Symposium S.SM06—Soft Organic and Hybrid Materials for Biointerfacing—Materials, Processes and Applications

Rapid and robust adhesion of wet tissues has critical importance for clinical applications such as wound closure and tissue repair as well as biointegrated devices for their stable yet functional operations and communications with the target tissues. For example, traumatic injuries and failure of prompt wound closure and hemostasis cause over 2 million deaths annually in the world; and the development of a broad range of biointegrated devices for therapeutic and diagnostic applications is one of the fastest growing fields in recent decades. However, conventional approaches such as sutures and staples have face numerous challenges including complications and problems caused by their non-continuous, tissue-damaging, and highly technical nature. While tissue adhesives and glues have been investigated as promising alternatives for sutures and staples, practical utility and impact of existing tissue adhesives and glues have been greatly dampened by several limitations including 1) incompatibility to wet tissues, 2) incompatibility to body fluids such as blood and mucus, 3) slow adhesion formation, 4) weak and brittle adhesion, and 5) inability to allow bioelectronic communication between tissue and adhered device. In this talk, we will introduce a set of novel bioinspired mechanisms and tissue adhesives capable of instant, strong, and conductive adhesion formation on various tissues covered by blood or mucus to address all abovementioned challenges. We will demonstrate a broad range of potential applications of these novel tissue adhesives and their implications in clinical, biomedical, and bioelectronic applications.

Bioelectronics are poised to revolutionize health care, providing exciting opportunities for therapeutics, health monitoring, prosthetics, and human augmentation. Yet, there remain significant barriers to long-term implantation of these technologies within the body. This is due in large part to inflammatory responses resulting from the severe mismatch in mechanical properties between conventional device components, which are rigid (E~GPa) and non-deformable, and biological tissues, which are significantly more soft (E~ kPa) and dynamic. With their high water content (70-99 wt%), hydrogels are capable of achieving tissue-level elastic moduli, though existing strategies to render hydrogels electrically conductive involve incorporating stiff, conductive additives into inert and stretchable hydrogels, necessitating a tradeoff between electrical and mechanical properties. Here, we present a new materials design strategy for conductive hydrogels that overcomes this tradeoff by decoupling mechanical from electrical properties through the use of two distinct, interpenetrating polymer networks. We first leverage the gel-forming capabilities of the conducting polymer poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) to form a macroscopically connected conductive network at remarkably low polymer concentrations (~1 wt%). The highly dilute yet interconnected conductive network enables us to orthogonally tune elastic modulus using a second, interpenetrating polymer network. Our unique design enables an unprecedented combination of mechanical tunability over 3 biologically-relevant orders of magnitude (8 kPa – 374 kPa), stretchability (up to 400%), elasticity, and electrical conductivity up to 23 S/m. To enable their integration into devices, we further introduce a novel method for patterning these materials with high resolution onto surfaces of planar and even curved objects. We overcome limitations precluding the use of conventional molding or lithographic methods by using a sacrificial metal pattern that can be oxidized in the presence of a PEDOT:PSS electrolyte to locally induce gelation only at the pattern interface. This materials design strategy and its corresponding new patterning method represent a significant step towards the development of next-generation bioelectronics that can seamlessly interface with biological targets over extended timescales.

In this talk, I will present our recent work on engineering soft electronic materials and their applications in biointerfacing

Bright and vivid colours found in living organisms are often the result of hierarchical nanostructured materials. Here we show that in the case of Flavobacterium IR1 colonies, the complex organisation of the cells in polycrystalline two-dimensional lattices is a distinctive fingerprint of the colony organisation. By combining an analytical analysis of the scattering response with numerical modelling, we obtain the exact inter-cells distance and cell diameter with a resolution comparable to conventional electron microscopy techniques. Such a precise understanding of the structure-to-function relation allows not only to fully describe their optical appearance, but it enables to gather insights on the mechanisms used for communication and their biological function. Further, the ability to genetically modify them allowed us to modify their colouration and control their optical appearance on-demand, enabling us to use such colonies as novel photonic living materials.

Gel based iontronics are attractive for epidermal electronics due to their compatible and tunable mechanical properties. Many receptive interface for birectional human-machine interactions require tactile sensors that are intrinsically soft, skin conformable and dynamically deformable. While addressable touch input can be realized using capacitive, resistive, piezoelectric or triboelectric signals, the output signal often requires integrated lighting for visual detection or optoelectronic signal feedback on a transparent interface. In addressing these neeeds, ionic conductors provide the advantages of optically transparent, skin compliant, ease of processibility and added novel functionality in the presence of ions and electrons transport.

We have demonstrated the use of conductive hydrogel composites as versatile strain sensors for monitoring of human motion. In addition, hydrogel ionic conductor was shown to be effective current collector by harnessing the electrical double layer for triboelectric nanogenerators, allowing them to be mounted onto skin or machine. On the other hand, we have formulated inkjet printable ionic gels with precise control of the rheological characteristics of gels. As a result, transparent deformable touch panels have been realized using the microscale patterning of ionic gel. The transparent touch interface is capable of remarkable signal fidelity under dynamic human-machine interactive conditions. We have further prepared thermally stable gels with self-healing ability and found applications in dielectric actuators, potentially used in biostimulation applications.

Pressure sensors with high sensitivity have uses ranging from pulse monitoring and plantar pressure measurement (10–100 kPa) to in vivo intraocular and intracranial pressure measurement (1–10 kPa). The sensitivity of capacitive pressure sensors is primarily determined by the modulus of a dielectric layer that reversibly deforms to produce an electrical signal. Crosslinked polymers provide a means to achieve good dielectric properties with low modulus relative to inorganic materials. Unfortunately, the mechanical properties of conventional linear polymer networks are constrained such that a lower limit on softness translates to poor capacitive pressure sensor performance. Here, we overcome this limitation by leveraging the intrinsic “super-soft” characteristic of bottlebrush polymers, which can be crosslinked to form solvent-free networks with moduli in a range matching that of biological tissues (1–100 kPa). A simple light-induced crosslinking strategy is introduced to facilitate device fabrication. Parallel plate capacitive pressure sensors constructed with these bottlebrush polymer networks exhibit up to a 53× increase in sensitivity compared to commonly used elastomers, e.g., PDMS (Sylgard 184). The sensors show pressure resolution on the order of 0.1 kPa, capable of differentiating subtle forces in the light touch regime. Transparent and flexible sensors fabricated using indium-tin-oxide (ITO)-coated poly(ethylene terephthalate) (PET) electrodes are shown to be functional in a bent configuration. This combination of contemporary synthetic chemistry and application-driven materials design accentuates the opportunities available at the intersection of science and engineering to advance soft, flexible, and biocompatible devices.

Conducting polymers (CPs) have been widely used as electroactive biointerfaces in applications such as DNA sensors, in electrically-stimulated tissue engineering and more recently in stretchable and conformable organic bioelectronics. However, the majority of these applications are based on the electropolymerized or solution deposited 2D films of CPs, and as such cannot fully probe the actual 3D cell environment within tissues and organs. Our approach to address that is based on a precise fabrication of individually addressable, high aspect ratio, 3D CP-pillar microelectrode arrays by means of ‘micro-extrusion printing’ using our in-house constructed system. The ‘printing’ principle is simple ‘extrusion’ of CP ‘ink’ from a micro-pipette into ‘pillars’, accompanied by evaporation of solvent (water) during the process. CP pillars of different aspect ratios (from 2 to 7000) were successfully fabricated, with excellent stability, mechanical properties and electrochemical properties [1].
Such 3D CP-pillar microelectrode arrays could be employed in variety of applications, from biological sensing to recording and electrically stimulating cells and tissues, with the design of the arrays being easily adjustable to a particular application.
Our demonstrated examples include: exosome capture, sensing and release - where the CP pillars can be easily functionalized for capturer/release of exosmes; and 3D electrical stimulation of human neural stem cells into a high-density of mature neurons and functional neural networks[2].
Overall, the 3D CP microelectrodes provide promising versatile substrates for a variety of bioelectronics applications, including where spatiotemporal control of individually electrically addressable microelectrodes is desired.
[1] P. Zhang, N. Aydemir, M. Alkaisi, D. E. Williams and J. Travas-Sejdic, Direct Writing and Characterization of Three-Dimensional Conducting Polymer PEDOT Arrays, ACS Appl. Mater. Interfaces, 2018, 10 (14), 11888-11895
[2] E. Tomaskovic-Crook, P. Zhang, A. Ahtiainen, H. Kaisvuo, C-Y. Lee, S. Beirne, Z. Aqrawe, D. Svirskis, J. Hyttinen, G. G Wallace, J. Travas-Sejdic, J. M Crook, Human Neural Tissues from Neural Stem Cells Using Conductive Biogel and Printed Polymer Microelectrode Arrays for 3D Electrical Stimulation, Adv. Healthcare Mater., 2019, DOI: 10.1002/adhm.201900425

Electrical stimulation of tissue and ultimately individual cells has not only played an essential role in our understanding of the structure and function of excitable tissue but continues to serve as the basis for a variety of therapeutic interventions for the treatment of disorders ranging from cardiac arrhythmias to Parkinson’s disease. Advances in technology have attempted to overcome barriers associated with the spatial resolution (i.e., who and where to stimulate) and the invasiveness of the process. Optogenetics has revolutionized the way we can record and affect the electrophysiology of cells and tissue, using light as the input/output (I/O) interface. Though optogenetics has developed at a great pace and is making profound scientific contributions, the core of the technique requires genetic modifications of the cells or organism. This presents challenges both in terms of achieving targeted gene expression and the potential deleterious consequences of the expression of foreign proteins, which have implications on clinical translation to humans and regulatory approval. We report our developed breakthrough hybrid-nanomaterial synthesis process to enable minimally invasive, remote and non-genetic light-induced control of targeted cell activity with high spatial-temporal resolution. We combine one-dimensional (1D) nanowires (NWs) and two-dimensional (2D) graphene flakes grown out-of-plane with tailor-made physical properties for highly controlled photostimulation. Photostimulation using NW templated 3D fuzzy graphene (NT-3DFG) is flexible due to its broadband absorption and does not generate cellular stress. Our light-based platform adds a powerful toolset to the basic scientists studying cell signaling within and between tissues. Last, this platform can be adapted to address challenges in tissue engineering, i.e. the much-needed non-genetic stimulation control of engineered tissues. By controlled delivery of the NT-3DFG we will be able to locally and selectively control cellular activity with high spatial and temporal resolution of 3D tissues.

Despite their significance in the aetiology of many diseases, cellular membranes are still an underexplored target for studying the mechanisms of diseases or drug therapies. Supported lipid bilayers (SLB), are a preferred model membrane system for cell membrane studies, including ion channel recording and pharmaceutical screening. However, to date, cell-free commercially available technologies for plasma membrane studies have been limited to synthetic membranes that lack the inherent complexity found in the membrane of the cell.

Here, we use vesicles derived from live cells to create cell-free native membrane models on top of active bio-transducers. These vesicles fuse on top of the desired substrates forming an SLB. In this work we use human embryonic kidney 293 cells (HEK) and a hydrated polymer-based transducer, based on poly(3,4-ethylenedioxythiophene): poly(styrenesulfonate) (PEDOT:PSS), instead of inorganic solid supports. This provides a fluid environment close to the physiologically relevant one, thus facilitating mobility of the transmembrane proteins (TMPs), which is a prerequisite for protein membrane studies. Moreover, the optical transparency of PEDOT:PSS ensures compatibility with standard optical methods allowing us to confirm the prescence and correct orientation of TMPs as well as the mobility (fluidity) of the bilayer using fluorescent microscopy techniques, such as fluorescence recovery after photobleaching (FRAP) and total internal reflection fluorescence (TIRF). These features enhance the native structural and functional properties of the membrane and ensure the usefulness of our platform as a physiologically relevant and predictive mimic of membrane molecular interactions.

