**1. Introduction**

There is a fundamental mismatch between biological systems, which are soft and deformable, and traditional electronics, which are rigid and impermeable to sweat and liquids [1–5]. This incongruity places a significant constraint on the development of bioelectronics systems [4,5]. Traditional systems cannot conform well to the human body, making most wearable devices susceptible to large noise during motion, uncomfortable and obtrusive to wear, and limited to very specific regions on the body, such as the wrist, chest, and finger, that allow for easy attachment of rigid systems [1,3]. Furthermore, rigid implantable electronics and surgical instruments cannot easily integrate with the soft systems for which they are targeted [2]. As a result, current applications of wearable electronics, biosensors, and implantable healthcare are highly limited, leaving millions of people with serious undiagnosed diseases and allowing the steady progression towards heart attack and stroke to remain undetected [2,5]. In contrast, recent advances in hybrid electronics have yielded new classes of electronic devices and sensors that integrate well with the human body [6–9]. These systems can achieve high stretchability or flexibility through two paradigms: first, metal depositions on the order of 10 µm or less can easily bend in accordance with Euler–Bernoulli theory because of their minimal height, and fractal

**Citation:** Zavanelli, N.; Kim, J.; Yeo, W.-H. Recent Advances in High-Throughput Nanomaterial Manufacturing for Hybrid Flexible Bioelectronics. *Materials* **2021**, *14*, 2973. https://doi.org/10.3390/ ma14112973

Academic Editor: Fabrizio Roccaforte

Received: 29 April 2021 Accepted: 27 May 2021 Published: 31 May 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

geometric patterns can be introduced to allow for stretching with minimal local strain as the patterns unfold [10]. Second, conductive nanomaterial–polymer matrices can be made intrinsically stretchable by maintaining conductive pathways as the polymer undergoes strain [11]. Both novel systems can stretch and deform when needed, allowing for seamless integration with the skin [8]. As a result, previously inaccessible physiological signals and implantable healthcare targets can be realized, promising a transformation in modern medicine [7]. Likewise, traditional biosensing methods, such as florescent microarrays, lateral flow immunoassays, DNA microarrays, enzyme-linked immunosorbent assays, and polymerase chain reaction-based methods require expensive reagents and laboratory equipment, and are limited by slow signal processing methods; however, fully printed sensors allow for real time, continuous biomarker quantification in a simple, affordable, and mass producible package [12,13]. Printed biomolecule sensors promise a transformative way to continuously assess crucial biomarkers, making their development critical in the future of healthcare development [12,14–16]. These systems were initially fabricated with traditional micro- and nano-electromechanical systems (MEMS/NEMS) approaches, but such techniques are poorly suited for the industrial scales necessary to commercialize hybrid electronics. For hybrid bioelectronics to achieve their potential, the same innovative spirit that led to the adoption of new materials must be applied to the study of new manufacturing approaches.

Fully printed electronics methods have gained significant interest in recent years because they are cheaper, more efficient, and more scalable than traditional MEMS/NEMS processes and capable of direct printing on many flexible and stretchable substrates, such as polyethylene terephthalate (PET), polyimide (PI), polydimethylsiloxane (PDMS), thermoplastic polyurethane (TPU) and paper [17–19]. However, these approaches are also limited by product throughputs and yields, making it very difficult to manufacture hybrid devices in a manner that would allow for their mass adoption [17]. For instance, aerosol jet printing has demonstrated very high print resolutions and control over material heights and microarchitectures, but the additive deposition of numerous nano thickness layers makes it by necessity a low-speed manufacturing option [20]. Inkjet printing is another attractive printing method, but it is limited by the requirement that particles are small and well dispersed enough not to clog the inkjet nozzle, and traditional inkjet printing is also too low throughput for industrial scales [17,21]. However, roll-to-roll inkjet printing has been demonstrated, making it a potential target for high-speed device manufacturing [22]. Electrohydrodynamic printing is an exciting new method that can overcome several of the key challenges in inkjet printing by pulling ionized inks directly to the substrate, but it is likewise limited by constrictive stand-off height requirements and low manufacturing yields [21]. In contrast, contact printing methods, such as screen, gravure, flexographic, slot die, and doctor blade printing are easily integrated with high throughput roll to roll systems, making them an excellent option for industrial scale hybrid bioelectronics manufacturing. A summary of each of the high throughput nanomaterial fabrication methods discussed in this review is provided in Table 1 [17,23–32].

There are four crucial design challenges that must be met to make high throughput manufacturing of hybrid bioelectronics a reality, as depicted in Figure 1 [16,33–39], and all four are highly interdependent on each other. First, conductive nanomaterials must be identified and produced based on the final application requirements. Second, these nanomaterials must be dispersed in a fully printable ink with rheology and viscosity well suited to the specific printing method. Third, innovative manufacturing techniques must be explored that can achieve scales suited for mass production. Finally, the printed inks must be sintered and cured after printing in a way that does not limit manufacturing speed.

In this review, we will summarize recent attempts to develop high-throughput manufacturing of nanomaterials for hybrid bioelectronics, with a specific focus on new printing methods, nanomaterial selection, synthesis, dispersion and printing, post-print processing and demonstrated applications. We will begin with a discussion on several of the key manufacturing methods under investigation, emphasizing how deposition physics leads

to key constraints on ink design, print resolutions, deposition heights, device yield, and print speed and novel approaches to push the field beyond its traditional limitations. Next, we will summarize the key nanomaterials that are used in printed bioelectronics. For each material, we will summarize the key mechanical, chemical, and electrical properties that determine the material's functionality, recent advances, and challenges in ink formulations, demonstrated bioelectronics devices fabricated with high throughput methods, and novel high throughput sintering methods. Finally, we will comment on the state-of-the-art in the field, assess the key limitations yet to be solved, and look forward to the future development of high-throughput nanomaterial manufacturing for soft bioelectronics.

**Figure 1.** Overview of high-throughput nanomaterial fabrication methods and applications in soft bioelectronics. (Figures are adapted or reprinted, clockwise from the top: (1) *RSC Adv.* (2013), 3, 24812, Copyright 2013, RSC, (2) *J. Nanoparticle Res.* (2016), 18, 285, Copyright 2106, Springer, (3,7) *Ind. Eng. Chem. Res.* (2019), 58, 43, 19909–19916, Copyright 2019, ACS, (4) *Adv. Mater. Interfaces* (2018), 5, 1701561. Copyright 2018, Wiley, (5) *Adv. Mater.* (2019), 31, 1806702. Copyright 2020, Wiley, (6) Creative Commons License CC BY from *J. Electrochem. Soc*. (2018), 165 B3084, (8) *ACS Appl. Mater. Interfaces* (2020), 12, 4146797–46803. Copyright 2020, ACS, (10) Creative Commons license CC BY from *Sci. Rep.* (2017), 7(1)).


**Table 1.**Summary of nanomaterial fabrication methods with key advantages and limitations.
