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The field of tissue engineering has progressed tremendously over the past few decades in its ability to fabricate functional tissue substitutes for regenerative medicine and pharmaceutical research. Conventional scaffold-based approaches are limited in their capacity to produce constructs with the functionality and complexity of native tissue. Three-dimensional (3D) bioprinting offers exciting prospects for scaffolds fabrication, as it allows precise placement of cells, biochemical factors, and biomaterials in a layer-by-layer process. Compared with traditional scaffold fabrication approaches, 3D bioprinting is better to mimic the complex microstructures of biological tissues and accurately control the distribution of cells. Here, we describe recent technological advances in bio-fabrication focusing on 3D bioprinting processes for tissue engineering from data processing to bioprinting, mainly inkjet, laser, and extrusion-based technique. We then review the associated bioink formulation for 3D bioprinting of human tissues, including biomaterials, cells, and growth factors selection. The key bioink properties for successful bioprinting of human tissue were summarized. After bioprinting, the cells are generally devoid of any exposure to fluid mechanical cues, such as fluid shear stress, tension, and compression, which are crucial for tissue development and function in health and disease. The bioreactor can serve as a simulator to aid in the development of engineering human tissues from in vitro maturation of 3D cell-laden scaffolds. We then describe some of the most common bioreactors found in the engineering of several functional tissues, such as bone, cartilage, and cardiovascular applications. In the end, we conclude with a brief insight into present limitations and future developments on the application of 3D bioprinting and bioreactor systems for engineering human tissue.

Generating 3D bone cell networks in vitro that mimic the dynamic process during early bone formation remains challenging. Here, we report a synthetic biodegradable microporous hydrogel for efficient formation of 3D networks from human primary cells, analysis of cell-secreted extracellular matrix (ECM) and microfluidic integration. Using polymerization-induced phase separation, we demonstrate dynamic in situ formation of microporosity (5–20 µm) within matrix metalloproteinase-degradable polyethylene glycol hydrogels in the presence of living cells. Pore formation is triggered by thiol-Michael-addition crosslinking of a viscous precursor solution supplemented with hyaluronic acid and dextran. The resulting microporous architecture can be fine-tuned by adjusting the concentration and molecular weight of dextran. After encapsulation in microporous hydrogels, human mesenchymal stromal cells and osteoblasts spread rapidly and form 3D networks within 24 hours. We demonstrate that matrix degradability controls cell-matrix remodeling, osteogenic differentiation, and deposition of ECM proteins such as collagen. Finally, we report microfluidic integration and proof-of-concept osteogenic differentiation of 3D cell networks under perfusion on chip. Altogether, this work introduces a synthetic microporous hydrogel to efficiently differentiate 3D human bone cell networks, facilitating future in vitro studies on early bone development. Generating 3D bone cell networks in vitro that mimic the dynamic process during early bone formation is vital for creating in vitro models of bone development for disease modeling and drug testing, but remains challenging. Herein, the authors report a synthetic biodegradable microporous hydrogel for in vitro generation of functional human bone cell networks in 3D and microfluidic integration.

The use of high-resolution imaging techniques will lead to a better understanding of the relative contribution of the different hierarchical levels to bone competence. Such information could help improve predictions of fracture risk, clarify the pathophysiology of skeletal diseases, and define the response to therapy. This Review focuses on three-dimensional approaches to hierarchical biomechanical imaging in the study of microstructural and ultrastructural bone failure. With recent advances in molecular medicine and disease treatment in osteoporosis, quantitative image processing of three-dimensional bone structures is critical in the context of bone quality assessment. Biomedical imaging technology such as MRI or CT is readily available, but few attempts have been made to expand the capabilities of these systems by integrating quantitative analysis tools and by exploring structure–function relationships in a hierarchical fashion. Nevertheless, such quantitative end points are an important factor for success in basic research and in the development of novel therapeutic strategies. CT is key to these developments, as it images and quantifies bone in three dimensions and provides multiscale biological imaging capabilities with isotropic resolutions of a few millimeters (clinical CT), a few tens of micrometers (microCT) and even as high as 100 nanometers (nanoCT). The technology enables the assessment of the relationship between microstructural and ultrastructural measures of bone quality and certain diseases or therapies. This Review focuses on presenting strategies for three-dimensional approaches to hierarchical biomechanical imaging in the study of microstructural and ultrastructural bone failure. From this Review, it can be concluded that biomechanical imaging is extremely valuable for the study of bone failure mechanisms at different hierarchical levels. Key Points Over the last decade, microCT has been established as a quantitative microscope, especially for the assessment of hard tissues MicroCT is fast, reliable and yields accurate and precise morphometric indices that are used for the diagnosis of disease and the monitoring of treatment regimens in both preclinical and clinical research Biomechanical imaging (i.e. the combination of time-lapsed microCT imaging and concomitant mechanical testing) enables the study of bone failure initiation and propagation in a hierarchical fashion Synchrotron radiation and advanced desktop nanoCT systems facilitate exploring the bone ultrastructure with submicrometer resolutions, enabling static quantitative morphometry of cortical bone canals and cell lacunae as well as biomechanical imaging of microcrack initiation and propagation

