Protein-Based Bioelectronics - ACS Biomaterials Science & Engineering

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Protein Based Bioelectronics Maria Torculas, Jethro Medina, Wei Xue, and Xiao Hu ACS Biomater. Sci. Eng., Just Accepted Manuscript • DOI: 10.1021/acsbiomaterials.6b00119 • Publication Date (Web): 20 Jun 2016 Downloaded from http://pubs.acs.org on June 25, 2016

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ACS Biomaterials Science & Engineering

Protein Based Bioelectronics Maria Torculas,†,‡,¶,# Jethro Medina,†,§,¶,# Wei Xue,†,¶ and Xiao Hu∗,†,k,⊥ Department of Physics and Astronomy, Rowan University, 201 Mullica Hill Rd., Glassboro, NJ, USA, Department of Electrical and Computer Engineering, Rowan University, 201 Mullica Hill Rd., Glassboro, NJ, USA, Department of Mechanical Engineering, Rowan University, 201 Mullica Hill Rd., Glassboro, NJ, USA, Department of Chemical Engineering, Rowan University, 201 Mullica Hill Rd., Glassboro, NJ, USA, Department of Biomedical and Translational Sciences, Rowan University, 201 Mullica Hill Rd., Glassboro, NJ, USA, and Department of Biomedical Engineering, Rowan University, 201 Mullica Hill Rd., Glassboro, NJ, USA E-mail: [email protected] Phone: 1-856-256-4860. Fax: 1-856-256-4478

Abstract The desire for flexible electronics is booming, and development of bioelectronics for health monitoring, internal body procedures, and other biomedical applications is heavily responsible for the growing market. Most current fabrication techniques for flexible bioelectronics, however, do not use materials that optimize both biocompatibility and mechanical properties. This review explores flexible electronic technologies, ∗

To whom correspondence should be addressed Department of Physics and Astronomy ‡ Department of Electrical and Computer Engineering ¶ Department of Mechanical Engineering § Department of Chemical Engineering k Department of Biomedical and Translational Sciences ⊥ Department of Biomedical Engineering # Contributed equally to this work †

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fabrication methods, and protein materials for biomedical applications. With favorable sustainability and biocompatibility, naturally-derived proteins are an exceptional alternative to synthetic materials currently used. Many proteins can take on various forms, such as fibers, films, and scaffolds. The fabrication of resistors and organic solar cells on silk has already been proven, and optoelectronics made of collagen and keratin have also been explored. The flexibility and biocompatibility of these materials along with their proven performance in electronics make them ideal materials in the advancement of biomedical devices.

Keywords flexible electronics, silk, collagen, keratin, elastin, protein substrate

Introduction The versatility of flexible electronics is certainly alluring, and research into the field has been on the rise. There has also been growing demand for such devices in health monitoring. Examples of bendable electronics that have been made include integrated circuits photovoltaic cells, light-emitting diodes (LEDs), and paper-like displays. 1–3 One of the biggest challenges to designing these new electronic systems is determining the optimum material. While some materials may offer preferable performance and ideal mechanical characteristics, in the long run, many of the manufacturing methods and created devices are not sustainable. Naturally occurring materials are of particular interest because of their sustainability, and the use of natural materials in electronics has been explored for decades. The performance of organic materials has been increasing significantly and can now be compared to the plastics, semiconductors, and other inorganic substrates currently used in most electronics. 4 Melanin, a naturally occurring pigmentary polymer, is an example of an organic materials that was determined to be an electric conductor in the 1970s. 5 In addition to conductivity,

