Technology Roadmap for Flexible Sensors.

Humans rely increasingly on sensors to address grand challenges and to improve quality of life in the era of digitalization and big data. For ubiquitous sensing, flexible sensors are developed to overcome the limitations of conventional rigid counterparts. Despite rapid advancement in bench-side research over the last decade, the market adoption of flexible sensors remains limited. To ease and to expedite their deployment, here, we identify bottlenecks hindering the maturation of flexible sensors and propose promising solutions. We first analyze challenges in achieving satisfactory sensing performance for real-world applications and then summarize issues in compatible sensor-biology interfaces, followed by brief discussions on powering and connecting sensor networks. Issues en route to commercialization and for sustainable growth of the sector are also analyzed, highlighting environmental concerns and emphasizing nontechnical issues such as business, regulatory, and ethical considerations. Additionally, we look at future intelligent flexible sensors. In proposing a comprehensive roadmap, we hope to steer research efforts towards common goals and to guide coordinated development strategies from disparate communities. Through such collaborative efforts, scientific breakthroughs can be made sooner and capitalized for the betterment of humanity.

Direct Laser 3D Printing of Organic Semiconductor Microdevices for Bioelectronics and Biosensors.

Fabrication of conductive and bioactive microdevices has garnered tremendous attention in the emerging biomedical fields, particularly organic bioelectronics and biosensing. Direct laser 3D printing based on two-photon polymerization (TPP) has shown great promise in construction of well-defined and multi-functional microdevices. Herein, we present a novel photosensitive resin for fabrication of highly conductive and bioactive microstructures via TPP. This resin is based on poly(ethylene glycol) diacrylate that is doped with poly (3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (organic semicoductor), and laminin (extracellular matrix protein) or glucose oxidase (biorecognition enzyme). We demonstrate the fabrication of hybrid microelectrodes, bioactive microstructures for cellular adhesion / spreading, and high-performance glucose biosensors. Clinical Relevance- Conductive and bioactive microelectronic devices based on the formulated resin can be utilized for neural recording / stimulation, tissue engineering, and biosensing applications.

Nanoparticle Rigidity for Brain Tumor Cell Uptake.

Nanoparticles (NPs) have emerged as versatile and widely used platforms for a variety of biomedical applications. For delivery purposes, while some of NPs' physiochemical aspects such as size and shape have been extensively studied, their mechanical properties remain understudied. Recent studies have reported NPs' rigidity as a significant factor for their cell interactions and uptake. Here, we aim to study how NPs' rigidity affects their interactions with brain glioma tumor cells. To produce NPs with different rigidities, we encapsulate poly(ethylene glycol) diacrylate (PEGDA) of different volume ratios (0, 10, 30 v/v%) within the lumen of nanoliposomes and study the uptake of these NPs in a glioblastoma cell line U87. PEGDA with volume ratios of 10 and 30% were selected to provide a significant increase of the elastic modulus of the hydrogel (0.1 to 4 MPa) as determined by compression testing. Dynamic light scattering (DLS) and zeta potential measurements indicated that despite differences in their core formulation, all examined NPs had a similar size range (106 to 132 nm) and surface charge (-2.0 to -3.0 mV). Confocal microscopy revealed that all NP groups accumulated inside U87 cells, and flow cytometry data showed that liposomes with a gel core (10 and 30 v/v% PEGDA) had significantly higher cellular uptake (up to 9-fold), compared to liposomes with an aqueous core. Notably, we did not find any substantial difference between the uptake of liposomes with PEGDA core of 10 and 30% volume ratios. Clinical Relevance- By providing an insight into how NP rigidity influences glioma tumor cellular uptake, this work would enable development of more effective therapeutics for brain cancer.

Multiphoton Lithography of Organic Semiconductor Devices for 3D Printing of Flexible Electronic Circuits, Biosensors, and Bioelectronics.

