronic medicine. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Diagnostic Tools > Biosensing

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