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Background Preeclampsia is a severe complication of pregnancy which is attributed to placental dysfunction. The retrotransposon, Paternal Expressed Gene 10 (PEG10) harbours critical placental functions pertaining to placental trophoblast cells. Limited evidence exists on whether PEG10 is involved in preeclampsia pathogenesis. This study characterised the expression and regulation of PEG10 in placentas from patients with early-onset preeclampsia compared to gestation-matched controls. Methods PEG10 expression was measured in plasma and placentas collected from patients with early-onset preeclampsia (< 34 weeks’) and gestation-matched controls using ELISA (protein) and RT-qPCR (mRNA). First-trimester human trophoblast stem cells (hTSCs) were used for in vitro studies. PEG10 expression was measured during hTSC differentiation and hTSC exposure to hypoxia (1% O 2 ) and inflammatory cytokines (IL-6 and TNFα) using RT-qPCR. Functional studies used PEG10 siRNA to measure the effect of reduced PEG10 on canonical TGF- β signalling and proliferation using luciferase and xCELLigence assays, respectively. Results PEG10 mRNA expression was significantly reduced in placentas from patients with early-onset preeclampsia (< 34 weeks’ gestation) relative to controls ( p  = 0.04, n  = 78 vs n  = 18 controls). PEG10 protein expression was also reduced in preeclamptic placentas ( p  = 0.03, n  = 5 vs n  = 5 controls, blinded assessment of immunohistochemical staining), but neither PEG10 mRNA nor protein could be detected in maternal circulation. PEG10 was most highly expressed in hTSCs, and its expression was reduced as hTSCs differentiated into syncytiotrophoblasts ( p  < 0.0001) and extravillous trophoblasts ( p  < 0.001). Trophoblast differentiation was not altered when hTSCs were treated with PEG10 siRNA ( n  = 5 vs n  = 5 controls). PEG10 was significantly reduced in hTSCs exposed to hypoxia ( p  < 0.01). PEG10 was also reduced in hTSCs treated with the inflammatory cytokine TNF α ( p  < 0.01), but not IL-6. PEG10 knocked down (siRNA) in hTSCs showed reduced activation of the canonical TGF-β signalling effector, the SMAD binding element ( p  < 0.05) relative to controls. PEG10 knockdown in hTSCs however was not associated with any significant alterations in proliferation. Conclusions Placental PEG10 is reduced in patients with early-onset preeclampsia. In vitro studies suggest that hypoxia and inflammation may contribute to PEG10 downregulation. Reduced PEG10 alters canonical TGF- β signalling, and thus may be involved in trophoblast dysfunction associated with this pathway.

Haptic technology has long been integrated into simulated (sim) environments to create a sense of realism and improve performance. In sim racing, force and vibrotactile feedback have been implemented into steering wheels to create a more realistic experience. However, little is understood about how these types of feedback convey information to the sim racer. This study aimed to decode the vibration frequencies transferred through the steering wheel to the user and investigate how these frequencies vary as the strength of each feedback channel is manipulated. Using a Noraxon Ultium EMG accelerometer, the movements of a Logitech G Pro sim racing wheel were recorded whilst four participants completed five clean laps across nine different conditions. During each condition, a combination of force feedback (0 nm, 6 nm, or 11 nm) and vibrotactile feedback (0%, 50%, or 100%) settings were altered. Accelerometer data were pre-processed and Fast Fourier Transforms were performed to allow examination of signal power at frequencies of up to 200 Hz. Two-way repeated measures ANOVAs were performed to investigate differences in power at relevant frequencies across conditions and laps. Wheel motion was predominantly contained within the 0-5 Hz (force feedback and racer input) and 25-30 Hz ranges. No significant differences were seen in 0-5 Hz power between conditions, but the 25-30 Hz range was observed to exponentially increase as vibrotactile feedback was linearly increased. Finally, 25-30 Hz power at a fixed vibrotactile feedback intensity significantly decreased when the force feedback intensity was increased. This study decodes the haptic feedback relayed to the user through a sim racing wheel and highlights atypical changes to signal amplitude across various frequency bands when altering force and vibrotactile feedback intensity.

Crosslinking and the resultant changes in mechanical properties have been shown to influence cellular activity within collagen biomaterials. With this in mind, we sought to determine the effects of crosslinking on both the compressive modulus of collagen-glycosaminoglycan scaffolds and the activity of osteoblasts seeded within them. Dehydrothermal, 1-ethyl-3-3-dimethyl aminopropyl carbodiimide and glutaraldehyde crosslinking treatments were first investigated for their effect on the compressive modulus of the scaffolds. After this, the most promising treatments were used to study the effects of crosslinking on cellular attachment, proliferation, and infiltration. Our experiments have demonstrated that a wide range of scaffold compressive moduli can be attained by varying the parameters of the crosslinking treatments. 1-Ethyl-3-3-dimethyl aminopropyl carbodiimide and glutaraldehyde treatments produced the stiffest scaffolds (fourfold increase when compared to dehydrothermal crosslinking). When cells were seeded onto the scaffolds, the stiffest scaffolds also showed increased cell number and enhanced cellular distribution when compared to the other groups. Taken together, these results indicate that crosslinking can be used to produce collagen–glycosaminoglycan scaffolds with a range of compressive moduli, and that increased stiffness enhances cellular activity within the scaffolds.

