Wireless, battery-free, subdermally implantable platforms for transcranial and long-range optogenetics in freely moving animals.

Wireless, battery-free, and fully subdermally implantable optogenetic tools are poised to transform neurobiological research in freely moving animals. Current-generation wireless devices are sufficiently small, thin, and light for subdermal implantation, offering some advantages over tethered methods for naturalistic behavior. Yet current devices using wireless power delivery require invasive stimulus delivery, penetrating the skull and disrupting the blood-brain barrier. This can cause tissue displacement, neuronal damage, and scarring. Power delivery constraints also sharply curtail operational arena size. Here, we implement highly miniaturized, capacitive power storage on the platform of wireless subdermal implants. With approaches to digitally manage power delivery to optoelectronic components, we enable two classes of applications: transcranial optogenetic activation millimeters into the brain (validated using motor cortex stimulation to induce turning behaviors) and wireless optogenetics in arenas of more than 1 m2 in size. This methodology allows for previously impossible behavioral experiments leveraging the modern optogenetic toolkit.

Wireless, battery-free subdermally implantable photometry systems for chronic recording of neural dynamics.

Recording cell-specific neuronal activity while monitoring behaviors of freely moving subjects can provide some of the most significant insights into brain function. Current means for monitoring calcium dynamics in genetically targeted populations of neurons rely on delivery of light and recording of fluorescent signals through optical fibers that can reduce subject mobility, induce motion artifacts, and limit experimental paradigms to isolated subjects in open, two-dimensional (2D) spaces. Wireless alternatives eliminate constraints associated with optical fibers, but their use of head stages with batteries adds bulk and weight that can affect behaviors, with limited operational lifetimes. The systems introduced here avoid drawbacks of both types of technologies, by combining highly miniaturized electronics and energy harvesters with injectable photometric modules in a class of fully wireless, battery-free photometer that is fully implantable subdermally to allow for the interrogation of neural dynamics in freely behaving subjects, without limitations set by fiber optic tethers or operational lifetimes constrained by traditional power supplies. The unique capabilities of these systems, their compatibility with magnetic resonant imaging and computed tomography and the ability to manufacture them with techniques in widespread use for consumer electronics, suggest a potential for broad adoption in neuroscience research.

Photocurable bioresorbable adhesives as functional interfaces between flexible bioelectronic devices and soft biological tissues.

Flexible electronic/optoelectronic systems that can intimately integrate onto the surfaces of vital organ systems have the potential to offer revolutionary diagnostic and therapeutic capabilities relevant to a wide spectrum of diseases and disorders. The critical interfaces between such technologies and living tissues must provide soft mechanical coupling and efficient optical/electrical/chemical exchange. Here, we introduce a functional adhesive bioelectronic-tissue interface material, in the forms of mechanically compliant, electrically conductive, and optically transparent encapsulating coatings, interfacial layers or supporting matrices. These materials strongly bond both to the surfaces of the devices and to those of different internal organs, with stable adhesion for several days to months, in chemistries that can be tailored to bioresorb at controlled rates. Experimental demonstrations in live animal models include device applications that range from battery-free optoelectronic systems for deep-brain optogenetics and subdermal phototherapy to wireless millimetre-scale pacemakers and flexible multielectrode epicardial arrays. These advances have immediate applicability across nearly all types of bioelectronic/optoelectronic system currently used in animal model studies, and they also have the potential for future treatment of life-threatening diseases and disorders in humans.

Assessment of an engineered endothelium via single-photon emission computed tomography.