In this study we carry out electrical characterization of membrane properties and interactions using both PEDOT:PSS-based electrodes and transistors (the Organic Electrochemical Transistor). This is based on measuring the ionic flux through the membrane via electrical impedance spectroscopy and transistor-characteristics. In this way, we can monitor biological interactions quantitatively and in real time, revealing useful information regarding the dynamics of membrane fusion. This allows for sensitive detection of minute changes of membrane properties, e.g. receptor binding events, changes in membrane potential and ion channel activity. As an example, we can observe differences in the electrical properties between the native membrane derived from HEK cells and a native membrane derived from HEK cells overexpressing the potassium ion channel TREK-1. Our device allows us to measure the chemically-induced gating of TREK-1 ion channels with the ability to distinguish between general ion channel activity and that of TREK-1, specifically. Overall, our results highlight the suitability of this platform for drug screening against ion channel targets paving the way for a scalable and cost-efficient alternative method to using whole cells e.g. patch clamp assays.

Lipid-protein complexes are the basis of pulmonary surfactants covering the respiratory surface and mediating gas exchange in lungs. Cardiolipin is a mitochondrial lipid overexpressed in mammalian lungs infected by bacterial pneumonia. In addition, increased oxygen supply (hyperoxia) is a pathological factor also critical in bacterial pneumonia. In this work we present the fabrication of a micrometer-size graphene-based sensor to measure oxygen permeation through pulmonary membranes. Combining oxygen sensing, X-ray scattering, and Atomic Force Microscopy, we discovered that mammalian pulmonary membranes suffer a structural transformation induced by cardiolipin. We observe that cardiolipin promotes the formation of periodic protein–free inter–membrane contacts with rhombohedral symmetry. Membrane contacts, or stalks, promote a significant increase in oxygen gas permeation which may bear significance for alveoli gas exchange imbalance in pneumonia.

In this talk, I will introduce our recent activity of conformable organic photonic systems. We have developed ultra-flexible and lightweight highly efficient, ultra-flexible, air-stable, three-color, organic light-emitting diodes (OLEDs). The total thickness of the devices, including the substrate and encapsulation layer, is only three micrometers, which is one order of magnitude thinner than the epidermal layer of the human skin. Due to the very thin substrate and neutral position, our device shows the highly flexibility and conformability. The OLEDs are directly laminated on the surface of skin and are used as indicators/displays. Furthermore, we have developed ultra-flexible organic imager which consists with a monolithically processed rectifying pixel and an organic photo diode. Our organic imager has pixel pitches as small as 50 µm, with resolutions of up to 262 ppi. Using our ultra-flexible organic imager, we succeed to measure the spatial photoplethysmography (PPG) mapping.

Integration of high performance ultra-flexible energy harvesters with energy storage units not only provides an efficient, stable self-powered source, but also realizes a volume miniaturization with reduced thickness and wiring requirements, which is an unprecedented demand for biomedical devices and wearable electronics. The main challenge for an efficient flexible self-powered system lies in the management between the stable operation with mechanical flexibility and long-term electrical performance, the proposed research task will focus on materials design, interface engineering, device configuration and reliable packaging technologies mainly based on organic components to tackle with the latent issues. Here we report flexible integrated photo-charging devices subsequently constructed based on ultra-thin efficient organic photovoltaics and supercapacitors via advanced design and power management, achieving high overall energy conversion and storage efficiency as well as maintaining superior system operation stability and mechanical flexibility for multifunctional wearable electronics.

Stretchable and conformable optoelectronic devices enable exciting applications in wearable electronics displays, human-machine interfaces as well as emerging soft robotics. We have developed a low-field emission electroluminescent device using a solvent processable self-healing dielectric material that exhibits high relative dielectric permittivity. Our device can be assembled facilely, which can then be stretched to 800% strain. The device also exhibits opto-healing from punctures or bifurcations. We achieved very low turn-on threshold voltages as low as 23 V, and can achieve an unprecedented electroluminescent brightness of >1000 cd m^-2. We further demonstrate the use of our device in soft robotics applications. Our soft, repeatably autonomous self-healing electroluminescent devices will enable applications in electronic skins and stretchable display interfaces that are easily reconfigurable, and robust to mechanical damage.

Reference:
Y.J. Tan et. al., A Transparent Self-healing and High-k Dielectric for Low-field Emission Stretchable Optoelectronics, Nature Materials (accepted).

As the role of flexible soft materials become more crucial for applications such as flexible displays in foldable mobile phones, compliant sensors and actuators in wearables, etc., new functional soft materials are needed to fill the roles previously fulfilled by rigid and bulky conventional materials. The field of haptic technology has recently seen emerging needs for integration into soft, flexible and even transparent interfaces. Since several decades ago, haptic feedback in electronic devices such as mobile phones, gaming controllers, are provided by bulky mechanical motors that vibrate the entire device upon application of an electric signal to give a tactile sensation to the users. In recent years, piezoceramics such as lead zirconate titanate are seen as a popular alternative due to its high performance and small form factor. However, their high stiffness, density and opacity prove to be a large obstacle in applications where flexibility, weight and transparency are crucial. In such applications, electroactive polymers (EAPs) serve as an excellent solution and have been a rapidly growing focus of research due to the wide range of potential applications such as energy harvesters, sensors and actuators, artificial muscles, etc. In reported methods to enhance the dielectric and electromechanical properties of EAPs, there is a compromise in at least one of these factors: electrical breakdown strength, transparency and flexibility.

In this work, we present an approach to enhance the output force of polymer actuators by increasing the dielectric permittivity and polarizability of the EAP, poly (vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) (P(VDF-TrFE-CTFE)), by incorporation of a conductive nanowire interlayer into the polymer matrix. The interlayer is formed by a network of highly conductive silver nanowires with high aspect ratio and enhances the dielectric permittivity and polarizability of the EAP over a broad range of frequencies including ultra low frequencies (e.g. 0.1 Hz) and the range of 200 to 300 Hz at which the mechanoreceptors in the human fingertips are most sensitive to. Through experiments and finite element modelling, the enhancement of dielectric properties were found to originate from charge accumulation at the nanowire/polymer interface and resulted in an output force double that of a neat EAP actuator. The higher output force can be used to improve tactile feedback perception of a human user and allows a 40% reduction in the actuator excitation voltage compared to that of a neat EAP actuator. Even with enhanced dielectric properties and output force, the composite actuator retains its transparency and flexibility without severe compromise in the electrical breakdown strength. The excellent transparency and flexibility of the modified EAP are promising for a wider range of possible applications such as direct and localized haptic feedback on flexible electronic displays, touch screens, etc.

Robot function is largely determined by the structural platform upon which it is built. The field of soft robotics aims to expand the design space by introducing unconventional robotic materials and methods to the engineering toolkit. In this talk, it is proposed that this increasing repertoire of robotic platforms be extended to include fabrics, which are known for their extreme deformability, versatility, and customizability. Possible fiber-based forms to achieve actuation, sensing, and stiffness control will be presented, including: (1) shape memory alloy ribbon as a thin-body actuator, which is effective at pure-bending motion, in contrast with typical fiber actuators that rely on axial contraction alone; (2) An in-fabric sensor that changes in resistance as the fabric weave is stretched and the gaps present between fibers are enlarged; and (3) A stiffness-changing fiber based on a glass-transition polymer epoxy with low-melting-point metallic alloy inclusions that is capable of a stiffness change of two orders of magnitude using Joule heating. By designing actuators, sensors, and structural components that conform to a fiber-based geometry, we show that simple fabrics can be functionalized to create damage-responsive tourniquets, self-deploying structures, and morphing airfoils.

The biological world relies on a variety of stimuli: chemical, electrical and also mechanical. For the fields of regenerative medicine and tissue engineering, understanding these cues is an important pathway for directing tissue behaviour.

Currently however, our understanding of the effect of mechanical stimulation on cell behaviour is poor, but it is becoming clear that these cues play an important role in regulating phenotype, recently being used to direct stem cell differentiation, for example [1]. A major issue for this field remains that the stiffness of biological tissue is many orders of magnitude lower than that of bulk materials such as polymers or ceramics. Work is being done to address this stiffness imbalance, the majority through the use of hydrogels [2], but this approach has some drawbacks, as the stiffness of a hydrogel is directly correlated to its chemistry, so in order to change the stiffness we require a change in chemistry. In addition, hydrogels fail to provide routes to actively direct cell behaviour whilst in culture.

In this work we utilise template wetting to create a tuneable, low stiffness surface through the use of nanostructuring to alter the effective surface stiffness of a widely used piezoelectric bio-polymer, poly-l-lactic acid [3]. By altering the length of the resulting nanotubes, we have successfully shown a strong preference by induced Pluripotent Stem Cells (iPSCs) for higher aspect ratio, softer, surfaces, and furthermore demonstrated the long term viability of this surface for cell growth. It is concluded that this nanostructuring presents a viable, controllable route to providing appropriate mechanical stimuli. Moreover, by exploiting the piezoelectric properties of the polymer there is the opportunity for active mechanical stimulation in culture. The implementation of this mechanical control opens up new avenues for detection, characterisation and stimulation of cell mechanobiology, paving the way towards an externally addressable lab-on-a-chip device.


[1] Sun, M., Chi, G., Li, P., Lv, S., Xu, J., Xu, Z., … Li, Y. (2018). Effects of Matrix Stiffness on the Morphology, Adhesion, Proliferation and Osteogenic Differentiation of Mesenchymal Stem Cells. International Journal of Medical Sciences, 15(3), 257–268. https://doi.org/10.7150/ijms.21620
[2] Caliari, S. R., & Burdick, J. A. (2016). A practical guide to hydrogels for cell culture. Nature Methods, 13(5), 405–414. https://doi.org/10.1038/nmeth.3839
[3] Smith, M., Lindackers, C., McCarthy, K., & Kar-Narayan, S. (2019). Enhanced Molecular Alignment in Poly-l-Lactic Acid Nanotubes Induced via Melt-Press Template-Wetting. Macromolecular Materials and Engineering, 304(3), 1800607. https://doi.org/10.1002/mame.201800607

Interfaces that link biological systems with machines are increasingly evolving beyond the electrical domain. Multi-modal bioelectronics aims to add chemical, optical, thermal or mechanical functionality to the capabilities of classical electrode arrays. When such systems are used in physical contact with tissues or cells, the need for overall mechanical compliance is crucial for their biointegration. This raises a question: how do we build multi-modal arrays of sensors and actuators with tissue-like softness?
In this talk I will present our efforts to adapt direct ink writing (multi-material 3D printing) for the purpose of fabricating elastic systems of electrodes, optrodes, thermotrodes, and chemotrodes. A palette of silicones, composites and hydrogels are used as inks, where each of the inks enables one interfacing modality. As an example of in vitro appliation, I will present multi-modal pacing and monitoring of stem cell derived cardiomyocytes. In vivo, I will present printed neuro-muscular implants tailored to specific anatomical niches and animal models. These developments are expected to contribute to the development of personalized platforms for bioelectronic medicine.

Enabled by new materials and device designs, a new generation of brain interface technologies is replacing bulkier, non-compliant systems with the aim of seamless electronic-biological interfaces with lower tissue damage, reduced immunogenicity, high-density, tunable spatial distribution, and long-term stability. Recent successful examples leveraging mechanically compliant materials have demonstrated major breakthrough in brain research using ultra-flexible systems for ECoGs recordings, and for depth electrodes.

However, connectorization of these ultra-flexible electrodes to traditional electronics remains a significant challenge. Current connectors, such as zero-insertion force (ZIF) devices, are limited to 64 or 128 channels at most. While these may then be stacked together this approach does not scale, limiting the maximum number of channels feasible.

