Engineering Proteins for PEDOT Dispersions: A New Horizon for Highly Mixed Ionic-Electronic Biocompatible Conducting Materials.

Poly (3,4-ethylenedioxythiophene) (PEDOT) doped with polystyrene sulfonate (PSS) is the most used conducting polymer from energy to biomedical applications. Despite its exceptional properties, there is a need for developing new materials that can improve some of its inherent limitations, e.g., biocompatibility. In this context, doping PEDOT is propose with a robust recombinant protein with tunable properties, the consensus tetratricopeptide repeated protein (CTPR). The doping consists of an oxidative polymerization, where the PEDOT chains are stabilized by the negative charges of the CTPR protein. CTPR proteins are evaluated with three different lengths (3, 10, and 20 identical CTPR units) and optimized varied synthetic conditions. These findings revealed higher doping rate and oxidized state of the PEDOT chains when doped with the smallest scaffold (CTPR3). These PEDOT:CTPR hybrids possess ionic and electronic conductivity. Notably, PEDOT:CTPR3 displayed an electronic conductivity of 0.016 S cm-1, higher than any other reported protein-doped PEDOT. This result places PEDOT:CTPR3 at the level of PEDOT-biopolymer hybrids, and brings it closer in performance to PEDOT:PSS gold standard. Furthermore, PEDOT:CTPR3 dispersion is successfully optimized for inkjet printing, preserving its electroactivity properties after printing. This approach opens the door to the use of these novel hybrids for bioelectronics.

Advances in Conductive Hydrogel for Spinal Cord Injury Repair and Regeneration.

Spinal cord injury (SCI) treatment represents a major challenge in clinical practice. In recent years, the rapid development of neural tissue engineering technology has provided a new therapeutic approach for spinal cord injury repair. Implanting functionalized electroconductive hydrogels (ECH) in the injury area has been shown to promote axonal regeneration and facilitate the generation of neuronal circuits by reshaping the microenvironment of SCI. ECH not only facilitate intercellular electrical signaling but, when combined with electrical stimulation, enable the transmission of electrical signals to electroactive tissue and activate bioelectric signaling pathways, thereby promoting neural tissue repair. Therefore, the implantation of ECH into damaged tissues can effectively restore physiological functions related to electrical conduction. This article focuses on the dynamic pathophysiological changes in the SCI microenvironment and discusses the mechanisms of electrical stimulation/signal in the process of SCI repair. By examining electrical activity during nerve repair, we provide insights into the mechanisms behind electrical stimulation and signaling during SCI repair. We classify conductive biomaterials, and offer an overview of the current applications and research progress of conductive hydrogels in spinal cord repair and regeneration, aiming to provide a reference for future explorations and developments in spinal cord regeneration strategies.

Bioelectricity-coupling patches for repairing impaired myocardium.

Cardiac abnormalities, which account for extensive burdens on public health and economy, drive necessary attempts to revolutionize the traditional therapeutic system. Advances in cardiac tissue engineering have expanded a highly efficacious platform to address cardiovascular events, especially cardiac infarction. Current efforts to overcome biocompatible limitations highlight the constructs of a conductive cardiac patch to accelerate the industrial and clinical landscape that is amenable for patient-accurate therapy, regenerative medicine, disease modeling, and drug delivery. With the notion that cardiac tissue synchronically contracts triggered by electrical pulses, the cardiac patches based on conductive materials are developed and treated on the dysfunctional heart. In this review, we systematically summarize distinct conductive materials serving as the most promising alternatives (conductive nanomaterials, conductive polymers, piezoelectric polymers, and ionic electrolytes) to achieve electric signal transmission and engineered cardiac tissues. Existing applications are discussed considering how these patches containing conductive candidates are fabricated into diverse forms with major strategies. Ultimately, we try to define a new concept as a bioelectricity-coupling patch that provides a favorable cardiac micro-environment for cardiac functional activities. Underlying challenges and prospects are presented regarding industrial processing and cardiovascular treatment of conductive patch progress. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease.

Conductive biomaterials for cardiac repair: A review.

