Polysaccharide-Based Theranostic Systems for Combined Imaging and Cancer Therapy: Recent Advances and Challenges.

Designing novel systems for efficient cancer treatment and improving the quality of life for patients is a prime requirement in the healthcare sector. In this regard, theranostics have recently emerged as a unique platform, which combines the benefits of both diagnosis and therapeutics delivery. Theranostics have the desired contrast agent and the drugs combined in a single carrier, thus providing the opportunity for real-time imaging to monitor the therapy results. This helps in reducing the hazards related to treatment overdose or underdose and gives the possibility of personalized therapy. Polysaccharides, as natural biomolecules, have been widely explored to develop theranostics, as they act as a matrix for simultaneously loading both contrast agents and drugs for their utility in drug delivery and imaging. Additionally, their remarkable physicochemical attributes (biodegradability, satisfactory safety profile, abundance, and diversity in functionality and charge) can be tuned via postmodification, which offers numerous possibilities to develop theranostics with desired characteristics. Hence, we provide an overview of recent advances in polysaccharide matrix-based theranostics for drug delivery combined with magnetic resonance imaging, computed tomography, positron emission tomography, single photon emission computed tomography, and ultrasound imaging. Herein, we also summarize the toxicity assessment of polysaccharides, associated contrast agents, and nanotoxicity along with the challenges and future research directions.

Carbon-based neural electrodes: promises and challenges.

Neural electrodes are primary functional elements of neuroelectronic devices designed to record neural activity based on electrochemical signals. These electrodes may also be utilized for electrically stimulating the neural cells, such that their response can be simultaneously recorded. In addition to being medically safe, the electrode material should be electrically conductive and electrochemically stable under harsh biological environments. Mechanical flexibility and conformability, resistance to crack formation and compatibility with common microfabrication techniques are equally desirable properties. Traditionally, (noble) metals have been the preferred for neural electrode applications due to their proven biosafety and a relatively high electrical conductivity. Carbon is a recent addition to this list, which is far superior in terms of its electrochemical stability and corrosion resistance. Carbon has also enabled 3D electrode fabrication as opposed to the thin-film based 2D structures. One of carbon's peculiar aspects is its availability in a wide range of allotropes with specialized properties that render it highly versatile. These variations, however, also make it difficult to understand carbon itself as a unique material, and thus, each allotrope is often regarded independently. Some carbon types have already shown promising results in bioelectronic medicine, while many others remain potential candidates. In this topical review, we first provide a broad overview of the neuroelectronic devices and the basic requirements of an electrode material. We subsequently discuss the carbon family of materials and their properties that are useful in neural applications. Examples of devices fabricated using bulk and nano carbon materials are reviewed and critically compared. We then summarize the challenges, future prospects and next-generation carbon technology that can be helpful in the field of neural sciences. The article aims at providing a common platform to neuroscientists, electrochemists, biologists, microsystems engineers and carbon scientists to enable active and comprehensive efforts directed towards carbon-based neuroelectronic device fabrication.

Gradient-Induced Mechanical Vibration of Neural Interfaces During MRI.

OBJECTIVE: Resonant vibrations of implanted structures during a magnetic resonance imaging (MRI) procedure pose a risk to the patient in the form of soft tissue irritation and degradation of the implant. In this paper, the mechanical behavior of implant structures in air, water, and viscoelastic materials was explored. METHODS: The static and dynamic transfer functions of various test samples in air and immersed in both water and hydrogels were analyzed. The laser-based acquisition method allowed for high-angular-resolution (10  µDeg) and high-dynamic-range (0-6 kHz) measurements. Additional MRI experiments were conducted to investigate the dependence of vibration strength on magnetic resonance (MR) sequence parameters in combination with the obtained transfer functions. RESULTS: The largest forces were found to be in the micronewton to millinewton range, which is comparable to forces applied during implantation. Of additional concern was the damping introduced by viscoelastic tissue, which was less than expected, leading to an underdamped system. In contrast to current wisdom, the imaging experiments demonstrated drastically different vibration amplitudes for identical gradient slew rates, but different timing parameters TR, mainly due to resonant amplification. CONCLUSION: The results showed that a safe force-free MR procedure depends not only on the gradient slew rate, but also and more drastically on the choice of secure timing parameters. SIGNIFICANCE: These findings delineate design improvements to achieve longevity of implants and will lead to increased patient safety during MRI. A prudent choice of mechanical characteristics of implanted structures is sufficient to avoid resonant excitation due to mismatched MR sequence parameters.

