Matthew J. Rowland

The role of the nitric oxide pathway in brain injury and its treatment--from bench to bedside.

Nitric oxide (NO) is a key signalling molecule in the regulation of cerebral blood flow. This review summarises current evidence regarding the role of NO in the regulation of cerebral blood flow at rest, under physiological conditions, and after brain injury, focusing on subarachnoid haemorrhage, traumatic brain injury, and ischaemic stroke and following cardiac arrest. We also review the role of NO in the response to hypoxic insult in the developing brain. NO depletion in ischaemic brain tissue plays a pivotal role in the development of subsequent morbidity and mortality through microcirculatory disturbance and disordered blood flow regulation. NO derived from endothelial nitric oxide synthase (eNOS) appears to have neuroprotective properties. However NO derived from inducible nitric oxide synthase (iNOS) may have neurotoxic effects. Cerebral NO donor agents, for example sodium nitrite, appear to replicate the effects of eNOS derived NO, and therefore have neuroprotective properties. This is true in both the adult and immature brain. We conclude that these agents should be further investigated as targeted pharmacotherapy to protect against secondary brain injury.

Responsive Double Network Hydrogels of Interpenetrating DNA and CB[8] Host–Guest Supramolecular Systems

A supramolecular double network hydrogel is presented by physical interpenetration of DNA and cucurbit[8]uril networks. In addition to exhibiting an increase in strength and thermal stability, the double network hydrogel possesses excellent properties such as stretchability, ductility, shear-thinning, and thixotropy. Moreover, it is enzymatically responsive to both nuclease and cellulase, as well as small molecules, showing great potential as a new soft material scaffold.

The control of cargo release from physically crosslinked hydrogels by crosslink dynamics

Controlled release of drugs and other cargo from hydrogels has been an important target for the development of next generation therapies. Despite the increasingly strong focus in this area of research, very little of the published literature has sought to develop a fundamental understanding of the role of molecular parameters in determining the mechanism and rate of cargo release. Herein, a series of physically crosslinked hydrogels have been prepared utilizing host-guest binding interactions of cucurbit[8]uril that are identical in strength (plateau modulus), concentration and structure, yet exhibit varying network dynamics on account of the use of different guests for supramolecular crosslinking. The diffusion of molecular cargo through the hydrogel matrix and the release characteristics from these hydrogels were investigated. It was determined that the release processes of the hydrogels could be directly correlated with the dynamics of the physical interactions responsible for crosslinking and corresponding time-dependent mesh size. These observations highlight that network dynamics play an indispensable role in determining the release mechanism of therapeutic cargo from a hydrogel, identifying that fine-tuning of the release characteristics can be gained through rational design of the molecular processes responsible for crosslinking in the carrier hydrogels.

Dynamically crosslinked materials via recognition of amino acids by cucurbit[8]uril

Hydrogels, an increasingly important class of material, have physical properties amenable to many potential uses, particularly in the biomedical area. Utilisation of hydrogels, however, relies not only on their mechanical properties but also on a favourable toxicity profile. Self assembly of polymers through naturally occurring and non-toxic units is therefore a very attractive option. The aromatic amino acids phenylalanine and tryptophan are two such molecular units that form 2 : 1 complexes with cucurbit[8]uril (CB[8]) with high binding equilibrium constants (Keq up to 1012 M-2). Herein, water soluble styrenic monomers were copolymerised with synthetically derived aromatic amino acid monomers of phenylalanine and tryptophan. The resulting polymers were shown to form dynamic and self-healing physically crosslinked hydrogels via recognition and binding of the amino acids to cucurbit[8]uril.

Study of boron–nitrogen dative bonds using azetidine inversion dynamics

A method for probing the strength of B-N dative bonds is reported. The activation parameters for nitrogen inversion in a series of azetidines tethered to boronate esters have been quantified by VT-NMR and the measured barriers correlated with data obtained by (11)B NMR, X-ray crystallography and MP2 calculations.

Bioinspired supramolecular fibers drawn from a multiphase self-assembled hydrogel

Significance Fiber materials have great impact on our daily lives, with their use ranging from textiles to functional reinforcements in composites. Although the manufacturing process of manmade fibers is potentially limited by extensive energy consumption, spiders can readily spin silk fibers at room temperature. Here, we report a class of material that is based on a self-assembled hydrogel constructed with dynamic host–guest cross-links between functional polymers. Supramolecular fibers can be drawn from this hydrogel at room temperature. The supramolecular fiber exhibits better tensile and damping properties than conventional regenerated fibers, such as viscose, artificial silks, and hair. Our approach offers a sustainable alternative to current fiber manufacturing strategies. Inspired by biological systems, we report a supramolecular polymer–colloidal hydrogel (SPCH) composed of 98 wt % water that can be readily drawn into uniform (∼6-μm thick) “supramolecular fibers” at room temperature. Functionalized polymer-grafted silica nanoparticles, a semicrystalline hydroxyethyl cellulose derivative, and cucurbit[8]uril undergo aqueous self-assembly at multiple length scales to form the SPCH facilitated by host–guest interactions at the molecular level and nanofibril formation at colloidal-length scale. The fibers exhibit a unique combination of stiffness and high damping capacity (60–70%), the latter exceeding that of even biological silks and cellulose-based viscose rayon. The remarkable damping performance of the hierarchically structured fibers is proposed to arise from the complex combination and interactions of “hard” and “soft” phases within the SPCH and its constituents. SPCH represents a class of hybrid supramolecular composites, opening a window into fiber technology through low-energy manufacturing.