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melanin was also proven to be capable of bistable switching, and has been touted as the first organic electronic device. 5 Polysaccharide nanocomposites have also been explored as a substrate for soft electronics, since the diversity in their molecular structures gives many options in the physical tunability of the resultant films. 6 Flexible electronic decals have been constructed using a combination of insoluble nanocrystalline sugar composites and watersoluble sugars that act as support. 7 Attempts have even been made to evaluate the usability of natural substrates, such as paper, which is made from plant-derived cellulose, 8 in electronics. There have been several reported methods for using paper in photovoltaics. Cellulose paper, however, has its fair share of drawbacks, particularly concerning mechanical integrity. 8 In trying to match the performance of synthetic materials, qualities such as biodegradability and biocompatibility are often neglected. 8 This poses a problem in terms of human usability for the devices created. However, protein materials are low cost and biodegradable, and a wide variety of macromolecular structures means they also have a long, diverse history of use outside of the realm of electronics 2 in applications that include films and scaffolds for tissue engineering. This review focuses on silk, collagen, keratin, elastin, and reflectin as natural protein materials that can be used in future bioelectronics and processed in a similar manner. For example, silk is a biopolymer that contains good mechanical properties ideal for biomedical purposes, and it can be used in many biodegradable applications. 9 The most commonly used type of silk is taken from Bombyx mori (silkworm) cocoons, which has been used for centuries in suturing applications. Collagen is an extracellular matrix (ECM) protein in connective tissue, such as skin and bone. 10 Keratin is found in in human skin, hair and teeth, posessing variable mechanical properties for bioelectronics. 11 Elastin is an essential protein found in the ECM of various flexible tissues. 12 Reflectin protein is found in the reflective skin tissue of squid, ideal for optics applications. 13 This review will summarize a few existing methods of manufacturing flexible electronics

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and problems associated with common materials used in flexible bioelectronics. It will also explain why the proteins mentioned are ideal biomaterials for future use in flexible electronics - specifically as flexible substrates - and describe a range of potential applications.

Flexible Bioelectronics The wearable technology industry, known also as ”wearables”, is a broad term that refers to electronics that can be worn on the body. These technologies come in different forms: disguised devices, integrated with jewelry and accessories, implantable devices, and smart clothing. 14 The convenience of wearable electronics for applications such as health monitoring and fitness tracking has encouraged research into flexible electronics that can be wrapped around various surfaces, contoured around nonlinear shapes, or woven directly into textiles. Traditional technologies use rigid silicon wafers 15 in the fabrication of integrated circuits, and with these wafers it is extremely challenging to achieve the levels of versatility necessary for continued growth in the wearables industry. However, thanks to new advances in materials, it is possible to create flexible circuits that can be used in applications inherently impossible for the planar integrated circuits available currently. 16 New research into flexible technology is fast growing in the last decade. 17–19 In August of 2015, the US Secretary of Defense announced a new Manufacturing Innovation Institute for Flexible Hybrid Electronics in San Jose, CA, with a total investment of over $171 million. This hub will lead a consortium of 162 companies, nonprofits, labs and universities 20 with the aim of pushing the limits of research in flexible electronics. Figure 1 shows the projected changes in the different ways flexible electronics are expected to be used. These new applications for electronic components are only possible with further research into bendable technology. 18,19 As development in flexible electronics rises, the applications become more diverse. One field that should expect growth is bioelectronics, where such technology will change the ways

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Another important step is the generation of power for such devices. 28 For medical devices in particular, the need for sustainable energy is paramount. Batteries play a large role in powering implantable biomedical devices. These systems primarily use lithium-ion complexes, utilizing iodine, manganese oxide, carbon monofluoride, and other cathodes. Lithium-iodine systems are used primarily for powering in the microampere range. When heated, the cell battery material reacts, producing a charge transfer complex. 29 Lithium-manganese dioxide systems power devices in the milliwatt range. This battery type is commonly used due to its high storage and energy distance. Lithium-carbon monofluoride batteries also power devices in the milliampere range as well. With low self-discharge, it is considered a ”medium rate power source”. 29 Other battery types have been developed, accounting for energy sustainability by being able to charge while implanted. Advances in battery-related technology are slowing down, opening up many opportunities to explore alternative energy sources such as biocompatible energy harvesters. These devices, for example, could harvest the body’s kinetic energy (from body motion). 30 Different transducers convert kinetic energy to electric using the following methods: piezoelectric, magnetic induction generator, or electrostatic transduction methods. Potential external sources of energy include energy transfer wirelessly or using thermal or solar sources.

