Development of Resorbable Phosphate-Based Glass Microspheres as MRI Contrast Media Agents.

In this research, resorbable phosphate-based glass (PBG) compositions were developed using varying modifier oxides including iron (Fe2O3), copper (CuO), and manganese (MnO2), and then processed via a rapid single-stage flame spheroidisation process to manufacture dense (i.e., solid) and highly porous microspheres. Solid (63-200 µm) and porous (100-200 µm) microspheres were produced and characterised via SEM, XRD, and EDX to investigate their surface topography, structural properties, and elemental distribution. Complementary NMR investigations revealed the formation of Q2, Q1, and Q0 phosphate species within the porous and solid microspheres, and degradation studies performed to evaluate mass loss, particle size, and pH changes over 28 days showed no significant differences among the microspheres (63-71 µm) investigated. The microspheres produced were then investigated using clinical (1.5 T) and preclinical (7 T) MRI systems to determine the R1 and R2 relaxation rates. Among the compositions investigated, manganese-based porous and solid microspheres revealed enhanced levels of R2 (9.7-10.5 s-1 for 1.5 T; 17.1-18.9 s-1 for 7 T) and R1 (3.4-3.9 s-1 for 1.5 T; 2.2-2.3 s-1 for 7 T) when compared to the copper and iron-based microsphere samples. This was suggested to be due to paramagnetic ions present in the Mn-based microspheres. It is also suggested that the porosity in the resorbable PBG porous microspheres could be further explored for loading with drugs or other biologics. This would further advance these materials as MRI theranostic agents and generate new opportunities for MRI contrast-enhancement oral-delivery applications.

Feasibility Study of a New Magnetic Resonance Imaging Mini-capsule Device to Measure Whole Gut Transit Time in Paediatric Constipation.

OBJECTIVE: In England, 27,500 children are referred annually to hospital with constipation. An objective measure of whole gut transit time (WGTT) could aid management. The current standard WGTT assessment, the x-ray radiopaque marker (ROM) test, gives poor definition of colonic anatomy and the radiation dose required is undesirable in children. Our objective was to develop an alternative magnetic resonance imaging (MRI) WGTT measure to the x-ray ROM test and to demonstrate its initial feasibility in paediatric constipation. METHODS: With the Nottingham Young Person's Advisory Group we developed a small (8 × 4 mm), inert polypropylene capsule shell filled with MRI-visible fat emulsion. The capsule can be imaged using MRI fat and water in-phase and out-of-phase imaging. Sixteen patients with constipation and 19 healthy participants aged 7 to 18 years old were recruited. Following a common ROM protocol, the participants swallowed 24 mini-capsules each day for 3 days and were imaged on days 4 and 7 using MRI. The number of successful studies (feasibility) and WGTT were assessed. Participants' EuroQoL Visual Analogue Scale were also collected and compared between the day before the taking the first set of mini-capsules to the day after the last MRI study day. RESULTS: The mini-capsules were imaged successfully in the colon of all participants. The WGTT was 78 ±â€Š35 hours (mean ±â€Šstandard deviation) for patients, and 36 ±â€Š16 hours, P < 0.0001 for healthy controls. Carrying out the procedures did not change the EuroQoL Visual Analogue Scale scores before and after the procedures. CONCLUSIONS: Magnetic Resonance Imaging in Paediatric Constipation was a first-in-child feasibility study of a new medical device to measure WGTT in paediatric constipation using MRI. The study showed that the new method is feasible and is well tolerated.

Magnetic Resonance Imaging Quantification of Fasted State Colonic Liquid Pockets in Healthy Humans.

