Single-sided magnetic resonance-based sensor for point-of-care evaluation of muscle.

Magnetic resonance imaging is a widespread clinical tool for the detection of soft tissue morphology and pathology. However, the clinical deployment of magnetic resonance imaging scanners is ultimately limited by size, cost, and space constraints. Here, we discuss the design and performance of a low-field single-sided magnetic resonance sensor intended for point-of-care evaluation of skeletal muscle in vivo. The 11 kg sensor has a penetration depth of >8 mm, which allows for an accurate analysis of muscle tissue and can avoid signal from more proximal layers, including subcutaneous adipose tissue. Low operational power and shielding requirements are achieved through the design of a permanent magnet array and surface transceiver coil. The sensor can acquire high signal-to-noise measurements in minutes, making it practical as a point-of-care tool for many quantitative diagnostic measurements, including T2 relaxometry. In this work, we present the in vitro and human in vivo performance of the device for muscle tissue evaluation.

Scalable, flexible carbon fiber electrode thread arrays for three-dimensional probing of neurochemical activity in deep brain structures of rodents.

We developed a flexible "electrode-thread" array for recording dopamine neurochemicals from a lateral distribution of subcortical targets (up to 16) transverse to the axis of insertion. Ultrathin (∼10 µm diameter) carbon fiber (CF) electrode-threads (CFETs) are clustered into a tight bundle to introduce them into the brain from a single-entry point. The individual CFETs splay laterally in deep brain tissue during insertion due to their innate flexibility. This spatial redistribution allows navigation of the CFETs towards deep brain targets spreading horizontally from the axis of insertion. Commercial "linear" arrays provide single-entry insertion but only allow measurements along the axis of insertion. Horizontally configured arrays inflict separate penetrations for each individual channel. We tested functional performance of our CFET arrays in vivo for recording dopamine and for providing lateral spread to multiple distributed sites in the rat striatum. Spatial spread was further characterized in agar brain phantoms as a function of insertion depth. We also developed protocols to slice the embedded CFETs within fixed brain tissue using standard histology. This method allowed extraction of the precise spatial coordinates of the implanted CFETs and their recording sites as integrated with immunohistochemical staining for surrounding anatomical, cytological, and protein expression labels. Our CFET array has the potential to unlock a wide range of applications, from uncovering the role of neuromodulators in synaptic plasticity, to addressing critical safety barriers in clinical translation towards diagnostic and adaptive treatment in Parkinson's disease and major mood disorders.

Actuated tissue engineered muscle grafts restore functional mobility after volumetric muscle loss.

Damage that affects large volumes of skeletal muscle tissue can severely impact health, mobility, and quality-of-life. Efforts to restore muscle function by implanting tissue engineered muscle grafts at the site of damage have demonstrated limited restoration of force production. Various forms of mechanical and biochemical stimulation have been shown to have a potentially beneficial impact on graft maturation, vascularization, and innervation. However, these approaches yield unpredictable and incomplete recovery of functional mobility. Here we show that targeted actuation of implanted grafts, via non-invasive transcutaneous light stimulation of optogenetic engineered muscle, restores motor function to levels similar to healthy mice 2 weeks post-injury. Furthermore, we conduct phosphoproteomic analysis of actuated engineered muscle in vivo and in vitro to show that repeated muscle contraction alters signaling pathways that play key roles in skeletal muscle contractility, adaptation to injury, neurite growth, neuromuscular synapse formation, angiogenesis, and cytoskeletal remodeling. Our study uncovers changes in phosphorylation of several proteins previously unreported in the context of muscle contraction, revealing promising mechanisms for leveraging actuated muscle grafts to restore mobility after volumetric muscle loss.

Scalable, flexible carbon fiber electrode thread arrays for three-dimensional spatial profiling of neurochemical activity in deep brain structures of rodents.