Protein Materials Material Overview Interest in using proteins for bioelectronics has grown rapidly due to their sustainable nature. 25 Silkworm silk, for instance, is easily derived from the cocoons of the appropriate moth larvae as they undergo metamorphosis while spider silk can be extracted directly from the spiders themselves. Keratin can be isolated from different animal hairs. Collagen has been extracted from fish scales 31 as well as tissues and hairs from many different sources. All of these examples have been incorporated into various optical, electrical, and pharmaceutical 9



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applications. Different ways of processing these fibrous proteins allow for a wide variety of applications depending on the structures formed after preparation, 32 as seen in Table 1. Table 1: Different applications of proteins in bioelectronics 33 Structure

Description

Processing Method

Applications

Films

Thin sheets of protein material

Protein cast upon molding substrate; Water is evaporated to form film structure

Sensors, optics, electrical insulation, substrates, drug stabilization, tube formation, nerve regeneration, corneal tissue

11,13,34

Electrospun fibers

Fibrous mat or scaffolds of nano- to micro- sized fiber diameters

Protein solution ejected onto flat or tubular surface through electrostatic charge differential

Wound healing, cardiovascular grafts, soft tissue repair, peripheral nerve regeneration

35,36

Native fibers

Ropes or fibrous mats; uniaxial strength

Boiled in sodium carbonate solution; Dried; Extracted from natural source

Ligament, tendon, and soft tissue repair

Sponge scaffolds

Porous molded scaffolds

Protein solution blended with leachable solutes, cast with mold, then leached using appropriate solvent system

Bone, cartilage, soft tissue repair, adipose

Hydrogels

Filamentous scaffold large amounts of water

Protein solution agitated (e.g. ultrasonic cavitation or vortex mixing), resulting in gelation

Dermal void filling, cell encapsulation, intervertebral disc

Protein solution dissolved with solvent system and post processed to produce desired particle sizes

Drug delivery, vascular applications, chemical processing

with

Microspheres Nano- to micro- size spheres

References

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38,39

Silk in particular has been used in tissue and ligament repair, 40 artificial blood vessels, biosensors, and nerve regenerators. Silk for such technology is obtained from spiders and silkworms. Different silkworm varieties, such as Bombyx mori, Tussah, and Eri silkworms, have produced silk used for the applications. 41 There has been extensive research on B. mori silk. 41 Although the most popular, other types of silk exist as well. Regarding spider silk, the most common spiders studied include Nephilia clavipes and Araneus diadematus. 42 Although spider silk has a long history in the textile industry, biomedical applications are relatively new. Collagen belongs to a family of proteins responsible for maintaining the structural integrity of tissues and supporting cell growth, particularly in vertebrates. 10 Type 1 collagen is an integral component of extracellular matrices, such as in skin, bone, corneas, and other 10


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connective tissue. 10 Biocompatibility of collagen-based bioelectronics is high due to its presence in the human body. 27,43,44 Keratin is a protein found in human skin, hair, and teeth. Depending on the amino acid levels, keratin can vary in its softness and smoothness. 11 For example, the epidermis is composed primarily of keratinocytes, which contain keratin filaments. The filaments are in dense bundles of varying thicknesses. Keratin is imperative in maintaining the mechanical and thermal properties of skin. 11 Elastin is a protein prevalent in the extracellular matrices of various flexible tissues. 12 More specifically, elastin is a major component of elastic fibers with a crosslinked heavy structure. Elastin is insoluble in nature, 12 driving research into elastin derivatives such as tropoelastin that are more soluble. In addition to advantageous structural properties, elastin enhances cell signaling. For example, elastin-based materials are ideal for applications in vascular stent material, 45 enhancing cell growth and increasing the biocompatibility of the stent material. Reflectin is a protein found in a species of bobtail squid, Euprymna scolopes, and in other cephalopods. The protein is located in the reflective skin tissue of the squid, 13 and similar proteins have been found in the embryos of the cuttlefish Sepia officinalis. The amino acid sequence of natural reflectin proteins was determined, easing the identification process from their source. The natural morphology of the reflectin tissue was also observed. With the chemical and physical characterization of these reflectin proteins, 46 it is easier to determine their potential applications, such as being processed into films for potential optics applications. 13 Cephalopods are well known for their rapid camouflage abilities; the construction of reflectin films represents one attempt to mimic natural photonic structures and to create an ideal material for light transmission to be used in optical bioelectronics. With varying morphologies and self-organizing properties, reflectin has the potential to grow in its applicable fields. In regards to protein component, silk is mainly made up of three amino acids, glycine,