In recent years, 3D printing of electronics have received growing attention due to their potential applications in emerging fields such as nanoelectronics and nanophotonics. Multiphoton lithography (MPL) is considered the state-of-the-art amongst the microfabrication techniques with true 3D fabrication capability owing to its excellent level of spatial and temporal control. Here, a homogenous and transparent photosensitive resin doped with an organic semiconductor material (OS), which is compatible with MPL process, is introduced to fabricate a variety of 3D OS composite microstructures (OSCMs) and microelectronic devices. Inclusion of 0.5 wt% OS in the resin enhances the electrical conductivity of the composite polymer about 10 orders of magnitude and compared to other MPL-based methods, the resultant OSCMs offer high specific electrical conductivity. As a model protein, laminin is incorporated into these OSCMs without a significant loss of activity. The OSCMs are biocompatible and support cell adhesion and growth. Glucose-oxidase-encapsulated OSCMs offer a highly sensitive glucose sensing platform with nearly tenfold higher sensitivity compared to previous glucose biosensors. In addition, this biosensor exhibits excellent specificity and high reproducibility. Overall, these results demonstrate the great potential of these novel MPL-fabricated OSCM devices for a wide range of applications from flexible bioelectronics/biosensors, to nanoelectronics and organ-on-a-chip devices.

Femtosecond Laser 3D-printing of Conductive Microelectronics for Potential Biomedical Applications.

Development of soft and conductive micro devices represents a demanding research topic in various biomedical applications, particularly organic bioelectronics. Among various fabrication methods, two-photon polymerization (2PP) using a wide range of photocurable inks is a promising 3D printing technique for construction of structures in submicron resolution. Herein, we introduce a novel conductive photosensitive resin by using poly (3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS) and poly(ethylene glycol) diacrylate), and fabricate 3D conductive polymeric microstructures via 2PP. In the developed resin, presence of PEDOT:PSS significantly enhances the electrical conductivity of microstructures (~ 10 orders of magnitude).Clinical Relevance- Conductive microdevices based on the PEDOT:PSS-doped resin open new avenues in a broad range of biomedical research areas including neural interfaces, biosensors, and bioelectronics.

Organic Semiconductor Nanotubes for Electrochemical Devices.

Electrochemical devices that transform electrical energy to mechanical energy through an electrochemical process have numerous applications ranging from soft robotics and micropumps to autofocus microlenses and bioelectronics. To date, achievement of large deformation strains and fast response times remains a challenge for electrochemical actuator devices operating in liquid wherein drag forces restrict the actuator motion and electrode materials/structures limit the ion transportation and accumulation. We report results for electrochemical actuators, electrochemical mass transfers, and electrochemical dynamics made from organic semiconductors (OSNTs). Our OSNTs electrochemical device exhibits high actuation performance with fast ion transport and accumulation and tunable dynamics in liquid and gel-polymer electrolytes. This device demonstrates an excellent performance, including low power consumption/strain, a large deformation, fast response, and excellent actuation stability. This outstanding performance stems from enormous effective surface area of nanotubular structure that facilitates ion transport and accumulation resulting in high electroactivity and durability. We utilize experimental studies of motion and mass transport along with the theoretical analysis for a variable-mass system to establish the dynamics of the electrochemical device and to introduce a modified form of Euler-Bernoulli's deflection equation for the OSNTs. Ultimately, we demonstrate a state-of-the-art miniaturized device composed of multiple microactuators for potential biomedical application. This work provides new opportunities for next generation electrochemical devices that can be utilized in artificial muscles and biomedical devices.

Tumor Targeted Delivery of an Anti-Cancer Therapeutic: An In Vitro and In Vivo Evaluation.