Here, we demonstrate an easy to use, massively scalable connector technology. Rather than using traditional amplifier electronics, we couple thousands of flexible electrodes directly to a CMOS pixel array, such as typically found in a camera or OLED display. These devices have millions of available pixels, and by taking advantage of the small, flexible nature of the electrodes we are able to attach thousands of electrodes in seconds. These form robust Ohmic contact that can be extensively cycled. We demonstrate the simplicity of the process, and show how it can be used to perform massively parallel neural recordings.

Understanding the complex neural circuitry and its correlation to specific behaviors requires spatially and temporally precise modulation of neuron subtypes in certain brain regions. For decades, neural stimulation has predominantly been achieved by traditional electrical stimulation electrodes. More recently, optogenetics, which utilizes visible light to achieve neural modulation by genetically expressing microbial opsins in mammalian cells, has gained great popularity due to its rapid and precise control of neural activities and its capability of dissecting neural circuitry by selectively modulating specific neuron subtypes. However, owing to the limited tissue penetration of visible light, invasive craniotomy and intracranial implantation of tethered optical fibers are usually required for in vivo optogenetic modulation. Here, we report a new method termed ‘sono-optogenetics’, which provides minimally invasive optogenetic neuromodulation in the brain without any scalp incision, craniotomy or brain implant. Sono-optogenetics delivers nanoscopic light sources—mechanoluminescent nanoparticles—via the endogenous blood circulation, and provides millisecond-timescale switching of 470 nm light emission for optogenetic neuromodulation via brain-penetrant focused ultrasound. Furthermore, the mechanoluminescent particles could be recharged by 400-nm photoexcitation light in superficial blood vessels during circulation, enabling repetitive through-scalp optogenetic stimulation. Unlike the conventional ‘outside-in’ approaches of optogenetics with fiber implantation, our method, which combines minimal-invasive ultrasound excitation and intravenous delivery of mechanoluminescent nanoparticles, provides an ‘inside-out’ approach to deliver nanoscopic light emitters via the intrinsic circulatory system and switch them on and off at any time and location of interest in the brain. We envisage that sono-optogenetics provides a unique tool of rapid screening of different target regions in the brain for optogenetic neural modulation, owing to the ease of changing the location of ultrasound focus in the brain by eliminating fiber optic implantation. Furthermore, sono-optogenetics can be used in other regions of the central and peripheral nervous systems, as well as in other organs such as the heart and lungs, which are usually refractory to fiber implantation due to structural and functional constraints, for precise modulation with optogenetic control of cell activity. In addition, reduction of the footprint and the weight of the ultrasound transducer, as well as the use of ultraflexible neural probes with neural-tissue-like mechanical compliance, may enable sono-optogenetic stimulation of deep-brain regions with simultaneous electrophysiology in a behavioral setting. We anticipate that this approach could also be extended to applications in much deeper brain regions in larger animals owing to the penetration depth of ultrasound reaching several centimeters. The manuscript based on this work “Sono-optogenetics: a circulation delivered rechargeable light source for minimally invasive optogenetics. Xiang Wu,^1,3,5 Xingjun Zhu,^1,3,5 Paul Chong,^2,3,5 Junlang Liu,^1,3 Louis N. Andre,^1,3 Kyrstyn S. Ong,^1,3 Kenneth Brinson Jr.,^1,3 Ali I. Mahdi,^1,3 Jiachen Li,¹ Lief E. Fenno,⁴ Huiliang Wang^4* and Guosong Hong^1,3*” has been reviewed at PNAS and the revision has been returned for further evaluation.

INTRODUCTION
Tissue adhesive nanofiber membranes present a synchronous capability of oral tissue regeneration and bio-sensing. Natural polymers such as chitosan, pectin and their combinations have been previously characterized for mucoadhesion ex vivo [1]. On a similar note, the mucoadhesion of gecko-inspired synthetic elastomer nanopatterns was enhanced via surface coating with oxidized sugar/ polysaccharide [2]. Taking cue from the aforementioned studies, electrospun nanofiber membranes of chitosan were modified by surface coating with oxidized pectin for oral tissue adhesion. Such tissue adhesive nanofiber membranes are employed for pH-responsive delivery of oral therapeutics.

EXPERIMENTAL METHODS
Chitosan nanofiber membranes were fabricated by electrospinning a 5 wt% of chitosan dissolved in trifluoroacetic acid-dichloromethane (TFA: DCM = 70:30 v/v) solvent system. The nanofiber membranes were spin coated with 0.05 and 0.5 wt% of periodate oxidized pectin. A texture analyzer (TA-XT-plus, Stable Micro Systems) was used for recording the adhesion properties of the nanofiber membranes ex vivo to porcine oesophagus and hydroxyapatite discs representing the mucosal and enamel surfaces, respectively. The nanofiber membranes loaded with oral antibiotics/ antimicrobial peptides were evaluated for pH-responsive release in 0.1 M acetate buffers of pH = 4.5, 5.5 and 6.5 and their consequent antimicrobial activity assessed against oral pathogens (Streptococci). The cytocompatibility of similar membranes was examined using human gingival fibroblasts.

RESULTS AND DISCUSSION
The 0.05 wt% oxidized pectin coating on chitosan nanofiber membranes elicited maximum detachment force and work of adhesion to porcine oesophagus suggesting enhanced muco-adhesion resulting from the synergistic interaction of the nanofiber topography and surface aldehydes from oxidized pectin with the mucosal proteins. A higher 0.5 wt% oxidized pectin coating only enhanced the detachment force, but reduced the work of adhesion to mucosal mimic. Overall, our ex vivo mucoadhesion results are in agreement with an earlier report of oxidized dextran coating mediated improvement of mucoadhesion of elastomeric nanopatterns [2]. On the contrary, the uncoated chitosan nanofiber membrane exhibited the strongest adhesion to hydroxyapatite discs. The greater abundance of cationic amines (-NH₃⁺) in pure chitosan promoted adhesion to negatively charged phosphates (-PO₄^3-) on hydroxyapatite surfaces. The in vitro cytocompatibility of the membranes was illustrated by co-culture with human gingival fibroblasts for 24 h. Lastly, the pH-responsive delivery of oral therapeutics was demonstrated via the antibacterial activity of antibiotic/ antimicrobial peptide loaded membranes against Streptococcus gordonii, a primary colonizer of oral prosthesis.

CONCLUSIONS
A synergistic combination of surface topography and surface chemistry can promote the tissue adhesion properties of nanofiber membranes to hard, soft or hard-soft tissue interfaces. The pH-responsive adhesive nanofiber membranes can be utilized for pH-induced delivery of oral therapeutics.

REFERENCES
[1] Hagesaether et al., Mucoadhesion and drug permeability of free mixed films of pectin and chitosan: An in vitro and ex vivo study, Eur. J. Pharm.Biopharm. 71 (2009) 325–331.
[2] Mahdavi et al., A biodegradable and biocompatible gecko-inspired tissue adhesive, PNAS, 2008, 105 (7) 2307–2312.

ACKNOWLEDGEMENTS
This study received support from the National Institute of Dental and Craniofacial Research of the National Institutes of Health, United States through the R01DE026117 grant funding.

Bioelectronics for modulating nervous system, such as the vagus nerve stimulator, demonstrate great promise in treating various neurological diseases. However, their fixed sizes and shapes cannot accommodate the rapid tissue growth and negatively influence normal developmental functions. For infants, children and adolescents, once the implanted devices are ‘outgrown’, additional surgeries are usually needed for device removal, followed by replacement. These tedious processes inevitably lead to repeated intervention and elevated complication rates. Although stretchable electronics with high elasticity is ideal for repeated motion and volumetric expansion of organs, they still cannot adapt to developmental tissue growth, which should not be restricted by any strain. Here, we address this limitation with Morphing Electronics (termed MorphE) which are designed and fabricated to suitably adapt to in vivo nerve tissue growth with zero strain. This is achieved by viscoplastic electronic materials (VEMs) that eliminate the stress and tissue constraint on growing tissue. In addition, water-insensitive self-healing property of the multilayered MorphE consisting of viscoplastic electrodes and a strain sensor allows fora reconfigurable platform for individualized implantation procedures. Animal study demonstrated that the soft and self-adapting MorphE showed no damage to the rat nerve after grown 2.4 times its initial diameter. This stable neural interface allowed chronic electrical stimulation and monitoring without disruption of functional behavior in developing rats. Our MorphE creates a new avenue for adaptive pediatric electronics medicine.

Neural prostheses are devices integrated with the neural tissue for diagnostic or therapeutic purposes, such as restoring impaired or lost functions. Despite a large variety of devices exists, a shared future is the presence of cables connecting the electrode-tissue interface to implantable electronic circuits for signal management. The presence of wires and connectors is a significant disadvantage for neural prostheses; in fact, they are weak points often leading to failure, they exert mechanical forces and tractions on the implant and the tissue, and they are often transcranial or transcutaneous connections that might lead to post-surgical complications, such as infection. Also, the use of implantable electronic units is another disadvantage. Several aspects limit their operation, such as power consumption, excessive heat generation, and high risk of failure in a wet environment due to leakage.
In neural prostheses, wireless electrodes are desirable. Retinal prostheses are a particular category of neural prostheses, in which wireless neuronal stimulation was achieved thanks to photovoltaic technology, that also avoids the need for active implantable electronic units. In the case of retinal stimulation, photovoltaic technology is intuitive since the retina is made to absorb light entering from the pupil naturally. Although photovoltaic retinal prostheses do not work with ambient and natural light, electrical stimulation is triggered by artificial light projected into the pupil and absorbed by semiconductor elements embedded into the stimulating pixels. This solution allows retinal prostheses to avoid a transscleral flat cable which limits the maximum number of stimulating pixels on the device and induce post-operative complications such as eye inflammation or leakage through the incision.
In the first part of this talk, the development and validation in-vitro and in-vivo of a wide-field, photovoltaic, and injectable retinal prosthesis will be reported. POLYRETINA is a wide-field epiretinal prosthesis which contains 10,499 photovoltaic electrodes (diameter of 80 µm and pitch of 120 µm) distributed with a pixel density of 80.33 pixels mm-2. The pixels cover an active area of 12.9 mm in diameter; thus, the prosthesis covers a visual angle of 46.3 °. Each pixel is composed by a conductive polymer (PEDOT:PSS) a bulk heterojunction (P3HT:PCBM) and a metallic cathode (Ti). The results obtained both in-vitro with retinal explants and in-vivo with large animal models will be reported.
In the second part of the talk, a novel visual prosthesis based on intra-neural stimulation of the optic nerve will be described. OpticSELINE is an intraneural 3D electrode array capable of selectively activating the optic nerve fibres to induce artificial vision. This technology is essential to overcome the exclusion criteria of retinal implants. The results from our in-vivo preclinical trial in large animals will be presented.
In conclusion, the use of photovoltaic technology to design novel neuroprostheses will be highlighted.

Electrocorticography (ECoG) is considered a gold standard for assessing neuronal activity in patients with epilepsy prior to surgical resection of epileptogenic zone [1]. During the procedure, ECoG electrode array is places on the surface of the brain between cerebral cortex and the skull bone. Although electrodes do not penetrate the brain tissue, implantation is still invasive and requires large craniotomy, which is traumatic and uncomfortable for the patient and expensive for the healthcare system. Herein, we demonstrate a novel approach to fabricate active and biocompatible shape memory polymer-based ECoG electrode array that can be implanted into tight subdural space through the small skull opening and unfold there triggered by the body temperature. The device fabrication includes 4 steps process: (i) synthesis of biocompatible poly(ε-caprolactone) (PCL) shape memory polymer and films production [2,3], (ii) gold pattern deposition on the films surface, (iii) insulation and (iv) laser micromachining to achieve the final material design. The developed electrode array demonstrates excellent shape memory properties by unfolding from 3 mm diameter tube into 40 x 40 mm flat sheet. Mechanical properties of the device are in line with the materials used in commercial and research ECoG electrode arrays. Moreover, due to small film thickness (200 μm) and low polymer matrix stiffness at body temperature, the electrode array has a potential to conform curvy brain surface improving measurement quality. Finally, gold patterns retain their conductivity after deformation and shape recovery proving the developed ECoG electrode array has a promising potential of being employed in the minimally invasive implantation application.

