Composition-dependent morphologies of CeO2 nanoparticles in the presence of Co-adsorbed H2O and CO2: a density functional theory study.

Catalytic activity is affected by surface morphology, and specific surfaces display greater activity than others. A key challenge is to define synthetic strategies to enhance the expression of more active surfaces and to maintain their stability during the lifespan of the catalyst. In this work, we outline an ab initio approach, based on density functional theory, to predict surface composition and particle morphology as a function of environmental conditions, and we apply this to CeO2 nanoparticles in the presence of co-adsorbed H2O and CO2 as an industrially relevant test case. We find that dissociative adsorption of both molecules is generally the most favourable, and that the presence of H2O can stabilise co-adsorbed CO2. We show that changes in adsorption strength with temperature and adsorbate partial pressure lead to significant changes in surface stability, and in particular that co-adsorption of H2O and CO2 stabilizes the {100} and {110} surfaces over the {111} surface. Based on the changes in surface free energy induced by the adsorbed species, we predict that cuboidal nanoparticles are favoured in the presence of co-adsorbed H2O and CO2, suggesting that cuboidal particles should experience a lower thermodynamic driving force to reconstruct and thus be more stable as catalysts for processes involving these species.

Inhibition of insulin-degrading enzyme in human neurons promotes amyloid-ß deposition.

Alzheimer's disease (AD) is characterised by the aggregation and deposition of amyloid-ß (Aß) peptides in the human brain. In age-related late-onset AD, deficient degradation and clearance, rather than enhanced production, of Aß contributes to disease pathology. In the present study, we assessed the contribution of the two key Aß-degrading zinc metalloproteases, insulin-degrading enzyme (IDE) and neprilysin (NEP), to Aß degradation in human induced pluripotent stem cell (iPSC)-derived cortical neurons. Using an Aß fluorescence polarisation assay, inhibition of IDE but not of NEP, blocked the degradation of Aß by human neurons. When the neurons were grown in a 3D extracellular matrix to visualise Aß deposition, inhibition of IDE but not NEP, increased the number of Aß deposits. The resulting Aß deposits were stained with the conformation-dependent, anti-amyloid antibodies A11 and OC that recognise Aß aggregates in the human AD brain. Inhibition of the Aß-forming ß-secretase prevented the formation of the IDE-inhibited Aß deposits. These data indicate that inhibition of IDE in live human neurons grown in a 3D matrix increased the deposition of Aß derived from the proteolytic cleavage of the amyloid precursor protein. This work has implications for strategies aimed at enhancing IDE activity to promote Aß degradation in AD.

Agarose Fluid Gels Formed by Shear Processing During Gelation for Suspended 3D Bioprinting.

The use of granular matrices to support parts during the bioprinting process was first reported by Bhattacharjee et al. in 2015, and since then, several approaches have been developed for the preparation and use of supporting gel beds in 3D bioprinting. This paper describes a process to manufacture microgel suspensions using agarose (known as fluid gels), wherein particle formation is governed by the application of shear during gelation. Such processing produces carefully defined microstructures, with subsequent material properties that impart distinct advantages as embedding print media, both chemically and mechanically. These include behaving as viscoelastic solid-like materials at zero shear, limiting long-range diffusion, and demonstrating the characteristic shear-thinning behavior of flocculated systems. On the removal of shear stress, however, fluid gels have the capacity to rapidly recover their elastic properties. This lack of hysteresis is directly linked to the defined microstructures previously alluded to; because of the processing, reactive, non-gelled polymer chains at the particle interface facilitate interparticle interactions-similar to a Velcro effect. This rapid recovery of elastic properties enables bioprinting high-resolution parts from low-viscosity biomaterials, as rapid reformation of the support bed traps the bioink in situ, maintaining its shape. Furthermore, an advantage of agarose fluid gels is the asymmetric gelling/melting transitions (gelation temperature of ~30 °C and melting temperature of ~90 °C). This thermal hysteresis of agarose makes it possible to print and culture the bioprinted part in situ without the supporting fluid gel melting. This protocol shows how to manufacture agarose fluid gels and demonstrates their use to support the production of a range of complex hydrogel parts within suspended-layer additive manufacture (SLAM).

A novel approach for the prevention of ionizing radiation-induced bone loss using a designer multifunctional cerium oxide nanozyme.