The limited effectiveness of current therapeutics against malignant brain gliomas has led to an urgent need for development of new formulations against these tumors. Chelator Dp44mT (di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone) presents a promising candidate to defeat gliomas due to its exceptional anti-tumor activity and its unique ability to overcome multidrug resistance. The goal of this study is to develop a targeted nano-carrier for Dp44mT delivery to glioma tumors and to assess its therapeutic efficacy in vitro and in vivo. Dp44mT is loaded into poly(ethylene glycol) (PEG)ylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) decorated with glioma-targeting ligand Interlukin 13 (IL13). IL13-conjugation enhanced the NP uptake by glioma cells and also improved their transport across an in vitro blood-brain-barrier (BBB) model. This targeted formulation showed an outstanding toxicity towards glioma cell lines and patient-derived stem cells in vitro, with IC50 values less than 125 nM, and caused no significant death in healthy brain microvascular endothelial cells. In vivo, when tested on a xenograft mouse model, IL13-conjugated Dp44mT-NPs reduced the glioma tumor growth by ≈62% while their untargeted counterparts reduced the tumor growth by only ≈16%. Notably, this formulation does not cause any significant weight loss or kidney/liver toxicity in mice, demonstrating its great therapeutic potential.

Development and in vitro assessment of an anti-tumor nano-formulation.

This study aims to develop a new anti-cancer formulation based on the chelator Dp44mT (Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone). Dp44mT has outstanding anti-tumor activity and the unique ability to overcome multidrug-resistance in cancer cells. This highly toxic compound has thus far only been applied in free form, limiting its therapeutic effectiveness. To reach its full therapeutic potential, however, Dp44mT should be encapsulated in a nano-carrier that would enable its selective and controlled delivery to malignant cells. As the first step towards this goal, here we encapsulate Dp44mT in nanoparticles (NPs) of poly(lactic-co-glycolic acid) (PLGA), characterize this nano-formulation, and evaluate its therapeutic potential against cancer cells in vitro. Our results showed that the Dp44mT-loaded NPs were homogenous in shape and size, and had good colloidal stability. These PLGA NPs also showed high encapsulation efficiency and loading capacity for Dp44mT and enabled the sustained and tunable release of this chelator. Dp44mT-NPs were uptaken by cancer cells, showed a strong and dose-dependent cytotoxicity towards these cells, and significantly increased apoptotic cell death, in both monolayer and spheroid tumor models. This formulation had a low-level of toxicity towards healthy control cells, indicating an inherent selectivity towards malignant cells. These results demonstrate the great potential of this novel Dp44mT-based nano-formulation for the use in cancer therapy.

Electrospinning of Highly Aligned Fibers for Drug Delivery Applications.

Electrospinning is a straightforward, cost-effective, and versatile technique for fabrication of polymeric micro/nanofibers with tunable structural properties. Controlling the size, shape, and spatial orientation of the electrospun fibers is crucial for utilization in drug delivery and tissue engineering applications. In this study, for the first time, we systematically investigate the effect of processing parameters, including voltage, syringe needle gauge, angular velocity of rotating wheel, syringe-collector distance, and flow rate on the size and alignment of electrospun PLGA fibers. Optimizing these parameters enabled us to produce highly aligned and monodisperse PLGA fibers (spatial orientation> 99% and coefficient of variation< 0.5). To assess the effect of fiber alignment on the release of encapsulated drugs from these fibers, we incorporated dexamethasone, an anti-inflammatory drug, within highly-aligned and randomly-oriented fibers with comparable diameters (~0.87 µm) and compared their release profiles. In-vitro release studies revealed that the aligned fibers had less burst release (~10.8% in 24 hr) and more sustained release (~8.8% average rate of change for 24 days) compared to the random fibers. Finally, the degradation modes of the aligned and random fibers after 25 days incubation were characterized and compared. The findings of this study can be applied for the development of 3D degradable aligned fibers for controlled drug release and tissue engineering applications.

Conducting Polymer Microtubes for Bioactuators.

