Melanin: Nature's 4th bioorganic polymer.

The pigments known as the melanins are widely recognized for their responsibility in the coloration of human skin, eyes, hair, and minimising the harmful effects of solar ultraviolet radiation. But specialists are aware that the melanins are present in all living kingdoms, barring viruses, and have functionality that extends beyond neutralizing ionising radiation. The ubiquitous presence of melanin in almost all human organs, recognized in recent years, as well as the presence of melanin in organisms that are evolutionarily distant from each other, indicate the fundamental importance of this class of material for all life forms. In this review, we argue for the need to accept melanins as the fourth primordial class of biological polymers, along with nucleic acids, proteins and polysaccharides. We consistently compare the properties of these canonical biological polymers with the properties of melanin and highlight key features that fundamentally distinguish melanins, their function and its mysteries.

Signatures of pancake bonding in hydrated eumelanin.

Pancake bonding phenomenology is applied for the first time in a bioorganic system, the pigment eumelanin, via a hydration-induced decrease of the interplanar distance down to 3.19 Å. The observation explains the long-term inconsistency between electron paramagnetic resonance and muon spin relaxation data for eumelanin.

The influence of copper ions on the transport and relaxation properties of hydrated eumelanin.

Eumelanin, the human skin pigment, is a poly-indolequinone material possessing a unique combination of physical and chemical properties. For numerous applications, the conductivity of eumelanin is of paramount importance. However, its hydration dependent conductivity is not well studied using transport-relaxation methods. Furthermore, there is no such work taking into account the simultaneous control of humidity as well as metal ion concentration. Here we present the first such study of the transport and relaxation characteristics of synthetic eumelanin doped with various Cu ion concentrations while controlling the humidity with a frequency range of 10-3 Hz-1 MHz. We found that Cu ions do not cause the appearance of additional relaxation processes, but partially slow down those present in neat eumelanin. In addition, considering previously published work, the key relaxation process observed in doped and undoped materials is associated with the moisture-induced synthesis of uncharged semiquinones and a corresponding increase in the overall aromaticity of the material.

The risk of delayed spinal cord injury in pediatric spinal deformity surgery.

Delayed spinal cord injury (SCI) hours or days after surgery, with uneventful monitoring and initial normal postoperative neurological examination, is a rare complication. Based on anecdotal evidence, the risk of delayed spinal cord injury might be higher than previously assumed. Therefore the aim of this study was to determine the risk of delayed SCI after pediatric spinal deformity surgery between 2013-2019 in the Netherlands. The total number of pediatric spinal deformity surgeries performed for scoliosis or kyphosis between 2013-2019 was obtained from the Dutch National Registration of Hospital Care. All eleven Dutch hospitals that perform pediatric spinal deformity surgery were contacted for occurrence of delayed SCI. From the identified patients with delayed SCI, the following data were collected: patient characteristics, details about the SCI, the surgical procedure, management and degree of improvement.2884 pediatric deformity surgeries were identified between 2013-2019. Seven patients (0.24%) with delayed SCI were reported: 3 idiopathic, 2 neuromuscular (including 1 kypho-scoliosis) and 2 syndromic scoliosis. The risk of delayed SCI after pediatric deformity surgery was 1:595 in idiopathic scoliosis, 1:214 in syndromic scoliosis, 1:201 in neuromuscular scoliosis. All seven patients had a documented normal neurological examination in the first postoperative period; neurological deficits were first diagnosed at a median 16h (range 2.5-40) after surgery. The risk of delayed SCI after pediatric deformity surgery is higher than previously reported, especially in patients with non-idiopathic scoliosis. Regular postoperative testing for late neurologic deficit should be performed for timely diagnosis and management of this devastating complication.

Systematic in situ hydration neutron reflectometry study on Nafion thin films.

Reported herein is a neutron reflectometry (NR) study on hydrated Nafion thin films (∼30 nm) on a silicon substrate with native oxide. The Nafion morphology is investigated systematically across the whole relative humidity range using both H2O and D2O vapours to enable a comparative study. By utilising this systematic approach two key results have been obtained. The first is that by leveraging the strong positive scattering signal from the D2O vapour, a complete and systematic water adsorption isotherm (Type II) for a Nafion thin film is produced. Utilising the slight negative scattering signal of the H2O enabled the quantification of the hydration dependent evolution of the formation of Nafion/water lamellae near the substrate surface. The number of lamellae layers increases continuously with hydration, and does not form abruptly. We also report the effects of swelling on the thin films across the relative humidity ranges. The work reported should prove useful in quantifying other hydration dependent properties of Nafion thin films such as conductivity and understanding Nafion/semiconductor based devices, as well as showcasing a NR methodology for other hydrophilic polymers.

