Tissues and cells in our body are strongly affected by electrical signals, such as electrical field and current, and at the same time utilize electrical signals as important factors that control physiological conditions [13]. For example, embryonic body development and tissue regeneration are known to involve electrical signals [14]. The simple examples include electrically excitable cells, such as neurons, cardiomyocytes, myoblasts, utilize electrical signals for the inherent functions [15]. Surprisingly, recent studies have revealed that other types of cells, such as stem cells, also respond to electrical stimulation and exhibit various cell behaviors [16]. Accordingly, there have been growing attentions to an effective way to deliver or record electrical signals to or from biological systems. To effectively mediate electrical signals between electrical sources (e.g., electrodes) and biological systems, materials that possess good electrical conductivity are required. Various conductive materials, including metals, metal oxides, carbon nanomaterials, and conductive polymers, have been extensively utilized to construct conductive interfaces. Among them, electrically conductive materials, polypyrrole (PPy), polythiophene (PT), and PEDOT, are conductive organic materials [17]. Compared to other conductive materials, these conductive polymers offer some important advantages, such as biocompatibility, ease in modification, lower rigidity, and redox activity. Consequently, these conductive polymers have been widely used as a whole materials or components in tissue scaffolds, sensors, biolectrodes, and so forth.
Native tissue and its environments are highly organized and their properties are harmonized to permit cues modulating biological activities. Depending on the physiological and pathological states, native environments actively respond and dynamically change their composition, structures, and bioactivities [18]. Therefore, profound effects have been made to incorporate the properties of the native environments such as ECM into biomaterials to create ‘artificial’ environments, of which strategy is known as ‘biomimetics’. Likewise, electrically conductive polymers can be tailored to delivery additional cues that the native tissues present. This approach will benefit the production of effective materials for a wide range of applications, such as regenerative medicine and long-term biocompatibility of the implants. In addition to electrical activity, important factors to be considered in fabricating biomimetic conductive biomaterials include mechanical rigidity, structures, and bioactivities. Note that biomimetic conductive materials should be designed and fabricated to achieve the best responses depending on the target biological system.
First, in comparison with the rigidity of conductive polymers (> MPa), the most tissues are softness with a few Pa (brain tissues) to kPa except bone [19]. This mechanical mismatch not only causes poor direction of cellular responses but also inflammatory tissue reactions [20]. For example, cells and tissues, especially stem cells, generally exhibit the fast and specified growth and differentiation when cultured with the materials present similar mechanical properties to the native tissues [21]. Hence, this indicates the needs of developing softer and flexible conductive materials. To this end, composite hybrid materials were fabricated by mixing or growing conductive polymers with elastic materials or hydrogels. Interestingly, conductive hydrogels can mimic the mechanical softness of the native soft tissues by presenting tens of kPa of Young’s modulus [22]. Yet, lowering the rigidity accompanies the impairment of electrical conductivities, which has to be overcome in the future studies. Still, since some biomedical applications need small currents, the conductive hydrogels will be useful.
Another important property is a structure, which can serve as biomimetic features of extracellular matrices including porosity, nano-/micro-structures, and orientation [23]. Advances in technologies enable the fabrication of such structurally effective conductive materials, which allow for the production of biologically important subcellular scaled features. For example, electron beam lithographic patterns of PPy could facilitate the polarization of embryonic hippocampal neurons [24]. Also, various fibrous structures of conductive polymers could be obtained by direct electrospinning, phase separation, and nano-coating of nanofibrous mats [25]. Interestingly, recent studies done by Hardy et al. demonstrated the enhanced osteogenesis of human mesenchymal stem cells cultured on PPy-silk nanofibers by electrical stimulation [26], suggesting the cooperative or additive roles of topographical cues and electrical cues as biomimetic functional materials. Likewise, a variety of conductive nanofibers have been produced for different types of cells.
Lastly, various biological active molecules are to be immobilized in/or conductive polymers by physical or chemical fashions. Since the effect interactions are often mediated by receptor-ligand binding, it will be critical to fabricate biologically active conductive materials by immobilizing ECM proteins, polysaccharides, and growth factors. In particular, anioinic proteins and mucopolysaccharides can be doped into oxidized conductive polymers, which can be easily produced during polymerization processes of conductive polymers [27]. Covalent immobilization of ECM proteins and growth factors enables prolonged interactions with cells without substantial consumption and signal regulation via binding with integrins and tyrosine kinase receptors, respectively. These signaling pathways finally affect gene expression levels of various genes related with proliferation, survival, and differentiation. For example, nerve growth factor immobilization onto conductive polymers have been attempted to enhance neural cell differentiation [28]. Interestingly, growth factors and electrical stimulation through conductive scaffolds could act together to induce the neurite formation and elongation. In addition, various ECM-derived peptides (e.g., Arg-Gly-Asp) were also incorporated into conductive polymer scaffolds to better mimic the native ECM, which could support attachment, growth and differentiation of various cells, such as neural cells [29], endothelial cells [30], cardiac cells [31], and fibroblasts [32]. For example, cell membrane mimicking conductive polymer having IKVAV (Ile-Lys-Val-Ala-Val) peptide and phosphorylcholine promoted neurite outgrowth and protein secretion on neural cells [33].
In summary, biomimetic conductive polymers can offer great promise to actively modulate biological systems. Still, better mimicry of characteristics of the target tissues and their demonstration will be desirable. High performance conductive polymer-based biomaterials will be greatly beneficial for applications of tissue engineering, drug delivery, and biocompatible bioelectrodes.