We developed a flexible "electrode-thread" array for recording dopamine neurochemical activity from a lateral distribution of subcortical targets (up to 16) transverse to the axis of insertion. Ultrathin (∼ 10 µm diameter) carbon fiber (CF) electrode-threads (CFETs) are clustered into a tight bundle to introduce them into the brain from a single entry point. The individual CFETs splay laterally in deep brain tissue during insertion due to their innate flexibility. This spatial redistribution allows navigation of the CFETs towards deep brain targets spreading horizontally from the axis of insertion. Commercial "linear" arrays provide single entry insertion but only allow measurements along the axis of insertion. Horizontally configured neurochemical recording arrays inflict separate penetrations for each individual channel (i.e., electrode). We tested functional performance of our CFET arrays in vivo for recording dopamine neurochemical dynamics and for providing lateral spread to multiple distributed sites in the striatum of rats. Spatial spread was further characterized using agar brain phantoms to measure electrode deflection as a function of insertion depth. We also developed protocols to slice the embedded CFETs within fixed brain tissue using standard histology techniques. This method allowed extraction of the precise spatial coordinates of the implanted CFETs and their recording sites as integrated with immunohistochemical staining for surrounding anatomical, cytological, and protein expression labels. Neurochemical recording operations tested here can be integrated with already widely established capabilities of CF-based electrodes to record single neuron activity and local field potentials, to enable multi-modal recording functions. Our CFET array has the potential to unlock a wide range of applications, from uncovering the role of neuromodulators in synaptic plasticity, to addressing critical safety barriers in clinical translation towards diagnostic and adaptive treatment in Parkinson's disease and major mood disorders.

Investigative needle core biopsies for multi-omics in Glioblastoma.

Glioblastoma (GBM) is a primary brain cancer with an abysmal prognosis and few effective therapies. The ability to investigate the tumor microenvironment before and during treatment would greatly enhance both understanding of disease response and progression, as well as the delivery and impact of therapeutics. Stereotactic biopsies are a routine surgical procedure performed primarily for diagnostic histopathologic purposes. The role of investigative biopsies - tissue sampling for the purpose of understanding tumor microenvironmental responses to treatment using integrated multi-modal molecular analyses ('Multi-omics") has yet to be defined. Secondly, it is unknown whether comparatively small tissue samples from brain biopsies can yield sufficient information with such methods. Here we adapt stereotactic needle core biopsy tissue in two separate patients. In the first patient with recurrent GBM we performed highly resolved multi-omics analysis methods including single cell RNA sequencing, spatial-transcriptomics, metabolomics, proteomics, phosphoproteomics, T-cell clonotype analysis, and MHC Class I immunopeptidomics from biopsy tissue that was obtained from a single procedure. In a second patient we analyzed multi-regional core biopsies to decipher spatial and genomic variance. We also investigated the utility of stereotactic biopsies as a method for generating patient derived xenograft models in a separate patient cohort. Dataset integration across modalities showed good correspondence between spatial modalities, highlighted immune cell associated metabolic pathways and revealed poor correlation between RNA expression and the tumor MHC Class I immunopeptidome. In conclusion, stereotactic needle biopsy cores are of sufficient quality to generate multi-omics data, provide data rich insight into a patient's disease process and tumor immune microenvironment and can be of value in evaluating treatment responses. One sentence summary: Integrative multi-omics analysis of stereotactic needle core biopsies in glioblastoma.

COVID-19 vaccine uptake among Arkansas public K-12 school teachers and staff.

In December 2020, the first coronavirus disease 2019 (COVID-19) vaccines received emergency use authorization from the Food and Drug Administration (FDA). To strategically allocate the limited availability of COVID-19 vaccines, the Advisory Committee on Immunization Practices (ACIP) developed a phased approach for eligibility that prioritized certain population groups that were more vulnerable to infection and severe outcomes. Public K-12 teachers and staff were included in Phase 1b. The Arkansas Department of Health (ADH) sought to evaluate the uptake of COVID-19 vaccines within this priority group. In partnership with the Arkansas Department of Education (ADE), ADH received a list of 66,076 certified staff, classified staff, and teachers within the public K-12 school system. This list was matched to the state immunization registry via deterministic methods across three identifiers: first name, last name and date of birth. Uptake was assessed and the population was characterized using descriptive analyses. After 13 weeks of availability, 34,783 (51.2 %) of public K-12 teachers and staff had received at least one dose and 29,870 (44.0 %) had completed the series. School districts with the least robust uptake of COVID-19 vaccines tended to be in more rural areas, with some districts having less than 10 % of teachers and staff with at least one dose. The proportion of public K-12 teachers and staff with at least one dose of any COVID-19 vaccine grew quickly between January 18th and February 14th (4 % to 43 %) but has plateaued in the most recent seven weeks (45 % to 51 %). Although not directly measured, it is possible that vaccine hesitancy could be a factor in the attenuated uptake of COVID-19 vaccines within certain factions of the Arkansas public K-12 teacher and staff population. Overcoming vaccine hesitancy during the COVID-19 vaccine rollout will be critical in bringing an end to the pandemic.

