Mechanics of biomimetic materials for tissue engineering of the intervertebral disc

Tissue engineering offers a paradigm shift in the treatment of back pain. Engineered intervertebral discs could replace degenerated tissue and overcome the limitations of current treatments that disrupt the biomechanics of the spine. New materials, which exhibit sophisticated mechanical responses, are needed to provide templates for tissue regeneration. These behaviours include time-dependent deformation---facilitating shock absorption and nutrient transfer---and strong material anisotropy and tensile-compressive nonlinearities---providing flexibility in controlled directions. In this work, frameworks for the design of materials with controllable structure-property relationships are developed. The time-dependent mechanical properties of composites of agar, alginate and gelatin hydrogels are investigated. It is shown that the time-dependent responses of the composites can be tuned over a wide range. It is then demonstrated that materials mimicking the fibre-reinforced nature of natural tissues can be developed by infiltrating thick electrospun fibre networks with alginate. These fibre-reinforced hydrogels have tensile and compressive properties that can be separately altered. To better understand the mechanical behaviour of these hydrogel-based materials, improved methods for characterising poroelastic and poroviscoelastic time-dependent material properties using indentation are developed. It is shown that poroviscoelastic relaxation is the product of separate poroelastic and viscoelastic relaxation responses. The techniques developed here provide a methodology to rapidly characterise the properties of time-dependent materials and to create materials with complex structure-property relationships similar to those found in natural tissues; they present a framework for biomimetic materials design. The work in this thesis can be used to inform the design of clinically relevant tissue engineering treatments and help the quarter of a million people each year who undergo spinal surgery to reduce back pain.This PhD was supported by the Cambridge Commonwealth Trus

Size effects in indentation of hydrated biological tissues

Fluid flow in biological tissues is important in both mechanical and biological contexts. Given the hierarchical nature of tissues, there are varying length scales at which time-dependent mechanical behavior due to fluid flow may be exhibited. Here, spherical nanoindentation and microindentation testings are used for the characterization of length scale effects in the mechanical response of hydrated tissues. Although elastic properties were consistent across length scales, there was a substantial difference between the time-dependent mechanical responses for large and small contact radii in the same tissue specimens. This difference was far more obvious when poroelastic analysis was used instead of viscoelastic analysis. Overall, indentation testing is a fast and robust technique for characterizing the hierarchical structure of biological materials from nanometer to micrometer length scales and is capable of making quantitative material property measurements to do with fluid flo

Ground-truthing' Chinese development finance in Africa: Field evidence from South Africa and Uganda

A new methodology, Tracking Under-Reported Financial Flows (TUFF), allows us to systematically gather open-source information - e.g. news reports, case studies, project inventories from embassy websites, and grant and loan data published by recipient governments - about Chinese development finance activities in Africa that can be updated and improved through crowd-sourcing. In this study we create and field-test a replicable 'ground-truthing' methodology following an established protocol to verify and update existing data with in-person interviews on Chinese development finance and site visits in Uganda and South Africa. Ground-truthing generally revealed close agreement between open-source data and answers to protocol questions from informants with official roles in the Chinese-funded project

Physical signatures of discontinuities of the time-dependent exchange-correlation potential

The exact exchange-correlation (XC) potential in time-dependent density-functional theory (TDDFT) is known to develop steps and discontinuities upon change of the particle number in spatially confined regions or isolated subsystems. We demonstrate that the self-interaction corrected adiabatic local-density approximation for the XC potential has this property, using the example of electron loss of a model quantum well system. We then study the influence of the XC potential discontinuity in a real-time simulation of a dissociation process of an asymmetric double quantum well system, and show that it dramatically affects the population of the resulting isolated single quantum wells. This indicates the importance of a proper account of the discontinuities in TDDFT descriptions of ionization, dissociation or charge transfer processes.Comment: 17 pages, 6 figure

Size effects in indentation of hydrated biological tissues

Fluid flow in biological tissues is important in both mechanical and biological contexts. Given the hierarchical nature of tissues, there are varying length scales at which time-dependent mechanical behavior due to fluid flow may be exhibited. Here, spherical nanoindentation and microindentation testings are used for the characterization of length scale effects in the mechanical response of hydrated tissues. Although elastic properties were consistent across length scales, there was a substantial difference between the time-dependent mechanical responses for large and small contact radii in the same tissue specimens. This difference was far more obvious when poroelastic analysis was used instead of viscoelastic analysis. Overall, indentation testing is a fast and robust technique for characterizing the hierarchical structure of biological materials from nanometer to micrometer length scales and is capable of making quantitative material property measurements to do with fluid flow

Variations in Tetrodotoxin Levels in Populations of Taricha granulosa are Expressed in the Morphology of Their Cutaneous Glands