The clinical translation of cell-based therapeutics often requires highly sensitive, non-invasive imaging tools to assess cell function and distribution in vivo. The objective of this research was to determine whether human Sodium-Iodide Symporter (hNIS) ectopic expression in endothelial cells (ECs) in combination with single-photon emission computed tomography (SPECT) is a feasible approach to non-invasively monitor the presence and viability of an engineered endothelium on expanded polytetrafluoroethylene (ePTFE). Human umbilical vein endothelial cells (HUVECs) were transduced with pLL3.7-hNIS via lentivirus with multiplicity of infection (MOI) of 0, 2, 5, and 10 (n = 4). Ectopic expression of hNIS in HUVECs via optimized lentiviral transduction (MOI 5) enabled cell uptake of a radioisotope that can be detected by SPECT without affecting endothelial cell viability, oxidative stress, or antithrombogenic functions. The viability and distribution of an engineered endothelium grown on ePTFE coated with the biodegradable elastomer poly(1, 8 octamethylene citrate) (POC) and exposed to fluid flow was successfully monitored non-invasively by SPECT. We report the feasibility of a non-invasive, highly sensitive and functional assessment of an engineered endothelium on ePTFE using a combination of SPECT and X-ray computed tomography (SPECT/CT) imaging and hNIS ectopic expression in ECs. This technology potentially allows for the non-invasive assessment of transplanted living cells in vascular conduits. Biotechnol. Bioeng. 2017;114: 2371-2377. © 2017 Wiley Periodicals, Inc.

High-resolution magnetic resonance imaging of ankle joints in murine arthritis discriminates inflammation and bone destruction in a quantifiable manner.

OBJECTIVE: The ability to noninvasively monitor the development of inflammatory arthritis longitudinally has become increasingly important in experimental rheumatology. Magnetic resonance imaging (MRI) allows for detailed examination of anatomic structures, as well as the assessment of joint and soft tissue inflammation. The aim of this study was to extend the use of MRI to include quantitative measurements of bone destruction in murine ankle joints. METHODS: Joint disease was measured serially using clinical, histologic, in vivo imaging system (IVIS), micro-computed tomography (micro-CT), and MRI techniques in mouse ankle joints, using the K/BxN serum transfer-induced acute arthritis and K/BxA(g7) chronic arthritis models. Ankle joint MRI was performed using a gradient-echo pulse sequence to evaluate bone destruction and a spin-echo sequence to evaluate inflammation (long T2 signal). RESULTS: Arthritic mice, as compared to control mice, demonstrated increased disease severity according to clinical, histologic, IVIS, and MRI measures. Following induction of arthritis, the majority of volume expansion of the long T2 signal occurred in a juxtaarticular, rather than intrarticular, manner within the ankle joints. Bone destruction in K/BxA(g7) mouse ankle joints was readily detectible by MRI. Linear regression analyses demonstrated significant correlations between the clinical score and joint radiance intensity assessed by IVIS, between the ankle joint width and increased long T2 signal on MRI, and between the bone volume obtained by micro-CT and bone volume obtained by MRI. CONCLUSION: MRI is an optimal technology for anatomic localization of articular and soft tissue changes during the development and progression of inflammatory arthritis. Future studies may combine MRI with in vivo labeling agents to investigate joint disease in a cell type-specific manner.

PGC1α-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension.

RATIONALE: Pulmonary arterial hypertension (PAH) is a lethal, female-predominant, vascular disease. Pathologic changes in PA smooth muscle cells (PASMC) include excessive proliferation, apoptosis-resistance, and mitochondrial fragmentation. Activation of dynamin-related protein increases mitotic fission and promotes this proliferation-apoptosis imbalance. The contribution of decreased fusion and reduced mitofusin-2 (MFN2) expression to PAH is unknown. OBJECTIVES: We hypothesize that decreased MFN2 expression promotes mitochondrial fragmentation, increases proliferation, and impairs apoptosis. The role of MFN2's transcriptional coactivator, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α), was assessed. MFN2 therapy was tested in PAH PASMC and in models of PAH. METHODS: Fusion and fission mediators were measured in lungs and PASMC from patients with PAH and female rats with monocrotaline or chronic hypoxia+Sugen-5416 (CH+SU) PAH. The effects of adenoviral mitofusin-2 (Ad-MFN2) overexpression were measured in vitro and in vivo. MEASUREMENTS AND MAIN RESULTS: In normal PASMC, siMFN2 reduced expression of MFN2 and PGC1α; conversely, siPGC1α reduced PGC1α and MFN2 expression. Both interventions caused mitochondrial fragmentation. siMFN2 increased proliferation. In rodent and human PAH PASMC, MFN2 and PGC1α were decreased and mitochondria were fragmented. Ad-MFN2 increased fusion, reduced proliferation, and increased apoptosis in human PAH and CH+SU. In CH+SU, Ad-MFN2 improved walking distance (381 ± 35 vs. 245 ± 39 m; P < 0.05); decreased pulmonary vascular resistance (0.18 ± 0.02 vs. 0.38 ± 0.14 mm Hg/ml/min; P < 0.05); and decreased PA medial thickness (14.5 ± 0.8 vs. 19 ± 1.7%; P < 0.05). Lung vascularity was increased by MFN2. CONCLUSIONS: Decreased expression of MFN2 and PGC1α contribute to mitochondrial fragmentation and a proliferation-apoptosis imbalance in human and experimental PAH. Augmenting MFN2 has therapeutic benefit in human and experimental PAH.

