Abstract Fiber photometry (FP) has become a tool of choice for in vivo monitoring of genetically encoded biosensors. The ability to record and optogenetically manipulate circuits through the same fiber stub is powerful, but limited, as biosensors typically do not sample membrane voltage, leaving the experimenter blind to the direct effects of opsin photoactivation. Here we developed the Photometry Device with Optogenetics and Electrophysiology (P-DOpE) probe, fabricated via a new convergence taper-break (CTB) method that integrates industry-standard silica optical waveguides with low-impedance metal electrodes that can be arranged in experimenter-defined configurations. We demonstrate that chronically implanted P-DOpE probes provide months-long recordings of local field potential, single unit recording, and fiber photometry, with parallel optogenetic circuit perturbation. Conducting fiber photometry with same-site optogenetic stimulation, we identified a robust fluorescence signal that scaled with network activity and survived biosensor antagonism. As this confound could not be eliminated with standard isosbestic controls, we propose a simple correction strategy. As a first application, we used the probe to test a proposed mechanism for focal modulation of noradrenergic signaling in and by cortical circuits receiving afferents from the locus coeruleus. We found that increasing spiking activity in CA1 amplifies noradrenergic signaling evoked by contextual arousal by ∼50%, but does not induce norepinephrine release in the absence of a phasic trigger – thus supporting the central prediction of the glutamate amplifies noradrenergic effects (GANE) hypothesis. The P-DOpE probe thus enables optogenetic manipulation and multimodal readout in a configurable low-cost, scalable, and robust format.

Neuroscience is at an exciting juncture at which large-scale in vivo electrophysiology, including in humans, is intersecting symbiotically with revolutionary computational and statistical methods. Maintaining this relationship requires increasingly advanced neural probes for multimodal interrogation of neural circuitry (e.g. perturbation experiments are of value to computational modeling). Here, we developed a low cost modular and reconfigurable recording and stimulation fiber-based neural probe (MoRF) fabricated via a first step thermal drawing process (TDP) and a second step thermal tapering process (TTP). We demonstrated the device modularity and reconfigurability in several functional variations of the same device, as well as the ability to adjust the distance between different sensing elements. We validated the electrical, optical and microfluidic drug delivery performance of the MoRF probe and demonstrated its in vivo electrophysiological recording and optogenetic stimulation capabilities in awake mice. ### Competing Interest Statement The authors have declared no competing interest. US NIH, R01NS123069

Diverse sources of inhibition serve to modulate circuits and control cell assembly spiking across various timescales. For example, in hippocampus area CA1 the competition between inhibition and excitation organizes spike timing of pyramidal cells (PYR) in network events, including sharp wave-ripples (SPW-R). Specific cellular-synaptic sources of inhibition in SPW-R remain unclear, as there are >20 types of GABAergic interneurons in CA1. Axo-axonic cells (AAC) are defined by their synaptic targeting of the axon initial segment of pyramidal cells, potently controlling spike output. The impact of AAC activity on SPW-R is controversial, due mainly to ambiguity of AAC identification. Here we monitored and manipulated opto-tagged AACs in behaving mice using silicon probe recordings. We found a large variability of AAC neurons, varying from enhanced to suppressed spiking during SPW-Rs, in contrast to the near-uniform excitation of other parvalbumin-expressing interneurons. AACs received convergent monosynaptic inputs from local pyramidal cell assemblies, which strongly influenced their participation in SPW-Rs. Optogenetic silencing of AACs increased power and duration of SPW-Rs, recruiting a greater number of PYR, suggesting AACs control SPW-R dynamics. We hypothesize that lateral inhibition by reciprocal PYR-AAC interactions thus supports the organization of cell assemblies in SPW-R.

Biomedical devices are indispensable in modern healthcare,significantly enhancing patients'quality of life.Recently,there has been a drastic increase in innovations for the fabrication of biomedical devices.Amongst these fabrication methods,the thermal drawing process has emerged as a versatile and scalable process for the development of advanced biomedical devices.By thermally drawing a macroscopic preform,which is meticulously designed and integrated with functional materials,hundreds of meters of multifunctional fibers are produced.These scalable flexible multifunctional fibers are embedded with functionalities such as electrochemical sensing,drug delivery,light delivery,temperature sensing,chemical sensing,pressure sensing,etc.In this review,we summarize the fabrication method of thermally drawn multifunctional fibers and highlight recent developments in thermally drawn fibers for modern biomedical application,including neural interfacing,chemical sensing,tissue engineering,cancer treatment,soft robotics and smart wearables.Finally,we discuss the existing challenges and future directions of this rapidly growing field.