References:
[1] Pondal-Sordo, Margarita, et al. "Epilepsy surgery involving the sensory-motor cortex." Brain 129.12 (2006): 3307-3314.
[2] Toncheva, Antoniya, et al. "Bilayer solvent and vapor-triggered actuators made of cross-linked polymer architectures via Diels–Alder pathways." Journal of Materials Chemistry B 5.28 (2017): 5556-5563.
[3] Toncheva, Antoniya, et al. "Fast IR-actuated shape-memory polymers using in situ silver nanoparticle-grafted cellulose nanocrystals." ACS applied materials & interfaces 10.35 (2018): 29933-29942.

Hydrogel/elastomer bilayers have a tunable shape morphing ability, excellent flexibility and good biocompatibility. Thus, they have been studied intensively for various applications such as wearable electronics, micro-actuators, and micro-robots. However, there are few studies of implanted electronics using a hydrogel/elastomer bilayer. Here, we fabricated a bilayer system with polydimethylsiloxane (PDMS)/polyacrylamide (PAAm). While PDMS works as the passive layer defining the motion of hydrogel, the PAAm active layer can respond to water and change the shape of the bilayer by swelling and deswelling[1].

To fabricate the bilayer, benzophenone was used to bond the wet PAAm hydrogel and PDMS with good reliability[2]. The bilayer remained integral after 72 hours in water. To demonstrate the shape morphing ability, the bilayer was rolled up into a tube and then expanded into a curved film due to swelling in water. For implantation, the shape morphing ability will create a compact structure to minimize the incision during surgery. After implantation, the device will unfurl to increase the size of the neural interface. Furthermore, the permanent 3D shape of the bilayer is tunable. Initial results showed that varying the concentrations of crosslinkers of the PAAm hydrogel allowed different curvatures to be achieved. A 25 mm long bilayer strip (thickness of PAAm: 200 μm, thickness of PDMS: 840 μm), with high monomer concentration (33.4 wt. %) and low crosslinker density (0.5 wt. %), demonstrated a curvature of 0.230 mm^-1. Another strip with the same dimension and a higher crosslinker density (1.3 wt. %) demonstrated a smaller curvature of 0.110 mm^-1. In addition to the properties of the PAAm hydrogel, the curvature also depends on the thickness ratio between the hydrogel and the elastomer layer. A bilayer bending beam model developed by Timoshenko was used to predict the curvature with different thicknesses[3]. By using the expansion ratio and elastic modulus previously reported[4][1], the result of the model showed that 1000 μm thick PDMS with 175 μm thick PAAm could achieve a bending degree of 180°. The results from the model can guide the designing of the thicknesses of the two layers.

The shape morphable bilayer will serve as a substrate for a retinal stimulating array that maximizes the size of the implanted electronics while minimizing the surgical trauma.

[1] S. Liu, E. Boatti, K. Bertoldi, and R. Kramer-Bottiglio, “Stimuli-induced bi-directional hydrogel unimorph actuators,” Extrem. Mech. Lett., vol. 21, pp. 35–43, 2018.
[2] H. Yuk, T. Zhang, G. A. Parada, X. Liu, and X. Zhao, “Skin-inspired hydrogel-elastomer hybrids with robust interfaces and functional microstructures,” Nat. Commun., vol. 7, no. May, pp. 1–11, 2016.
[3] B. Y. S. Timoshenko, “Analysis of bi-metal thermostats,” no. l, pp. 233–255.
[4] J. Kim, C. Kim, Y. S. Song, S. G. Jeong, T. S. Kim, and C. S. Lee, “Reversible self-bending soft hydrogel microstructures with mechanically optimized designs,” Chem. Eng. J., vol. 321, pp. 384–393, 2017.

A great demand exists for nongenetic optical neuromodulation technologies. We report on our developments of ultrathin organic optoelectronic devices for neurostimulation. All of these devices rely on far red/near infrared irradiation in the tissue transparency window to actuate nanoscale organic semiconductor components. Our flagship technology is the organic electrolytic photocapacitor (OEPC) – a device that mimics biphasic current-pulse neurostimulation and thus transduces an optical signal into directly-evoked action potentials in neurons. These devices are not only wireless, but also 100-1000 times thinner than most existing technologies. Making implants with as small as possible mechanical footprint improves the efficacy of bioelectronic medical treatments by minimizing the risk for inflammation and making surgical implantation less invasive. We will present our results on pushing the limits of efficiency and stability, with benchmarking of performance using in vitro and ex vivo models, and cover our developments of peripheral nerve stimulation implants.

Organic mixed ionic/electronic conductors have elicited much interest lately as the enablers of a “new wave” of organic electronic devices in the biomedical space. In this talk I will start by exploring how the microstructure of the polymer interacts with the electrolyte and the effect of the electrolyte on the characteristics of electrochemical transistors. I will then show some applications of these materials in the sensor space ranging from flexible sensors to quantify electrolytes in sweat to biomimetic sensors to determine antibiotic activity of small molecules and detect the presence of pathogens. Finally I will show how devices based on these materials can be modulated by neuron-like cells where neurotransmitters elicit both short and long term potentiation in the device demonstrating a first building block of a new type of brain-machine interface.

Wearable health monitoring has garnered considerable interest from the health care industry as an evolutionary alternative to standard practices with the ability to provide rapid, off-site diagnosis and patient-monitoring. In particular, sweat-based wearable biosensors offer a non-invasive route to continuously monitor a variety of biomarkers for a range of physiological conditions. Both the accessibility and wealth information of sweat make it an ideal target for non-invasive devices that can aid in early diagnosis of disease or to monitor athletic performance.

Here, we demonstrate the integration of ammonium (NH₄⁺) and calcium (Ca²⁺) ion-selective membranes with a poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) organic electrochemical transistor (OECT) for multiplexed sensing of NH₄⁺ and Ca²⁺ in sweat with high sensitivity and selectivity. The presented wearable sweat sensor is designed by combining a flexible and stretchable styrene-ethylene-butene-styrene substrate with a laser-patterned microcapillary channel array for direct sweat acquisition and delivery to the ion-selective OECT. The resulting dermal sensor exhibits a wide working range between 0.01 mM to 100 mM, well within the physiological levels of NH₄⁺ and Ca²⁺ in sweat. The integrated devices are successfully implemented with both ex-situ measurements and on human subjects with real-time analysis using a wearable sensor assembly.

Controlled cell release is an important strategy in tissue engineering which deliver live cells to the repair sites in human bodies with well-designed cell density and distribution that mimic targeted tissues and facilitate tissue regeneration. Bicontinuous interfacially jammed emulsion gels (“bijels”) are a new class of materials consisting of two interpenetrating continuous liquid phases. Bijels can be used as templates for fabricating bijels-derived bicontinuous structures having interconnected channels. These channels (“pores”) in bicontinuous structures can provide desired space for cell encapsulation, proliferation and migration in tissue engineering while enabling the transport of nutrients and bioactive molecules. However, pore sizes of bijels-derived bicontinuous structures are normally small. To realize their potential in tissue engineering, bijels-derived bicontinuous structures with larger pore sizes need to be made for cell encapsulation and delivery. Our research has developed new methods for fabricating bijels and bijels-derived structures. In this investigation, bijels-derived polymer-hydrogel hybrids with normal pore size (~30 μm) and large pore size (~60 μm) were produced, and human dermal fibroblasts (HDFs) and osteoblast precursor cell line (MC3T3 cells) were encapsulated in respective hybrid. The cells were encapsulated in the crosslinked alginate hydrogel (with different crosslinking degrees) of polymer-hydrogel hybrids. The hybrids were then cultured for different periods to study controlled cell release. SEM examinations showed successful fabrication of cell-encapsulated polymer-hydrogel bicontinuous structures and the degradation of alginate hydrogel during culture. The cell release process was studied using confocal microscopy and SEM. Live/Dead assay and MTT assay were also used in the studies. It was observed that live cells were locked in hybrid structures at the beginning and were gradually released since Day 1 during culture. Both HDFs and MC3T3 cells exhibited good cell viability and proliferation after their release and were able to migrate from the channels of hybrid structures to the surface of hybrids and to the outer culture plate. The two types of cells displayed different release behaviors. In the bijels-derived hybrids with small pore size (~30 μm), HDFs were released significantly slower than MC3T3 cells. The major release period of encapsulated HDFs was 24 h later than the major release period of encapsulated MC3T3 cells. For the bijels-derived hybrids with large pore size (~60 μm), the release rates of HDFs and MC3T3 cells were similar. A possible explanation for the differences is that the sizes of cells and pores in hybrids could affect cell release. HDFs have a larger cell size (~50 μm) than MC3T3 cells (20-30 μm), which may have caused slower release of HDFs in bijels-derived hybrids with small pore size. This investigation has demonstrated that bijel-derived bicontinuous hybrid structures are a good vehicle for cell delivery in tissue engineering. By controlling the pore size of hybrid structures, the release of different types of cells could be controlled. The released live cells could proliferate well and migrate in and outside the hybrid structures.

A common material used for large-scale 3D printing is a composite consisting of acrylonitrile butadiene styrene (ABS) polymer compounded with carbon fiber (CF/ABS). However, the high cost of CF/ABS indicates a market for 3D printing with bioderived materials. Natural lignocellulosic fibers have the advantages of biodegradability, abundance, low density, low cost, and easy availability. In the present study, poplar fibers (Populus spp.) were modified using cellulose nanofibril (CNF) slurry (~ 3 wt% solid). The modified CNF/poplar fibers were used to reinforce ABS. The biocomposites obtained were characterized using techniques including tensile testing, differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), rheometer, thermogravimetric analysis (TGA), and scanning electron microscope (SEM). The tensile strength and Young’s modulus of neat ABS were 36 MPa and 1,901 MPa, respectively. After the addition of CNF/poplar fibers into ABS, the tensile strength and Young’s modulus of the biocomposites increased by 19% and 143%, respectively. The physical treatment of doping CNF solution on poplar fibers was found to be an effective technique to improve the thermomechanical properties of biocomposites.

Tissue-engineered scaffolds play an important role in the repair or regeneration of tissues and organs. Scaffolds provide strength, stability, and support for cell and tissue development and growth. Common scaffold materials are natural and synthetic polymers, however, each one has its own limitations and different disadvantages. Interestingly, in order to promote the mechanical properties and increase the bioactivity, the composite systems composed of various sources or types of polymers can retain the advantages of each material. Furthermore, composite polymer systems have the ability to allow stem cell adhesion and differentiation and to carry drug molecules and special biological molecules, like growth factor and enzyme. Research on composite scaffolds is focused on identifying composites with enhanced mechanical properties, sustained drug-releasing capabilities and the ability to support tissue development and growth.

In this study, we produced and characterized a novel nanocomposite polymer scaffold composed of poly-ethylene oxide (PEO), polycaprolactone (PCL) and halloysite clay nanotubes (HNTs). PGS, a polymer with repeating -O-CH₂-CH₂- units, and PCL, a hydrophobic aliphatic polyester with exceptional biodegradable and biocompatible properties, were used in combination with HNTs to form nanocomposite polymer scaffolds. The nanocomposite polymer scaffold thin films were prepared by solution blow spraying, which is an easy and convenient way to make fibers and films. We characterized the structural, morphological, thermal and functional properties of these novel nanocomposite polymer (PEO-PCL-HNT) scaffolds. The nanocomposite polymer scaffolds should be biocompatible and resorbable, maintain long-term cellular viability and functionality, have the ability to induce cellular differentiation leading to complex tissue formation, have the improved mechanical properties to support cell growth and have sustained-release capabilities.