Machine-learning aided in situ drug sensitivity screening predicts treatment outcomes in ovarian PDX tumors.

Long-term treatment outcomes for patients with high grade ovarian cancers have not changed despite innovations in therapies. There is no recommended assay for predicting patient response to second-line therapy, thus clinicians must make treatment decisions based on each individual patient. Patient-derived xenograft (PDX) tumors have been shown to predict drug sensitivity in ovarian cancer patients, but the time frame for intraperitoneal (IP) tumor generation, expansion, and drug screening is beyond that for tumor recurrence and platinum resistance to occur, thus results do not have clinical utility. We describe a drug sensitivity screening assay using a drug delivery microdevice implanted for 24 h in subcutaneous (SQ) ovarian PDX tumors to predict treatment outcomes in matched IP PDX tumors in a clinically relevant time frame. The SQ tumor response to local microdose drug exposure was found to be predictive of the growth of matched IP tumors after multi-week systemic therapy using significantly fewer animals (10 SQ vs 206 IP). Multiplexed immunofluorescence image analysis of phenotypic tumor response combined with a machine learning classifier could predict IP treatment outcomes against three second-line cytotoxic therapies with an average AUC of 0.91.

Participation in Fraternity and Sorority Activities and the Spread of COVID-19 Among Residential University Communities - Arkansas, August 21-September 5, 2020.

Preventing transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), in colleges and universities requires mitigation strategies that address on- and off-campus congregate living settings as well as extracurricular activities and other social gatherings (1-4). At the start of the academic year, sorority and fraternity organizations host a series of recruitment activities known as rush week; rush week culminates with bid day, when selections are announced. At university A in Arkansas, sorority rush week (for women) was held during August 17-22, 2020, and consisted of on- and off-campus social gatherings, including an outdoor bid day event on August 22. Fraternity rush week (for men) occurred during August 27-31, with bid day scheduled for September 5. During August 22-September 5, university A-associated COVID-19 cases were reported to the Arkansas Department of Health (ADH). A total of 965 confirmed and probable COVID-19 cases associated with university A were identified, with symptom onset occurring during August 20-September 5, 2020; 31% of the patients with these cases reported involvement in any fraternity or sorority activity. Network analysis identified 54 gatherings among all linkages of cases to places of residence and cases to events, 49 (91%) were linked by participation in fraternity and sorority activities accounting for 42 (72%) links among gatherings. On September 4, university A banned gatherings of ≥10 persons, and fraternity bid day was held virtually. The rapid increase in COVID-19 cases was likely facilitated by on- and off-campus congregate living settings and activities, and health departments should work together with student organizations and university leadership to ensure compliance with mitigation measures.

A portable single-sided magnetic-resonance sensor for the grading of liver steatosis and fibrosis.

Low-cost non-invasive diagnostic tools for staging the progression of non-alcoholic chronic liver failure from fatty liver disease to steatohepatitis are unavailable. Here, we describe the development and performance of a portable single-sided magnetic-resonance sensor for grading liver steatosis and fibrosis using diffusion-weighted multicomponent T2 relaxometry. In a diet-induced mouse model of non-alcoholic fatty liver disease, the sensor achieved overall accuracies of 92% (Cohen's kappa, κ = 0.89) and 86% (κ = 0.78) in the ex vivo grading of steatosis and fibrosis, respectively. Localization of the measurements in living mice through frequency-dependent spatial encoding led to an overall accuracy of 87% (κ = 0.81) for the grading of steatosis. In human liver samples, the sensor graded steatosis with an overall accuracy of 93% (κ = 0.88). The use of T2 relaxometry as a sensitive measure in fully automated low-cost magnetic-resonance devices at the point of care would alleviate the accessibility and cost limits of magnetic-resonance imaging for diagnosing liver disease and assessing liver health before liver transplantation.

Platform for micro-invasive membrane-free biochemical sampling of brain interstitial fluid.