Tetrodotoxin (TTX), one of the most toxic substances in nature, is present in bacteria, invertebrates, fishes, and amphibians. Marine organisms seem to bioaccumulate TTX from their food or acquire it from symbiotic bacteria, but its origin in amphibians is unclear. Taricha granulosa can exhibit high TTX levels, presumably concentrated in skin poison glands, acting as an agent of selection upon predatory garter snakes (Thamnophis). This co-evolutionary arms race induces variation in T. granulosa TTX levels, from very high to undetectable. Using morphology and biochemistry, we investigated differences in toxin localization and quality between two populations at the extremes of toxicity. TTX concentration within poison glands is related to the volume of a single cell type in which TTX occurs exclusively in distinctive secretory granules, suggesting a relationship between granule structure and chemical composition. TTX was detected in mucous glands in both populations, contradicting the general understanding that these glands do not secrete defensive chemicals and expanding currently held interpretations of amphibian skin gland functionality. Skin secretions of the two populations differed in low-mass molecules and proteins. Our results demonstrate that interpopulation variation in TTX levels is related to poison gland morphology

Colours and pigments in late ukiyo-e art works: A preliminary non-invasive study of Japanese woodblock prints to interpret hyperspectral images using in-situ point-by-point diffuse reflectance spectroscopy

Dyes and pigments have been used in traditional Japanese woodblock printings in the ukiyo-e style for several centuries. However, the possible introduction of new European pigments and the extraordinary quality of the works of the later period led to take a keen interest in the analytical study of these ukiyo-e prints manufactured at the end of the 19th century. The present research discusses the analytical results of the series Bijin juni kagetsu (“Beauties in the Twelve Months”) by Shuntei, dated in 1898–1899. Due to the characteristics of this type of artworks, diffuse reflectance spectroscopy (DRS) has been chosen as a portable, non-invasive analytical technique to identify pigments and colorants used in the woodblock prints. The analytical possibilities offered by the in-situ point-by-point DRS as a preliminary tool to better interpret hyperspectral imaging (HSI) data were highlighted. Reflectance spectra of more than 190 points sampled throughout the artwork were recorded between 360 and 740 nm, and characterised. Throughout an statistical classification of the spectral data using unsupervised pattern recognition methods, twenty-two different colour composition was confirmed. These groups of reflectance spectra were then identified according the presence of characteristic maxima, minima and inflection points in every spectrum. Some micro-samples extracted from the pigments still remained in a woodblock (used for a 20th century print) were analysed by FESEM-EDS to better interpret some reflectance spectra. Traditional Japanese pigments (like vermilion, red lead, and indigo) and synthetic materials introduced in the 18th and 19th centuries (Prussian blue, synthetic arsenic sulphides, eosin, and methyl violet or crystal violet) were identified in the Shuntei''s series colours, together with some mixtures of pigments to prepare blue, green, orange and purple. Based on these twenty-two reflectance patterns, the point-by-point spectra make easier the task of interpreting the very complex HSI data, and reduce the time of treatment and interpretation required by HSI

Prediction of first cardiovascular disease event in 2.9 million individuals using Danish administrative healthcare data:a nationwide, registry-based derivation and validation study

AIMS: The aim of this study was to derive and validate a risk prediction model with nationwide coverage to predict the individual and population-level risk of cardiovascular disease (CVD). METHODS AND RESULTS: All 2.98 million Danish residents aged 30–85 years free of CVD were included on 1 January 2014 and followed through 31 December 2018 using nationwide administrative healthcare registries. Model predictors and outcome were pre-specified. Predictors were age, sex, education, use of antithrombotic, blood pressure-lowering, glucose-lowering, or lipid-lowering drugs, and a smoking proxy of smoking-cessation drug use or chronic obstructive pulmonary disease. Outcome was 5-year risk of first CVD event, a combination of ischaemic heart disease, heart failure, peripheral artery disease, stroke, or cardiovascular death. Predictions were computed using cause-specific Cox regression models. The final model fitted in the full data was internally-externally validated in each Danish Region. The model was well-calibrated in all regions. Area under the receiver operating characteristic curve (AUC) and Brier scores ranged from 76.3% to 79.6% and 3.3 to 4.4. The model was superior to an age-sex benchmark model with differences in AUC and Brier scores ranging from 1.2% to 1.5% and −0.02 to −0.03. Average predicted risks in each Danish municipality ranged from 2.8% to 5.9%. Predicted risks for a 66-year old ranged from 2.6% to 25.3%. Personalized predicted risks across ages 30–85 were presented in an online calculator (https://hjerteforeningen.shinyapps.io/cvd-risk-manuscript/). CONCLUSION: A CVD risk prediction model based solely on nationwide administrative registry data provided accurate prediction of personal and population-level 5-year first CVD event risk in the Danish population. This may inform clinical and public health primary prevention efforts