Myocardial infarction (MI) is one of the fatal diseases in humans. Its incidence is constantly increasing annually all over the world. The problem is accompanied by the limited regenerative capacity of cardiomyocytes, yielding fibrous scar tissue formation. The propagation of electrical impulses in such tissue is severely hampered, negatively influencing the normal heart pumping function. Thus, reconstruction of the internal cardiac electrical connection is currently a major concern of myocardial repair. Conductive biomaterials with or without cell loading were extensively investigated to address this problem. This article introduces a detailed overview of the recent progress in conductive biomaterials and fabrication methods of conductive scaffolds for cardiac repair. After that, the advances in myocardial tissue construction in vitro by the restoration of intercellular communication and simulation of the dynamic electrophysiological environment are systematically reviewed. Furthermore, the latest trend in the study of cardiac repair in vivo using various conductive patches is summarized. Finally, we discuss the achievements and shortcomings of the existing conductive biomaterials and the properties of an ideal conductive patch for myocardial repair. We hope this review will help readers understand the importance and usefulness of conductive biomaterials in cardiac repair and inspire researchers to design and develop new conductive patches to meet the clinical requirements. STATEMENT OF SIGNIFICANCE: After myocardial infarction, the infarcted myocardial area is gradually replaced by heterogeneous fibrous tissue with inferior conduction properties, resulting in arrhythmia and heart remodeling. Conductive biomaterials have been extensively adopted to solve the problem. Summarizing the relevant literature, this review presents an overview of the types and fabrication methods of conductive biomaterials, and focally discusses the recent advances in myocardial tissue construction in vitro and myocardial repair in vivo, which is rarely covered in previous reviews. As well, the deficiencies of the existing conductive patches and their construction strategies for myocardial repair are discussed as well as the improving directions. Confidently, the readers of this review would appreciate advantages and current limitations of conductive biomaterials/patches in cardiac repair.

Regenerative rehabilitation with conductive biomaterials for spinal cord injury.

The individual approaches of regenerative medicine efforts alone and rehabilitation efforts alone have not yet fully restored function after severe spinal cord injury (SCI). Regenerative rehabilitation may be leveraged to promote regeneration of the spinal cord tissue, and promote reorganization of the regenerated neural pathways and intact spinal circuits for better functional recovery for SCI. Conductive biomaterials may be a linchpin that empowers the synergy between regenerative medicine and rehabilitation approaches, as electrical stimulation applied to the spinal cord could facilitate neural reorganization. In this review, we discuss current regenerative medicine approaches in clinical trials and the rehabilitation, or neuromodulation, approaches for SCI, along with their respective translational limitations. Furthermore, we review the translational potential, in a surgical context, of conductive biomaterials (e.g., conductive polymers, carbon-based materials, metallic nanoparticle-based materials) as they pertain to SCI. While pre-formed scaffolds may be difficult to translate to human contusion SCIs, injectable composites that contain blended conductive components and can form within the injury may be more translational. However, given that there are currently no in vivo SCI studies that evaluated conductive materials combined with rehabilitation approaches, we discuss several limitations of conductive biomaterials, including demonstrating safety and efficacy, that will need to be addressed in the future for conductive biomaterials to become SCI therapeutics. Even so, the use of conductive biomaterials creates a synergistic opportunity to merge the fields of regenerative medicine and rehabilitation and redefine what regenerative rehabilitation means for the spinal cord. STATEMENT OF SIGNIFICANCE: For spinal cord injury (SCI), the individual approaches of regenerative medicine and rehabilitation are insufficient to fully restore functional recovery; however, the goal of regenerative rehabilitation is to combine these two disparate fields to maximize the functional outcomes. Concepts similar to regenerative rehabilitation for SCI have been discussed in several reviews, but for the first time, this review considers how conductive biomaterials may synergize the two approaches. We cover current regenerative medicine and rehabilitation approaches for SCI, and the translational advantages and disadvantages, in a surgical context, of conductive biomaterials used in biomedical applications that may be additionally applied to SCI. Furthermore, we identify the current limitations and translational challenges for conductive biomaterials before they may become therapeutics for SCI.

Electroconductive biomaterials for cardiac tissue engineering.