In Vivo Mapping of Myocardial Injury Outside the Infarct Zone: Tissue at an Intermediate Pathological State.

BACKGROUND: The goal was to determine the feasibility of mapping the injured-but-not-infarcted myocardium using 99mTc-duramycin in the postischemic heart, with spatial information for its characterization as a pathophysiologically intermediate tissue, which is neither normal nor infarcted. METHODS AND RESULTS: Coronary occlusion was conducted in Sprague Dawley rats with preconditioning and 30-minute ligation. In vivo single-photon emission computed tomography was acquired after 3 hours (n=6) using 99mTc-duramycin, a phosphatidylethanolamine-specific radiopharmaceutical. The 99mTc-duramycin+ areas were compared with infarct and area-at-risk (n=8). Cardiomyocytes and endothelial cells were isolated for gene expression profiling. Cardiac function was measured with echocardiography (n=6) at 4 weeks. In vivo imaging with 99mTc-duramycin identified the infarct (3.9±2.4% of the left ventricle and an extensive area 23.7±2.2% of the left ventricle) with diffuse signal outside the infarct, which is pathologically between normal and infarcted (apoptosis 1.8±1.6, 8.9±4.2, 13.6±3.8%; VCAM-1 [vascular cell adhesion molecule 1] 3.2±0.8, 9.8±4.1, 15.9±4.2/mm2; tyrosine hydroxylase 14.9±2.8, 8.6±4.4, 5.6±2.2/mm2), with heterogeneous changes including scattered micronecrosis, wavy myofibrils, hydropic change, and glycogen accumulation. The 99mTc-duramycin+ tissue is quantitatively smaller than the area-at-risk (26.7% versus 34.4% of the left ventricle, P=0.008). Compared with infarct, gene expression in the 99mTc-duramycin+-noninfarct tissue indicated a greater prosurvival ratio (BCL2/BAX [B-cell lymphoma 2/BCL2-associated X] 7.8 versus 5.7 [cardiomyocytes], 3.7 versus 3.2 [endothelial]), and an upregulation of ion channels in electrophysiology. There was decreased contractility at 4 weeks (regional fractional shortening -8.6%, P<0.05; circumferential strain -52.9%, P<0.05). CONCLUSIONS: The injured-but-not-infarcted tissue, being an intermediate zone between normal and infarct, is mapped in vivo using phosphatidylethanolamine-based imaging. The intermediate zone contributes significantly to cardiac dysfunction.

An implantable device for wireless monitoring of diverse physio-behavioral characteristics in freely behaving small animals and interacting groups.

Comprehensive, continuous quantitative monitoring of intricately orchestrated physiological processes and behavioral states in living organisms can yield essential data for elucidating the function of neural circuits under healthy and diseased conditions, for defining the effects of potential drugs and treatments, and for tracking disease progression and recovery. Here, we report a wireless, battery-free implantable device and a set of associated algorithms that enable continuous, multiparametric physio-behavioral monitoring in freely behaving small animals and interacting groups. Through advanced analytics approaches applied to mechano-acoustic signals of diverse body processes, the device yields heart rate, respiratory rate, physical activity, temperature, and behavioral states. Demonstrations in pharmacological, locomotor, and acute and social stress tests and in optogenetic studies offer unique insights into the coordination of physio-behavioral characteristics associated with healthy and perturbed states. This technology has broad utility in neuroscience, physiology, behavior, and other areas that rely on studies of freely moving, small animal models.