Introduction: Hydrogels have potential in many biomedical applications such as tissue engineering and drug delivery system.¹ Among those, Polysaccharide-based hydrogels sucha as hyaluronic acid (HA) have been extensively studied for tissue engineering applications, for example cartilage tissue engineering, partly because they are involved in cellular processes such as proliferation, morphogenesis, and wound repair. A number of polysaccharide-based hydrogels were designed, synthesized by free radical polymerization and their properties were analyzed in vitro and in vivo. In this study, we hypothesized that the properties of polysaccharide-based hydrogels can be controlled and enhanced by combining with small molecules (e.g., proteins) or large molecules (e.g., PEG-based hydrogels). To test this hypothesis, novel biodegradable polysaccharide-based hydrogels were developed by combining polysaccharides (e.g., hyaluronic acid or HA) with PEG based macromers such as PEG sebacic acid diacrylates (PEGSDA) via free radical polymerization under mild conditions. Their physicochemical properties (e.g., swelling ratios) as well as biological properties were evaluated
Materials &Methods: Polysaccharide-based hydrogels were synthesized by free radical polymerization under mild conditions and their properties were controlled by incorporation of proteins (e.g., collagen or growth factors) or synthetic polymers such as polyethylene glycol (PEG). Physicochemical properties and in vitro and in vivo biological properties were investigated using mesenchymal stem cells (MSCs) and rat mandibular defect models.
Results: The chitosan-based hydrogels conjugated with collagen and/or growth factors were well synthesized under mild condtions. Growth factors were delivered from the hydrogel systems in a controlled manner. The encapsulated MSCs showed their potential of condrogenic differentiation in vitro. The physically crosslinked chitosan-based hydrogels revealed their capability of bone regeneration on the critical-sized defects (CSD) in rat mandibular. In addition, the physicochemical properties of hyaluronic acid-based polysaccharide hydrogels can be controlled by combining them with PEG-based hydrogels.
Conclusion: Polysaccharide-based hydrogels with well controlled their properties can be synthesized by incorporations of additives such as growth factors or synthetic hydrogels. These hybrid polysaccharide-based hydrogels can be useful as tissue engineering scaffolds and drug delivery systems to repair or regenerate the defects in organs or tissues, caused by injuries or diseases.

Acknowledgement: This study is supported by the National Research Foundation of Korea (NRF) Grants (NRF-2016R1D1A3B01008280).

References
[1] Allen TM, Cullis PR. Drug delivery systems: Entering the mainstream. Science. 2004;303:1818-22.

Recently, wearable sensors attract tremendous interest as real-time monitoring of physiological activities or environmental conditions becomes more important for many smart devices. Screen printing of sensing materials directly on fabric could not only enhance portability but also improve productivity by enabling a roll-to-roll process. Here, we present a solid-state pH sensor formed by a reliable screen printing technique. The pH sensor consists of two patterned electrodes. One is made of polyaniline(PANI)-carbon nanotube(CNT)-agarose composite. PANI, CNT, and agarose are a pH-sensing material, a conducting filler, and a binder and matrix material, respectively. For preliminary test, the composite in a paste state is deposited by doctor blade method with thickness of 150 um. The film shows negative dependence on pH condition: e.g. higher potential at lower pH. The other electrode is a “reference” electrode, made of Ag/AgCl thin film with ion-selective solid membrane. The resulting electrode shows similar current-voltage curves with commercial Ag/AgCl reference electrode. Finally, the compositions of PANI film as well as the conditions for screen printing such as mesh thickness, printing temperature & speed, etc. are optimized, to establish the continuous, roll-to-roll process of a pH-sensor patterned directly on fabric by the screen printing.

In the presence of moisture, surfaces are an ideal support for the development of biofilms containing bacteria that can be pathogenic. This poses a real public health, economic or even environmental problems in view of the use of biocides to eradicate this phenomenon. Due to the rise of multi-drug resistant microorganism, the investigation of new antibacterial coating is extremely requested.

The goal of this study is the development of a new regenerative antimicrobial coating based on polydopamine, containing haloamine (or N-halamine) functions (>N-Cl or/and >N-Br) that have oxidative properties due to the oxidation state +I of Cl or Br ^1,2. Thus, the antimicrobial activity of N-halamines is attributable to halogen exchange reactions between N-halamines and microorganisms, leading to death of the microorganisms. N-halamines are broad-spectrum biocidal groups due to their mode of action, i.e. oxidation, bacteria should not develop resistance, unlike after repeated use of antiobiotics.

The protection of surfaces with N-halamine compounds requires the immobilization of amine, amide or imine functions that will be transformed into haloamine either during synthesis or by post-treatment in the presence of NaOCl or NaOBr. The originality of this antibacterial coating is its regenerative proprieties. In fact, N-halamines, after contact with bacteria, can be regenerated by simple immersion of the coating in a diluted bleach recharge.

The purpose of this study was to investigate the synthesis and the antibacterial properties of a new N-halamine coating based on polydopamine (PDA). First the formation of the PDA coating by oxidative polymerization of dopamine in aqueous solution was studied and characterized. The thickness of the deposited layer reached a constant value around 50 nm after 24h of functionalization. Then this film was chlorinated by contact with a NaOCl solution in order to form on and into the coating chloramine functions. An amount of 10¹⁶ at/cm² of chlorine was successfully grafted into the surface. Finally, the antibacterial properties of the modified PDA coating were evaluated by testing its properties toward Escherichia coli. Bacterial viability in contact with the PDA-Cl film evaluated by epifluorescence microscopy revealed promising results.

References
1- Antimicrobial N-halamine polymers and coatings: A review of their synthesis, characterization and applications. F. Hui, C. Debiemme-Chouvy, Biomacromolecules 2013, 14, 585-601.
2- N-halamine coating formed via the electroreduction of in situ generated diazonium cations: toward antimicrobial surfaces. S. Gao, H. Cachet, C. Debiemme-Chouvy. Surf. Interface Anal. 2016, 48, 630-635.

Stimuli-responsive materials, or smart materials, has been intensively studied for decades and numerous interesting materials have been developed. Among them, materials with controllable mechanical properties have found use in a wide variety of applications including aerospace, civil applications, and implantable medical devices. However, synthetic hydrogels are the most heavily investigated. Considering its sustainability, a biodegradable polylactic acid (PLA) based free-stand film with controllable mechanical properties was developed. It was found that through chain end modification with anthracene (AN), PLA experiences a 10-fold increase in toughness with no change in tensile strength. Interestingly, after 365 nm UV light irradiation, AN modified PLA became brittle and tensile strength increased by 20%. π-π* stacking of AN groups was proposed to be the mechanism behind the toughening, and light induced dimerization of two AN group resulted in the brittleness. Based on the light reversible dimerization nature of the AN group, light with different wavelengths (365 nm and 254 nm) can be used to control the mechanical properties of newly developed PLA+AN materials in solid state.

Development of near-infrared (NIR) laser triggered photo cancer therapy is highly desirable but still a big challenge. Herein, NaYF₄:Yb/Er Upconversion Nanoparticles (UCNPs) was rationally synthesized through a novel low-temperature hydrothermal method, exhibiting photoluminescence emissions at the wavelength of 538, 653 and 839 nm, under 980 nm laser radiation. The UCNPs were firstly surface-modified with silanization of tetraethyl orthosilicate (TEOS) and aminopropyltrimethoxysilane (APTMS) for water solubility improvement and amine terminals decoration. Subsequently, via a carbodiimide coupling reaction, UCNPs were grafted with benzoyloxy pyrrolidine based C₆₀ derivatives, as photosensitizers. Finally, gold nanorods (AuNRs) with localized surface plasmon resonance (LSPR) at 980 nm were synthesized, carboxylic polyethylene glycol (PEG) functionalized and covalently conjugated around the UCNPs-C₆₀ nanocomposite to obtain a multifunctional nanoplatform for photothermal therapy (PTT) and photodynamic therapy (PDT). Notably, under NIR laser irradiation, singlet oxygen was effectively generated from an upconverting photodynamic combination of UCNPs and C₆₀, while localized hyperthermia was simultaneously induced by LSPR activity of AuNRs. The therapeutic efficacy was validated in vitro on breast cancer cell lines MCF-7 and MDA-MB-231 by various microscopic and biochemical studies under a significantly mild NIR irradiation and low dosage of the nanoplatforms. Furthermore, according to cell viability comparative analysis, such nanocomposite presents a remarkable synergistic therapeutic effect by the combination of PTT and PDT. Overall, this work provides an innovative strategy for the design and understanding of clinical phototherapeutics.

Spherical titanium barium nanoparticles with an average size about 100 nm in the tetragonal crystal phase were obtained by peroxide synthesis and then with formation of OH groups on its surface by hydrogen peroxide. To prevent their agglomeration and reduce the toxic effect, the surface of nanoparticles was chemically modified with sodium oleate and chitosan. Influence of surface modification by these compounds on piezoresponse force microscopy and their structure were investigated.

Optical manipulation of fluid or droplet has long been investigated for applications in microfluidics. The light-induced thermocapillary effect is one of the strategies in optical control of liquid. We demonstrate the laser-induced deformation of ferrofluid surfaces with ultra-violet to infra-red lasers. The surface deformation reaches the bottom and breaks the liquid, achieving the highest liquid deformation thickness for over 1000 μm. The deformation process and rupture are related to strong Marangoni effect, high laser absorption and low viscosity of ferrofluid. As applications of the laser-controlled ferrofluid, we show that a ferrofluid droplet in the capillary can be easily moved horizontally and vertically by the illumination of a laser beam. We also demonstrate that letters and patterns can be written on the black surface of ferrofluid thin film with a laser beam even with a common laser pointer. Laser manipulation of ferrofluid also makes it a controlling vehicle for varieties of liquid or droplets.

We have prepared various all-organic magnetic soft materials containing a cyclic nitroxide radical moiety as a spin source [1]. In this talk, we report the preparation of all-organic magnetic nanoemulsions composed of the non-ionic surfactant and the hydrophobic nitroxide radical compound [2]. The properties of the nanoemulsions have been investigated by small angle neutron scattering (SANS) and dynamic light scattering (DLS) analyses, EPR spectroscopy, and MRI method. The nanoemulsions showed high colloidal stability, high reduction resistance to ascorbic acid, low cytotoxicity and an enough contrast enhancement in the proton longitudinal relaxation time (T1)-weighted MR images in (-)-PBS in vitro and in vivo. Furthermore, an additional hydrophobic anticancer drug such as Taxol® was simultaneously encapsulated inside the nanoemulsions. We expect that the drug-loaded nanoemulsions can be used as a biocompatible magnetic drug carrier for MRI-visible targeted delivery system.
[1] a) Uchida, Y.et al. J. Mater. Chem. 2009, 19, 6877; b) Uchida, Y. et al. J. Am. Chem. Soc. 2010, 132, 9746; c) Takemoto, Y. et al. Soft Matter 2015, 11, 5563 [2] K. Nagura, N. Komatsu, R. Tamura, et al., Chem. Eur. J., 23, 15713 (2017); K. Nagura, N. Komatsu, R. Tamura, et al., Nanotechnology, 30, 224002 (2019); K. Nagura, N. Komatsu, R. Tamura, et al., Pharmaceutics, 11, 42 (2019).