The rate and extent of drug dissolution and absorption from solid oral dosage forms is highly dependent on the volume of liquid in the gastrointestinal tract (GIT). However, little is known about the time course of GIT liquid volumes after drinking a glass of water (8 oz), particularly in the colon, which is a targeted site for both locally and systemically acting drug products. Previous magnetic resonance imaging (MRI) studies offered novel insights on GIT liquid distribution in fasted humans in the stomach and small intestine, and showed that freely mobile liquid in the intestine collects in fairly distinct regions or "pockets". Based on this previous pilot data, we hypothesized that (1) it is possible to quantify the time course of the volume and number of liquid pockets in the undisturbed colon of fasted healthy humans following ingestion of 240 mL, using noninvasive MRI methods; (2) the amount of freely mobile water in the fasted human colon is of the order of only a few milliliters. Twelve healthy volunteers fasted overnight and underwent fasted abdominal MRI scans before drinking 240 mL (∼8 fluid ounces) of water. After ingesting the water they were scanned at frequent intervals for 2 h. The images were processed to quantify freely mobile water in the total and regional colon: ascending, transverse, and descending. The fasted colon contained (mean ± SEM) 11 ± 5 pockets of resting liquid with a total volume of 2 ± 1 mL (average). The colonic fluid peaked at 7 ± 4 mL 30 min after the water drink. This peak fluid was distributed in 17 ± 7 separate liquid pockets in the colon. The regional analysis showed that pockets of free fluid were found primarily in the ascending colon. The interindividual variability was very high; the subjects showed a range of number of colonic fluid pockets from 0 to 89 and total colonic freely mobile fluid volume from 0 to 49 mL. This is the first study measuring the time course of the number, regional location, and volume of pockets of freely mobile liquid in the undisturbed colon of fasted humans after ingestion of a glass of water. Novel insights into the colonic fluid environment will be particularly relevant to improve our understanding and design of the in vivo performance of controlled release formulations targeted to the colon. The in vivo quantitative information presented here can be input into physiologically based mechanistic models of dissolution and absorption, and can be used in the design and set up of novel in vitro performance tools predictive of the in vivo environment.

Colon length in pediatric health and constipation measured using magnetic resonance imaging and three dimensional skeletonization.

Recent magnetic resonance imaging (MRI) studies showed that colonic volumes in children are different between health and functional constipation. The length of the colon has however been rarely measured and principally using unphysiological colon preparations or cadaver studies. The main objective of this study was to measure the length of the undisturbed colon in children with functional constipation (FC) and healthy controls. Here, the colon of 19 healthy controls (10-18 years old) and 16 children with FC (7-18 years old) was imaged using MRI. Different regions of the colon (ascending, transverse, descending, and sigmoid-rectum) were first segmented manually on the MRI images. Three-dimensional skeletonization image analysis methods were then used to reduce the regions of interest to a central, measurable line. Total colon length (corrected for body surface area) in healthy controls was 56±2 cm/m2 (mean±SEM). Total colon length was significantly longer in children with FC 69±3 cm/m2 compared to controls (p = 0.0037). The colon regions showing the largest differences between groups were the ascending colon (p = 0.0479) and the sigmoid-rectum (p = 0.0003). In a linear regression model, there was a positive significant correlation between total colon length and age (R = 0.45, p = 0.0064), height (R = 0.49, p = 0.0031), weight (R = 0.46, p = 0.0059) and colon volume (R = 0.4543, p = 0.0061). Our findings showed significant differences in colon lengths between healthy controls and children with constipation. A new objective diagnostic imaging endpoint such as colon length may help to improve knowledge of colon morphology and function and, in turn, understanding of colon functional pathology.

Size and Number of Food Boluses in the Stomach after Eating Different Meals: Magnetic Resonance Imaging Insights in Healthy Humans.

Oral processing of food results in the formation of food boluses, which are then swallowed and reach the stomach for further digestion. The number, size and surface properties of the boluses will affect their processing and emptying from the stomach. Knowledge of these parameters, however, is incomplete due to limitations of the techniques used. In this work, non-invasive magnetic resonance imaging (MRI) was used for the first time to measure boluses in the stomach a few minutes after swallowing. Three groups of nine healthy participants were fed three different meals: chicken and roasted vegetables (Meal 1), bread and jam (Meal 2) and cheese and yogurt (Meal 3), and then, their stomach content was imaged. The median number of boluses within the stomach was 282, 106 and 9 for Meal 1, Meal 2 and Meal 3 (p < 0.0001) with an average volume of 0.47 mL, 2.4 mL and 13.6 mL, respectively (p < 0.0001). The cohesiveness as well as the meal composition seem to play a key role in the resulting boluses. These new in vivo data from undisturbed organ imaging can improve knowledge of the digestion process, which will, in turn, inform in vitro and in silico modelling of digestion, thus improving their in vitro/in vivo relevance.