Myocardial infarction (MI) is still the leading cause of mortality worldwide. The success of cell-based therapies and tissue engineering strategies for treatment of injured myocardium have been notably hindered due to the limitations associated with the selection of a proper cell source, lack of engraftment of engineered tissues and biomaterials with the host myocardium, limited vascularity, as well as immaturity of the injected cells. The first-generation approaches in cardiac tissue engineering (cTE) have mainly relied on the use of desired cells (e.g., stem cells) along with non-conductive natural or synthetic biomaterials for in vitro construction and maturation of functional cardiac tissues, followed by testing the efficacy of the engineered tissues in vivo. However, to better recapitulate the native characteristics and conductivity of the cardiac muscle, recent approaches have utilized electroconductive biomaterials or nanomaterial components within engineered cardiac tissues. This review article will cover the recent advancements in the use of electrically conductive biomaterials in cTE. The specific emphasis will be placed on the use of different types of nanomaterials such as gold nanoparticles (GNPs), silicon-derived nanomaterials, carbon-based nanomaterials (CBNs), as well as electroconductive polymers (ECPs) for engineering of functional and electrically conductive cardiac tissues. We will also cover the recent progress in the use of engineered electroconductive tissues for in vivo cardiac regeneration applications. We will discuss the opportunities and challenges of each approach and provide our perspectives on potential avenues for enhanced cTE. STATEMENT OF SIGNIFICANCE: Myocardial infarction (MI) is still the primary cause of death worldwide. Over the past decade, electroconductive biomaterials have increasingly been applied in the field of cardiac tissue engineering. This review article provides the readers with the leading advances in the in vitro applications of electroconductive biomaterials for cTE along with an in-depth discussion of injectable/transplantable electroconductive biomaterials and their delivery methods for in vivo MI treatment. The article also discusses the knowledge gaps in the field and offers possible novel avenues for improved cardiac tissue engineering.

Engineering Tissues of the Central Nervous System: Interfacing Conductive Biomaterials with Neural Stem/Progenitor Cells.

Conductive biomaterials provide an important control for engineering neural tissues, where electrical stimulation can potentially direct neural stem/progenitor cell (NS/PC) maturation into functional neuronal networks. It is anticipated that stem cell-based therapies to repair damaged central nervous system (CNS) tissues and ex vivo, "tissue chip" models of the CNS and its pathologies will each benefit from the development of biocompatible, biodegradable, and conductive biomaterials. Here, technological advances in conductive biomaterials are reviewed over the past two decades that may facilitate the development of engineered tissues with integrated physiological and electrical functionalities. First, one briefly introduces NS/PCs of the CNS. Then, the significance of incorporating microenvironmental cues, to which NS/PCs are naturally programmed to respond, into biomaterial scaffolds is discussed with a focus on electrical cues. Next, practical design considerations for conductive biomaterials are discussed followed by a review of studies evaluating how conductive biomaterials can be engineered to control NS/PC behavior by mimicking specific functionalities in the CNS microenvironment. Finally, steps researchers can take to move NS/PC-interfacing, conductive materials closer to clinical translation are discussed.

Conductive polypyrrole-encapsulated silk fibroin fibers for cardiac tissue engineering.

Polypyrrole (PPy) has been utilized in smart scaffolds to improve the functionality of the engineered cardiac tissue. Compared to the commonly used aqueous coating, here, PPy was blended into silk fibroin (SF) solution to electrospin conductive PPy-encapsulated SF nanofibers. Combinations of various SF concentrations (5%, 7%, and 12%) and different PPy-to-SF ratios (15:85, 30:70, and 40:60) were compared. PPy reduced the fiber diameter (0.431 ± 0.060 µm), better-mimicking the myocardium fibrils. Conductive mats with 7% SF showed the closest mechanical properties (1.437 ± 0.044 MPa) to the native myocardium; meanwhile, a PPy-to-SF ratio of 15:85 exhibited sufficient electrical conductivity for cardiomyocytes (CMs). In vitro studies using three different types of CM demonstrated that the hybrid mats support CM contraction. Primary neonatal rat CMs on the mat with a PPy-to-SF ratio of 15:85 were elongated and orientated anisotropically with locally organized sarcomeric striations. By contrast, human-induced pluripotent stem cell derived-CMs on the mat with a PPy-to-SF ratio of 30:70 exhibited the strongest contractions. Contraction synchrony was further improved by external stimulation. Taken together, these findings indicated the great potential of the PPy-encapsulated SF electrospun mat for cardiac tissue engineering.

Multifunctional Conductive Biomaterials as Promising Platforms for Cardiac Tissue Engineering.

Adult cardiomyocytes are terminally differentiated cells that result in minimal intrinsic potential for the heart to self-regenerate. The introduction of novel approaches in cardiac tissue engineering aims to repair damages from cardiovascular diseases. Recently, conductive biomaterials such as carbon- and gold-based nanomaterials, conductive polymers, and ceramics that have outstanding electrical conductivity, acceptable mechanical properties, and promoted cell-cell signaling transduction have attracted attention for use in cardiac tissue engineering. Nevertheless, comprehensive classification of conductive biomaterials from the perspective of cardiac cell function is a subject for discussion. In the present review, we classify and summarize the unique properties of conductive biomaterials considered beneficial for cardiac tissue engineering. We attempt to cover recent advances in conductive biomaterials with a particular focus on their effects on cardiac cell functions and proposed mechanisms of action. Finally, current problems, limitations, challenges, and suggested solutions for applications of these biomaterials are presented.