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serine, and alanine. Due to a combination of polar (serine, glycine) and nonpolar (alanine) amino acids in the structure, silk can be dissolved in numerous solvents for film fabrication. Collagen is mainly composed of the following amino acids: glycine, proline (and hydroxyproline), and arginine. Being composed primarily of three nonpolar (glycine, prline, hydroxyproline) amino acids, nonpolar solvents would be the best candidates for materials generation. Reflectin is composed primarily of relatively rare amino acids: tyrosine, methionine, arginine, and tryptophan. 46 With a combination of polar and nonpolar amino acids, reflectin has affinity to both polar and nonpolar solvents. The amino acid composition of keratin 23 is primarily glycine and alanine. With a composition of two nonpolar residues, nonpolar solvents are ideal for fabricating keratin-based films.

Preparation Bombyx mori silk, as previously stated, is the most commonly used silk for biomedical applications, and its preparation is well-documented. The process begins by separating silk fibers from the silkworm cocoons through degumming. 47 The degumming process involves soaking the cocoons in a boiling water and salt solution, separating the fibers from other proteins. Most silk consists of two main proteins, fibroin (70 - 80 mol%) and sericin (20 - 30 mol%). Sericin is highly soluble in hot water and can be separated from the fibroin. Other substances separated through the degumming include waxes, carbohydrates, and inorganic material. 48 The fibers are then rinsed using distilled water after about 20 minutes in the hot water bath. It should be noted that the preparation process of other natural fibrous proteins is almost universal. For instance, it can be seen in Figure 5 that the isolation and casting of keratin derived from cashmere wool follows an almost identical process to silk. 25 The first steps of preparing silk for use are to remove sericin and dirt by boiling the cocoons and allowing them to dry; likewise, the wool hairs are also boiled to remove outside impurities. 25 This is a process known as degumming. After degumming, the fibers are dissolved in the appropriate 12


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Through PLD, the target keratin material is vaporized by a laser and is deposited onto a substrate to become a thin film. 23 Collagen-based films were fabricated and tested for used in various types of flexible electronics. 57 Collagen films are fabricated similarly to silk films. Pulse laser deposition has also been used to make collagen thin films. 23 From infrared spectroscopy and atomic force microscopy, collagen properties were maintained after laser treatment. Elastin composites with other proteins further widen its applications. Crimping collagen and elastin material together, for example, enhance mechanical and structural properties preferable for tissue engineering. 58 Crimped fibers were attached to an acrylic plate, then reinforced by elastin.

Protein Biocompatibility Biocompatibility is one of the key advantages of using natural materials such as proteinbased natural materials. Protein is an ideal biomaterial due to its adaptability to different types of environments. For example, when incorporating silk scaffolds for bone and other tissue engineering applications, the scaffolds can be made with a high compressive modulus and high compressive strength to mimic bone. 40 Silk fibroin was freeze-dried, mixed with potassium bromide, and pressed into pellets. Pellet morphologies, cell adhesion, cylindrical shape, and porosities were analyzed in order to compare to bone tissue. Mechanical strength, compressibility, and other aspects were determined to compare to bone tissue as well. 40 The scaffolds showed adequate cell adhesion for a highly porous material with a high compressive modulus and compressive strength. Silk fibroin also exhibits minimized immune response when implanted, as shown by limited presence of macrophages or antibodies. 59–61 A study comparing the immune response of silk, collagen, and PLA materials both in vitro (using human-derived bone marrow mesenchymal stem cells) and in vivo (using implanted rat-derived mesenchymal stem cells) has shown that silk elicits a far smaller immune response than the other materials tested. 61 Com16