Conducting polymer (CP) actuators are promising devices for biomedical applications such as artificial muscles and drug delivery systems. Here, we report a tri-layer actuator based on poly(pyrrole) (PPy) microtubes (PPy MTs) doped with poly(sodium-p-styrenesulfonate) (PSS) and constructed on a passive layer of gold-coated poly-propylene (PP) film. The PPy MTs were fabricated using electrochemical deposition of PPy around poly(lactic-co-glycolic acid) (PLGA) fiber templates, followed by template removal. The PPy MTs were subjected to a redox process using cyclic voltammetry in 0.1 M NaPSS electrolyte solution as the potential was swept between -0.8 V and +0.4 V for 5 cycles at the scan rates of 10, 50, 100, and 200 mV/s. The bending behavior of the PPy MTs actuator was investigated by measuring the deflection of actuator tip resulting from the expansion/contraction strain of PPy MTs. The PPy MTs actuator showed a reversible bending movement during each potential cycle. The maximum deflection of actuator decreased by increasing the scan rate that was confirmed by calculating the actuation strain generated during each cycle at various scan rates.

Direct Measurement of Mass Transport in Actuation of Conducting Polymers Nanotubes.

Nanostructured Conducting polymer (CP) actuators are promising materials for biomedical applications such as drug release systems. However, understanding the actuation behavior at the nano-scale has not yet been explored. In this work, poly(3,4-ethylenedioxythiophene) (PEDOT) and poly(pyrrole) (PPy) nanotubes doped with a large counter ion (i.e. poly(styrene sodium sulfonate) (PSS)) were fabricated using electrochemical deposition of PEDOT and PPy around poly(L-lactide) (PLLA) nanofiber templates, followed by template removal in chloroform. The actuation and mass transport behavior of PPy and PEDOT nanotubes were investigated and compared. The nanotubes were subjected to a redox process using cyclic voltammetry in 0.1M NaPSS electrolyte solution as the potential swept between -0.8 V and +0.4 V for 20 cycles at 10, 50, 100, and 200 mV/s scan rates. The mass transport behavior of these nanotubes was characterized via electrochemical quartz crystal microbalance (EQCM) technique. The EQCM results showed that PEDOT nanotubes had a higher mass exchange capability than their PPy counterparts, especially at higher scan rates. Also, it was revealed that PPy nanotubes were more sensitive to the scan rate than the PEDOT nanotubes, and the maximum mass exchange capability of the PPy nanotubes was noticeably reduced by increasing the scan rate.

Aligned Conducting Polymer Nanotubes for Neural Prostheses.

The long-term performance of neural microelectrodes relies on biocompatibility and sensitivity of the electrode-tissue interface. Current neural electrodes are limited by poor electrical performance including high initial impedance and low charge storage capacity. In addition, they are mechanically hard which causes cellular reactive response to the implanted electrode. In this report, we have demonstrated a new templating method for fabrication of highly aligned conducting polymer nanotube. The structure of nanotubes can be precisely modulated by varying the time of electropolymerization. The electrical performance of poly(pyrrole) (PPY) and poly(3,4-ethylenedioxythiophine) (PEDOT) nanotubes including impedance and charge storage capacity were studied and compared as the surface morphology and structure of nanotube varied during the fabrication process. PEDOT nanotubes were found to have lower impedance than PPY nanotubes. By contrast, PPY nanotubes were shown to have higher charge storage capacity. These finding suggest that aligned conducting polymer nanotubes may enhance the long-term performance of neural microelectrodes.

Conducting polymer microcontainers for biomedical applications.

Advancement in the development of metallic-based implantable micro-scale bioelectronics has been limited by low signal to noise ratios and low charge injection at electrode-tissue interfaces. Further, implantable electrodes lose their long-term functionality because of unfavorable reactive tissue responses. Thus, substantial incentive exists to produce bioelectronics capable of delivering therapeutic compounds while improving electrical performance. Here, we have produced hollow poly(pyrrole) microcontainers (MCs) using poly(lactic-co-glycolic) acid (PLGA) as degradable templates. We demonstrate that the effective surface area of the electrode increases significantly as deposition charge density is increased, resulting in a 91% decrease in impedance and an 85% increase in charge storage capacity versus uncoated gold electrodes. We also developed an equivalent circuit model to quantify the effect of conducting polymer film growth on impedance. These MC-modified electrodes offer the potential to improve the electrical properties of implantable bioelectronics, as well as provide potential controlled release avenues for drug delivery applications.

Tunable nanostructured conducting polymers for neural interface applications.

