Quantitative architectural description of tissue engineering scaffolds

Arguably one of the most specialised subtopics in porous materials research is that of tissue engineering scaffolds. The porous architecture of these scaffolds is a key variable in determining biological response. However, techniques for characterising these materials tend to vary widely in the literature. There is a need for a set of transferable and effective methods for architectural characterisation. In this review, four key areas of importance are addressed. First, the definition and interpretation of pore size are considered in relation to fluid transport properties, by analogy with filtration research. Second, the definition of interconnectivity is discussed using insight obtained from cement and concrete research. Third, the issue of data scalability is addressed by consideration of percolation theory, as implemented for the study of geological materials. Finally, emerging techniques such as confocal and multiphoton microscopy are discussed. These methods allow the three-dimensional observation of pore strut arrangement, as well holding great potential for understanding changes in pore architecture under dynamic conditions

Multiple Cardiac Rhabdomyomas Visualised Using Micro-CT in a Case of Tuberous Sclerosis

Cardiac rhabdomyoma is the most common tumour of the heart in infancy and childhood, representing approximately 60% of all primary cardiac tumours in these age groups. Though they have a tendency to regress with advancing age and are histologically benign, rhabdomyomas may cause mechanical obstruction to blood flow, arrhythmia, congestive cardiac failure and death and may be associated with underlying genetic syndromes such as tuberous sclerosis. We present the case of a primigravida in her early 20s with no significant medical history who was referred to the Fetal Medicine Unit at 34 weeks' gestation following the detection of an irregular fetal heartbeat. An anomaly scan at 20 weeks had been reported as normal

Structural determinants of hydration, mechanics and fluid flow in freeze-dried collagen scaffolds.

UNLABELLED: Freeze-dried scaffolds provide regeneration templates for a wide range of tissues, due to their flexibility in physical and biological properties. Control of structure is crucial for tuning such properties, and therefore scaffold functionality. However, the common approach of modeling these scaffolds as open-cell foams does not fully account for their structural complexity. Here, the validity of the open-cell model is examined across a range of physical characteristics, rigorously linking morphology to hydration and mechanical properties. Collagen scaffolds with systematic changes in relative density were characterized using Scanning Electron Microscopy, X-ray Micro-Computed Tomography and spherical indentation analyzed in a time-dependent poroelastic framework. Morphologically, all scaffolds were mid-way between the open- and closed-cell models, approaching the closed-cell model as relative density increased. Although pore size remained constant, transport pathway diameter decreased. Larger collagen fractions also produced greater volume swelling on hydration, although the change in pore diameter was constant, and relatively small at ∼6%. Mechanically, the dry and hydrated scaffold moduli varied quadratically with relative density, as expected of open-cell materials. However, the increasing pore wall closure was found to determine the time-dependent nature of the hydrated scaffold response, with a decrease in permeability producing increasingly elastic rather than viscoelastic behavior. These results demonstrate that characterizing the deviation from the open-cell model is vital to gain a full understanding of scaffold biophysical properties, and provide a template for structural studies of other freeze-dried biomaterials. STATEMENT OF SIGNIFICANCE: Freeze-dried collagen sponges are three-dimensional microporous scaffolds that have been used for a number of exploratory tissue engineering applications. The characterization of the structure-properties relationships of these scaffolds is necessary to understand their biophysical behavior in vivo. In this work, the relationship between morphology and physical properties in the dry and hydrated states was investigated across a range of solid concentrations in the scaffolds. The quantitative results provided can aid the design of scaffolds with a target trade-off between mechanical properties and structural features important for their biological activity.Engineering and Physical Sciences Research Council CDT in Nanoscience and Nanotechnology (NanoDTC)This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.actbio.2016.05.02

Stillbirth and intrauterine fetal death: factors affecting determination of cause of death at autopsy