"A little (PPI) MAGIC can take you a long way" : involving children and young people in research from inception of a novel medical device to multi-centre clinical trial Roald Dahl, James and the Giant Peach (1961).

BACKGROUND: There is often a great urgency to be inclusive when conducting research and to focus efforts with groups and communities that can be referred to as marginalised. This is especially the case in research concerning medical devices aimed at children and young people (CYP). Although involvement methodology has developed over the last two decades, it can be challenging to involve and engage CYP with confidence and clarity of purpose. MAIN BODY: Our aim was to provide a reflective narrative account of the involvement of CYP, over a period of 5 years, in a research project from conception of a new paediatric medical device through to practical application. We explored a model of patient and public involvement (PPI) through the Nottingham Young Persons Advisory Group (YPAG), part of the National Institute for Health Research (NIHR) GenerationR Alliance, in a NIHR funded research project. The YPAG designed and created a model of the human gut, co-designed the Transicap™ mini-capsules and their packaging, co-produced patient information sheets, came up with the idea to disseminate through a project website and co-wrote and created animation videos. The YPAG involvement continued through the writing and award of the follow-on research grant (MAGIC2). During this process the YPAG modified the clinical study protocol insisting that all participants in the control arm were given the imaging test results as well, save for a delayed reading compared to the intervention arm. CONCLUSION: Involvement of the YPAG over the last 5 years, led to the development of a mutually beneficial partnership, enabling genuine knowledge exchange between researchers and CYP. This influenced the design, plans and actions of the MAGIC study and well into the subsequent MAGIC2 follow-on project. Moreover, these involvement models applied within a feasibility study setting, have enhanced the realism and pragmatism of the study, contributing to the project's overall success.

Colonic Volume Changes in Paediatric Constipation Compared to Normal Values Measured Using MRI.

BACKGROUND: Functional constipation in children is common. Management of this condition can be challenging and is often based on symptom reports. Increased, objective knowledge of colonic volume changes in constipation compared to health could provide additional information. However, very little data on paediatric colonic volume is available except from methods that are invasive or require unphysiological colonic preparations. OBJECTIVES: (1) To measure volumes of the undisturbed colon in children with functional constipation (FC) using magnetic resonance imaging (MRI) and provide initial normal range values for healthy controls, and (2) to investigate possible correlation of colonic volume with whole gut transit time (WGTT). METHODS: Total and regional (ascending, transverse, descending, sigmoid, and rectum) colon volumes were measured from MRI images of 35 participants aged 7-18 years (16 with FC and 19 healthy controls), and corrected for body surface area. Linear regression was used to explore the relationship between total colon volume and WGTT. RESULTS: Total colonic volume was significantly higher, with a median (interquartile range) of 309 mL (243-384 mL) for the FC group than for the healthy controls of 227 mL (180-263 mL). The largest increase between patients and controls was in the sigmoid colon-rectum region. In a linear regression model, there was a positive significant correlation between total colonic volume and WGTT (R = 0.56, p = 0.0005). CONCLUSIONS: This initial study shows increased volumes of the colon in children with FC, in a physiological state, without use of any bowel preparation. Increased knowledge of colonic morphology may improve understanding of FC in this age group and help to direct treatment.

Measurement of fasted state gastric antral motility before and after a standard bioavailability and bioequivalence 240 mL drink of water: Validation of MRI method against concomitant perfused manometry in healthy participants.