Lung ¹8F-fluorodeoxyglucose positron emission tomography for diagnosis and monitoring of pulmonary arterial hypertension.

RATIONALE: Pulmonary arterial hypertension (PAH) is a proliferative arteriopathy associated with glucose transporter-1 (Glut1) up-regulation and a glycolytic shift in lung metabolism. Glycolytic metabolism can be detected with the positron emission tomography (PET) tracer (18)F-fluorodeoxyglucose (FDG). OBJECTIVES: The precise cell type in which glycolytic abnormalities occur in PAH is unknown. Moreover, whether FDG-PET is sufficiently sensitive to monitor PAH progression and detect therapeutic regression is untested. We hypothesized that increased lung FDG-PET reflects enhanced glycolysis in vascular cells and is reversible in response to effective therapies. METHODS: PAH was induced in Sprague-Dawley rats by monocrotaline or chronic hypoxia (10% oxygen) in combination with Sugen 5416. Monocrotaline rats were treated with oral dichloroacetate or daily imatinib injections. FDG-PET scans and pulmonary artery acceleration times were obtained weekly. The origin of the PET signal was assessed by laser capture microdissection of airway versus vascular tissue. Metabolism was measured in pulmonary artery smooth muscle cell (PASMC) cultures, using a Seahorse extracellular flux analyzer. MEASUREMENTS AND MAIN RESULTS: Lung FDG increases 1-2 weeks after monocrotaline (when PAH is mild) and is normalized by dichloroacetate and imatinib, which both also regress medial hypertrophy. Glut1 mRNA is up-regulated in both endothelium and PASMCs, but not airway cells or macrophages. PASMCs from monocrotaline rats are hyperproliferative and display normoxic activation of hypoxia-inducible factor-1α (HIF-1α), which underlies their glycolytic phenotype. CONCLUSIONS: HIF-1α-mediated Glut1 up-regulation in proliferating vascular cells in PAH accounts for increased lung FDG-PET uptake. FDG-PET is sensitive to mild PAH and can monitor therapeutic changes in the vasculature.

New semi-automated tool for the quantitation of MR imaging to estimate in vivo muscle disease severity in mice.

The pathology in Duchenne muscular dystrophy (DMD) is characterized by degenerating muscle fibers, inflammation, fibro-fatty infiltrate, and edema, and these pathological processes replace normal healthy muscle tissue. The mdx mouse model is one of the most commonly used preclinical models to study DMD. Mounting evidence has emerged illustrating that muscle disease progression varies considerably in mdx mice, with inter-animal differences as well as intra-muscular differences in pathology in individual mdx mice. This variation is important to consider when conducting assessments of drug efficacy and in longitudinal studies. Magnetic resonance imaging (MRI) is a non-invasive method that can be used qualitatively or quantitatively to measure muscle disease progression in the clinic and in preclinical models. Although MR imaging is highly sensitive, image acquisition and analysis can be time intensive. The purpose of this study was to develop a semi-automated muscle segmentation and quantitation pipeline that can quickly and accurately estimate muscle disease severity in mice. Herein, we show that the newly developed segmentation tool accurately divides muscle. We show that measures of skew and interdecile range based on segmentation sufficiently estimate muscle disease severity in healthy wildtype and diseased mdx mice. Moreover, the semi-automated pipeline reduced analysis time by nearly 10-fold. Use of this rapid, non-invasive, semi-automated MR imaging and analysis pipeline has the potential to transform preclinical studies, allowing for pre-screening of dystrophic mice prior to study enrollment to ensure more uniform muscle disease pathology across treatment groups, improving study outcomes.

Open thoracic surgical implantation of cardiac pacemakers in rats.