Injectable hydrogels were discovered as attractive materials for bone tissue engineering applications given their outstanding biocompatibility, high water content, and versatile fabrication platforms into materials with different physiochemical properties. However, traditional hydrogels suffer from weak mechanical strength, limiting their use in heavy load-bearing areas. Thus, the fabrication of mechanically robust injectable hydrogels that are suitable for load-bearing environments is of great interest. Successful material design for bone tissue engineering requires an understanding of the composition and structure of the material chosen, as well as the appropriate selection of biomimetic natural or synthetic materials. This review focuses on recent advancements in materials–design considerations and approaches to prepare mechanically robust injectable hydrogels for bone tissue engineering applications. We outline the materials–design approaches through a selection of materials and fabrication methods. Finally, we discuss unmet needs and current challenges in the development of ideal materials for bone tissue regeneration and highlight emerging strategies in the field.

Osteoporotic vertebrae are a uniquely challenging tissue for local delivery due to the complex geometry of cancellous bone, the proximity of the spinal cord, and the need for reliable site retention. These challenges can be met with the use of stimuli responsive, state transiting formulations by leveraging their unique capacity for minimally invasive implantation as a liquid, sol-gel transition in response to stimuli, and finally, release of a loaded therapeutic. Here, we present the formulation development of a thermosensitive methylcellulose-collagen hydrogel, functionalised with controlled release simvastatin, recently shown to enhance osteogenesis while also impeding osteoclast activity. We first optimised a formulation with collagen content of 0.4% / to achieve a thermosensitive system with sol-gel transition at 29 °C, shear-thinning/injectable properties, low cytotoxicity, and high biocompatibility. Incorporation of nano-hydroxyapatite for enhanced bone tissue mimicry revealed optimal performance at 100% /collagen content, showing long-term hydrolytic stability, maintaining more than 100% of its mass after 28 days. A loading concentration of 1 mg of simvastatin to 1 g of hydrogel displayed sustained release of simvastatin over 35 days. Finally, the release of simvastatin from the hydrogel into in vitro conditions prevented the formation of osteoclasts but failed to boost osteogenesis. Together these findings reveal a series of desirable stimuli-responsive hydrogel properties, achieving minimally invasive application coupled with sustained release of a hydrophobic compound, which is potentially useful for spatially complex bone regeneration. Further this work demonstrates the challenge of dosing sustained release systems to achieve simultaneous osteogenesis and anti-osteoclastogenic effects.

Preeclampsia, a life-threatening hypertensive disorder of pregnancy, is a leading cause of maternal and perinatal morbidity and mortality. Its early-onset form (EO-PE), requiring delivery before 34 weeks of gestation, is particularly severe and closely linked to defective trophoblast differentiation. Here, we identify BRCA1-associated protein 1 (BAP1) and its cofactors ASXL2 and ASXL3 as upregulated in EO-PE placentas. Enforced BAP1 expression in human trophoblast stem cells reinforced epithelial identity, enhanced adhesion, and impaired both extravillous trophoblast differentiation and syncytiotrophoblast formation. Integrated transcriptomic and proteomic analyses revealed suppression of lineage-specific pathways alongside maintenance of progenitor-like and pro-inflammatory signatures. In trophoblast organoids, an excess of BAP1 disrupted syncytial maturation and induced interferon-driven pathways overlapping with EO-PE transcriptomes. Together, these findings establish BAP1 as a key regulator of human trophoblast differentiation and implicate its dysregulation in the pathogenesis of EO-PE, providing mechanistic insight into the cellular basis of placental dysfunction.

Purpose of Review This review aims to explore the potential of biomimetic hydrogels as an alternative to bone cement in vertebral body stenting (VBS), a minimally invasive treatment for vertebral compression fractures. Recent Findings The use of bone cement in VBS procedures can lead to complications such as incomplete fracture reduction and cement leakage. Biomimetic hydrogels have gained significant attention as potential biomaterial alternatives for VBS due to their unique properties, including tuneable therapeutic and mechanical properties. Over the past decade, there has been significant advancements in the development of biomimetic hydrogels for bone regeneration, employing a wide range of approaches to enhance the structural and functional properties of hydrogels. Summary Biomimetic hydrogels hold significant promise as safer and reparative alternatives to bone cement for VBS procedures. However, further research and development in this field are necessary to explore the full potential of hydrogel-based systems for vertebral bone repair.