Neurochemical dysregulation underlies many pathologies and can be monitored by measuring the composition of brain interstitial fluid (ISF). Existing in vivo tools for sampling ISF do not enable measuring large rare molecules, such as proteins and neuropeptides, and thus cannot generate a complete picture of the neurochemical connectome. Our micro-invasive platform, composed of a nanofluidic pump coupled to a membrane-free probe, enables sampling multiple neural biomarkers in parallel. This platform outperforms the state of the art in low-flow pumps by offering low volume control (single stroke volumes, <3 nl) and bidirectional fluid flow (<100 nl/min) with negligible dead volume (<30 nl) and has been validated in vitro, ex vivo, and in vivo in rodents. ISF samples (<1.5 µL) can be processed via liquid chromatography-tandem mass spectrometry. These label-free liquid biopsies of the brain could yield a deeper understanding of the onset, mechanism, and progression of diverse neural pathologies.

Simultaneous recording and marking of brain microstructures.

The vast majority of techniques to study the physiology of the nervous system involve inserting probes into the brain for stimulation, recording, or sampling. Research is increasingly uncovering the fine microstructure of the brain, each of its regions with dedicated functions. Accurate knowledge of the placement of probes interrogating these regions is critical. We have developed a customizable concentric marking electrode (CME) consisting of an iron core within a 125 µm-stainless steel (SS) sheath for co-localization of targeted regions in the brain. We used a dielectric layer stack of SiO2, Al2O3, SiO2 to electrically encapsulate the iron core and minimize exposure area to avoid significant increases in inflammatory response triggered by the probes. The CME can record multi-neuronal extracellular firing patterns. Appropriate electrical polarity of the iron and SS components controls the deposition of iron microdeposits on brain tissue. We show that in vivo labels by this method can be as small as 100 µm, visible via noninvasive magnetic resonance imaging (MRI) as well as post-mortem histology, and illustrate how deposit size can be tuned by varying stimulus parameters. We targeted the CA3 area of the hippocampus in adult rats and demonstrate that iron microdeposits are remarkably stable and persist up to 10 months post-deposition. Using a single probe for recording and marking avoids inaccuracies with re-insertion of separate probes and utilizes iron microdeposits as valuable fiducial markers in vivo and ex vivo.

Computationally Guided Intracerebral Drug Delivery via Chronically Implanted Microdevices.

Treatments for neurologic diseases are often limited in efficacy due to poor spatial and temporal control over their delivery. Intracerebral delivery partially overcomes this by directly infusing therapeutics to the brain. Brain structures, however, are nonuniform and irregularly shaped, precluding complete target coverage by a single bolus without significant off-target effects and possible toxicity. Nearly complete coverage is crucial for effective modulation of these structures. We present a framework with computational mapping algorithms for neural drug delivery (COMMAND) to guide multi-bolus targeting of brain structures that maximizes coverage and minimizes off-target leakage. Custom-fabricated chronic neural implants leverage rational fluidic design to achieve multi-bolus delivery in rodents through a single infusion of radioactive tracer (Cu-64). The resulting spatial distributions replicate computed spatial coverage with 5% error in vivo, as detected by positron emission tomography. COMMAND potentially enables accurate, efficacious targeting of discrete brain regions.

Dehydration assessment via a portable, single sided magnetic resonance sensor.

PURPOSE: Undiagnosed dehydration compromises health outcomes across many populations. Existing dehydration diagnostics require invasive bodily fluid sampling or are easily confounded by fluid and electrolyte intake, environment, and physical activity limiting widespread adoption. We present a portable MR sensor designed to measure intramuscular fluid shifts to identify volume depletion. METHODS: Fluid loss is induced via a mouse model of thermal dehydration (37°C; 15-20% relative humidity). We demonstrate quantification of fluid loss induced by hyperosmotic dehydration with multicomponent T2 relaxometry using both a benchtop NMR system and MRI localized to skeletal muscle tissue. We then describe a miniaturized (~1000 cm3 ) portable (~4 kg) MR sensor (0.28 T) designed to identify dehydration-induced fluid loss. T2 relaxometry measurements were performed using a Carr-Purcell-Meiboom-Gill pulse sequence in ~4 min. RESULTS: T2 values from the portable MR sensor exhibited strong (R2 = 0.996) agreement with benchtop NMR spectrometer. Thermal dehydration induced weight loss of 4 to 11% over 5 to 10 h. Fluid loss induced by thermal dehydration was accurately identified via whole-animal NMR and skeletal muscle. The portable MR sensor accurately identified dehydration via multicomponent T2 relaxometry. CONCLUSION: Performing multicomponent T2 relaxometry localized to the skeletal muscle with a miniaturized MR sensor provides a noninvasive, physiologically relevant measure of dehydration induced fluid loss in a mouse model. This approach offers sensor portability, reduced system complexity, fully automated operation, and low cost compared with MRI. This approach may serve as a versatile and portable point of care technique for dehydration monitoring.