Spatially resolved epigenomic profiling is critical for understanding biology in the mammalian brain. Single-cell spatial epigenomic assays were developed recently for this purpose, but they remain costly and labor intensive for examining brain tissues across substantial dimensions and surveying a collection of brain samples. Here, we demonstrate an approach, epigenomic tomography, that maps spatial epigenomes of mouse brain at the scale of centimeters. We individually profiled neuronal and glial fractions of mouse neocortex slices with 0.5 mm thickness. Tri-methylation of histone 3 at lysine 27 (H3K27me3) or acetylation of histone 3 at lysine 27 (H3K27ac) features across these slices were grouped into clusters based on their spatial variation patterns to form epigenomic brain maps. As a proof of principle, our approach reveals striking dynamics in the frontal cortex due to kainic-acid-induced seizure, linked with transmembrane ion transporters, exocytosis of synaptic vesicles, and secretion of neurotransmitters. Epigenomic tomography provides a powerful and cost-effective tool for characterizing brain disorders based on the spatial epigenome.

Having reliable tools for recording and manipulating circuit activity are essential to understand the complex patterns of neural dynamics that underlie brain function. We present Tetro-DOpE (Tetrode-like Drug delivery, Optical stimulation, and Electrophysiology) probes that can simultaneously record and manipulate neural activity in behaving rodents. We fabricated thin multifunctional fibers (<50 μm) using the scalable convergence thermal drawing process. Then, the thin fibers are bundled, similar to tetrode fabrication, to produce Tetro-DOpE probes. We demonstrated the multifunctionality (i.e., electrophysiology, optical stimulation, and drug delivery) of our probe in head-fixed behaving mice. Furthermore, we assembled a six-shank probe mounted on a microdrive which enabled stable recordings of over months when chronically implanted in freely behaving mice. These in vivo experiments demonstrate the potential of customizable, low cost, and accessible multifunctional Tetro-DOpE probes for investigation of neural circuitry in behaving animals.

technique for embedding fibres with semiconductor devices produces defect-free strands that are hundreds of metres long. Garments woven with these threads offer a tantalizing glimpse of the wearable electronics of the future.

Flexible and stretchable strain sensors are in high demand in sports performance monitoring, structural health monitoring, and biomedical applications. However, existing stretchable soft sensors, primarily based on soft polymer materials, often suffer from drawbacks, including high hysteresis, low durability, and delayed response. To overcome these limitations, a stretchable miniature fiber sensor comprised of a stretchable core tightly coiled with parallel conductive wires is introduced. This fiber sensor is flexible and stretchable while exhibiting low hysteresis, a remarkable theoretical resolution of 0.015%, a response time of <30 milliseconds, and excellent stability after extensive cycling tests of over 16 000 cycles. To understand and predict the capacitive sensor response of the proposed sensor, an analytical expression is derived and proved to have good agreements with both experimental results and numerical simulation. The potential of the strain sensor as a wearable device is demonstrated by embedding it into belts, gloves, and knee protectors. Additionally, the sensor can extend its applications beyond wearable devices, as demonstrated by its integration into bladder and life safety rope monitoring systems. The sensor is envisioned to have applications in the field of sports performance evaluations, health care monitoring, and structural safety assessments.

Understanding the neural basis of behavior requires monitoring and manipulating combinations of physiological elements and their interactions in behaving animals. We developed a thermal tapering process enabling fabrication of low-cost, flexible probes combining ultrafine features: dense electrodes, optical waveguides, and microfluidic channels. Furthermore, we developed a semi-automated backend connection allowing scalable assembly. We demonstrate T-DOpE (Tapered Drug delivery, Optical stimulation, and Electrophysiology) probes achieve in single neuron-scale devices (1) high-fidelity electrophysiological recording (2) focal drug delivery and (3) optical stimulation. The device tip can be miniaturized (as small as 50 µm) to minimize tissue damage while the ~20 times larger backend allows for industrial-scale connectorization. T-DOpE probes implanted in mouse hippocampus revealed canonical neuronal activity at the level of local field potentials (LFP) and neural spiking. Taking advantage of the triple-functionality of these probes, we monitored LFP while manipulating cannabinoid receptors (CB1R; microfluidic agonist delivery) and CA1 neuronal activity (optogenetics). Focal infusion of CB1R agonist downregulated theta and sharp wave-ripple oscillations (SPW-Rs). Furthermore, we found that CB1R activation reduces sharp wave-ripples by impairing the innate SPW-R-generating ability of the CA1 circuit.