The direct synthesis of water soluble iron oxide nanoparticles with both controlled size and functional groups on the surface has gained intensive interests. In this study, ultrasmall iron oxide nanoparticles (IONPs) with different functional groups were successfully synthesized via one-pot synthesis. The IONPs are prepared by first thermal decomposition of iron acetylacetonate Fe(acac)₃ precursor in diethylene glycol (DEG), followed by mixing the surface ligands at the end of the reaction. This facile synthesis method enabled binding of different surface materials such as dopamine hydrochloride (Dopa), polyethylene glycol with thiol end group (thiol-PEG), and polyacrylic acid (PAA) onto the IONPs. The size growth of IONPs can be well controlled as evidenced by transmission electron microscopy (TEM) studies. The high water stability of nanoparticles was correlated with the change of hydrodynamic size and zeta potential. While TEM results showed no significant change in the nanoparticles core size before and after surface modification, hydrodynamic size slightly increases due to the presence of ligands molecules on the surface. The attachment of surface ligands was studied by FTIR and TGA. FTIR results indicated the corresponding functional group for each surface ligands as a result of surface modification. In addition, we confirmed the introduce of functional groups by bioconjugation of fluorescence dyes on to the surface. The magnetic resonance phantom study show that the resulted nanoparticles can be used for T1-weighted MRI imaging. The effect of surface ligands on the relaxivities of IONPs were also studied.

Stimuli sensitive adhesives can be cured with temperature, UVA, and voltage. However, heat and light cured adhesives are limited to heat-sensitive and transparent substrates. Electrochemically mediated adhesive curing (i.e. electrocuring) can be utilized on a wide range of substrates including heat- sensitive and opaque surfaces. When an applied voltage potential is raised above a certain threshold, voltage activation initiates the diazirine groups to crosslink neighboring surfaces. Under the influence of direct current (1-3 mA), electrocuring progresses from the cathode to the anode but the maximum migration of the electrocuring is limited to 60-70% of the surface area. The application of alternating current (AC) is hypothesized to improve the electrocuring progression resulting in 100% surface activation, with a subsequent improvement in material properties. Structure-activity relationships of DC vs. AC currents are evaluated for the migration rate, shear modulus, gelation time, and adhesion strength of Voltaglue. Complete progression is achieved under AC stimulation and the maximum bioadhesion strength achieved for AC is 33 % higher than that for DC stimulation.

The detection and monitoring of volatile organic compounds (VOCs) are vital to numerous applications, such as long-term exposure to health issues, environmental protection, and chemical process control. Many previous attempts have successfully demonstrated portable chemiresistive devices on either conductive nanoparticle polymer composites or metal oxide semiconductor-based thin films. Nevertheless, composite sensors suffer from low sensitivity while thin-film sensors have limited flexibility. In this work, a carbon nanotubes (CNTs) and graphene nanoplatelets (GnPs) filled thermoplastic polyurethane (TPU) fiber sensor is investigated with engineered micro-scale multiple layers. Through controlling the solvent exchange process, a self-induced hollow core with high porosity is formed and is utilized to transport vapor flow with high VOCs/CNTs/GnPs interactions. The sensitivity is greatly enhanced, up to 60 ppm for xylene, comparing to traditional polymer composite sensors, usually over 1000 ppm. Additionally, the highly flexible polymer matrix, similar to traditional piezoresistor, enables the detection of different deformations, such as vibration at 0.3% strain, under different VOCs concentrations with distinct signal patterns. The unique multi-layer structure also provides pressure sensing application to as low as 6.89 kPa (1 psi) with high reversibility. This work provides new insights on the design and fabrication of complex polymer composite structures that enable more sensitive chemiresistors with piezoresistivity behavior.

Self-assembly of nanocrystals to form superlattices and mesocrystals is typically thought of in terms of colloidal forces and liquid crystal ordering. Considerations of shape and solvent entropy dominate the controls on organization while atomic-scale details are of lesser importance due to the fairly homogeneous nature of the building blocks. Proteins offer unique advantages over inorganic particles as nanoscale building blocks, including monodisperse structures and patchy interactions that are both atomically precise and tuneable. For this reason, ordered assemblies of protein building blocks exhibit a wide range of structural motifs including 1D nanofibers and tubes, 2D lattices and 3D capsids and frameworks. Protein-based systems have the further advantage that they are readily assembled in interrogated in mild aqueous conditions, making them amenable to molecular resolution imaging techniques that provide a unique window into the assembly process. Here we report on two systems of engineered proteins. The first consists of a highly patchy 4-fold symmetric protein building block (L-rhamnulose-1-phosphate aldolase; RhuA), whose self-assembly is driven at the shortest length scale by disulphide bonds designed into four corners of the protein. By introducing a charged, atomically patterned substrate and varying charge states via solution ionic strength, we achieve simultaneous control of four different classes of interactions (covalent bonding, electrostatic surface templating, dipole-dipole interactions and desolvation-induced complexation) to yield four distinct, precisely patterned 2D crystals. The second system consists of a de novo designed rod-shaped helical repeat whose length can be set arbitrarily in units of one repeat. These MicaN proteins are designed to interact in an epitaxial manner with the K⁺-sublattice of mica. Variation of the design created an end-to-end hydrophobic interactions that were either dimeric at both ends or trimeric interface at one end and dimeric at the other. As with RhuA, we show that the interplay of the specific intermolecular interactions, regional electrostatic interactions and global colloidal forces lead to a variety of distinct ordered phases. In all cases, in situ AFM reveals the development of order and its relationship to protein design and surface and solution interactions. The results provide a mechanistic picture of assembly by patchy protein building blocks that links pathways and outcomes to the influence of interactions over many length scales.

The design of polymeric materials like multiblock copolymers (MBCs) is guided by the requirements of specific applications but demands an understanding of structure-function relationships.¹ MBC materials provide a complex hierarchical structure. The chemical nature, the number length of integrated building blocks, as well as their sequence structure (e.g. alternating or random) impact the phase morphology. This organisation level largely influences the macroscopic mechanical properties such as deformability and the modulus.^2-4
We hypothesized that a strictly alternating sequence should favour crystallization and in this way the elastic properties. Well-defined multiblock copolymers (MBCs) composed of two different hydrophobic, semi-crystalline blocks providing domains with well-separated melting temperatures (T_ms) were thought to differ e.g. in the elongation at break just controlled by the polymer architecture of the MBC designed as strictly alternating (MBCs_alt) or random (MBCs_ran). Accordingly, two different types of MBCs (MBC_alt and MBC_ran) were synthesized from the same type of precursor building blocks and compared.
Three different series of MBCs_alt or MBCs_ran were created by means of high-throughput synthesis by coupling oligo(ε-caprolactone) (OCL) of different molecular weights (2, 4, and 8 kDa) with oligotetrahydrofuran (OTHF, 2.9 kDa) via Steglich esterification whereby the blocks were designed either as macrodiol or as macrodicarboxylic acid. The maximum of weight average molecular weight (M_w) of MBCs_alt of the three different series were 70,000 g^.mol^-1, 160,000 g^.mol^-1, and 190,000 g^.mol^-1 and increased with increase of the chain length of the OCL block. This increase in the maximum M_w was also observed for the series of MBCs_ran, where maximum M_w of 100,000 g^.mol^-1, 130,000 g^.mol^-1, and 160,000 g^.mol^-1 were obtained.
While the average phase size between the domains of the amorphous phase increased from 100 nm to 600 nm for MBCs_ran when the M_w increased the strictly alternating structure limited the demixing between OCL and OTHF blocks resulting in an almost constant average phase size between the amorphous phase domains with raising M_w.
Comparing MBCs_ran a more proncounced amorphous phase separation was observed with increasing OCL block length size and was attributed to higher phase separation tendency of a mixed OCL and OTHF mixed amorphous phase.
The increase in M_w of MBCs resulted in a reduced degree of crystallinity as detected by transmission electron microscopy and x-ray scattering experiments attributed a decreased phase separation tendency. When the chain length of OCL building blocks was increased, the tendency for phase separation was facilitated, which was attributed to the decrease in chain mobility within the MBCs. For MBC_alt compared to MBC_ran the crystallinity was lower and decrease in crystallinity with raising M_w was lower, which both was attributed to the confined crystallization in MBC_alt. For all MBCs a decrease of both T_ms associated to the melting of the OCL and OTHF domains was observed when the molecular weight increased. T_m (OTHF) of MBCs_ran was always higher than T_m (OTHF) of MBCs_alt, which was attributed to a confined crystalline lamella growth of OTHF incorporated in alternating copolymers. In addition, the complex modulus of MBCs_alt was almost half as high when compared to MBCs_ran.
In this way this study demonstrates the pronounced role of the block length and sequence structure in MBCs and enables a quantitative elucidation of the structure-function relationship when two semi-crystalline block segments are utilized for the design of block copolymers.

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With the exponential increase in the demand for flat-panel displays, portable electronics, and biomedical devices, considerable attention has been directed towards the fabrication of highly efficient organic light-emitting diodes (OLEDs). Several techniques and methods were presented but the single-unit phosphorescent OLEDs have demonstrated a maximum external quantum efficiency (EQE) limit of 25% without additional out-coupling aid. In order to overcome this efficiency barrier, new exotic materials are to be investigated with exceptional properties like an interfacial dipole, exciton generation, and charge balance.

Herein, we present the robust contribution of a widely used antibiotic; ampicillin in optoelectronics.¹ The optimum fusion of ampicillin with Poly(3,4-ethylenedioxythiophene): poly(styrenesulfonate) (PEDOT: PSS) considerably improved the device efficiency of a single-unit green phosphorescent OLED. The charge distribution over ampicillin’s structure due to the presence of primary, secondary and tertiary amine along with the lactam ring was found to be the key parameter. The concentration-dependent analysis of the mixture (ampicillin-PEDOT:PSS) revealed that the addition of 25% ampicillin in PEDOT:PSS provided a horizontal interfacial dipole. The dipole suppressed the hole injection by lowering the work function of the anode and improved the charge balance. Moreover, the parallel arrangement of molecules facilitated the generation of J-aggregations which contributed extra excitons to the device. Consequently, the values of current efficiency (120 cd/A), EQE (35%) and power efficiency (70 lm/W) boosted by J-aggregated excitons were demonstrated, which to our knowledge are the highest reported efficiencies.¹ The EQEs were analyzed using integrating sphere and variable-angle measurements, which demonstrated a Lambertian emission trend. The devices with penicillin-PEDOT:PSS were also fabricated for cross-evaluation, where the only difference in penicillin structure as compared to ampicillin is the absence of primary amine. The resulting EQE of the penicillin devices was found to be ~11% lesser than that of the ampicillin devices. This indicated that the specific molecular structure and interfacial dipole generated by ampicillin was the crucial aspect to obtain higher efficiency (EQE ~35.1%). Further, the concentration (25, 40, and 75%) and time (2 days, 1 month, and 2 years) dependent interactions of ampicillin with PEDOT:PSS, and their role in device performance was systematically investigated by analyzing the physical, chemical, electrical, and optical properties of the layers.¹

The investigation of dynamic properties using antibiotic materials such as ampicillin opens new horizons for the technical advancements in the field of optoelectronics. The work presented here provides a facile, cost-effective and nature-friendly method to enhance the efficiency of the OLED devices and has high potential to be applied in photovoltaic and biomedical devices.

1 Hafeez, H. et al. The effect of introducing antibiotics into organic light-emitting diodes. Communications Physics 2, 1-13 (2019). (Url: https://www.nature.com/articles/s42005-019-0228-3)

Chitin nanofiber (ChNF) is one of a promising eco-friendly material because it is non-toxic, biocompatible, robust, and sustainable. It is also the most abundant marine polysaccharide. The b-ChNF is known to show piezoelectric properties due to its intrinsic molecular polarization arising from the non-centrosymmetric crystal structure. This work, we demonstrate a b-phase dominant ChNF/poly(vinylidene fluoride) (PVDF)-based flexible piezoelectric nanogenerators (PENGs) that exhibit superior electrical output. The PVDF is incorporated with ChNF to significantly enhance its piezoelectric properties. This is primarily because of the electrostatic interaction between the α-ChNF and the CH₂/CF₂ dipoles, the crystallinity of the b-ChNF and b-PVDF are increased. The ChNF/PVDF film is characterized by scanning electron microscopy (SEM), polarizing optical microscope (POM), and peak force TUNA (PF-TUNA), x-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), and Raman spectroscopy to investigate the optical and piezoelectric properties of the ChNF/PVDF film. The ChNF/PVDF film exhibits superior remnant polarization ~10.8 μC/cm².

