Nanomaterials in neuromodulation: what is the potential?

KEYWORDS:

• Nanomaterials
• neuromodulation
• deep brain stimulation
• nanoparticle
• magnetic field

1. Introduction

A wide range of neuromodulation technologies has been explored for their applicability and effectiveness in modulating neural tissue, ranging from tethered devices to nano-scale approaches [1–3]. Neuromodulation often involves controlled electrical alterations of neuronal activity in real-time. Deep brain stimulation (DBS) has emerged as one of the most successful techniques in managing clinical symptoms in a number of neurological disorders such as Parkinson’s Disease (PD) [1]. Despite improving motor symptoms, it requires an invasive surgical procedure that carries the potential risk of complications. In fact, 15–34% of the patients undergoing DBS require follow-up interventions for electrode replacement or removal due to hardware malfunctions or infection[4]. Moreover, the average cost of DBS for a patient with PD over 5 years is US$186,244 [5]. As a consequence, many patients are reluctant to undergo this procedure, which has led the technique to be under-utilized for the eligible patient population [6]. Alternatively, several noninvasive neurostimulation techniques have been developed and used, such as transcranial magnetic stimulation [7], transcranial direct current stimulation, vagal nerve stimulation [8], transcranial alternating current stimulation [9], and focused ultrasound for alleviating symptoms of neurological and psychological disorders [10]. However, compared to DBS, these techniques lack targeting precision and adequate penetration when deep subcortical structures are concerned.

To overcome these obstacles and meet the rising demand for better neuromodulation therapies, alternative neurostimulation approaches inspired by material sciences have been proposed. In pre-clinical research, recently developed nano-scale particles and milli-scale devices have been investigated due to their versatile implementation potentials. The main advantage of using nanomaterials and/or milli-scale devices for neuromodulation is that they have the potential to be minimally invasive, cost-effective, and biocompatible compared to conventional tethered devices. Here we highlight the key advances in utilization of these technologies using the body-of-literature available at the time of writing.

2. Nanotechnology enables novel modalities for neuromodulation

In neuromodulation, nanomaterials act as signal transducers for an external energy source such as a magnetic field. The core elements of these nanomaterials are often metallic, which allow them to transduce magnetic energy into either mechanical, thermal, or electrical energy, eventually generating action potentials [11]. Nevertheless, several other energy sources such as light and ultrasonic waves have also been used to stimulate the administrated nanomaterials. For instance, lanthanide-based up-conversion nanoparticles (UCNPs) enable the conversion of low-energy photons into high-energy photons, and vice versa, when using near-infrared (NIR) radiation. Excited UCNPs can generate multiple emission bandwidths, which can serve as a multi-color light source for optogenetic systems. In these studies, a combined NIR source and multi-chromatic UCNPs with excitation-specific luminescence were shown to enable selective activation or inhibition of distinct neuronal populations that were expressing specific opsins [12,13]. In addition, ultrasonic waves have also been used to power internally implanted barium titanate (BaTiO3) piezoelectric stimulators for the restoration of involuntary movements in a rat model of spinal cord injury [14,15]. The piezoelectric stimulators were stimulated at 1 MHz in short 200 μs sinusoidal burst pulses at the lumbosacral spinal cord using an external transceiver to generate evoked potentials in the hind limbs of paralyzed animals [14].