The importance of water content on the conductivity of biomaterials and bioelectronic devices.

Conductive biocompatible-, bioinspired- and biomaterials are increasing in importance, especially in bioelectronic applications where these materials are used in a variety of devices. Given the intended purpose of many of these devices is to interface with the human body, a pertinent issue is the effect of water from the environment on the electrical properties of the materials and devices. A researcher on biomaterials may currently not be aware, but the conductivity of these materials and device performances can be significantly altered with the presence of hydration in the environment. Examples will be given to highlight the problem that the conductivity of biomaterials can change by orders of magnitude depending on water content. Furthermore, case studies will be discussed in which control of the water content was key to understanding the underlying charge transport mechanism of conductive biomaterials. Examples of various devices and their response to hydration content will also be covered. Finally, this perspective will also mention the various methods of hydration control (including contrast studies) that can be used to perform careful work on conductive biomaterials and devices. Overall, water content should be considered an environmental variable as important as temperature to control for sound scientific investigation and to yield understanding of conductive biomaterials and bioelectronic devices.

Water-Activated Semiquinone Formation and Carboxylic Acid Dissociation in Melanin Revealed by Infrared Spectroscopy.

Eumelanin is a widespread biomacromolecule pigment in the biosphere and has been widely investigated for numerous bioelectronics and energetic applications. Many of these applications depend on eumelanin's ability to conduct proton current at various levels of hydration. The origin of this behavior is connected to a comproportionation reaction between oxidized and reduced monomer moieties and water. A hydration-dependent FTIR spectroscopic study on eumelanin is presented herein, which allows for the first time tracking the comproportionation reaction via the gradual increase of the overall aromaticity of melanin monomers in the course of hydration. We identified spectral features associated with the presence of specific "one and a half" C𝌁O bonds, typical for o-semiquinones. Signatures of semiquinone monomers with internal hydrogen bonds and that carboxylic groups, in contrast to semiquinones, begin to dissociate at the very beginning of melanin hydration were indicated. As such, we suggest a modification to the common hydration-dependent conductivity mechanism and propose that the conductivity at low hydration is dominated by carboxylic acid protons, whereas higher hydration levels manifest semiquinone protons.

Integrated bioelectronic proton-gated logic elements utilizing nanoscale patterned Nafion.

A central endeavour in bioelectronics is the development of logic elements to transduce and process ionic to electronic signals. Motivated by this challenge, we report fully monolithic, nanoscale logic elements featuring n- and p-type nanowires as electronic channels that are proton-gated by electron-beam patterned Nafion. We demonstrate inverter circuits with state-of-the-art ion-to-electron transduction performance giving DC gain exceeding 5 and frequency response up to 2 kHz. A key innovation facilitating the logic integration is a new electron-beam process for patterning Nafion with linewidths down to 125 nm. This process delivers feature sizes compatible with low voltage, fast switching elements. This expands the scope for Nafion as a versatile patternable high-proton-conductivity element for bioelectronics and other applications requiring nanoengineered protonic membranes and electrodes.

Interfacial water morphology in hydrated melanin.

The importance of electrically functional biomaterials is increasing as researchers explore ways to utilise them in novel sensing capacities. It has been recognised that for many of these materials the state of hydration is a key parameter that can heavily affect the conductivity, particularly those that rely upon ionic or proton transport as a key mechanism. However, thus far little attention has been paid to the nature of the water morphology in the hydrated state and the concomitant ionic conductivity. Presented here is an inelastic neutron scattering (INS) experiment on hydrated eumelanin, a model bioelectronic material, in order to investigate its 'water morphology'. We develop a rigorous new methodology for performing hydration dependent INS experiments. We also model the eumelanin dry spectra with a minimalist approach whereas for higher hydration levels we are able to obtain difference spectra to extract out the water scattering signal. A key result is that the physi-sorbed water structure within eumelanin is dominated by interfacial water with the number of water layers between 3-5, and no bulk water. We also detect for the first time, the potential signatures for proton cations, most likely the Zundel ion, within a biopolymer/water system. These new signatures may be general for soft proton ionomer systems, if the systems are comprised of only interfacial water within their structure. The nature of the water morphology opens up new questions about the potential ionic charge transport mechanisms within hydrated bioelectronics materials.