Genetic engineering and implantable bioelectronics have transformed investigations of cardiovascular physiology and disease. However, the two approaches have been difficult to combine in the same species: genetic engineering is applied primarily in rodents, and implantable devices generally require larger animal models. We recently developed several miniature cardiac bioelectronic devices suitable for mice and rats to enable the advantages of molecular tools and implantable devices to be combined. Successful implementation of these device-enabled studies requires microsurgery approaches that reliably interface bioelectronics to the beating heart with minimal disruption to native physiology. Here we describe how to perform an open thoracic surgical technique for epicardial implantation of wireless cardiac pacemakers in adult rats that has lower mortality than transvenous implantation approaches. In addition, we provide the methodology for a full biocompatibility assessment of the physiological response to the implanted device. The surgical implantation procedure takes ~40 min for operators experienced in microsurgery to complete, and six to eight surgeries can be completed in 1 d. Implanted pacemakers provide programmed electrical stimulation for over 1 month. This protocol has broad applications to harness implantable bioelectronics to enable fully conscious in vivo studies of cardiovascular physiology in transgenic rodent disease models.

A wireless and battery-less implant for multimodal closed-loop neuromodulation in small animals.

Fully implantable wireless systems for the recording and modulation of neural circuits that do not require physical tethers or batteries allow for studies that demand the use of unconstrained and freely behaving animals in isolation or in social groups. Moreover, feedback-control algorithms that can be executed within such devices without the need for remote computing eliminate virtual tethers and any associated latencies. Here we report a wireless and battery-less technology of this type, implanted subdermally along the back of freely moving small animals, for the autonomous recording of electroencephalograms, electromyograms and body temperature, and for closed-loop neuromodulation via optogenetics and pharmacology. The device incorporates a system-on-a-chip with Bluetooth Low Energy for data transmission and a compressed deep-learning module for autonomous operation, that offers neurorecording capabilities matching those of gold-standard wired systems. We also show the use of the implant in studies of sleep-wake regulation and for the programmable closed-loop pharmacological suppression of epileptic seizures via feedback from electroencephalography. The technology can support a broader range of applications in neuroscience and in biomedical research with small animals.

Wireless multi-lateral optofluidic microsystems for real-time programmable optogenetics and photopharmacology.

In vivo optogenetics and photopharmacology are two techniques for controlling neuronal activity that have immense potential in neuroscience research. Their applications in tether-free groups of animals have been limited in part due to tools availability. Here, we present a wireless, battery-free, programable multilateral optofluidic platform with user-selected modalities for optogenetics, pharmacology and photopharmacology. This system features mechanically compliant microfluidic and electronic interconnects, capabilities for dynamic control over the rates of drug delivery and real-time programmability, simultaneously for up to 256 separate devices in a single cage environment. Our behavioral experiments demonstrate control of motor behaviors in grouped mice through in vivo optogenetics with co-located gene delivery and controlled photolysis of caged glutamate. These optofluidic systems may expand the scope of wireless techniques to study neural processing in animal models.

Wireless implantable optical probe for continuous monitoring of oxygen saturation in flaps and organ grafts.

Continuous, real-time monitoring of perfusion after microsurgical free tissue transfer or solid organ allotransplantation procedures can facilitate early diagnosis of and intervention for anastomotic thrombosis. Current technologies including Doppler systems, cutaneous O2-sensing probes, and fluorine magnetic resonance imaging methods are limited by their intermittent measurements, requirements for skilled personnel, indirect interfaces, and/or their tethered connections. This paper reports a wireless, miniaturized, minimally invasive near-infrared spectroscopic system designed for uninterrupted monitoring of local-tissue oxygenation. A bioresorbable barbed structure anchors the probe stably at implantation sites for a time period matched to the clinical need, with the ability for facile removal afterward. The probe connects to a skin-interfaced electronic module for wireless access to essential physiological parameters, including local tissue oxygenation, pulse oxygenation, and heart rate. In vitro tests and in vivo studies in porcine flap and kidney models demonstrate the ability of the system to continuously measure oxygenation with high accuracy and sensitivity.

A transient, closed-loop network of wireless, body-integrated devices for autonomous electrotherapy.