Pseudo-continuous arterial spin labelling MRI for non-invasive, whole-brain, serial quantification of cerebral blood flow following aneurysmal subarachnoid haemorrhage.

Delayed cerebral ischaemia (DCI) is the major cause of mortality and morbidity following aneurysmal subarachnoid haemorrhage (SAH). Recent experimental evidence from animal models has highlighted the need for non-invasive and robust measurements of brain tissue perfusion in patients in order to help understand the pathophysiology underlying DCI. Quantitative, serial, whole-brain cerebral perfusion measurements were obtained with pseudo-continuous arterial spin labelling (PCASL) magnetic resonance imaging (MRI) in six SAH patients acutely following endovascular coiling. This technique requires no injected contrast or radioactive isotopes. MRI scanning was well tolerated. Artefact from endovascular coils was minimal. PCASL MRI was able to detect time-dependent and patient-specific changes in voxel-wise and regional cerebral blood flow. These changes reflected changes in clinical condition. Data obtained in healthy controls using the same experimental protocol confirm the reliability and reproducibility of these results. This is the first study to use whole-brain, quantitative PCASL to identify time-dependent changes in cerebral blood flow at the tissue level in the acute period following SAH. This technique has the potential to better understand changes in cerebral pathophysiology as a consequence of aneurysm rupture.

Hybrid organic-inorganic supramolecular hydrogel reinforced with CePO4 nanowires

We report a method to enhance the stiffness in the rheological yield strain of cucurbit[8]uril (CB[8])-based hydrogels by introducing inorganic nanowires (NWs) into the supramolecular networks. The supramolecular hydrogel is comprised of methylviologen-functionalised poly(vinyl alcohol) (PVA-MV), hydroxyethyl cellulose with naphthyl moieties (HEC-Np) and CB[8] macrocyclic hosts. The gel structure can be effectively enhanced by the framework supporting effects of cerous phosphate NWs and additional hydrogen bonding interactions between the NWs and the PVA-MV/HEC-Np polymers. The high aspect ratio NWs serve as a “skeleton” for the network providing extra physical crosslinks, resulting in a single continuous phase hybrid supramolecular network with improved strength, presenting a general approach to reinforce soft materials.

Adverse respiratory effects of opioids for chronic breathlessness: learning lessons from chronic pain.

Fear of fatal respiratory depression is a major driver limiting opioid prescription for persistent breathlessness in chronic obstructive pulmonary disease (COPD) [1–6], but is this fear warranted? In a recent systematic review and meta-analysis, Verberkt et al. [7] did not detect significant or clinically relevant respiratory adverse events associated with opioid treatment for chronic breathlessness in COPD. Rather, they concluded that “clinicians’ fears of respiratory obtundation with low-dose opioids seem to be unfounded”. Here, we critically evaluate these conclusions. Chronic breathlessness: beware adverse effects of opioids; no new evidence for safety or efficacy in long-term use http://ow.ly/vXWv30hVcMS

Calcium channel blockade with nimodipine reverses MRI evidence of cerebral oedema following acute hypoxia.

Acute cerebral hypoxia causes rapid calcium shifts leading to neuronal damage and death. Calcium channel antagonists improve outcomes in some clinical conditions, but mechanisms remain unclear. In 18 healthy participants we: (i) quantified with multiparametric MRI the effect of hypoxia on the thalamus, a region particularly sensitive to hypoxia, and on the whole brain in general; (ii) investigated how calcium channel antagonism with the drug nimodipine affects the brain response to hypoxia. Hypoxia resulted in a significant decrease in apparent diffusion coefficient (ADC), a measure particularly sensitive to cell swelling, in a widespread network of regions across the brain, and the thalamus in particular. In hypoxia, nimodipine significantly increased ADC in the same brain regions, normalizing ADC towards normoxia baseline. There was positive correlation between blood nimodipine levels and ADC change. In the thalamus, there was a significant decrease in the amplitude of low frequency fluctuations (ALFF) in resting state functional MRI and an apparent increase of grey matter volume in hypoxia, with the ALFF partially normalized towards normoxia baseline with nimodipine. This study provides further evidence that the brain response to acute hypoxia is mediated by calcium, and importantly that manipulation of intracellular calcium flux following hypoxia may reduce cerebral cytotoxic oedema