Melanin, the What, the Why and the How: An Introductory Review for Materials Scientists Interested in Flexible and Versatile Polymers.

Today, western society is facing challenges to create new medical technologies to service an aging population as well as the ever-increasing e-waste of electronic devices and sensors. A key solution to these challenges will be the use of biomaterials and biomimetic systems. One material that has been receiving serious attention for its biomedical and device applications is eumelanin. Eumelanin, or commonly known as melanin, is nature's brown-black pigment and is a poly-indolequinone biopolymer, which possess unique physical and chemical properties for material applications. Presented here is a review, aimed at polymer and other materials scientists, to introduce eumelanin as a potential material for research. Covered here are the chemical and physical structures of melanin, an overview of its unique physical and chemical properties, as well as a wide array of applications, but with an emphasis on device and sensing applications. The review is then finished by introducing interested readers to novel synthetic protocols and post synthesis fabrication techniques to enable a starting point for polymer research in this intriguing and complex material.

Shedding Light on the Free Radical Nature of Sulfonated Melanins.

Melanin, an important class of natural pigment found in the human body, has stood out as a promising bioelectronic material due to its rather unique collection of electrical properties and biocompatibility. Among the available melanin derivatives, the sulfonated form has proven to not only be able to produce homogeneous device quality thin films with excellent adhesion, even on hydrophobic surfaces, but also to act as an ion to electron transducing element. It has recently been shown that the transport physics (and dominant carrier generation) may be related to a semiquinone free radical species in these materials. Hence, a better understanding of the paramagnetic properties of sulfonated derivatives could shed light on their charge transport behavior and thus enable improvement in regard to use in bioelectronics. Motivated by this question, in this work, different sulfonated melanin derivatives were investigated by hydration-controlled, continuous-wave X-band electron paramagnetic resonance spectroscopy and electronic structure calculations. Our results show that sulfonated melanin behaves similarly to non-functionalized melanin, but demonstrates a less pronounced response to humidity vis-à-vis standard melanin. We thus speculate on the structural and charge transport behavior in light of these differences with a view to further engineering structure-property relationships.

Engineering proton conductivity in melanin using metal doping.

Long range electrical conduction in biomaterials is an increasingly active area of research, which includes systems such as the conductive pili, proteins, biomacromolecules, biocompatible conductive polymers and their derivatives. One material of particular interest, the human skin pigment melanin, is a long range proton conductor and recently demonstrated as capable of proton-to-electron transduction in a solid-state electrochemical transistor platform. In this work, a novel "doping strategy" is proposed to enhance and control melanin's proton conductivity, potentially enhancing its utility as a transducing material. By chelating the transition metal ion Cu(ii) into the bio-macromolecular matrix, free proton concentration and hence conductivity can be modulated. We confirm these observations by demonstrating enhanced performance in a next generation electrochemical transistor. Finally, the underlying mechanism is investigated via the use of a novel in situ hydration-controlled electron paramagnetic resonance study, deducing that the enhanced proton concentration is due to controlling the internal solid-state redox chemistry of the intrinsic polyindolequinone structure. This doping strategy should be open to any transition metal ions that bind to hydroquinone systems (e.g. polydopamine). As such, the tailoring strategy could make other soft solid-state ionic systems more accessible to applications in bioelectronics, leading to the creation of higher performance ion-electron coupled devices.

Abduction treatment in stable hip dysplasia does not alter the acetabular growth: results of a randomized clinical trial.