Despite the significant advantages of Shape Memory Polymers (SMPs), material processing and production challenges have limited their applications. Recent advances in fiber manufacturing offer a novel approach to processing polymers, broadening the functions of fibers beyond optical applications. In this study, a thermal drawing technique for SMPs to fabricate Shape Memory Polymer Fibers (SMPFs) tailored for medical applications, featuring programmable stiffness and shape control is developed. Rheological and differential scanning calorimetry analyses are conducted to assess SMP's compatibility with the proposed thermal drawing process and applications, leading to the production of multilumen, multimaterial SMPFs activated at body temperature. Different properties of SMPFs are investigated in three medical devices: stiffness-adjustable catheters, softening neural interface, and shape-programmable cochlear implants. Comprehensive characterization of these devices demonstrates the potential of thermally drawn SMPs to be employed in a wide range of applications demanding programmable mechanical properties.

Small-scale robots capable of remote active steering and navigation offer great potential for biomedical applications. However, the current design and manufacturing procedure impede their miniaturization and integration of various diagnostic and therapeutic functionalities. Herein, submillimeter fiber robots that can integrate navigation, sensing, and modulation functions are presented. These fiber robots are fabricated through a scalable thermal drawing process at a speed of 4 meters per minute, which enables the integration of ferromagnetic, electrical, optical, and microfluidic composite with an overall diameter of as small as 250 µm and a length of as long as 150 m. The fiber tip deflection angle can reach up to 54o under a uniform magnetic field of 45 mT. These fiber robots can navigate through complex and constrained environments, such as artificial vessels and brain phantoms. Moreover, Langendorff mouse hearts model, glioblastoma micro platforms, and in vivo mouse models are utilized to demonstrate the capabilities of sensing electrophysiology signals and performing a localized treatment. Additionally, it is demonstrated that the fiber robots can serve as endoscopes with embedded waveguides. These fiber robots provide a versatile platform for targeted multimodal detection and treatment at hard-to-reach locations in a minimally invasive and remotely controllable manner.

Table S1. Identified differential protein spots between SCC-15 and SCC-15/PYM cell lines.

A bidirectional brain interface with both "write" and "read" functions can be an important tool for fundamental studies and potential clinical treatments for neurological diseases. Here we report a miniaturized multifunctional fiber based optoacoustic emitter (mFOE) that first integrates simultaneous non-genetic optoacoustic stimulation for "write" and electrophysiology recording of neural circuits for "read". The non-genetic feature addresses the challenges of the viral transfection required by optogenetics in primates and human. The orthogonality between optoacoustic waves and electrical field provides a solution to avoid the interference between electrical stimulation and recording. We first validated the non-genetic stimulation function of the mFOE in rat cultured neurons using calcium imaging. In vivo application of mFOE for successful simultaneous optoacoustic stimulation and electrical recording of brain activities was confirmed in mouse hippocampus in both acute and chronical applications up to 1 month. Minimal brain tissue damage has been confirmed after these applications. The capability of non-genetic neural stimulation and recording enabled by mFOE opens up new possibilities for the investigation of neural circuits and brings new insights into the study of ultrasound neurostimulation.

Small-scale robots capable of remote active steering and navigation offer great potential for biomedical applications. However, the current design and manufacturing procedure impede their miniaturization and integration of various diagnostic and therapeutic functionalities. Here, we present a robotic fiber platform for integrating navigation, sensing, and therapeutic functions at a submillimeter scale. These fiber robots consist of ferromagnetic, electrical, optical, and microfluidic components, fabricated with a thermal drawing process. Under magnetic actuation, they can navigate through complex and constrained environments, such as artificial vessels and brain phantoms. Moreover, we utilize Langendorff mouse hearts model, glioblastoma microplatforms, and in vivo mouse models to demonstrate the capabilities of sensing electrophysiology signals and performing localized treatment. Additionally, we demonstrate that the fiber robots can serve as endoscopes with embedded waveguides. These fiber robots provide a versatile platform for targeted multimodal detection and treatment at hard-to-reach locations in a minimally invasive and remotely controllable manner.

This paper reports a serial frequency-division multiplexed fiber Bragg gratings with magneto-strictive polymer coatings fabricated by thermal drawing method. The sensors were demonstrated on quasi-distributive AC magnetic field sensing.

Understanding the neural basis of behavior requires monitoring and manipulating combinations of physiological elements and their interactions in behaving animals. Here we developed a thermal tapering process (TTP) which enables the fabrication of novel, low-cost, flexible probes that combine ultrafine features of dense electrodes, optical waveguides, and microfluidic channels. Furthermore, we developed a semi-automated backend connection allowing scalable assembly of the probes. We demonstrate that our T-DOpE ( T apered D rug delivery, Op tical stimulation, and E lectrophysiology) probe achieves in a single neuron-scale device (1) high-fidelity electrophysiological recording (2) focal drug delivery and (3) optical stimulation. With a tapered geometry, the device tip can be minimized (as small as 50 μm) to ensure minimal tissue damage while the backend is ~20 times larger allowing for direct integration with industrial-scale connectorization. Acute and chronic implantation of the probes in mouse hippocampus CA1 revealed canonical neuronal activity at the level of local field potentials and spiking. Taking advantage of the triple-functionality of the T-DOpE probe, we monitored local field potentials with simultaneous manipulation of endogenous type 1 cannabinoid receptors (CB1R; via microfluidic agonist delivery) and CA1 pyramidal cell membrane potential (optogenetic activation). Electro-pharmacological experiments revealed that focal infusion of CB1R agonist CP-55,940 in dorsal CA1 downregulated theta and sharp wave-ripple oscillations. Furthermore, using the full electro-pharmacological-optical feature set of the T-DOpE probe we found that CB1R activation reduces sharp wave-ripples (SPW-Rs) by impairing the innate SPW-R-generating ability of the CA1 circuit.