Electrophysiological signals of the body provide critical information to assess the functionalities of organs or to diagnose diseases. In order to detect minute biological signals effectively, three-dimensional (3D) electrodes are required to minimize the tissue-electrode impedance and to form conformal interfaces with tissues. However, conventional approaches to form 3D-structured electrodes are based on photolithographic patterning and etching, and these processes result in the low variety of 3D structures limited to certain crystallographic planes of materials. Also, the poor selectivity of materials and their high stiffness easily damage tissues and obstruct the effective signal recording.
Herein, the 3D electrode arrays composed of tissue-compatible soft metals have been formed by high-resolution direct printing. Various form factors of 3D electrodes with different heights (20 to 100 μm), diameters (5 to 30 μm) and the tip morphologies (sharpness) are printed and studied in terms of the tissue-electrode interfaces. While conventional materials for 3d microelectrode arrays have compatibility problems such as inflammation or the detachment of tissues because of a modulus mismatch, our 3D electrodes based on soft metals have Young’s modulus at least five orders of magnitude lower than that of platinum and silicon which are conventional materials for bioelectrodes. When human dermal fibroblasts are directly seeded to test the viability of the soft 3D electrodes, over 80% of cells were viable after 7 days with adhesion to the surfaces of electrodes. The improvement of signal transfer, including the signal-to-noise ratio of biopotentials and the persistency of signals at the tissue-electrode interface, can be found by an in-vitro recording of neurons directly cultured on the 3D soft electrode arrays with a comparison to the platinum-based two-dimensional electrode arrays.

Understanding and controlling dynamics of gels at fluid-fluid interfaces is critical for a plethora of bioinspired and biointerfaces since hydrogels can be biocompatible, compliant, and responsive to a number of orthogonal stimuli. Herein, we use Dissipative Particle Dynamics simulations to focus on the shape changes of a nanogel as it adsorbs from the aqueous phase onto the interface between two immiscible fluids effectively acting as compatibilizer. Upon adsorption at the interface, the hydrogel spreads over the interface adopting various shapes depending on its size and crosslink density. We characterize these shapes by the shape anisotropy and an effective extent of spreading. We highlight the differences between these characteristics for cubic and spherical nanogels and show that the choice of the cubic shape over the spherical one results in a wider range of topographies that could be dynamically prescribed onto the soft interface due to the gels’ adsorption. Further, we focus on the interactions between multiple gels placed at the fluid-fluid interface. We show that controlling the shapes and clustering of the gels at the interfaces via variations in solvent quality results in tailoring dynamics and topography of soft nanostructured interfaces. Hence our findings provide insights into design of nanostructured bioinspired and biointerfaces with topographies controlled externally or by the properties of the surrounding bioenvironment.

Magnetic resonance imaging (MRI) is a powerful non-invasive imaging technique, the effectiveness of which can be improved through the introduction of contrast agents (CAs).¹ Magnetic iron oxide nanoparticles have demonstrated excellent potential in biomedicine and have been used as clinical MRI contrast agents (e.g. Feridex, Resovist), though their popularity has plummeted recently due to their low efficacy. There is therefore a real need for new contrast agents with excellent MRI contrast capabilities and good biocompatibility.

The importance of the strong interactions between neighbouring magnetic nanoparticles has been well documented when producing high performance MRI contrast agents. These interactions, and thus the anisotropy, can be increased in a number of different ways. One such method, is via the utilisation of biopolymers, such as DNA and heparin, as templating stabilisers.^2–4 However, the inherently high polydispersity of such biopolymers, means that a lack of precise control over these vital interparticle interactions. To remedy this we have exploited synthetic analogues of the naturally occurring anti-coagulant heparin, to be used as a templating stabiliser in the production of iron oxide-based MRI contrast agents.⁵ This new family of negative contrast agents demonstrates excellent MRI contrast capabilities (r₂ values reaching 434.2 mM^-1s^-1 at 25 ^οC and 23 MHz, several times higher than similar commercial analogues). Such behaviour results from additional control over the polymers molecular weight and thus number of sulfonate seeding sites. This affords the oppportunity to finely tune interactions between neighbouring particles and therefore the MRI properties of said contrast agents. Variable field relaxometry provided unexpected but important insights into the dynamic environment of the hydrated materials, providing reasoning for their exceptional MRI behavior. Thanks to the polymer’s templating backbone and flexible conformation in aqueous suspensions, nanocomposites appear to behave as “multi-core” clustered species, enhancing interparticle interactions whilst retaining necessary water diffusion.
The vital importance of anisotropy and the interactions between superparamagnetic nanoparticles on resulting MR contrast has been further investigated through the production of permanent 1-dimensional magnetic nanostructures. Building on the templating effects of sulfonated polyelectrolytes we discuss a novel magnetically driven one-pot synthetic strategy to produce 1-D contrast agents which boast excellent MRI capabilities.

1. Chem. Soc. Rev., 2015, 44, 4501–4516.
2. J. Mater. Chem. B, 2016, 4, 12–15.
3. J. Am. Chem. Soc., 2008, 130, 4214–4215.
4. Chem. Commun., 2004, 22, 2560
5. Polym. Chem., 2017, 8, 5513

A great demand exists for nongenetic optical neuromodulation technologies. We report on our developments of ultrathin organic optoelectronic devices for neurostimulation. All of these devices rely on far red/near infrared irradiation in the tissue transparency window to actuate nanoscale organic semiconductor components. Our flagship technology is the organic electrolytic photocapacitor (OEPC) – a device that mimics biphasic current-pulse neurostimulation and thus transduces an optical signal into directly-evoked action potentials in neurons. These devices are not only wireless, but also 100-1000 times thinner than most existing technologies. Making implants with as small as possible mechanical footprint improves the efficacy of bioelectronic medical treatments by minimizing the risk for inflammation and making surgical implantation less invasive. We will present our results on pushing the limits of efficiency and stability, with benchmarking of performance using in vitro and ex vivo models, and cover our developments of peripheral nerve stimulation implants.

Interfaces that link biological systems with machines are increasingly evolving beyond the electrical domain. Multi-modal bioelectronics aims to add chemical, optical, thermal or mechanical functionality to the capabilities of classical electrode arrays. When such systems are used in physical contact with tissues or cells, the need for overall mechanical compliance is crucial for their biointegration. This raises a question: how do we build multi-modal arrays of sensors and actuators with tissue-like softness?
In this talk I will present our efforts to adapt direct ink writing (multi-material 3D printing) for the purpose of fabricating elastic systems of electrodes, optrodes, thermotrodes, and chemotrodes. A palette of silicones, composites and hydrogels are used as inks, where each of the inks enables one interfacing modality. As an example of in vitro appliation, I will present multi-modal pacing and monitoring of stem cell derived cardiomyocytes. In vivo, I will present printed neuro-muscular implants tailored to specific anatomical niches and animal models. These developments are expected to contribute to the development of personalized platforms for bioelectronic medicine.

Neural prostheses are devices integrated with the neural tissue for diagnostic or therapeutic purposes, such as restoring impaired or lost functions. Despite a large variety of devices exists, a shared future is the presence of cables connecting the electrode-tissue interface to implantable electronic circuits for signal management. The presence of wires and connectors is a significant disadvantage for neural prostheses; in fact, they are weak points often leading to failure, they exert mechanical forces and tractions on the implant and the tissue, and they are often transcranial or transcutaneous connections that might lead to post-surgical complications, such as infection. Also, the use of implantable electronic units is another disadvantage. Several aspects limit their operation, such as power consumption, excessive heat generation, and high risk of failure in a wet environment due to leakage.
In neural prostheses, wireless electrodes are desirable. Retinal prostheses are a particular category of neural prostheses, in which wireless neuronal stimulation was achieved thanks to photovoltaic technology, that also avoids the need for active implantable electronic units. In the case of retinal stimulation, photovoltaic technology is intuitive since the retina is made to absorb light entering from the pupil naturally. Although photovoltaic retinal prostheses do not work with ambient and natural light, electrical stimulation is triggered by artificial light projected into the pupil and absorbed by semiconductor elements embedded into the stimulating pixels. This solution allows retinal prostheses to avoid a transscleral flat cable which limits the maximum number of stimulating pixels on the device and induce post-operative complications such as eye inflammation or leakage through the incision.
In the first part of this talk, the development and validation in-vitro and in-vivo of a wide-field, photovoltaic, and injectable retinal prosthesis will be reported. POLYRETINA is a wide-field epiretinal prosthesis which contains 10,499 photovoltaic electrodes (diameter of 80 µm and pitch of 120 µm) distributed with a pixel density of 80.33 pixels mm-2. The pixels cover an active area of 12.9 mm in diameter; thus, the prosthesis covers a visual angle of 46.3 °. Each pixel is composed by a conductive polymer (PEDOT:PSS) a bulk heterojunction (P3HT:PCBM) and a metallic cathode (Ti). The results obtained both in-vitro with retinal explants and in-vivo with large animal models will be reported.
In the second part of the talk, a novel visual prosthesis based on intra-neural stimulation of the optic nerve will be described. OpticSELINE is an intraneural 3D electrode array capable of selectively activating the optic nerve fibres to induce artificial vision. This technology is essential to overcome the exclusion criteria of retinal implants. The results from our in-vivo preclinical trial in large animals will be presented.
In conclusion, the use of photovoltaic technology to design novel neuroprostheses will be highlighted.

Bioelectronics are poised to revolutionize health care, providing exciting opportunities for therapeutics, health monitoring, prosthetics, and human augmentation. Yet, there remain significant barriers to long-term implantation of these technologies within the body. This is due in large part to inflammatory responses resulting from the severe mismatch in mechanical properties between conventional device components, which are rigid (E~GPa) and non-deformable, and biological tissues, which are significantly more soft (E~ kPa) and dynamic. With their high water content (70-99 wt%), hydrogels are capable of achieving tissue-level elastic moduli, though existing strategies to render hydrogels electrically conductive involve incorporating stiff, conductive additives into inert and stretchable hydrogels, necessitating a tradeoff between electrical and mechanical properties. Here, we present a new materials design strategy for conductive hydrogels that overcomes this tradeoff by decoupling mechanical from electrical properties through the use of two distinct, interpenetrating polymer networks. We first leverage the gel-forming capabilities of the conducting polymer poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) to form a macroscopically connected conductive network at remarkably low polymer concentrations (~1 wt%). The highly dilute yet interconnected conductive network enables us to orthogonally tune elastic modulus using a second, interpenetrating polymer network. Our unique design enables an unprecedented combination of mechanical tunability over 3 biologically-relevant orders of magnitude (8 kPa – 374 kPa), stretchability (up to 400%), elasticity, and electrical conductivity up to 23 S/m. To enable their integration into devices, we further introduce a novel method for patterning these materials with high resolution onto surfaces of planar and even curved objects. We overcome limitations precluding the use of conventional molding or lithographic methods by using a sacrificial metal pattern that can be oxidized in the presence of a PEDOT:PSS electrolyte to locally induce gelation only at the pattern interface. This materials design strategy and its corresponding new patterning method represent a significant step towards the development of next-generation bioelectronics that can seamlessly interface with biological targets over extended timescales.