Injectable conductive hydrogel can reduce pacing threshold and enhance efficacy of cardiac pacemaker.

Background: Pacemaker implantation is currently used in patients with symptomatic bradycardia. Since a pacemaker is a lifetime therapeutic device, its energy consumption contributes to battery exhaustion, along with its voltage stimulation resulting in local fibrosis and greater resistance, which are all detrimental to patients. The possible resolution for those clinical issues is an injection of a conductive hydrogel, poly-3-amino-4-methoxybenzoic acid-gelatin (PAMB-G), to reduce the myocardial threshold voltage for pacemaker stimulation. Methods: PAMB-G is synthesized by covalently linking PAMB to gelatin, and its conductivity is measured using two-point resistivity. Rat hearts are injected with gelatin or PAMB-G, and pacing threshold is evaluated using electrocardiogram and cardiac optical mapping. Results: PAMB-G conductivity is 13 times greater than in gelatin. The ex vivo model shows that PAMB-G significantly enhances cardiac tissue stimulation. Injection of PAMB-G into the stimulating electrode location at the myocardium has a 4 times greater reduction of pacing threshold voltage, compared with electrode-only or gelatin-injected tissues. Multi-electrode array mapping reveals that the cardiac conduction velocity of PAMB-G group is significantly faster than the non- or gelatin-injection groups. PAMB-G also reduces pacing threshold voltage in an adenosine-induced atrial-ventricular block rat model. Conclusion: PAMB-G hydrogel reduces cardiac pacing threshold voltage, which is able to enhance pacemaker efficacy.

Self-Assembling Hydrogel Structures for Neural Tissue Repair.

Hydrogel materials have been employed as biological scaffolds for tissue regeneration across a wide range of applications. Their versatility and biomimetic properties make them an optimal choice for treating the complex and delicate milieu of neural tissue damage. Aside from finely tailored hydrogel properties, which aim to mimic healthy physiological tissue, a minimally invasive delivery method is essential to prevent off-target and surgery-related complications. The specific class of injectable hydrogels termed self-assembling peptides (SAPs), provide an ideal combination of in situ polymerization combined with versatility for biofunctionlization, tunable physicochemical properties, and high cytocompatibility. This review identifies design criteria for neural scaffolds based upon key cellular interactions with the neural extracellular matrix (ECM), with emphasis on aspects that are reproducible in a biomaterial environment. Examples of the most recent SAPs and modification methods are presented, with a focus on biological, mechanical, and topographical cues. Furthermore, SAP electrical properties and methods to provide appropriate electrical and electrochemical cues are widely discussed, in light of the endogenous electrical activity of neural tissue as well as the clinical effectiveness of stimulation treatments. Recent applications of SAP materials in neural repair and electrical stimulation therapies are highlighted, identifying research gaps in the field of hydrogels for neural regeneration.

Electronic Conductivity in Biomimetic α-Helical Peptide Nanofibers and Gels.

Examples of long-range electronic conductivity are rare in biological systems. The observation of micrometer-scale electronic transport through protein wires produced by bacteria is therefore notable, providing an opportunity to study fundamental aspects of conduction through protein-based materials and natural inspiration for bioelectronics materials. Borrowing sequence and structural motifs from these conductive protein fibers, we designed self-assembling peptides that form electronically conductive nanofibers under aqueous conditions. Conductivity in these nanofibers is distinct for two reasons: first, they support electron transport over distances orders of magnitude greater than expected for proteins, and second, the conductivity is mediated entirely by amino acids lacking extended conjugation, π-stacking, or redox centers typical of existing organic and biohybrid semiconductors. Electrochemical transport measurements show that the fibers support ohmic electronic transport and a metallic-like temperature dependence of conductance in aqueous buffer. At higher solution concentrations, the peptide monomers form hydrogels, and comparisons of the structure and electronic properties of the nanofibers and gels highlight the critical roles of α-helical secondary structure and supramolecular ordering in supporting electronic conductivity in these materials. These findings suggest a structural basis for long-range electronic conduction mechanisms in peptide and protein biomaterials.