The disability, mortality and costs due to ionizing radiation (IR)-induced osteoporotic bone fractures are substantial and no effective therapy exists. Ionizing radiation increases cellular oxidative damage, causing an imbalance in bone turnover that is primarily driven via heightened activity of the bone-resorbing osteoclast. We demonstrate that rats exposed to sublethal levels of IR develop fragile, osteoporotic bone. At reactive surface sites, cerium ions have the ability to easily undergo redox cycling: drastically adjusting their electronic configurations and versatile catalytic activities. These properties make cerium oxide nanomaterials fascinating. We show that an engineered artificial nanozyme composed of cerium oxide, and designed to possess a higher fraction of trivalent (Ce3+) surface sites, mitigates the IR-induced loss in bone area, bone architecture, and strength. These investigations also demonstrate that our nanozyme furnishes several mechanistic avenues of protection and selectively targets highly damaging reactive oxygen species, protecting the rats against IR-induced DNA damage, cellular senescence, and elevated osteoclastic activity in vitro and in vivo. Further, we reveal that our nanozyme is a previously unreported key regulator of osteoclast formation derived from macrophages while also directly targeting bone progenitor cells, favoring new bone formation despite its exposure to harmful levels of IR in vitro. These findings open a new approach for the specific prevention of IR-induced bone loss using synthesis-mediated designer multifunctional nanomaterials.

Regulation of Mesenchymal Stem Cell Morphology Using Hydrogel Substrates with Tunable Topography and Photoswitchable Stiffness.

Cell function can be directly influenced by the mechanical and structural properties of the extracellular environment. In particular, cell morphology and phenotype can be regulated via the modulation of both the stiffness and surface topography of cell culture substrates. Previous studies have highlighted the ability to design cell culture substrates to optimise cell function. Many such examples, however, employ photo-crosslinkable polymers with a terminal stiffness or surface profile. This study presents a system of polyacrylamide hydrogels, where the surface topography can be tailored and the matrix stiffness can be altered in situ with photoirradiation. The process allows for the temporal regulation of the extracellular environment. Specifically, the surface topography can be tailored via reticulation parameters to include creased features with control over the periodicity, length and branching. The matrix stiffness can also be dynamically tuned via exposure to an appropriate dosage and wavelength of light, thus, allowing for the temporal regulation of the extracellular environment. When cultured on the surface of the hydrogels, the morphology and alignment of immortalised human mesenchymal stem cells can be directly influenced through the tailoring of surface creases, while cell size can be altered via changes in matrix stiffness. This system offers a new platform to study cellular mechanosensing and the influence of extracellular cues on cell phenotype and function.

Emulating Human Tissues and Organs: A Bioprinting Perspective Toward Personalized Medicine.

The lack of in vitro tissue and organ models capable of mimicking human physiology severely hinders the development and clinical translation of therapies and drugs with higher in vivo efficacy. Bioprinting allow us to fill this gap and generate 3D tissue analogues with complex functional and structural organization through the precise spatial positioning of multiple materials and cells. In this review, we report the latest developments in terms of bioprinting technologies for the manufacturing of cellular constructs with particular emphasis on material extrusion, jetting, and vat photopolymerization. We then describe the different base polymers employed in the formulation of bioinks for bioprinting and examine the strategies used to tailor their properties according to both processability and tissue maturation requirements. By relating function to organization in human development, we examine the potential of pluripotent stem cells in the context of bioprinting toward a new generation of tissue models for personalized medicine. We also highlight the most relevant attempts to engineer artificial models for the study of human organogenesis, disease, and drug screening. Finally, we discuss the most pressing challenges, opportunities, and future prospects in the field of bioprinting for tissue engineering (TE) and regenerative medicine (RM).

A Preliminary Evaluation of the Pro-Chondrogenic Potential of 3D-Bioprinted Poly(ester Urea) Scaffolds.

Degeneration of articular cartilage (AC) is a common healthcare issue that can result in significantly impaired function and mobility for affected patients. The avascular nature of the tissue strongly burdens its regenerative capacity contributing to the development of more serious conditions such as osteoarthritis. Recent advances in bioprinting have prompted the development of alternative tissue engineering therapies for the generation of AC. Particular interest has been dedicated to scaffold-based strategies where 3D substrates are used to guide cellular function and tissue ingrowth. Despite its extensive use in bioprinting, the application of polycaprolactone (PCL) in AC is, however, restricted by properties that inhibit pro-chondrogenic cell phenotypes. This study proposes the use of a new bioprintable poly(ester urea) (PEU) material as an alternative to PCL for the generation of an in vitro model of early chondrogenesis. The polymer was successfully printed into 3D constructs displaying adequate substrate stiffness and increased hydrophilicity compared to PCL. Human chondrocytes cultured on the scaffolds exhibited higher cell viability and improved chondrogenic phenotype with upregulation of genes associated with type II collagen and aggrecan synthesis. Bioprinted PEU scaffolds could, therefore, provide a potential platform for the fabrication of bespoke, pro-chondrogenic tissue engineering constructs.