Motion prediction enables simulated MR-imaging of freely moving model organisms.

Magnetic resonance tomography typically applies the Fourier transform to k-space signals repeatedly acquired from a frequency encoded spatial region of interest, therefore requiring a stationary object during scanning. Any movement of the object results in phase errors in the recorded signal, leading to deformed images, phantoms, and artifacts, since the encoded information does not originate from the intended region of the object. However, if the type and magnitude of movement is known instantaneously, the scanner or the reconstruction algorithm could be adjusted to compensate for the movement, directly allowing high quality imaging with non-stationary objects. This would be an enormous boon to studies that tie cell metabolomics to spontaneous organism behaviour, eliminating the stress otherwise necessitated by restraining measures such as anesthesia or clamping. In the present theoretical study, we use a phantom of the animal model C. elegans to examine the feasibility to automatically predict its movement and position, and to evaluate the impact of movement prediction, within a sufficiently long time horizon, on image reconstruction. For this purpose, we use automated image processing to annotate body parts in freely moving C. elegans, and predict their path of movement. We further introduce an MRI simulation platform based on bright field videos of the moving worm, combined with a stack of high resolution transmission electron microscope (TEM) slice images as virtual high resolution phantoms. A phantom provides an indication of the spatial distribution of signal-generating nuclei on a particular imaging slice. We show that adjustment of the scanning to the predicted movements strongly reduces distortions in the resulting image, opening the door for implementation in a high-resolution NMR scanner.

Glassy carbon microelectrodes minimize induced voltages, mechanical vibrations, and artifacts in magnetic resonance imaging.

The recent introduction of glassy carbon (GC) microstructures supported on flexible polymeric substrates has motivated the adoption of GC in a variety of implantable and wearable devices. Neural probes such as electrocorticography and penetrating shanks with GC microelectrode arrays used for neural signal recording and electrical stimulation are among the first beneficiaries of this technology. With the expected proliferation of these neural probes and potential clinical adoption, the magnetic resonance imaging (MRI) compatibility of GC microstructures needs to be established to help validate this potential in clinical settings. Here, we present GC microelectrodes and microstructures-fabricated through the carbon micro-electro-mechanical systems process and supported on flexible polymeric substrates-and carry out experimental measurements of induced vibrations, eddy currents, and artifacts. Through induced vibration, induced voltage, and MRI experiments and finite element modeling, we compared the performances of these GC microelectrodes against those of conventional thin-film platinum (Pt) microelectrodes and established that GC microelectrodes demonstrate superior magnetic resonance compatibility over standard metal thin-film microelectrodes. Specifically, we demonstrated that GC microelectrodes experienced no considerable vibration deflection amplitudes and minimal induced currents, while Pt microelectrodes had significantly larger currents. We also showed that because of their low magnetic susceptibility and lower conductivity, the GC microelectrodes caused almost no susceptibility shift artifacts and no eddy-current-induced artifacts compared to Pt microelectrodes. Taken together, the experimental, theoretical, and finite element modeling establish that GC microelectrodes exhibit significant MRI compatibility, hence demonstrating clear clinical advantages over current conventional thin-film materials, further opening avenues for wider adoption of GC microelectrodes in chronic clinical applications.

Automatic Adaptive Gain for Magnetic Resonance Sensitivity Enhancement.

The decaying nature of magnetic resonance (MR) signals results in a decreasing signal-to-quantization noise ratio (SQNR) over the acquisition time. Here we describe a method to enhance the SQNR, and thus the overall signal-to-noise ratio (SNR), by dynamically adapting the gain of the receiver before analog-to-digital conversion (ADC). This is in contrast to a standard experiment in which the gain is fixed for a single data acquisition and is thus adjusted only for the first points of the signal. The gain adjustment in our method is done automatically in a closed loop fashion by using the envelope of the MR signal as the control signal. Moreover, the method incorporates a robust mechanism that runs along with signal acquisition to monitor the gain modulation, enabling precise recovery of the signals. The automatic adaptive gain (AGAIN) method requires minimal additional hardware and is thus general and can be implemented in the signal path of any commercial spectrometer system. We demonstrate an SNR enhancement factor of 2.64 when applied to a custom spectrometer, while a factor of 1.4 was observed when applied to a commercial spectrometer.

