Single-Crystal Silicon Nanotubes, Hollow Nanocones, and Branched Nanotube Networks.

We report a general approach for the synthesis of single-crystal silicon nanotubes, involving epitaxial deposition of silicon shells on germanium nanowire templates followed by removal of the germanium template by selective wet etching. By exploiting advances in the synthesis of germanium nanowires, we were able to rationally tune the nanotube internal diameters (5-80 nm), wall thicknesses (3-12 nm), and taper angles (0-9°) and additionally demonstrated branched silicon nanotube networks. Field effect transistors fabricated from p-type nanotubes exhibited a strong gate effect, and fluid transport experiments demonstrated that small molecules could be electrophoretically driven through the nanotubes. These results demonstrate the suitability of silicon nanotubes for the design of nanoelectrofluidic devices.

Neural implants without brain surgery.

Injectable bioprobes record single-neuron activity from within blood vessels.

An Integrated Optogenetic and Bioelectronic Platform for Regulating Cardiomyocyte Function.

We report an integrated optogenetic and bioelectronic platform for stable and long-term modulation and monitoring of cardiomyocyte function in vitro. Optogenetic inputs were achieved through expression of a photoactivatable adenylyl cyclase (bPAC), that when activated by blue light caused a dose-dependent and time-limited increase in autonomous cardiomyocyte beat rate. Bioelectronic readouts were achieved through an integrated planar multi-electrode array (MEA) that provided real-time readouts of electrophysiological activity from 32 spatially-distinct locations. Irradiation at 27 µW/mm2 resulted in a ca. 14% increase in beat rate within 20-25 minutes, which remained stable for at least 2 hours. The beating rate could be cycled through repeated "on" and "off' states, and its magnitude was a monotonic function of irradiation intensity. Our integrated platform opens new avenues in bioelectronic medicine, including closed-loop feedback systems, with potential applications for cardiac regulation including arrhythmia diagnosis and intervention.

Morphological Factors that Underlie Neural Sensitivity to Stimulation in the Retina.

Retinal prostheses are a promising therapeutic intervention for patients afflicted by outer retinal degenerative diseases like retinitis pigmentosa and age-related macular degeneration. While significant advances in the development of retinal implants have been made, the quality of vision elicited by these devices remains largely sub-optimal. The variability in the responses produced by retinal devices is most likely due to the differences between the natural cell type-specific signaling that occur in the healthy retina vs. the non-specific activation of multiple cell types arising from artificial stimulation. In order to replicate these natural signaling patterns, stimulation strategies must be capable of preferentially activating specific RGC types. To design more selective stimulation strategies, a better understanding of the morphological factors that underlie the sensitivity to prosthetic stimulation must be developed. This review will focus on the role that different anatomical components play in driving the direct activation of RGCs by extracellular stimulation. Briefly, it will (1) characterize the variability in morphological properties of α-RGCs, (2) detail the influence of morphology on the direct activation of RGCs by electric stimulation, and (3) describe some of the potential biophysical mechanisms that could explain differences in activation thresholds and electrically evoked responses between RGC types.

Photo-cross-linkable, insulating silk fibroin for bioelectronics with enhanced cell affinity.

Bioelectronic scaffolds that support devices while promoting tissue integration could enable tissue hybrids with augmented electronic capabilities. Here, we demonstrate a photo-cross-linkable silk fibroin (PSF) derivative and investigate its structural, electrical, and chemical properties. Lithographically defined PSF films offered tunable thickness and <1-µm spatial resolution and could be released from a relief layer yielding freestanding scaffolds with centimeter-scale uniformity. These constructs were electrically insulating; multielectrode arrays with PSF-passivated interconnects provided stable electrophysiological readouts from HL-1 cardiac model cells, brain slices, and hearts. Compared to SU8, a ubiquitous biomaterial, PSF exhibited superior affinity toward neurons which we attribute to its favorable surface charge and enhanced attachment of poly-d-lysine adhesion factors. This finding is of significant importance in bioelectronics, where tight junctions between devices and cell membranes are necessary for electronic communication. Collectively, our findings are generalizable to a variety of geometries, devices, and tissues, establishing PSF as a promising bioelectronic platform.