OBJECTIVE: The gastrointestinal environment in which drug products need to disintegrate before the drug can dissolve and be absorbed has not been studied in detail due to limitations, especially invasiveness of existing techniques. Minimal in vivo data is available on undisturbed gastrointestinal motility to improve relevance of predictive dissolution models and in silico tools such as physiologically-based pharmacokinetic models. Recent advances in magnetic resonance imaging methods could provide novel data and insights that can be used as a reference to validate and, if necessary, optimize these models. The conventional method for measuring gastrointestinal motility is via a manometric technique involving intubation. Nevertheless, it is feasible to measure gastrointestinal motility with magnetic resonance imaging. The aim of this study was is to develop and validate a magnetic resonance imaging method using the most recent semi-automated analysis method against concomitant perfused manometry method. MATERIAL AND METHODS: Eighteen healthy fasted participants were recruited for this study. The participants were intubated with a water-perfused manometry catheter. Subsequently, stomach motility was assessed by cine-MRI acquired at intervals, of 3.5min sets, at coronal oblique planes through the abdomen and by simultaneous water perfused manometry, before and after administration of a standard bioavailability / bioequivalence 8 ounces (~240mL) drink of water. The magnetic resonance imaging motility images were analysed using Spatio-Temporal Motility analysis STMM techniques. The area under the curve of the gastric motility contractions was calculated for each set and compared between techniques. The study visit was then repeated one week later. RESULTS: Data from 15 participants was analysed. There was a good correlation between the MRI antral motility plots area under the curve and corresponding perfused manometry motility area under the curve (r = 0.860) during both antral contractions and quiescence. CONCLUSION: Non-invasive dynamic magnetic resonance imaging of gastric antral motility coupled with recently developed, semi-automated magnetic resonance imaging data processing techniques correlated well with simultaneous, 'gold standard' water perfused manometry. This will be particularly helpful for research purposes related to oral absorption where the absorption of a drug is highly depending on the underlying gastrointestinal processes such as gastric emptying, gastrointestinal motility and availability of residual fluid volumes. CLINICAL TRIAL: This trial was registered at ClinicalTrials.gov as NCT03191045.

Imaging Measurement of Whole Gut Transit Time in Paediatric and Adult Functional Gastrointestinal Disorders: A Systematic Review and Narrative Synthesis.

BACKGROUND: functional gastrointestinal disorders (FGID) are common conditions in children and adults, often associated with abnormalities of whole gut transit. Currently, transit tests can be performed using several imaging methods, including tracking of radiopaque markers, gamma scintigraphy with the use of radioisotopes, magnetic tracking methods, tracking of movement of wireless motility capsules, and emerging magnetic resonance imaging (MRI) approaches. OBJECTIVES: to review recent literature on diagnostic imaging techniques used to investigate whole gut transit in FGIDs. METHODS: a systematic review was carried out. The different techniques are described briefly, with particular emphasis on contemporary literature and new developments, particularly in the field of MRI. CONCLUSIONS: emerging MRI capsule marker methods are promising new tools to study whole gut transit in FGIDs.

Alginate and HM-pectin in sports-drink give rise to intra-gastric gelation in vivo.

The addition of gelling polysaccharides to sport-drinks may provide improved tolerability of drinks with high concentration of digestible carbohydrates (CHO), otherwise known to increase the risk of gastro-intestinal complaints among athletes under prolonged exercise. The physico-chemical properties of a drink containing 14 wt% of digestible CHO (0.7 : 1 fructose and maltodextrin-ratio), 0.2 wt% of HM-pectin/alginate and 0.06 wt%. sodium chloride were examined under in vitro gastric conditions using rheology and large deformation testing. The in vivo gelling behaviour of the drink was studied using magnetic resonance imaging of subjects at rest together with blood glucose measurements. The in vivo results confirm gelation of the test drink, with no gel remaining in the stomach at 60 min and blood glucose values were similar to control. The physico-chemical characterisation of the acidified test drink confirms the formation of a weak gel through which low Mw CHO can diffuse.