Here, we report a novel method for automated characterization of bulk tissue 3D spatial properties based on reverse engineering-driven non-planar tool path planning and robotically-directed sensing. The method incorporates information on object (e.g., tissue) and inspection tool (e.g., sensor) geometry for automated inspection of tissue mechanical and dielectric properties across macroscopic nonplanar domains as large as 44 cm $^{2}$ . The process avoids the need for manual sensor-tissue integration processes. The impact and the utility of the method were demonstrated by automated mapping of 3D spatial distributions of mechanical and dielectric properties of plant and animal tissues using multiple complementary impedimetric-based sensors of varying types and form factor, including rigid micro-electromechanical systems (MEMS) and flexible multi-functional fibers. Applications to automated characterization of food quality (e.g., type and age) are provided, including 3D spatial mapping of plant and animal tissue mechanical and dielectric property distributions. Ultimately, automated methods for 3D spatial inspection of plant and animal tissue properties are critical to agriculture, food processing, organ transplantation, and biomanufacturing industries. Note to Practitioners —This article is motivated by the need for automating the inspection of soft 3D biological objects. Here, we present a method that generates 3D quality maps of tissue properties using several sensors. The proposed tool path planning program outputs a customized tissue-conforming path for inspection based on the topographical features of the tissue. Hence, this method enables high-throughput, spatially-resolved, minimally-invasive, and reliable inspection of soft 3D biological objects. Applications to inspection of food quality were provided using two impedimetric-based sensors. Practitioners can directly apply the framework to inspection of other tissue properties and soft objects. This work provides an advance in automated methods for inspection, and real-time monitoring of tissue 3D property distributions, which reduces the need for manual tissue handling and requirement for sensor-product interface prior to characterization. This work can be implemented in various biomanufacturing applications and industries, including food safety and quality control, tissue engineering, and organ transplantation, to ensure the quality and safety of macroscopic tissue-engineered medical and food products.

A bidirectional brain interface with both "write" and "read" functions can be an important tool for fundamental studies and potential clinical treatments for neurological diseases. Herein, a miniaturized multifunctional fiber-based optoacoustic emitter (mFOE) is reported thatintegrates simultaneous optoacoustic stimulation for "write" and electrophysiology recording of neural circuits for "read". Because of the intrinsic ability of neurons to respond to acoustic wave, there is no requirement of the viral transfection. The orthogonality between optoacoustic waves and electrical field provides a solution to avoid the interference between electrical stimulation and recording. The stimulation function of the mFOE is first validated in cultured ratcortical neurons using calcium imaging. In vivo application of mFOE for successful simultaneous optoacoustic stimulation and electrical recording of brain activities is confirmed in mouse hippocampus in both acute and chronical applications up to 1 month. Minor brain tissue damage is confirmed after these applications. The capability of simultaneous neural stimulation and recording enabled by mFOE opens up new possibilities for the investigation of neural circuits and brings new insights into the study of ultrasound neurostimulation.

The Materials Genome Initiative (MGI) seeks to accelerate the discovery and engineering of advanced materials via high-throughput experimentation (HTE), which is a challenging task, given the common trade-off between design for optimal processability vs performance. Here, we report a HTE method based on automated formulation, synthesis, and multiproperty characterization of bulk soft materials in well plate formats that enables accelerated engineering of functional composite hydrogels with optimized properties for processability and performance. The method facilitates rapid high-throughput screening of hydrogel composition-property relations for multiple properties in well plate formats. The feasibility and utility of the method were demonstrated by application to several functional composite hydrogel systems, including alginate/poly(N-isopropylacrylamide) (PNIPAM) and poly(ethylene glycol) dimethacrylate (PEGDMA)/poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS) hydrogels. The HTE method was leveraged to identify formulations of conductive PEGDMA/PEDOT:PSS composite hydrogels for optimized performance and processability in three-dimensional (3D) printing. This work provides an advance in experimental methods based on automated dispensing, mixing, and sensing for the accelerated engineering of soft functional materials.