The energetics of carbonated PuO2 surfaces affects nanoparticle morphology: a DFT+U study.

Radiolytic corrosion of actinide materials represent an issue for the long term storage and disposal of nuclear materials. Molecular species adsorbed at the surface of the actinides may impact the rate of radiolysis, and as the surfaces corrode, the soluble toxic and radioactive species leach into groundwater. It is therefore critical to characterise the surface composition of actinides. Here, we employ ab initio modelling to determine the surface composition of PuO2 with respect to adsorbed CO2. We found that CO2 interacts strongly with the surface forming carbonate species. By mapping the energetics of this interaction, we then calculate the temperature of desorption, finding that surface morphology has a strong impact on the adsorption of CO2, with the {100} being the most and the {111} the least affected by carbonation. Finally, we predict the effect of carbonation on the morphology of PuO2 nanoparticles as a function of temperature and pressure, finding that truncated octahedral is the preferred morphology. This modelling strategy helps characterise surface compensition and nanoparticle morphology, and we discuss the implication for radiolytically driven dispersal of material into the environment.

Blended alginate/collagen hydrogels promote neurogenesis and neuronal maturation.

Brain extracellular matrix (ECM) is complex, heterogeneous and often poorly replicated in traditional 2D cell culture systems. The development of more physiologically relevant 3D cell models capable of emulating the native ECM is of paramount importance for the study of human induced pluripotent stem cell (iPSC)-derived neurons. Due to its structural similarity with hyaluronic acid, a primary component of brain ECM, alginate is a potential biomaterial for 3D cell culture systems. However, a lack of cell adhesion motifs within the chemical structure of alginate has limited its application in neural culture systems. This study presents a simple and accessible method of incorporating collagen fibrils into an alginate hydrogel by physical mixing and controlled gelation under physiological conditions and tests the hypothesis that such a substrate could influence the behaviour of human neurons in 3D culture. Regulation of the gelation process enabled the penetration of collagen fibrils throughout the hydrogel structure as demonstrated by transmission electron microscopy. Encapsulated human iPSC-derived neurons adhered to the blended hydrogel as evidenced by the increased expression of α1, α2 and ß1 integrins. Furthermore, immunofluorescence microscopy revealed that encapsulated neurons formed complex neural networks and matured into branched neurons expressing synaptophysin, a key protein involved in neurotransmission, along the neurites. Mechanical tuning of the hydrogel stiffness by modulation of the alginate ionic crosslinker concentration also influenced neuron-specific gene expression. In conclusion, we have shown that by tuning the physicochemical properties of the alginate/collagen blend it is possible to create different ECM-like microenvironments where complex mechanisms underpinning the growth and development of human neurons can be simulated and systematically investigated.

Tissue Engineering 3D Neurovascular Units: A Biomaterials and Bioprinting Perspective.

Neurovascular dysfunction is a central process in the pathogenesis of stroke and most neurodegenerative diseases, including Alzheimer's disease. The multicellular neurovascular unit (NVU) combines the neural, vascular and extracellular matrix (ECM) components in an important interface whose correct functioning is critical to maintain brain health. Tissue engineering is now offering new tools and insights to advance our understanding of NVU function. Here, we review how the use of novel biomaterials to mimic the mechanical and functional cues of the ECM, coupled with precisely layered deposition of the different cells of the NVU through 3D bioprinting, is revolutionising the study of neurovascular function and dysfunction.

Suspended Manufacture of Biological Structures.

A method for the production of complex cell-laden structures is reported, which allows high-levels of spatial control over mechanical and chemical properties. The potential of this method for producing complicated tissues is demonstrated by manufacturing a complex hard/soft tissue interface and demonstrating that cell phenotype can be maintained over four weeks of culture.

Controlling the rheology of gellan gum hydrogels in cell culture conditions.

Successful culturing of tissues within polysaccharide hydrogels is reliant upon specific mechanical properties. Namely, the stiffness and elasticity of the gel have been shown to have a profound effect on cell behaviour in 3D cell cultures and correctly tuning these mechanical properties is critical to the success of culture. The usual way of tuning mechanical properties of a hydrogel to suit tissue engineering applications is to change the concentration of polymer or its cross-linking agents. In this study sonication applied at various amplitudes was used to control mechanical properties of gellan gum solutions and gels. This method enables the stiffness and elasticity of gellan gum hydrogels cross-linked with DMEM to be controlled without changing either polymer concentration or cross-linker concentration. Controlling the mechanical behaviour of gellan hydrogels impacted upon the activity of alkaline phosphatase (ALP) in encapsulated MC3T3 pre-osteoblasts. This shows the potential of applying a simple technique to generate hydrogels where tissue-specific mechanical properties can be produced that subsequently influence cell behaviour.