Identification and local delivery of vasodilators for the reduction of ureteral contractions.

Kidney stones and ureteral stents can cause ureteral colic and pain. By decreasing contractions in the ureter, clinically prescribed oral vasodilators may improve spontaneous stone passage rates and reduce the pain caused by ureteral stenting. We hypothesized that ureteral relaxation can be improved via the local administration of vasodilators and other smooth muscle relaxants. Here, by examining 18 candidate small molecules in an automated screening assay to determine the extent of ureteral relaxation, we show that the calcium channel blocker nifedipine and the Rho-kinase inhibitor ROCKi significantly relax human ureteral smooth muscle cells. We also show, by using ex vivo porcine ureter segments and sedated pigs that, with respect to the administration of a placebo, the local delivery of a clinically deployable formulation of the two drugs reduced ureteral contraction amplitude and frequency by 90% and 50%, respectively. Finally, we show that standard oral vasodilator therapy reduced contraction amplitude by only 50% and had a minimal effect on contraction frequency. Locally delivered ureteral relaxants therefore may improve ureter-related conditions.

An interventional image-guided microdevice implantation and retrieval method for in-vivo drug response assessment.

PURPOSE: Recently developed implantable microdevices can perform multi-drug response assessment of cancer drugs in-vivo, with potential to develop highly optimized personalized cancer treatment strategies. However, minimally invasive/interventional image-guided methods of in-vivo microdevice implantation, securement, and retrieval are needed for broad clinical translation. Here we demonstrate proof-of-concept of an interventional microdevice implantation and retrieval method for personalized drug response assessment, using ex-vivo phantom, ex-vivo tissue, and in-vivo murine models. METHODS: A method for minimally-invasive microdevice implantation and retrieval was developed, by which a custom-prototyped 6 mm retrievable microdevice can be implanted into a live tumor, deliver drugs into 10 discrete regions of adjacent tissue, and retrieved along with the adjacent drug-exposed tissue with a custom-prototyped retrieval needle device to allow in-vivo multi-drug response assessment. Computed tomography (CT) and ultrasound (US)-guided minimally invasive microdevice implantation and retrieval were tested in ex-vivo phantom and tissue models. Successful retrieval was defined as retrieval of the microdevice and adjacent core phantom/tissue sample containing at least 4/10 drug delivery sites. Subsequently, 10 implantation and retrieval trials in phantom models were performed using bi-axial and tri-axial retrieval needles; success rates were calculated and compared using a two-proportion z-test and the number of successfully retrieved drug release sites per microdevice was calculated and compared using a one-tailed independent t-test. Finally, five microdevices, each containing ten reservoirs preloaded with chemotherapy agent Doxorubicin, were implanted into mouse tumors in-vivo, secured for 24-h during drug release, and microdevice/tissue retrieval was performed under ultrasound guidance. Fluorescence microscopy of the retrieved tissue was used to confirm drug delivery and apoptosis staining assessed in-vivo tissue response; correlation of drug release and apoptosis staining were used to assess in-vivo drug efficacy. RESULTS: Image-guided microdevice implantation and retrieval were successful in ex-vivo phantom and tissue models with both US and CT guidance. Bi-axial retrieval success rate was significantly higher than triaxial retrieval in ex-vivo phantom trials (90% vs 50%, z = 1.95, P = 0.026), and had nonsignificantly higher number of retrieved drug-release sites per microdevice (8.3 vs 7.0, t = 1.37, P = 0.097). Bi-axial retrieval was successful in all five in-vivo mouse tumor models, and allowed in-vivo drug response assessment at up to ten discrete drug delivery sites per microdevice. An average of 6.8/10 discrete tumor sites containing micro-doses of delivered drug were retrieved per in-vivo attempt (min 5, max 10, std 1.93). Tissue regions of drug delivery, as assessed with fluorescent Doxorubicin drug signal, correlated with regions of apoptosis staining in all in-vivo models, indicating drug efficacy. No bleeding, microdevice migration, or other complications were noted during implantation, 24-h observation, or retrieval. CONCLUSIONS: The demonstrated image-guided minimally invasive microdevice implantation and retrieval method is similar to routine outpatient biopsy procedures, obviates the need for surgery, and can be performed at varying depths under CT and/or US guidance. There is potential for this method to enable clinical translation of in-vivo personalized drug response assessment/prediction in a much larger number of patients than currently possible.