Magnetic fields, in particular, are the most commonly used energy source to power nanomaterials, partially because they are cheap to generate and mostly inert to non-magnetic substances. For instance, magneto-mechanic nanoparticles (MMNPs) can act on mechanosensitive ion channels, effectively modulating or inducing neuronal action potentials. The m-Torquer system, as used by Lee and coworkers, is composed of a magnetic torquer and a rotating circular magnet array (CMA). The m-Torquer system is composed of octahedral magnetic nanoparticles with a diameter of 500 nm. The M2 region of the premotor cortex of mice was bilaterally targeted with adenovirus-containing Myc897-Piezo1 (Ad-Piezo1) followed by the delivery of m-Torquer into the right hemisphere. This was done to specifically target the m-Torquer with the Myc-antibody. Magneto-thermal nanoparticles (MTNPs), on the other hand, act by activating a heat-sensitive element, such as the capsaicin receptor (transient receptor potential cation channel subfamily V member 1, TRPV1). When exposed to an alternating magnetic field, the nanoparticles dissipate energy as heat, which triggers the reversible firing of TRPV1-transfected neurons [3]. Recent studies have shown that neuromodulation via these particles can reverse motor deficits in a neurotoxin-induced mouse model of PD. This was indicated by an increased expression of c-Fos cells (a neural activity marker) in motor pathways [3]. With regard to targeting, the introduction of exogenous molecules along with matching antibodies has shown to enable highly specific binding to the target and a better MTNPs distribution [16,17]. Although these technologies allow for cell-specific neuromodulation, they require genetically modifying cells, which could create regulatory barriers to their clinical translation. In addition, gene editing impairs the translatability of some of those studies as they introduce and target exogenous molecules. Therefore, attempts have been made to circumvent this issue by using materials that transduce the applied energy into electrical charges directly so that there is no need for the transfection of exogenous actuators.

Two-phase magnetoelectric nanoparticles (MENPs) consisting of magnetostrictive and piezoelectric components generate electric charges in the presence of a magnetic field, which have been used to electrically stimulate neurons. In a recent study, Nguyen and coworkers have conducted magnetic stimulation using MENPs in cortical slices ex vivo. After the application of external alternating (AC) and direct current (DC) magnetic fields, the MENPs produced local and network neuromodulation. In addition, neurostimulation was achieved without affecting the cell viability and astroglia activity, indicating the safety of this approach [18]. In line with this, our recent in vivo study demonstrated that we could power the MENPs with a magnetic field to remotely generate electric polarization of the MENPs and locally modulate neuronal activity. This was sufficient to alter specific motor pathways and change animal behavior [2]. DBS with MENPs does not require genetic tissue modification to express cell membrane ion channels or any other actuator. However, this is at the cost of being unspecific for cell-types. To improve the selectivity of this approach, different antibody coatings can be used for targeted delivery. In pre-clinical settings, nanomaterials have shown to be compatible with precise cell targeting by tailored antibodies. However, it should be noted that using antibodies for cell targeting, as seen in MMNPs and MTNPs, may slow down molecular turnover in the membrane with uncertain effects on cell excitability [19].

2.1. Surface coating of the nanomaterials

When using nanomaterials for neurostimulation, different coatings and core components are preferred for each specific purpose. Coatings can be used to stabilize the nanomaterials in aqueous solutions; to direct them toward specific targets, and/or to improve their biocompatibility. For the particle’s core, different materials and structures will yield different transducing effects. This variety of nanomaterials and their potential applications is wide and has been recently reviewed by Dominguez-Paredes and colleagues [11]. As such, additional layers are often added to the core to provide added functionalities. Covalent modifications require highly controlled reaction conditions while providing more stable bonds with the transducing nanomaterial. On the other hand, non-covalent modifications require less precise matching and milder reaction conditions. They can also undergo a higher number of chemical interactions per molecule, albeit the stoichiometry and orientation of these interactions are hard to control [11]. Nanomaterials need to be stable in the blood and the brain parenchyma, hence coatings such as silica-shells or propylene glycol monomethyl ether acetate (PMA)-shells are sometimes applied to stabilize the core metallic materials. For example, in magnetic nanomaterials, a non-covalent coating with an amphipathic polymer such as dodecyl-grafted poly-(isobutylene-alt-maleic anhydride/PMA) or PMA-shell has been used to functionalize magnetic nanoparticles in aqueous solutions [20]. Furthermore, surface modifications are also applied to facilitate the crossing of biological barriers and to enable tissue targeting [21]. In addition, the immune system will identify the nanomaterial as foreign and therefore immune recognition needs to be avoided to enhance the nanomaterial’s functionality and distribution. For instance, poly-ethyl-glycol (PEG) is one of the immune-recognition-avoiding layers which can be added in nanomaterial designs [11].