Objectives There have been several attempts to classify cause of death (CoD) in stillbirth; however, all such systems are subjective, allowing for observer bias and making comparisons between systems challenging. This study aimed to examine factors relating to determination of CoD using a large dataset from two specialist centers in which observer bias had been reduced by classifying findings objectively and assigning CoD based on predetermined criteria. Methods Detailed autopsy reports from intrauterine deaths in the second and third trimesters during 2005–2013 were reviewed and findings entered into a specially designed database, in which CoD was assigned using predefined objective criteria. Data regarding CoD categories and factors affecting determination of CoD were examined. Results There were 1064 intrauterine deaths, including 246 early intrauterine fetal deaths (IUFD) (< 20 weeks), 179 late IUFDs (20–23 weeks) and 639 stillbirths (≥ 24 weeks' gestation). Overall, around 40% (n = 412) had a clear CoD identified, whilst around 60% (n = 652) were classified as ‘unexplained’, including around half with identified risk factors or lesions of uncertain significance, with the remaining half (n = 292 (45%)) being entirely unexplained. A stepwise increase in the proportion of unexplained deaths was observed with increasing maceration. Black and Asian women had significantly greater proportions of deaths due to ascending infection, whilst women aged over 40 years had significantly increased placenta-related CoDs. There was no significant difference in CoD distribution according to maternal body mass index or with increasing postmortem interval. Around half of those with an identifiable CoD could be identified from clinical review and external fetal examination or imaging, with most of the remainder being determined following placental examination. Conclusions Based on objective criteria, many intrauterine deaths throughout gestation remain unexplained despite autopsy examination. The rate of unexplained death varies from around 30% to 60% depending on interpretation of the significance of features. CoD determination is dependent on both the classification system used and subjective interpretation, such that variation in the proportion of ‘unexplained’ cases is based largely on speculation regarding mechanisms of death. Novel methods to determine objectively the mechanism of death at postmortem examination are required

Stillbirth and intrauterine fetal death: contemporary demographic features of >1000 cases from an urban population

OBJECTIVES: Of 780 000 births annually in the UK, around 3300 are stillborn, a rate of approximately 4 per 1000 births. Traditional epidemiological associations are based on historic data. The aim of this study was to document contemporary demographic findings in a large series of > 1000 deaths in utero in London and compare these with national datasets. METHODS: From a dedicated database, including > 400 data fields per case, of fetal, infant and pediatric autopsies performed at Great Ormond Street Hospital and St George's Hospital, London, we extracted information on all intrauterine deaths, excluding terminations of pregnancy, from 2005 to 2013, inclusive. Demographic data were analyzed according to the gestational age at which fetal death occurred (second-trimester intrauterine fetal death (IUFD), subdivided into early (1000 autopsies in cases of intrauterine death, these data highlight the increased risk for fetal loss associated with maternal demographic factors in contemporary clinical practice, particularly associations with increased maternal age and body mass index. Among women in whom an intrauterine death occurs, maternal ethnicity, mode of conception and gynecological history are associated with differing timing of fetal loss. Further research is required to understand the mechanisms involved in such maternal factors in order to develop preventative strategies

Stillbirth and intrauterine fetal death: role of routine histological organ sampling to determine cause of death.

OBJECTIVES: Guidelines for the investigation of intrauterine death and sudden unexpected death in infancy (SUDI) recommend, based on expert opinion, autopsy procedures and tissue sampling strategies for histological analysis. Although stillbirth is much more common than SUDI, there have been no large-scale studies published which evaluate the usefulness of histological evaluation of specific organs in stillbirth for determining cause of death. Our aim was to evaluate the use of macroscopic and microscopic assessment of internal organs to determine cause of intrauterine death. METHODS: As part of a larger study evaluating several aspects of autopsy findings in intrauterine death, a dedicated database was used to collate antenatal and postmortem examination details for cases of intrauterine death examined between 2005 and 2013 at two tertiary specialist centers in London, UK. Histological findings for all organs were examined in relation to the final cause of death, as determined by objective criteria. RESULTS: Among 1064 intrauterine deaths, the majority (> 80%) of cases had internal organs that were normal on both macroscopic and microscopic examination. There was no case in which histological cardiac examination provided the cause of death when the macroscopic appearance of the heart was normal. Microscopic examination of lung tissue revealed 13 (1%) cases with histological abnormalities that provided the cause of death when the macroscopic appearance was normal, but there was only one (0.1%) case in which the diagnosis would not have been apparent on placental examination: a case of congenital cytomegalovirus infection. There was no case in which microscopic examination of macroscopically normal liver, kidneys, adrenals, spleen, thymus, intestines, pancreas, brain or thyroid provided the cause of death. CONCLUSION: In this large series of autopsies in cases of intrauterine death, only around 1% of cases demonstrated histological abnormalities which provided the cause of death when the internal organs appeared normal macroscopically. There was no case in which routine histological examination of most tissues provided diagnostically useful information that was not apparent from other examinations, such as placental pathology. There is little benefit, purely in terms of determining cause of death, in obtaining tissue from most macroscopically normal organs for routine histological examination