Fluid assessment in dialysis patients by point-of-care magnetic relaxometry.

Magnetic resonance imaging (MRI) is a powerful diagnostic tool, but its use is restricted to the scanner suite. Here, we demonstrate that a bedside nuclear magnetic resonance (NMR) sensor can assess fluid status changes in individuals at a fraction of the time and cost compared to MRI. Our study recruited patients with end-stage renal disease (ESRD) who were regularly receiving hemodialysis treatments with intradialytic fluid removal as a model of volume overload and healthy controls as a model of euvolemia. Quantitative T 2 measurements of the lower leg of patients with ESRD immediately before and after dialysis were compared to those of euvolemic healthy controls using both a 0.28-T bedside single-voxel NMR sensor and a 1.5-T clinical MRI scanner. In the MRI data, we found that the first sign of fluid overload was an expanded muscle extracellular fluid (ECF) space, a finding undetectable at this stage using physical exam. A decrease in muscle ECF upon fluid removal was similarly detectable with both the bedside sensor and MRI. Bioimpedance measurements performed comparably to the bedside NMR sensor but were generally worse than MRI. These findings suggest that bedside NMR may be a useful method to identify fluid overload early in patients with ESRD and potentially other hypervolemic patient populations.

Steerable Microinvasive Probes for Localized Drug Delivery to Deep Tissue.

Enhanced understanding of neuropathologies has created a need for more advanced tools. Current neural implants result in extensive glial scarring and are not able to highly localize drug delivery due to their size. Smaller implants reduce surgical trauma and improve spatial resolution, but such a reduction requires improvements in device design to enable accurate and chronic implantation in subcortical structures. Flexible needle steering techniques offer improved control over implant placement, but often require complex closed-loop control for accurate implantation. This study reports the development of steerable microinvasive neural implants (S-MINIs) constructed from borosilicate capillaries (OD = 60 µm, ID = 20 µm) that do not require closed-loop guidance or guide tubes. S-MINIs reduce glial scarring 3.5-fold compared to prior implants. Bevel steered needles are utilized for open-loop targeting of deep-brain structures. This study demonstrates a sinusoidal relationship between implant bevel angle and the trajectory radius of curvature both in vitro and ex vivo. This relationship allows for bevel-tipped capillaries to be steered to a target with an average error of 0.23 mm ± 0.19 without closed-loop control. Polished microcapillaries present a new microinvasive tool for chronic, predictable targeting of pathophysiological structures without the need for closed-loop feedback and complex imaging.

A gastric resident drug delivery system for prolonged gram-level dosing of tuberculosis treatment.

Multigram drug depot systems for extended drug release could transform our capacity to effectively treat patients across a myriad of diseases. For example, tuberculosis (TB) requires multimonth courses of daily multigram doses for treatment. To address the challenge of prolonged dosing for regimens requiring multigram drug dosing, we developed a gastric resident system delivered through the nasogastric route that was capable of safely encapsulating and releasing grams of antibiotics over a period of weeks. Initial preclinical safety and drug release were demonstrated in a swine model with a panel of TB antibiotics. We anticipate multiple applications in the field of infectious diseases, as well as for other indications where multigram depots could impart meaningful benefits to patients, helping maximize adherence to their medication.

Cellular-scale probes enable stable chronic subsecond monitoring of dopamine neurochemicals in a rodent model.

Chemical signaling underlies both temporally phasic and extended activity in the brain. Phasic activity can be monitored by implanted sensors, but chronic recording of such chemical signals has been difficult because the capacity to measure them degrades over time. This degradation has been attributed to tissue damage progressively produced by the sensors and failure of the sensors themselves. We report methods that surmount these problems through the development of sensors having diameters as small as individual neuronal cell bodies (<10 µm). These micro-invasive probes (µIPs) markedly reduced expression of detectable markers of inflammation and tissue damage in a rodent test model. The chronically implanted µIPs provided stable operation in monitoring sub-second fluctuations in stimulation-evoked dopamine in anesthetized rats for over a year. These findings demonstrate that monitoring of chemical activity patterns in the brain over at least year-long periods, long a goal of both basic and clinical neuroscience, is achievable.