Heart-on-a-Chip Model with Integrated Extra- and Intracellular Bioelectronics for Monitoring Cardiac Electrophysiology under Acute Hypoxia.

We demonstrated a bioelectronic heart-on-a-chip model for studying the effects of acute hypoxia on cardiac function. A microfluidic channel enabled rapid modulation of medium oxygenation, which mimicked the regimes induced by a temporary coronary occlusion and reversibly activated hypoxia-related transduction pathways in HL-1 cardiac model cells. Extracellular bioelectronics provided continuous readouts demonstrating that hypoxic cells experienced an initial period of tachycardia followed by a reduction in beat rate and eventually arrhythmia. Intracellular bioelectronics consisting of Pt nanopillars temporarily entered the cytosol following electroporation, yielding action potential (AP)-like readouts. We found that APs narrowed during hypoxia, consistent with proposed mechanisms by which oxygen deficits activate ATP-dependent K+ channels that promote membrane repolarization. Significantly, both extra- and intracellular devices could be multiplexed, enabling mapping capabilities unachievable by other electrophysiological tools. Our platform represents a significant advance toward understanding electrophysiological responses to hypoxia and could be applicable to disease modeling and drug development.

Ultrasensitive Phototriggered Local Anesthesia.

An injectable local anesthetic producing repeatable on-demand nerve block would be desirable for pain management. Here we present a phototriggerable device to achieve repeatable and adjustable on-demand local anesthesia in superficial or deep tissues, consisting of gold nanorods attached to low temperature sensitive liposomes (LTSL). The particles were loaded with tetrodotoxin and dexmedetomidine. Near-infrared light (NIR, 808 nm, continuous wave) could heat gold nanorods at low fluence (short duration and low irradiance), leading to rapid release of payload. In vivo, 1-2 min of irradiation at ≤272 mW/cm2 produced repeatable and adjustable on-demand infiltration anesthesia or sciatic nerve blockade with minimal toxicity. The nerve block intensity and duration correlated with the irradiance and duration of the applied light.

Phototriggered Local Anesthesia.

We report a phototriggerable formulation enabling in vivo repeated and on-demand anesthesia with minimal toxicity. Gold nanorods (GNRs) that can convert near-infrared (NIR) light into heat were attached to liposomes (Lip-GNRs), enabling light-triggered phase transition of their lipid bilayers with a consequent release of payload. Lip-GNRs containing the site 1 sodium channel blocker tetrodotoxin and the α2-adrenergic agonist dexmedetomidine (Lip-GNR-TD) were injected subcutaneously in the rat footpad. Irradiation with an 808 nm continuous wave NIR laser produced on-demand and repeated infiltration anesthesia in the rat footpad in proportion to the irradiance, with minimal toxicity. The ability to achieve on-demand and repeated local anesthesia could be very beneficial in the management of pain.

Prospects for near-infrared technology in remotely triggered drug delivery.

Remotely triggered drug delivery devices have recently been realized as injectable or implantable formulations that enable the patient or physician to control the timing and dose of drug release over an extended period. Such devices could increase patient compliance, maximize therapeutic effectiveness and minimize side effects. They can be triggered by near-infrared (NIR) light, which can harmlessly and painlessly pass through tissue at controlled doses and exposure times. We discuss the use of NIR-triggered devices and materials, with examples. Safety issues and future prospects are also addressed.

Near-infrared-actuated devices for remotely controlled drug delivery.