2.2. Tissue delivery of the nanomaterials

Once the nanomaterials are stabilized for blood circulation, they need to be introduced into the brain parenchyma. Most studies to date have been conducted by invasively delivering the nanomaterial in question into the targeted area. However, current advances in blood-brain barrier (BBB) disruption could provide the possibility of delivering them via the bloodstream. This can be done by transiently opening the BBB using focused ultrasounds (FUS); osmotic disruption of the BBB; or hijacking ligand-receptor interactions without disrupting the BBB [22,23]. In addition, after intravenously injecting nanomaterials, external magnetic guidance can be applied to directly extravasate the nanomaterials and guide them to the brain [18,24].

2.3. Parenchymal retention and tissue clearance

Lastly, the dynamics of nanomaterial retention in the brain parenchyma is poorly understood to date. Ideally, nanomaterials should remain in the parenchyma for as long as possible, in the minimal concentration needed, whilst causing the least amount of cell damage. Super-paramagnetic iron-oxide nanoparticles (SPIONPs) coated with dextran were injected into the striatum of rats and were gradually cleared out from the brain parenchyma at the injection site in about two weeks (presumably with a contribution of glial cells), with clearing times of up to eight weeks depending on nanoparticle concentration [25]. In addition, striking novel studies have discovered that gadolinium-based magnetic resonant imaging (MRI) contrast agents show long-term brain retention and deposition. Seemingly, these particles (3–350 nm in size) had been well-tolerated in the brain parenchyma and tissue clearance was slow or absent [26]. Other experimental reports in vivo also indicate that using nanomaterials appears to be safe and to not cause significant tissue damage. For instance, MENPs were well tolerated in the brain parenchyma and did not affect cell viability in our rodent study [2]. This could predict that those nanomaterials can remain safely in the brain for prolonged periods of time, yet future studies will be key to appropriately characterize their retention and clearance over time.

2.4. Milli-scale materials

Advances in material sciences have also led to an increase in using milli-scale devices for neural stimulation, and have shown promising results that could benefit the scientific community. Magnetoelectric (ME)- converters are milli-scale devices that are placed subdurally and act similarly to MENPs. These ME transducers convert low magnitude (<1 mT) and low-frequency (∼300 kHz) magnetic fields into electric fields that can power custom integrated circuits or stimulate nearby tissue. In addition, the ME-converter was able to electrically stimulate a rat sciatic nerve at a distance of 4 cm from the energy source [27]. Clinical application of milli-scale devices is more promising as these can be used to modulate the peripheral nervous system as well as cortical areas in the central nervous system with none or minimally invasive procedures. Future research will be indispensable to optimize this technology and investigate whether it allows targeting deep brain areas.

3. Conclusion

In summary, the use of nanomaterials as nanoelectrodes shows promise as a new solution for wireless neural devices. As this field is still in its infancy, future research will be critical to understanding the potentials and limitations of this technology. Furthermore, research into noninvasive delivery routes, toxicity, and cell/tissue targeting specificity will help bring this technology closer to clinical application. A substantial number of studies have tested nanomaterials for neuromodulation, but the majority of those have used in vitro or in silico models. The application of these nanomaterials in animal models of neurological and psychiatric disorders will help to clarify the main components driving their therapeutic effect, and the mechanisms that may underlie patient responses. Clarifying these aspects will direct more rational and effective decision-making in translating the use of the nanomaterials to the clinic. To conclude, it is important to recognize that several novel ethical considerations arise when developing brain implants with nano-scale materials. Especially, the excitement regarding the use of innovative nano-scale materials should not be at the cost of compromising patient safety and long-term safety assurances. In this regard, research ethics guidelines will likely require reconsideration to acknowledge these issues [28].

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

F Alosaimi thanks King Abdulaziz University for his PhD scholarship.

Additional information

Funding

This paper was not funded.