Temporary postoperative cardiac pacing requires devices with percutaneous leads and external wired power and control systems. This hardware introduces risks for infection, limitations on patient mobility, and requirements for surgical extraction procedures. Bioresorbable pacemakers mitigate some of these disadvantages, but they demand pairing with external, wired systems and secondary mechanisms for control. We present a transient closed-loop system that combines a time-synchronized, wireless network of skin-integrated devices with an advanced bioresorbable pacemaker to control cardiac rhythms, track cardiopulmonary status, provide multihaptic feedback, and enable transient operation with minimal patient burden. The result provides a range of autonomous, rate-adaptive cardiac pacing capabilities, as demonstrated in rat, canine, and human heart studies. This work establishes an engineering framework for closed-loop temporary electrotherapy using wirelessly linked, body-integrated bioelectronic devices.

HiSStology: high spectral and spatial resolution magnetic resonance imaging detection of vasculature validated by histology and micro-computed tomography.

High spectral and spatial resolution (HiSS) data, acquired with echo-planar spectroscopic imaging (EPSI), can be used to acquire water spectra from each small image voxel. These images are sensitive to changes in local susceptibility caused by superparamagnetic iron oxide particles (SPIO); therefore, we hypothesized that images derived from HiSS data are very sensitive to tumor neovasculature following injection of SPIO. Accurate image registration was used to validate HiSS detection of neovasculature with histology and micro-computed tomographic (microCT) angiography. Athymic nude mice and Copenhagen rats were inoculated with Dunning AT6.1 prostate tumor cells in the right hind limb. The tumor region was imaged pre- and post-intravenous injection of SPIO. Three-dimensional assemblies of the CD31-stained histologic slices of the mouse legs and the microCT images of the rat vascular casts were registered with EPSI. The average distance between HiSS-predicted regions of high vascular density on magnetic resonance imaging and CD31-stained regions on histology was 200 µm. Similarly, vessels identified by HiSS in the rat images coincided with vasculature in the registered microCT image. The data demonstrate a strong correlation between tumor vasculature identified using HiSS and two gold standards: histology and microCT angiography.

High-resolution MRI of excised human prostate specimens acquired with 9.4T in detection and identification of cancers: validation of a technique.

PURPOSE: To evaluate feasibility of high-resolution, high-field ex vivo prostate magnetic resonance imaging (MRI) as an aid to guide pathologists' examination and develop in vivo MRI methods. MATERIALS AND METHODS: Unfixed excised prostatectomy specimens (n = 9) were obtained and imaged immediately after radical prostatectomy under an Institutional Review Board-approved protocol. High-resolution T2-weighted (T2W) MRI of specimens were acquired with a Bruker 9.4 T scanner to correlate with whole-mount histology. Additionally, T2 and apparent diffusion coefficient (ADC) maps were generated. RESULTS: By visual inspection of the nine prostate specimens imaged, high-resolution T2W MRI showed improved anatomical detail compared to published low-resolution images acquired at 4 T as published by other investigators. Benign prostatic hyperplasia, adenocarcinomas, curvilinear duct architecture distortion due to adenocarcinomas, and normal radial duct distribution were readily identified. T2 was ≈10 msec longer (P < 0.03) and the ADC was ≈1.4 times larger (P < 0.002) in the normal peripheral zone compared to the peripheral zone with prostate cancer. CONCLUSION: Differences in T2 and ADC between benign and malignant tissue are consistent with in vivo data. High-resolution, high-field MRI has the potential to improve the detection and identification of prostate structures. The protocols and techniques developed in this study could augment routine pathological analysis of surgical specimens and guide treatment of prostate cancer patients.

Targeted design of a recombinant tracer for SPECT renal imaging.