Background The effect of bracing over natural history of stable dysplastic hips is not well known. This multicenter randomized trial aimed at objectifying the effect of abduction treatment versus active surveillance in infants of 3 to 4 months of age. Methods Patients were randomized to either Pavlik harness or active surveillance group. Ultrasound was repeated at 6 and 12 weeks post randomization. The primary outcome was the degree of dysplasia using the Graf α-angle at 6 months of age. The measurement of the acetabular index (AI) on plain pelvis X-rays was used to identify persistent dysplasia after 9 months and walking age (after 18 months). Findings The Pavlik harness group (n = 55) and active surveillance group (n = 49) were comparable for predictors of outcome. At 12 weeks follow-up the mean α-angle was 60.5° ± 3.8° in the Pavlik harness group and 60.0° ± 5.6° in the active surveillance group. (p = 0.30). Analysis of secondary outcomes (standard of care) showed no treatment differences for acetabular index at age 10 months (p = 0.82) and walking age (p = 0.35). Interpretation Pavlik harness treatment of stable but sonographic dysplastic hips has no effect on acetabular development. Eighty percent of the patients will have a normal development of the hip after twelve weeks. Therefore, we recommend observation rather than treatment for stable dysplastic hips.

Redox chemistry in the pigment eumelanin as a function of temperature using broadband dielectric spectroscopy.

Conductive biomolecular systems are investigated for their promise of new technologies. One biomolecular material that has garnered interest for device applications is eumelanin. Its unusual properties have led to its incorporation in a wide set of platforms including transistor devices and batteries. Much of eumelanin's conductive properties are due to a solid state redox comproportionation reaction. However, most of the work that has been done to demonstrate the role of the redox chemistry in eumelanin has been via control of eumelanin's hydration content with scant attention given to temperature dependent behavior. Here we demonstrate for the first time consistency between hydration and temperature effects for the comproportionation conductivity model utilizing dielectric spectroscopy, heat capacity measurements, frequency scaling phenomena and recognizing that activation energies in the range of ∼0.5 eV correspond to proton dissociation events. Our results demonstrate that biomolecular conductivity models should account for temperature and hydration effects coherently.

Microbial nanowires - Electron transport and the role of synthetic analogues.

Electron transfer is central to cellular life, from photosynthesis to respiration. In the case of anaerobic respiration, some microbes have extracellular appendages that can be utilised to transport electrons over great distances. Two model organisms heavily studied in this arena are Shewanella oneidensis and Geobacter sulfurreducens. There is some debate over how, in particular, the Geobacter sulfurreducens nanowires (formed from pilin nanofilaments) are capable of achieving the impressive feats of natural conductivity that they display. In this article, we outline the mechanisms of electron transfer through delocalised electron transport, quantum tunnelling, and hopping as they pertain to biomaterials. These are described along with existing examples of the different types of conductivity observed in natural systems such as DNA and proteins in order to provide context for understanding the complexities involved in studying the electron transport properties of these unique nanowires. We then introduce some synthetic analogues, made using peptides, which may assist in resolving this debate. Microbial nanowires and the synthetic analogues thereof are of particular interest, not just for biogeochemistry, but also for the exciting potential bioelectronic and clinical applications as covered in the final section of the review. STATEMENT OF SIGNIFICANCE: Some microbes have extracellular appendages that transport electrons over vast distances in order to respire, such as the dissimilatory metal-reducing bacteria Geobacter sulfurreducens. There is significant debate over how G. sulfurreducens nanowires are capable of achieving the impressive feats of natural conductivity that they display: This mechanism is a fundamental scientific challenge, with important environmental and technological implications. Through outlining the techniques and outcomes of investigations into the mechanisms of such protein-based nanofibrils, we provide a platform for the general study of the electronic properties of biomaterials. The implications are broad-reaching, with fundamental investigations into electron transfer processes in natural and biomimetic materials underway. From these studies, applications in the medical, energy, and IT industries can be developed utilising bioelectronics.

[Distal femur fracture in a woman with a lower limb prosthesis.] / Distale femurfractuur bij vrouw met onderbeenprothese.

BACKGROUND: People who use a lower limb prosthesis can fracture their distal femur after a trivial fall; however, this kind of fracture is uncommon. CASE DESCRIPTION: A 53-year-old woman with a trans-tibial prosthesis fell in her kitchen. She felt pain just above the socket of the prosthesis, was unable to get up and her knee and leg were swollen. Radiographic imaging showed a distal femur fracture, for which she received a non-operative treatment with a stump cast. In consultation with the rehabilitation physician she received a conventional lower limb prosthesis after consolidation of the fracture. She mobilised adequately and was able to resume her activities at home and at work. CONCLUSION: Distal femur fractures in patients with a lower limb prosthesis can be recognised through pain just above the socket of the prosthesis. Conservative treatment, including the use of a stump cast, followed by mobilisation with an adapted prosthesis under supervision of a rehabilitation physician often results in a good outcome in terms of functionality.