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paratively, more macrophages were present around the collagen implant, implying a more pronounced immune response. 61 An in-depth exploration on the biocompatibility of different types of collagens for different implant applications showed that allogeneic collagen grafts show minimal immune response. 27 Even xenogeneic collagen grafts do not necessarily spur implant rejection: The presence of antibodies, which is a sign of some sort of immune response, may in fact be a harmless side effect. 27,44 Likewise, keratin hydrogels and scaffolds have been shown to allow fibroblast proliferation in vitro, 62 and it has even been proven that keratin biomaterials have encouraged increased anti-inflammatory macrophage response. 63 Implanted xenogeneic elastin scaffolds have also shown little immune response. 44 Elastincoated polymers have tissue engineering and bioelectronic applications as well. Polypropylene fumarate (PPF) material has suitable mechanical properties, such as flexibility and strength, and biodegradability. Due to its inert nature, it can be enhanced by an elastin coating to elicit physiological functionality in its surrounding area. 45 With elastin promoting cell growth, for example, elastin-coated PPF can be used to fabricate ideal stents with controlled drug elution, cell growth promotion, high biocompatibility, and biodegradation. 45 Although reflectin has not been studied in as much depth as the other mentioned proteins, it has still been shown to facilitate the growth of neural stem cells. 64

Mechanical Properties As biomaterials, these proteins possess favorable qualities, mechanically and biologically. Table 2 compares modulus and break strain values for silkworm silk, spider silk, collagen, keratin, and polylactic acid (PLA). The greater the modulus, the greater force must be applied to stretch or compress the material to the same extent. Deforming a silk-based material will require more force than collagen and PLA. The break strain value for both B. mori silk and spider silk are greater than that of PLA, portraying the higher durability of silk materials. 4 17



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Table 2: Comparison of mechanical properties of protein materials. (Recreated with permission from. 4 Copyright (2012) John Wiley & Sons). Material Modulus [GPa] Collagen 0.0018-0.046 Cross-linked Collagen 0.4-0.8 ◦ 65 Keratin (50 C) 0.276-0.424 Keratin (70 ◦ C) 66 0.617-0.777 Polylactic Acid 1.2-3.0 B. mori (w/ sericin)1 5-12 1 B. mori (w/o sericin) 15-17 N. clavipes silk 11-13 1

Break Strain [%] 24-68 12-16 5-7 1.6-2.6 2-6 19 4-16 17-18

UTS [MPa] 0.9-7.4 47-72 19-33 9.2-13.8 28-50 500 610-690 875-972

Sericin is a protein separated from silk fibers during degumming

Integration of Substrate and Electronics One of the key challenges in protein bioelectronics research is the mismatch between the soft substrates and the rigid electronic components. 67 In protein-based electronic systems, the protein substrates are highly flexible and stretchable, allowing a large amount of deformation. By comparison, many of the electronic components are fabricated with inorganic materials such as silicon, gold, and SiO2. These materials are inherently rigid and brittle with their fracture strain values limited to 1% or lower. This challenge has led to multiple studies on the adhesion properties of inorganic materials on flexible substrates. 67–70 The mechanics of flexible and stretchable electronics have been investigated both experimentally and theoretically. 71–73 The mechanics of a device will change depending on the application and the amount of deformation needed. 72 Some electronic systems can be simplified and modeled as a beam under pure bending. The flexed beam has a neutral plane where the strain remains zero. 72 The structures above the neutral plane are under tension and the ones below are under compression, or vice versa. The tensile/compressive strain ǫ of a particular structure, which is proportional to its distance from the neutral plane, can be seen in Equation 1.

ǫ= 18

y ρ


(1)

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In Equation 1, y is the distance between the structure and the neutral plane and ρ is the bending radius of the neutral plane. Therefore, in traditional flexible electronic designs, it is recommended that the brittle components should be placed along or very close to the neutral plane. This can reduce the overall deformation of the brittle structures. The beam theory can be adjusted for flexible electronics with multiple layers. Multiple neutral planes can appear in a layered structure due to large shear strain between adjacent layers. This multi-neutral-plane theory has been validated by analytical approaches, finiteelement modeling (FEM), and experimental results. 74 The strain distribution of a tri-layer structure can be seen in Equation 2.

ε=

   y1 −d1  ,  ρ    (

h2 h h h −y1 )( 21 −d1 )−( 22 +y1 )( 21 +d2 ) 2 ρh2

       ys −ds , ρ

if −

h1 2

< y1

Protein-Based Bioelectronics - ACS Biomaterials Science & Engineering

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