Pressure sensors with high sensitivity have uses ranging from pulse monitoring and plantar pressure measurement (10–100 kPa) to in vivo intraocular and intracranial pressure measurement (1–10 kPa). The sensitivity of capacitive pressure sensors is primarily determined by the modulus of a dielectric layer that reversibly deforms to produce an electrical signal. Crosslinked polymers provide a means to achieve good dielectric properties with low modulus relative to inorganic materials. Unfortunately, the mechanical properties of conventional linear polymer networks are constrained such that a lower limit on softness translates to poor capacitive pressure sensor performance. Here, we overcome this limitation by leveraging the intrinsic “super-soft” characteristic of bottlebrush polymers, which can be crosslinked to form solvent-free networks with moduli in a range matching that of biological tissues (1–100 kPa). A simple light-induced crosslinking strategy is introduced to facilitate device fabrication. Parallel plate capacitive pressure sensors constructed with these bottlebrush polymer networks exhibit up to a 53× increase in sensitivity compared to commonly used elastomers, e.g., PDMS (Sylgard 184). The sensors show pressure resolution on the order of 0.1 kPa, capable of differentiating subtle forces in the light touch regime. Transparent and flexible sensors fabricated using indium-tin-oxide (ITO)-coated poly(ethylene terephthalate) (PET) electrodes are shown to be functional in a bent configuration. This combination of contemporary synthetic chemistry and application-driven materials design accentuates the opportunities available at the intersection of science and engineering to advance soft, flexible, and biocompatible devices.

Gel based iontronics are attractive for epidermal electronics due to their compatible and tunable mechanical properties. Many receptive interface for birectional human-machine interactions require tactile sensors that are intrinsically soft, skin conformable and dynamically deformable. While addressable touch input can be realized using capacitive, resistive, piezoelectric or triboelectric signals, the output signal often requires integrated lighting for visual detection or optoelectronic signal feedback on a transparent interface. In addressing these neeeds, ionic conductors provide the advantages of optically transparent, skin compliant, ease of processibility and added novel functionality in the presence of ions and electrons transport.

We have demonstrated the use of conductive hydrogel composites as versatile strain sensors for monitoring of human motion. In addition, hydrogel ionic conductor was shown to be effective current collector by harnessing the electrical double layer for triboelectric nanogenerators, allowing them to be mounted onto skin or machine. On the other hand, we have formulated inkjet printable ionic gels with precise control of the rheological characteristics of gels. As a result, transparent deformable touch panels have been realized using the microscale patterning of ionic gel. The transparent touch interface is capable of remarkable signal fidelity under dynamic human-machine interactive conditions. We have further prepared thermally stable gels with self-healing ability and found applications in dielectric actuators, potentially used in biostimulation applications.

Conducting polymers (CPs) have been widely used as electroactive biointerfaces in applications such as DNA sensors, in electrically-stimulated tissue engineering and more recently in stretchable and conformable organic bioelectronics. However, the majority of these applications are based on the electropolymerized or solution deposited 2D films of CPs, and as such cannot fully probe the actual 3D cell environment within tissues and organs. Our approach to address that is based on a precise fabrication of individually addressable, high aspect ratio, 3D CP-pillar microelectrode arrays by means of ‘micro-extrusion printing’ using our in-house constructed system. The ‘printing’ principle is simple ‘extrusion’ of CP ‘ink’ from a micro-pipette into ‘pillars’, accompanied by evaporation of solvent (water) during the process. CP pillars of different aspect ratios (from 2 to 7000) were successfully fabricated, with excellent stability, mechanical properties and electrochemical properties [1].
Such 3D CP-pillar microelectrode arrays could be employed in variety of applications, from biological sensing to recording and electrically stimulating cells and tissues, with the design of the arrays being easily adjustable to a particular application.
Our demonstrated examples include: exosome capture, sensing and release - where the CP pillars can be easily functionalized for capturer/release of exosmes; and 3D electrical stimulation of human neural stem cells into a high-density of mature neurons and functional neural networks[2].
Overall, the 3D CP microelectrodes provide promising versatile substrates for a variety of bioelectronics applications, including where spatiotemporal control of individually electrically addressable microelectrodes is desired.
[1] P. Zhang, N. Aydemir, M. Alkaisi, D. E. Williams and J. Travas-Sejdic, Direct Writing and Characterization of Three-Dimensional Conducting Polymer PEDOT Arrays, ACS Appl. Mater. Interfaces, 2018, 10 (14), 11888-11895
[2] E. Tomaskovic-Crook, P. Zhang, A. Ahtiainen, H. Kaisvuo, C-Y. Lee, S. Beirne, Z. Aqrawe, D. Svirskis, J. Hyttinen, G. G Wallace, J. Travas-Sejdic, J. M Crook, Human Neural Tissues from Neural Stem Cells Using Conductive Biogel and Printed Polymer Microelectrode Arrays for 3D Electrical Stimulation, Adv. Healthcare Mater., 2019, DOI: 10.1002/adhm.201900425

In this talk, I will introduce our recent activity of conformable organic photonic systems. We have developed ultra-flexible and lightweight highly efficient, ultra-flexible, air-stable, three-color, organic light-emitting diodes (OLEDs). The total thickness of the devices, including the substrate and encapsulation layer, is only three micrometers, which is one order of magnitude thinner than the epidermal layer of the human skin. Due to the very thin substrate and neutral position, our device shows the highly flexibility and conformability. The OLEDs are directly laminated on the surface of skin and are used as indicators/displays. Furthermore, we have developed ultra-flexible organic imager which consists with a monolithically processed rectifying pixel and an organic photo diode. Our organic imager has pixel pitches as small as 50 µm, with resolutions of up to 262 ppi. Using our ultra-flexible organic imager, we succeed to measure the spatial photoplethysmography (PPG) mapping.

Electrical stimulation of tissue and ultimately individual cells has not only played an essential role in our understanding of the structure and function of excitable tissue but continues to serve as the basis for a variety of therapeutic interventions for the treatment of disorders ranging from cardiac arrhythmias to Parkinson’s disease. Advances in technology have attempted to overcome barriers associated with the spatial resolution (i.e., who and where to stimulate) and the invasiveness of the process. Optogenetics has revolutionized the way we can record and affect the electrophysiology of cells and tissue, using light as the input/output (I/O) interface. Though optogenetics has developed at a great pace and is making profound scientific contributions, the core of the technique requires genetic modifications of the cells or organism. This presents challenges both in terms of achieving targeted gene expression and the potential deleterious consequences of the expression of foreign proteins, which have implications on clinical translation to humans and regulatory approval. We report our developed breakthrough hybrid-nanomaterial synthesis process to enable minimally invasive, remote and non-genetic light-induced control of targeted cell activity with high spatial-temporal resolution. We combine one-dimensional (1D) nanowires (NWs) and two-dimensional (2D) graphene flakes grown out-of-plane with tailor-made physical properties for highly controlled photostimulation. Photostimulation using NW templated 3D fuzzy graphene (NT-3DFG) is flexible due to its broadband absorption and does not generate cellular stress. Our light-based platform adds a powerful toolset to the basic scientists studying cell signaling within and between tissues. Last, this platform can be adapted to address challenges in tissue engineering, i.e. the much-needed non-genetic stimulation control of engineered tissues. By controlled delivery of the NT-3DFG we will be able to locally and selectively control cellular activity with high spatial and temporal resolution of 3D tissues.

As the role of flexible soft materials become more crucial for applications such as flexible displays in foldable mobile phones, compliant sensors and actuators in wearables, etc., new functional soft materials are needed to fill the roles previously fulfilled by rigid and bulky conventional materials. The field of haptic technology has recently seen emerging needs for integration into soft, flexible and even transparent interfaces. Since several decades ago, haptic feedback in electronic devices such as mobile phones, gaming controllers, are provided by bulky mechanical motors that vibrate the entire device upon application of an electric signal to give a tactile sensation to the users. In recent years, piezoceramics such as lead zirconate titanate are seen as a popular alternative due to its high performance and small form factor. However, their high stiffness, density and opacity prove to be a large obstacle in applications where flexibility, weight and transparency are crucial. In such applications, electroactive polymers (EAPs) serve as an excellent solution and have been a rapidly growing focus of research due to the wide range of potential applications such as energy harvesters, sensors and actuators, artificial muscles, etc. In reported methods to enhance the dielectric and electromechanical properties of EAPs, there is a compromise in at least one of these factors: electrical breakdown strength, transparency and flexibility.

In this work, we present an approach to enhance the output force of polymer actuators by increasing the dielectric permittivity and polarizability of the EAP, poly (vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) (P(VDF-TrFE-CTFE)), by incorporation of a conductive nanowire interlayer into the polymer matrix. The interlayer is formed by a network of highly conductive silver nanowires with high aspect ratio and enhances the dielectric permittivity and polarizability of the EAP over a broad range of frequencies including ultra low frequencies (e.g. 0.1 Hz) and the range of 200 to 300 Hz at which the mechanoreceptors in the human fingertips are most sensitive to. Through experiments and finite element modelling, the enhancement of dielectric properties were found to originate from charge accumulation at the nanowire/polymer interface and resulted in an output force double that of a neat EAP actuator. The higher output force can be used to improve tactile feedback perception of a human user and allows a 40% reduction in the actuator excitation voltage compared to that of a neat EAP actuator. Even with enhanced dielectric properties and output force, the composite actuator retains its transparency and flexibility without severe compromise in the electrical breakdown strength. The excellent transparency and flexibility of the modified EAP are promising for a wider range of possible applications such as direct and localized haptic feedback on flexible electronic displays, touch screens, etc.

Robot function is largely determined by the structural platform upon which it is built. The field of soft robotics aims to expand the design space by introducing unconventional robotic materials and methods to the engineering toolkit. In this talk, it is proposed that this increasing repertoire of robotic platforms be extended to include fabrics, which are known for their extreme deformability, versatility, and customizability. Possible fiber-based forms to achieve actuation, sensing, and stiffness control will be presented, including: (1) shape memory alloy ribbon as a thin-body actuator, which is effective at pure-bending motion, in contrast with typical fiber actuators that rely on axial contraction alone; (2) An in-fabric sensor that changes in resistance as the fabric weave is stretched and the gaps present between fibers are enlarged; and (3) A stiffness-changing fiber based on a glass-transition polymer epoxy with low-melting-point metallic alloy inclusions that is capable of a stiffness change of two orders of magnitude using Joule heating. By designing actuators, sensors, and structural components that conform to a fiber-based geometry, we show that simple fabrics can be functionalized to create damage-responsive tourniquets, self-deploying structures, and morphing airfoils.

Enabled by new materials and device designs, a new generation of brain interface technologies is replacing bulkier, non-compliant systems with the aim of seamless electronic-biological interfaces with lower tissue damage, reduced immunogenicity, high-density, tunable spatial distribution, and long-term stability. Recent successful examples leveraging mechanically compliant materials have demonstrated major breakthrough in brain research using ultra-flexible systems for ECoGs recordings, and for depth electrodes.

However, connectorization of these ultra-flexible electrodes to traditional electronics remains a significant challenge. Current connectors, such as zero-insertion force (ZIF) devices, are limited to 64 or 128 channels at most. While these may then be stacked together this approach does not scale, limiting the maximum number of channels feasible.

Here, we demonstrate an easy to use, massively scalable connector technology. Rather than using traditional amplifier electronics, we couple thousands of flexible electrodes directly to a CMOS pixel array, such as typically found in a camera or OLED display. These devices have millions of available pixels, and by taking advantage of the small, flexible nature of the electrodes we are able to attach thousands of electrodes in seconds. These form robust Ohmic contact that can be extensively cycled. We demonstrate the simplicity of the process, and show how it can be used to perform massively parallel neural recordings.

Organic mixed ionic/electronic conductors have elicited much interest lately as the enablers of a “new wave” of organic electronic devices in the biomedical space. In this talk I will start by exploring how the microstructure of the polymer interacts with the electrolyte and the effect of the electrolyte on the characteristics of electrochemical transistors. I will then show some applications of these materials in the sensor space ranging from flexible sensors to quantify electrolytes in sweat to biomimetic sensors to determine antibiotic activity of small molecules and detect the presence of pathogens. Finally I will show how devices based on these materials can be modulated by neuron-like cells where neurotransmitters elicit both short and long term potentiation in the device demonstrating a first building block of a new type of brain-machine interface.