A reservoir that could be remotely triggered to release a drug would enable the patient or physician to achieve on-demand, reproducible, repeated, and tunable dosing. Such a device would allow precise adjustment of dosage to desired effect, with a consequent minimization of toxicity, and could obviate repeated drug administrations or device implantations, enhancing patient compliance. It should exhibit low off-state leakage to minimize basal effects, and tunable on-state release profiles that could be adjusted from pulsatile to sustained in real time. Despite the clear clinical need for a device that meets these criteria, none has been reported to date to our knowledge. To address this deficiency, we developed an implantable reservoir capped by a nanocomposite membrane whose permeability was modulated by irradiation with a near-infrared laser. Irradiated devices could exhibit sustained on-state drug release for at least 3 h, and could reproducibly deliver short pulses over at least 10 cycles, with an on/off ratio of 30. Devices containing aspart, a fast-acting insulin analog, could achieve glycemic control after s.c. implantation in diabetic rats, with reproducible dosing controlled by the intensity and timing of irradiation over a 2-wk period. These devices can be loaded with a wide range of drug types, and therefore represent a platform technology that might be used to address a wide variety of clinical indications.

A Stiff Injectable Biodegradable Elastomer.

Injectable materials often have shortcomings in mechanical and drug-eluting properties that are attributable to their high water contents. A water-free, liquid four-armed PEG modified with dopamine end groups is described which changed from liquid to elastic solid by reaction with a small volume of Fe3+ solution. The elastic modulus and degradation times increased with increasing Fe3+ concentrations. Both the free base and the water-soluble form of lidocaine could be dissolved in the PEG4-dopamine and released in a sustained manner from the cross-linked matrix. PEG4-dopamine was retained in the subcutaneous space in vivo for up to 3 weeks with minimal inflammation. This material's tailorable mechanical properties, biocompatibility, ability to incorporate hydrophilic and hydrophobic drugs and release them slowly are desirable traits for drug delivery and other biomedical applications.

Materials to clinical devices: technologies for remotely triggered drug delivery.

BACKGROUND: Technologies in which a remote trigger is used to release drug from an implanted or injected device could enable on-demand release profiles that enhance therapeutic effectiveness or reduce systemic toxicity. A number of new materials have been developed that exhibit sensitivity to light, ultrasound, or electrical or magnetic fields. Delivery systems that incorporate these materials might be triggered externally by the patient, parent or physician to provide flexible control of dose magnitude and timing. OBJECTIVES: To review injectable or implantable systems that are candidates for translation to the clinic, or ones that have already undergone clinical trials. Also considered are applicability in pediatrics and prospects for the future of drug delivery systems. METHODS: We performed literature searches of the PubMed and Science Citation Index databases for articles in English that reported triggerable drug delivery devices, and for articles reporting related materials and concepts. RESULTS: Approaches to remotely-triggered systems that have clinical potential were identified. Ideally, these systems have been engineered to exhibit controlled on-state release kinetics, low baseline leak rates, and reproducible dosing across multiple cycles. CONCLUSIONS: Advances in remotely-triggered drug delivery have been brought about by the convergence of numerous scientific and engineering disciplines, and this convergence is likely to play an important part in the current trend to develop systems that provide more than one therapeutic modality. Preclinical systems must be carefully assessed for biocompatibility, and engineered to ensure pharmacokinetics within the therapeutic window. Future drug delivery systems may incorporate additional modalities, such as closed-loop sensing or onboard power generation, enabling more sophisticated drug delivery regimens.

Nanowired three-dimensional cardiac patches.

Engineered cardiac patches for treating damaged heart tissues after a heart attack are normally produced by seeding heart cells within three-dimensional porous biomaterial scaffolds. These biomaterials, which are usually made of either biological polymers such as alginate or synthetic polymers such as poly(lactic acid) (PLA), help cells organize into functioning tissues, but poor conductivity of these materials limits the ability of the patch to contract strongly as a unit. Here, we show that incorporating gold nanowires within alginate scaffolds can bridge the electrically resistant pore walls of alginate and improve electrical communication between adjacent cardiac cells. Tissues grown on these composite matrices were thicker and better aligned than those grown on pristine alginate and when electrically stimulated, the cells in these tissues contracted synchronously. Furthermore, higher levels of the proteins involved in muscle contraction and electrical coupling are detected in the composite matrices. It is expected that the integration of conducting nanowires within three-dimensional scaffolds may improve the therapeutic value of current cardiac patches.