Mental health disorders among children and youth are causing significant burden on health care systems. Hence, identifying cost-effective interventions is important for effective mental health care allocation. Although model-based economic evaluations are an essential component of assessing cost-effectiveness, evidence are limited in the context of child and youth mental health care. The objective was to systematically review the model-based economic evaluations of mental health interventions for children and youth. Methods Four databases (MEDLINE, EMBASE, PsycINFO and Web of Science) were searched using appropriate search terms to retrieve model-based economic evaluations of mental health interventions for children and youth. The reporting quality of the included studies were appraised using the Consolidated health economic evaluation reporting standards (CHEERS) checklist. Results The database search yielded 1921 records. Of the 12 selected for review, 66% were published after year 2015. Most of the studies were related to anxiety and post-traumatic stress disorder. There were eight cost-utility studies, three cost-effectiveness studies, and one study using both forms of analysis. Six studies used Markov models, three used decision trees, and three studies used both types of models. However, the model structure, health states, time horizon, and economic perspective showed wide variation. The reporting quality of the included studies varied from 91 to 96%. Conclusion Model based mental health economic evaluations among children and youth are increasingly being reported in recent research. The included studies used Markov models and decision trees, either alone or in combination, and the majority of the articles were of good reporting quality.

Porous collagen-glycosaminoglycan (collagen-GAG) scaffolds have shown promising clinical results for wound healing; however, these scaffolds do not replace the dermal and epidermal layer simultaneously and rely on local endogenous signaling to direct healing. Functionalizing collagen-GAG scaffolds with signaling factors, and/or additional matrix molecules, could help overcome these challenges. An ideal candidate for this is platelet-rich plasma (PRP) as it is a natural reservoir of growth factors, can be activated to form a fibrin gel, and is available intraoperatively. We tested the factors released from PRP (PRPr) and found that at specific concentrations, PRPr enhanced cell proliferation and migration and induced angiogenesis to a greater extent than fetal bovine serum (FBS) controls. This motivated us to develop a strategy to successfully incorporate PRP homogeneously within the pores of the collagen-GAG scaffolds. The composite scaffold released key growth factors for wound healing (FGF, TGFβ) and vascularization (VEGF, PDGF) for up to 14 days. In addition, the composite scaffold had enhanced mechanical properties (when compared to PRP gel alone), while providing a continuous upper surface of extracellular matrix (ECM) for keratinocyte seeding. The levels of the factors released from the composite scaffold were sufficient to sustain proliferation of key cells involved in wound healing, including human endothelial cells, mesenchymal stromal cells, fibroblasts, and keratinocytes; even in the absence of FBS supplementation. In functional and vascularization assays, our composite scaffold demonstrated increased angiogenic and vascularization potential, which is known to lead to enhanced wound healing. Upon pro-inflammatory induction, macrophages released lower levels of the pro-inflammatory marker MIP-1α when treated with PRPr; and released higher levels of the anti-inflammatory marker IL1-ra upon both pro- and anti-inflammatory induction when treated with the composite scaffold. Finally, our composite scaffold supported a co-culture system of human fibroblasts and keratinocytes that resulted in an epidermal-like layer, with keratinocytes constrained to the surface of the scaffold; by contrast, keratinocytes were observed infiltrating the PRP-free scaffold. This novel composite scaffold has the potential for rapid translation to the clinic by isolating PRP from a patient intraoperatively and combining it with regulatory approved scaffolds to enhance wound repair.

The pore structure of three-dimensional scaffolds used in tissue engineering has been shown to significantly influence cellular activity. As the optimal pore size is dependant on the specifics of the tissue engineering application, the ability to alter the pore size over a wide range is essential for a particular scaffold to be suitable for multiple applications. With this in mind, the aim of this study was to develop methodologies to produce a range of collagen–glycosaminoglycan (CG) scaffolds with tailored mean pore sizes. The pore size of CG scaffolds is established during the freeze-drying fabrication process. In this study, freezing temperature was varied (−10°C to −70°C) and an annealing step was introduced to the process to determine their effects on pore size. Annealing is an additional step in the freeze-drying cycle that involves raising the temperature of the frozen suspension to increase the rate of ice crystal growth. The results show that the pore size of the scaffolds decreased as the freezing temperature was reduced. Additionally, the introduction of an annealing step during freeze-drying was found to result in a significant increase (40%) in pore size. Taken together, these results demonstrate that the methodologies developed in this study can be used to produce a range of CG scaffolds with mean pore sizes from 85 to 325 μm. This is a substantial improvement on the range of pore sizes that were possible to produce previously (96–150 μm). The methods developed in this study provide a basis for the investigation of the effects of pore size on both in vitro and in vivo performance and for the determination of the optimal pore structure for specific tissue engineering applications.