Recent years have led to a rapid increase in the development of neurotechnologies for diagnosis, monitoring, and treatment of conditions with neurological targets. The central driving force has been the need for next-generation devices to treat neural injury and disease, where current pharmaceutical or conventional bioelectronics have been unable to impart sufficient therapeutic effects. The advent of new therapies and advanced technologies has resulted in a reemergence of the concept of superhuman performance. This is a hypothetical possibility that is enabled when bionics are used to augment the neural system and has included the notions of improved cognitive ability and enhancement of hearing and seeing beyond the limitations of a healthy human. It is quite conceivable that a bionic eye could be used for night vision; however, the damage to both the neural system and surrounding tissues in placing such a device is only considered acceptable in the case of a patient that can obtain improvement in quality of life. There are also critical limitations that have hindered clinical translation of high-resolution neural interfaces, despite significant advances in biomaterial and bioelectronics technologies, including the advent of biohybrid devices. Surgical damage and foreign body reactions to such devices can be reduced but not eliminated, and these engineering solutions to reduce inflammation present additional challenges to the long-term performance and medical regulation. As a result, while bioelectronics has seen concepts from science fiction realized, there remains a significant gap to their use as enhancements beyond medical therapies.
I. THE EMERGENCE OF BIOELECTRONIC TECHNOLOGIES
Bioelectronics is a field that has seen rapid expansion across the recent decade as researchers and industry have explored interfacing devices with electroactive cells of the body to elicit novel insights and deliver new therapies (Solazzo et al., 2019; Vitale and Litt, 2018), leading to the evolution of a bionic man (Fig. 1). While traditional bioelectronic technologies, such as pacemakers, cochlear implants, electroencephalograms (EEGs), and electromyograms (EMG), have been in the clinic for over 50 years, the development of neuropsychiatric treatments, electroceuticals, and closed loop systems has only reached the clinic within the recent decade (Portillo-Lara et al., 2021). These advances have been driven by major funding across the globe including government initiatives, such as the EU Human Brain Project, the US BRAIN initiative, and the NIH SPARC initiative, and new commercial initiatives, such as Neurolink and Galvani Bioelectronics (Mathieson et al., 2021; Royal Society, 2019). This has led to approved, medically regulated bioelectronic therapies for the treatment of a range of conditions spanning epilepsy, depression, immune conditions, tremor disorders, blindness, and spinal cord injury. However, it has also been postulated that these technologies could be harnessed to achieve extra-ordinary abilities such as improved cognition, night vision, and other enhanced perception when placed in healthy humans (“Elon Musk's Neuralink Is Neuroscience Theater|MIT Technology Review,” 2021). While the lines between science fiction and medical therapies have blurred substantially over the recent decades (Portillo-Lara et al., 2021), there is still a wide gap between state-of-the-art neurotechnology and the complexity, organization, and filtering processes of the human nervous system and, in particular, the brain (Maoz, 2021).
To contextualize the current bioelectronic technologies, the leading bionic eye devices can improve the mobility of a blind patient without the use of visual aids; however, patients with these devices remain legally blind (Finn et al., 2018). Despite this, it is feasible that bionic eyes could be used to enable night vision, as these devices use external cameras to detect the environment (Sarosh et al., 2019; Lovell et al., 2007). In hearing, where cochlear implants have been in use for over 40 years, the spectrum of sounds detected through 3500 inner hair cells in the normally hearing human ear is more simplistically represented by 22 electrodes in an augmenting implant (Dalrymple et al., 2020; Joung, 2013). This has been found to be sufficient for helping deaf children learn to vocally communicate but presents major limitations for sound sourcing in a crowded room and ability to perceive complex sounds such as music. Ideally, an augmenting device for replacing or correcting functions of the nervous system would enable connections between devices and individual cells (Goding et al., 2017; Grill et al., 2009). This resolution of communication would theoretically enable devices to replicate healthy human neural functions and potentially reach levels of optimization that could be considered superhuman. However, fundamental challenges in engineering have prevented the development of such high-resolution technologies. Primarily, these challenges have included the ability to safely reduce the size of electrodes, the inflammatory and foreign body response caused by synthetic and, in particular, high stiffness device materials, and the capability to miniaturize electronics and retain high fidelity data transfer to external computers (Mehdi et al., 2015).