Magnetically triggered nanocomposite membranes: a versatile platform for triggered drug release.

Drug delivery devices based on nanocomposite membranes containing thermoresponsive nanogels and superparamagnetic nanoparticles have been demonstrated to provide reversible, on-off drug release upon application (and removal) of an oscillating magnetic field. We show that the dose of drug delivered across the membrane can be tuned by engineering the phase transition temperature of the nanogel, the loading density of nanogels in the membrane, and the membrane thickness, allowing for on-state delivery of model drugs over at least 2 orders of magnitude (0.1-10 µg/h). The zero-order kinetics of drug release across the membranes permit drug doses from a specific device to be tuned according to the duration of the magnetic field. Drugs over a broad range of molecular weights (500-40000 Da) can be delivered by the same membrane device. Membrane-to-membrane and cycle-to-cycle reproducibility is demonstrated, suggesting the general utility of these membranes for drug delivery.

Nanotechnological strategies for engineering complex tissues.

Tissue engineering aims at developing functional substitutes for damaged tissues and organs. Before transplantation, cells are generally seeded on biomaterial scaffolds that recapitulate the extracellular matrix and provide cells with information that is important for tissue development. Here we review the nanocomposite nature of the extracellular matrix, describe the design considerations for different tissues and discuss the impact of nanostructures on the properties of scaffolds and their uses in monitoring the behaviour of engineered tissues. We also examine the different nanodevices used to trigger certain processes for tissue development, and offer our view on the principal challenges and prospects of applying nanotechnology in tissue engineering.

Remotely triggerable drug delivery systems.

Triggerable drug delivery systems enable on-demand controlled release profiles that may enhance therapeutic effectiveness and reduce systemic toxicity. Recently, a number of new materials have been developed that exhibit sensitivity to visible light, near-infrared (NIR) light, ultrasound, or magnetic fields. This responsiveness can be triggered remotely to provide flexible control of dose magnitude and timing. Here we review triggerable materials that range in scale from nano to macro, and are activated by a range of stimuli.

Nanowire transistor arrays for mapping neural circuits in acute brain slices.

Revealing the functional connectivity in natural neuronal networks is central to understanding circuits in the brain. Here, we show that silicon nanowire field-effect transistor (Si NWFET) arrays fabricated on transparent substrates can be reliably interfaced to acute brain slices. NWFET arrays were readily designed to record across a wide range of length scales, while the transparent device chips enabled imaging of individual cell bodies and identification of areas of healthy neurons at both upper and lower tissue surfaces. Simultaneous NWFET and patch clamp studies enabled unambiguous identification of action potential signals, with additional features detected at earlier times by the nanodevices. NWFET recording at different positions in the absence and presence of synaptic and ion-channel blockers enabled assignment of these features to presynaptic firing and postsynaptic depolarization from regions either close to somata or abundant in dendritic projections. In all cases, the NWFET signal amplitudes were from 0.3-3 mV. In contrast to conventional multielectrode array measurements, the small active surface of the NWFET devices, approximately 0.06 microm(2), provides highly localized multiplexed measurements of neuronal activities with demonstrated sub-millisecond temporal resolution and, significantly, better than 30 microm spatial resolution. In addition, multiplexed mapping with 2D NWFET arrays revealed spatially heterogeneous functional connectivity in the olfactory cortex with a resolution surpassing substantially previous electrical recording techniques. Our demonstration of simultaneous high temporal and spatial resolution recording, as well as mapping of functional connectivity, suggest that NWFETs can become a powerful platform for studying neural circuits in the brain.