Advancement in the development of traditional metallic-based implantable electrodes for neural interfacing has reached a plateau in recent years in terms of their ability to provide safe, long-term, and high resolution stimulation and/or recording. The reduction of electrode size enables higher selectivity through increased electrodes per implant device; however, it also results in lower sensitivity at electrode-tissue interfaces. This limitation can be addressed through the utilization of conducting polymer (CP) coatings, which increase the effective surface area. In this work, we investigate the surface roughness of two common conducting polymers; poly(pyrrole) (PPy) and poly(3,4-ethylenedioxythiophene) (PEDOT) in the form of films deposited using both potentiostatic (PSTAT) and galvanostatic (GSTAT) methods. We found that the surface roughness of both CP films can be increased by over 90% through control of both deposition time and applied electrical deposition (current for GSTAT and voltage for PSTAT). The impedance of PPy-modified electrodes was found to decrease by up to 88%. This study shows that the surface roughness of CPs can be modulated to control electrical properties of neural electrodes and may improve the cellular response of neurons.

Conducting Polymer Microcups for Organic Bioelectronics and Drug Delivery Applications.

An ideal neural device enables long-term, sensitive, and selective communication with the nervous system. To accomplish this task, the material interface should mimic the biophysical and the biochemical properties of neural tissue. By contrast, microfabricated neural probes utilize hard metallic conductors, which hinder their long-term performance because these materials are not intrinsically similar to soft neural tissue. This study reports a method for the fabrication of monodisperse conducting polymer microcups. It is demonstrated that the physical surface properties of conducting polymer microcups can be precisely modulated to control electrical properties and drug-loading/release characteristics.

Conducting Polymers for Neural Prosthetic and Neural Interface Applications.

Neural-interfacing devices are an artificial mechanism for restoring or supplementing the function of the nervous system, lost as a result of injury or disease. Conducting polymers (CPs) are gaining significant attention due to their capacity to meet the performance criteria of a number of neuronal therapies including recording and stimulating neural activity, the regeneration of neural tissue and the delivery of bioactive molecules for mediating device-tissue interactions. CPs form a flexible platform technology that enables the development of tailored materials for a range of neuronal diagnostic and treatment therapies. In this review, the application of CPs for neural prostheses and other neural interfacing devices is discussed, with a specific focus on neural recording, neural stimulation, neural regeneration, and therapeutic drug delivery.

High performance conducting polymer nanofiber biosensors for detection of biomolecules.

Sensitive detection and selective determination of the physiologically important chemicals involved in brain function have drawn much attention for the diagnosis and treatment of brain diseases and neurological disorders. This paper reports a novel method for fabrication of enzyme entrapped-conducting polymer nanofibers that offer higher sensitivity and increased lifetime compared to glucose sensors that are based on conducting polymer films.

Hydrogel-mediated direct patterning of conducting polymer films with multiple surface chemistries.

A new methodology for selective electropolymerization of conducting polymer films using wet hydrogel stamps is presented. The ability of this simple method to generate patterned films of conducting polymers with multiple surface chemistries in a one-step process and to incorporate fragile biomolecules in these films is demonstrated.

A review of organic and inorganic biomaterials for neural interfaces.

Recent advances in nanotechnology have generated wide interest in applying nanomaterials for neural prostheses. An ideal neural interface should create seamless integration into the nervous system and performs reliably for long periods of time. As a result, many nanoscale materials not originally developed for neural interfaces become attractive candidates to detect neural signals and stimulate neurons. In this comprehensive review, an overview of state-of-the-art microelectrode technologies provided fi rst, with focus on the material properties of these microdevices. The advancements in electro active nanomaterials are then reviewed, including conducting polymers, carbon nanotubes, graphene, silicon nanowires, and hybrid organic-inorganic nanomaterials, for neural recording, stimulation, and growth. Finally, technical and scientific challenges are discussed regarding biocompatibility, mechanical mismatch, and electrical properties faced by these nanomaterials for the development of long-lasting functional neural interfaces.