Rationale: A robust radiopharmaceutical has high uptake in the target and low retention in non-target tissues. However, traditional tracers for renal imaging that chemically chelate 99mTc are excreted through the renal route with transient resident time in the kidney. Following a rational design approach, we constructed a protein-based radiotracer, designated PBT-Fc, to sequentially bind tubular neonatal Fc-receptor and subsequently proximal tubular basement membrane for its targeted sequestration in kidney parenchyma. In this process, the tracer participates in physiologic glomerular filtration and tubular reabsorption while escaping lysosomal catabolism and urinary clearance. Methods: To specifically target renal receptors in navigating the urinary passage in the kidney, we produced a recombinant fusion protein with two separate functional parts: a polybasic PBT segment derived from human Vascular Endothelial Growth Factor and Fc segment of IgG1. The chimeric fusion of PBT-Fc was labeled with radionuclide 99mTc and tested in rodent models of kidney diseases. Planar scintigraphy and single-photon emission computerized tomography (SPECT) were performed to evaluate renal-specificity of the tracer. Results: When injected in mouse and rat, following a brief 10 - 15 min dynamic redistribution phase in circulation, ~ 95% of the [99mTc]-PBT-Fc signal was concentrated in the kidney and lasted for hours without urinary loss or surrounding tissue activities. Long-lasting tracer signals in the kidney cortex in conjunction with SPECT greatly augmented the image quality in detecting pathological lesions in a variety of disease models, including ischemic acute kidney injury, drug-induced renal toxicity, and chronic kidney disease from renin-angiotensin system (RAS) overactivation. Conclusion: Exclusive renal retention of the recombinant radiotracer greatly facilitated static-phase signal acquisition by SPECT and achieved submillimeter spatial resolution of kidney alternations in glomerular and tubular disease models.

Preclinical Applications of Multi-Platform Imaging in Animal Models of Cancer.

In animal models of cancer, oncologic imaging has evolved from a simple assessment of tumor location and size to sophisticated multimodality exploration of molecular, physiologic, genetic, immunologic, and biochemical events at microscopic to macroscopic levels, performed noninvasively and sometimes in real time. Here, we briefly review animal imaging technology and molecular imaging probes together with selected applications from recent literature. Fast and sensitive optical imaging is primarily used to track luciferase-expressing tumor cells, image molecular targets with fluorescence probes, and to report on metabolic and physiologic phenotypes using smart switchable luminescent probes. MicroPET/single-photon emission CT have proven to be two of the most translational modalities for molecular and metabolic imaging of cancers: immuno-PET is a promising and rapidly evolving area of imaging research. Sophisticated MRI techniques provide high-resolution images of small metastases, tumor inflammation, perfusion, oxygenation, and acidity. Disseminated tumors to the bone and lung are easily detected by microCT, while ultrasound provides real-time visualization of tumor vasculature and perfusion. Recently available photoacoustic imaging provides real-time evaluation of vascular patency, oxygenation, and nanoparticle distributions. New hybrid instruments, such as PET-MRI, promise more convenient combination of the capabilities of each modality, enabling enhanced research efficacy and throughput.

The Therapeutic and Diagnostic Potential of Amyloid ß Oligomers Selective Antibodies to Treat Alzheimer's Disease.

Improvements have been made in the diagnosis of Alzheimer's disease (AD), manifesting mostly in the development of in vivo imaging methods that allow for the detection of pathological changes in AD by magnetic resonance imaging (MRI) and positron emission tomography (PET) scans. Many of these imaging methods, however, use agents that probe amyloid fibrils and plaques-species that do not correlate well with disease progression and are not present at the earliest stages of the disease. Amyloid ß oligomers (AßOs), rather, are now widely accepted as the Aß species most germane to AD onset and progression. Here we report evidence further supporting the role of AßOs as pathological instigators of AD and introduce promising anti-AßO diagnostic probes capable of distinguishing the 5xFAD mouse model from wild type mice by PET and MRI. In a developmental study, Aß oligomers in 5xFAD mice were found to appear at 3 months of age, just prior to the onset of memory dysfunction, and spread as memory worsened. The increase of AßOs is prominent in the subiculum and correlates with concomitant development of reactive astrocytosis. The impact of these AßOs on memory is in harmony with findings that intraventricular injection of synthetic AßOs into wild type mice induced hippocampal dependent memory dysfunction within 24 h. Compelling support for the conclusion that endogenous AßOs cause memory loss was found in experiments showing that intranasal inoculation of AßO-selective antibodies into 5xFAD mice completely restored memory function, measured 30-40 days post-inoculation. These antibodies, which were modified to give MRI and PET imaging probes, were able to distinguish 5xFAD mice from wild type littermates. These results provide strong support for the role of AßOs in instigating memory loss and salient AD neuropathology, and they demonstrate that AßO selective antibodies have potential both for therapeutics and for diagnostics.