The structural impact of water sorption on device-quality melanin thin films.

The melanins are a class of pigmentary bio-macromolecules ubiquitous in the biosphere. They possess an intriguing set of physico-chemical properties and have been shown to exhibit hybrid protonic-electronic electrical conductivity, a feature derived from a process termed chemical self-doping driven by the sorption of water. Although the mechanism underlying the electrical conduction has been established, how the sorbed water interacts with the melanin structure at the physical level has not. Herein we use neutron reflectometry to study changes in the structure of synthetic melanin thin films as a function of H2O and D2O vapour pressure. Water is found to be taken up evenly throughout the films, and by employing the contrast effect, the existence of labile protons through reversible deuterium exchange is demonstrated. Finally, we determine a sorption isotherm to enable quantification of the melanin-water interactions.

Hybrid Nanowire Ion-to-Electron Transducers for Integrated Bioelectronic Circuitry.

A key task in the emerging field of bioelectronics is the transduction between ionic/protonic and electronic signals at high fidelity. This is a considerable challenge since the two carrier types exhibit intrinsically different physics and are best supported by very different materials types-electronic signals in inorganic semiconductors and ionic/protonic signals in organic or bio-organic polymers, gels, or electrolytes. Here we demonstrate a new class of organic-inorganic transducing interface featuring semiconducting nanowires electrostatically gated using a solid proton-transporting hygroscopic polymer. This model platform allows us to study the basic transducing mechanisms as well as deliver high fidelity signal conversion by tapping into and drawing together the best candidates from traditionally disparate realms of electronic materials research. By combining complementary n- and p-type transducers we demonstrate functional logic with significant potential for scaling toward high-density integrated bioelectronic circuitry.

Heavy Water as a Probe of the Free Radical Nature and Electrical Conductivity of Melanin.

Melanins are pigmentary macromolecules found in many locations throughout nature including plants and vertebrate animals. It was recently proposed that the predominant brown-black pigment eumelanin is a mixed ionic-electronic conductor which has led to renewed interest in its basic properties as a model bioelectronic material. This exotic hybrid electrical behavior is strongly dependent upon hydration and is closely related to the free radical content of melanin which is believed to be a mixed population of two species: the semiquinone (SQ) and a carbon-centered radical (CCR). The predominant charge carrier is the proton that is released during the formation of the SQ radical and controlled by a comproportionation equilibrium reaction. In this paper we present a combined solid-state electron paramagnetic resonance (EPR), adsorption, and hydrated conductivity study using D2O as a probe. We make specific predictions as to how the heavy isotope effect, in contrast to H2O, should perturb the comproportionation equilibrium and the related outcome as far as the electrical conductivity is concerned. Our EPR results confirm the proposed two-spin mechanism and clearly demonstrate the power of combining macroscopic measurements with observations from mesoscopic probes for the study of bioelectronic materials.

Hydration-controlled X-band EPR spectroscopy: a tool for unravelling the complexities of the solid-state free radical in eumelanin.

Melanin, the human skin pigment, is found everywhere in nature. Recently it has gained significant attention for its potential bioelectronic properties. However, there remain significant obstacles in realizing its electronic potential, in particular, the identity of the solid-state free radical in eumelanin, which has been implicated in charge transport. We have therefore undertaken a hydration-controlled continuous-wave electron paramagnetic resonance study on solid-state eumelanin. Herein we show that the EPR signal from solid-state eumelanin arises predominantly from a carbon-centered radical but with an additional semiquinone free radical component. Furthermore, the spin densities of both of these radicals can be manipulated using water and pH. In the case of the semiquinone radical, the comproportionation reaction governs the pH- and hydration-dependent behavior. In contrast, the mechanism underlying the carbon-centered radical's pH- and hydration-dependent behavior is not clear; consequently, we have proposed a new destacking model in which the intermolecular structure of melanin is disordered due to π-π destacking, brought about by the addition of water or increased pH, which increases the proportion of semiquinone radicals via the comproportionation reaction.