Socioeconomic predictors of crisis and clinical pathways among people contacting a mental health crisis line

Objective: Crisis lines are the first mental health service contact point for many people, making them a vital community and public health intervention. Given the current and potential utility of crisis lines, better understanding the characteristics, socioeconomic factors and subsequent referral pathways of callers is critical to identifying targeted ways to improve such services. Study Design: The dataset captured calls to the Cheshire & Wirral Partnership NHS Foundation Trust (CWP) crisis line between August 2020 and August 2021. Calls were examined if self-harm, risk to self, or overdose were reported by the caller. Descriptive analyses were conducted to produce a clinical and demographic profile of the callers using the crisis line. Results: Call handlers were significantly more likely to call 999, hand over to a practitioner and less likely to provide advice and guidance if self-harm, risk to self or overdose was reported. Social issues were found to be significantly associated with all 3 outcomes: self-harm, risk to self and overdose. Conclusion: The current study provides the first exploratory analysis of the socioeconomic factors and resultant care pathways for those contacting a UK crisis line service. The findings have important implications for community early intervention efforts to reduce self-harm and suicidal behaviours

Reappraising myocardial fibrosis in severe aortic stenosis: an invasive and non-invasive study in 133 patients

Aims: To investigate myocardial fibrosis (MF) in a large series of severe aortic stenosis (AS) patients using invasive biopsy and non-invasive imaging. Methods and results: One hundred thirty-three patients with severe, symptomatic AS accepted for surgical aortic valve replacement underwent cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) and extracellular volume fraction (ECV) quantification. Intra-operative left ventricular (LV) biopsies were performed by needle or scalpel, yielding tissue with (n = 53) and without endocardium (n = 80), and compared with 10 controls. Myocardial fibrosis occurred in three patterns: (i) thickened endocardium with a fibrotic layer; (ii) microscopic scars, with a subendomyocardial predominance; and (iii) diffuse interstitial fibrosis. Collagen volume fraction (CVF) was elevated (P < 0.001) compared with controls, and higher (P < 0.001) in endocardium-containing samples with a decreasing CVF gradient from the subendocardium (P = 0.001). Late gadolinium enhancement correlated with CVF (P < 0.001) but not ECV. Both LGE and ECV correlated independently (P < 0.001) with N-terminal pro-brain natriuretic peptide and high-sensitivity-troponin T. High ECV was also associated with worse LV remodelling, left ventricular ejection fraction and functional capacity. Combining high ECV and LGE better identified patients with more adverse LV remodelling, blood biomarkers and histological parameters, and worse functional capacity than each parameter alone. Conclusion: Myocardial fibrosis in severe AS is complex, but three main patterns exist: endocardial fibrosis, microscars (mainly in the subendomyocardium), and diffuse interstitial fibrosis. Neither histological CVF nor the CMR parameters ECV and LGE capture fibrosis in its totality. A combined, multi-parametric approach with ECV and LGE allows best stratification of AS patients according to the response of the myocardial collagen matrix

Genomic architecture of inflammatory bowel disease in five families with multiple affected individuals.

Currently, the best clinical predictor for inflammatory bowel disease (IBD) is family history. Over 163 sequence variants have been associated with IBD in genome-wide association studies, but they have weak effects and explain only a fraction of the observed heritability. It is expected that additional variants contribute to the genomic architecture of IBD, possibly including rare variants with effect sizes larger than the identified common variants. Here we applied a family study design and sequenced 38 individuals from five families, under the hypothesis that families with multiple IBD-affected individuals harbor one or more risk variants that (i) are shared among affected family members, (ii) are rare and (iii) have substantial effect on disease development. Our analysis revealed not only novel candidate risk variants but also high polygenic risk scores for common known risk variants in four out of the five families. Functional analysis of our top novel variant in the remaining family, a rare missense mutation in the ubiquitin ligase TRIM11, suggests that it leads to increased nuclear factor of kappa light chain enhancer in B-cells (NF-κB) signaling. We conclude that an accumulation of common weak-effect variants accounts for the high incidence of IBD in most, but not all families we analyzed and that a family study design can identify novel rare variants conferring risk for IBD with potentially large effect size, such as the TRIM11 p.H414Y mutation