II. BIOHYBRID APPROACHES FOR SUPER-RESOLUTION
Rapid development of nano and microscale electronics has led to impressive scalability in hardware and data transfer, mitigating the limitations in signal processing. However, the interface with the human body and, in particular, the electrodes has experienced significant hurdles to clinical applications, despite a wide variety of innovations. To obtain high specificity of neural control, it is necessary to be close to the target cells, making implantable devices preferable over noninvasive wearable devices. In an attempt to improve device communication and mediate the foreign body response at the implant site, the development of soft, organic based electronics and biohybrid technologies incorporating biomolecules and even cells have been proposed (Aregueta-Robles et al., 2014; Portillo-Lara et al., 2021; Kamm et al., 2018). Flexible electronics based on conductive polymers (Novikov et al., 2020; Cuttaz et al., 2021) or carbon conductors (Bareket-Keren and Hanein, 2013; Varnava, 2020) embedded within hydrogels and elastomers have provided an alternative to stiff metallic implantable electrodes. These approaches reduce the long-term foreign body response that results in insulative scar tissue isolating electronic devices but do not remove the risk and tissue damage associated with surgical implantation. The design of highly miniaturized probe electrodes has shown significant promise in reducing implantation damage while remaining imperceptible to local immune cells (Varnava, 2020); however, retaining a robust electrical connection to hardware and safely delivering stimulation to tissues through such a small interface remains an engineering challenge. An alternative approach that aims to reduce device invasiveness is the use of remotely addressable systems (Xu et al., 2020), where magnetic or thermal stimulation of injected nanomaterials enables activation of the nervous tissue (Chen et al., 2015; Portillo-Lara et al., 2021). The latter innovation has significant potential for reducing surgically induced damage but presents new challenges to accurate placement of nanomaterials and the ability to continue it to stimulate or record from an area of the nervous system as cells undergo renewal and remodeling, displacing the mediating nanomaterial target.
In APL Bioengineering, biohybrid technologies have presented advances within the fields of tissue engineering (Kaufman et al., 2020; Ehsanipour et al., 2021), neurophysiology (Maoz, 2021), and in vitro culture models (Kamm et al., 2018). The integration of electronics within culture systems to enable organ and lab-on-chip has demonstrated how recordings from complex tissues can be enabled by combining the principles of tissue engineering with bioelectronics (Visone et al., 2018; Maoz, 2021). Learning from these tissue engineering approaches, such as those detailed in Oksdath et al. (2018) and Ehsanipour et al. (2021), has been critical to the development of implantable bioelectronics that are more readily integrated into the soft, electroexcitable tissues. Maclean et al. (2018) reviewed biomaterials for traumatic brain injury, outlining the design criteria for an ideal material that promotes integration of cortical neurons. The adoption of these criteria for interfacing brain electronics has led to the development of living bioelectronics (Goding et al., 2017; Vallejo-Giraldo et al., 2021), where cells encapsulated at the surface of bionic devices can promote synaptic connections to the endogenous nervous system. These biohybrid technologies present the first steps toward cell level connections that could facilitate super-resolution connections between devices and the human body.
While these advances in electronics combined with biomaterials and tissue engineering do not preclude the development of super-resolution implantable bioelectronics, there is still critical understanding of neural system development, repair, and remodeling (Maoz, 2021) that must be gained to enable safe and effective placement of enhancing technologies. This knowledge gap largely precludes the use of these devices as augmenting technologies beyond the natural capacity of the non-impaired neural system (Portillo-Lara et al., 2021). Implantable devices are known to impart substantial injury during the surgical placement (Menciassi and Iacovacci, 2020) and while engineering approaches can reduce injury, there remains a significant gap in understanding the impact of intervention on brain plasticity and rewiring (Mateos-Aparicio and Rodríguez-Moreno, 2019). It is known that over time, neural networks will undergo changes according to the inputs, including electrical, magnetic, or optoelectronic stimulation (Huang et al., 2020; Crawford and San-Miguel, 2020). This has been to the benefit of patients impacted by disorders of the neural system, such that cells that have not been degraded by disease or injury can be recruited to help replace a lost functionality. Intervention within a fully functional, healthy neural system will cause damage that could lead to loss of natural function following surgery; however, changes in the neural network as a result of the implant stimulation could impart a range of side effects, the impact of which is entirely unchartered (Drew, 2019). It is feasible to consider that in an attempt to impart improved cognition, damage or reprogramming within the cortex could result in significant changes to a subjects neuropsychiatric state or logical reasoning. The risk of these unknowns highlights the need for extreme caution in suggesting that bioelectronics could be used to realize superhuman.
III. SUPERHUMAN THERAPEUTICS NOT SUPERPOWERS
It is clear that neurotechnologies and, in particular, implantable technologies have undergone rapid advances across the recent decade, enabling a range of new therapeutic interventions. In particular, the merging of approaches learned from tissue engineering, biomaterials, and bionics has facilitated the emergence of the field of organic and living bioelectronics that has the capacity to enable higher resolution technologies. These new methods of intervention coupled with developments in computational methods and microelectronics will continue to blur the lines between science fiction and healthcare; however, super-resolution devices and augmentation to produce performance beyond the functioning healthy nervous system remain a futuristic hypothetical.
Dr. Roberto Portillo-Lara is acknowledged for contributing the artwork in Fig. 1. The author acknowledges funding from the UK Engineering and Physical Sciences Research Council under Project Nos. EP/R004498/1, EP/W00061X/1, and EP/T020970/1; and the European Research Council under Project No. 771985.