Parahydrogen based NMR hyperpolarisation goes micro: an alveolus for small molecule chemosensing.

Complex mixtures, commonly encountered in metabolomics and food analytics, are now routinely measured by nuclear magnetic resonance (NMR) spectroscopy. Since many samples must be measured, one-dimensional proton (1D 1H) spectroscopy is the experiment of choice. A common challenge in complex mixture 1H NMR spectroscopy is spectral crowding, which limits the assignment of molecular components to those molecules in relatively high abundance. This limitation is exacerbated when the sample quantity itself is limited and concentrations are reduced even further during sample preparation for routine measurement. To address these challenges, we report a novel microfluidic NMR platform integrating signal enhancement via parahydrogen induced hyperpolarisation. The platform simultaneously addresses the challenges of handling small sample quantities through microfluidics, the associated decrease in signal given the reduced sample quantity by Signal Amplification by Reversible Exchange (SABRE), and overcoming spectral crowding by taking advantage of the chemosensing aspect of the SABRE effect. SABRE at the microscale is enabled by an integrated PDMS membrane alveolus, which provides bubble-free hydrogen gas contact with the sample solution. With this platform, we demonstrate high field NMR chemosensing of microliter sample volumes, nanoliter detection volumes, and micromolar concentrations corresponding to picomole molecular sensitivity.

Should patients with brain implants undergo MRI?

Patients suffering from neuronal degenerative diseases are increasingly being equipped with neural implants to treat symptoms or restore functions and increase their quality of life. Magnetic resonance imaging (MRI) would be the modality of choice for the diagnosis and compulsory postoperative monitoring of such patients. However, interactions between the magnetic resonance (MR) environment and implants pose severe health risks to the patient. Nevertheless, neural implant recipients regularly undergo MRI examinations, and adverse events are rarely reported. However, this should not imply that the procedures are safe. More than 300 000 cochlear implant recipients are excluded from MRI, unless the indication outweighs the excruciating pain. For 75 000 deep brain stimulation (DBS) recipients quite the opposite holds true: MRI is considered an essential part of the implantation procedure and some medical centres deliberately exceed safety regulations, which they refer to as crucially impractical. Permanent MRI-related neurological dysfunctions in DBS recipients have occurred in the past when manufacturer recommendations were exceeded. Within the last few decades, extensive effort has been invested to identify, characterise and quantify the occurring interactions. Yet today we are still far from a satisfying solution concerning a safe and beneficial MR procedure for all implant recipients. To contribute, we intend to raise awareness of the growing concern, summon the community to stop absurdities and instead improve the situation for the increasing number of patients. Therefore, we review implant safety in the MRI literature from an engineering point of view, with a focus on cochlear and DBS implants as success stories of neural implants in clinical practice. We briefly explain fundamental phenomena which can lead to patient harm, and point out breakthroughs and errors made. Then, we end with conclusions and strategies to avoid future implants from being contraindicated in MR examinations. We believe that implant recipients should enter MRI, but before doing so, it should be made sure that the procedure is reasonable.

3D Carbon Scaffolds for Neural Stem Cell Culture and Magnetic Resonance Imaging.

3D glassy carbon structures with percolated macropores are obtained by pyrolysis of chemically synthesized cryogels featuring tunable porosity. These batch-fabricated structures are used as scaffolds for culturing neural stem cells (NSCs) and are characterized by magnetic resonance imaging (MRI). With the aid of MRI, the successful cultivation of NSCs on a glassy carbon surface and the precise 3D locations of these cell clusters within the opaque scaffold are demonstrated. MRI also yields pore morphology and porosity analyses, pre- and post-pyrolysis. This integrated approach yields a complete 3D dataset of the NSC network, which enables the visual inspection of the morphological details of individual cell clusters without disturbing them or destroying the scaffold. Reported experimental methodology is expected to have an impact on studies designed to understand the mechanism of neurodegenerative disease (ND) development, and can serve as a protocol for the culture of various other types of cells that display compatibility with glassy carbon surfaces.