The photovoltaic industry is dominated by crystalline silicon solar cells. Although interdigitated back-contact cells have yielded the highest efficiency, both-sides-contacted cells are the preferred choice in industrial production due to their lower complexity. Here we show that omitting the layers at the front side that provide lateral charge carrier transport is the key to excellent optoelectrical properties for both-sides-contacted cells. This results in a conversion efficiency of 26.0%. In contrast to standard industrial cells with a front side p–n junction, this cell exhibits the p–n junction at the back surface in the form of a full-area polycrystalline silicon-based passivating contact. A detailed power-loss analysis reveals that this cell balances electron and hole transport losses as well as transport and recombination losses in general. A systematic simulation study led to some fundamental design rules for future >26% efficiency silicon solar cells and demonstrates the potential and the superiority of these back-junction solar cells. Front- and back-junction silicon photovoltaics dominate the market thanks to a lower manufacturing complexity compared with that of other device designs yet advances in efficiency remain elusive. Richter et al. now present an optimized design for the front and back junctions that leads to a 26.0%-efficient cell.

Mechanical loading plays a major role in bone remodeling and fracture healing. Mimicking the concept of mechanical loading of bone has been widely studied in bone tissue engineering by perfusion cultures. Nevertheless, there is still debate regarding the in-vitro mechanical stimulation regime. This study aims at investigating the effect of two different flow rates (vlow = 0.001m/s and vhigh = 0.061m/s) on the growth of mineralized tissue produced by human mesenchymal stromal cells cultured on 3-D silk fibroin scaffolds. The flow rates applied were chosen to mimic the mechanical environment during early fracture healing or during bone remodeling, respectively. Scaffolds cultured under static conditions served as a control. Time-lapsed micro-computed tomography showed that mineralized extracellular matrix formation was completely inhibited at vlow compared to vhigh and the static group. Biochemical assays and histology confirmed these results and showed enhanced osteogenic differentiation at vhigh whereas the amount of DNA was increased at vlow. The biological response at vlow might correspond to the early stage of fracture healing, where cell proliferation and matrix production is prominent. Visual mapping of shear stresses, simulated by computational fluid dynamics, to 3-D micro-computed tomography data revealed that shear stresses up to 0.39mPa induced a higher DNA amount and shear stresses between 0.55mPa and 24mPa induced osteogenic differentiation. This study demonstrates the feasibility to drive cell behavior of human mesenchymal stromal cells by the flow velocity applied in agreement with mechanical loading mimicking early fracture healing (vlow) or bone remodeling (vhigh). These results can be used in the future to tightly control the behavior of human mesenchymal stromal cells towards proliferation or differentiation. Additionally, the combination of experiment and simulation presented is a strong tool to link biological responses to mechanical stimulation and can be applied to various in-vitro cultures to improve the understanding of the cause-effect relationship of mechanical loading.

The clinical standard therapy for large bone defects, typically addressed through autograft or allograft donor tissue, faces significant limitations. Tissue engineering offers a promising alternative strategy for the regeneration of substantial bone lesions. In this study, we harnessed poly(ethylene glycol) (PEG)-based hydrogels, optimizing critical parameters including stiffness, incorporation of arginine-glycine-aspartic acid (RGD) cell adhesion motifs, degradability, and the release of BMP2 to promote bone formation. In vitro we demonstrated that human bone marrow derived stromal cell (hBMSC) proliferation and spreading strongly correlates with hydrogel stiffness and adhesion to RGD peptide motifs. Moreover, the incorporation of the osteogenic growth factor BMP2 into the hydrogels enabled sustained release, effectively inducing bone regeneration in encapsulated progenitor cells. When used in vivo to treat calvarial defects in rats, we showed that hydrogels of low and intermediate stiffness optimally facilitated cell migration, proliferation, and differentiation promoting the efficient repair of bone defects. Our comprehensive in vitro and in vivo findings collectively suggest that the developed hydrogels hold significant promise for clinical translation for bone repair and regeneration by delivering sustained and controlled stimuli from active signaling molecules.

Autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental conditions. In fMRI studies, including most machine learning studies seeking to distinguish ASD from typical developing (TD) samples, cohorts differing in gender and symptom severity composition are often treated statistically as one ‘ASD group.’ Using resting-state functional connectivity (FC) data, we implemented random forest to build diagnostic classifiers in four ASD samples including a total of 656 participants ( N ASD  = 306, N TD  = 350, ages 6–18). Groups were manipulated to titrate heterogeneity of gender and symptom severity and partially overlapped. Each sample differed on inclusionary criteria: (1) all genders, unrestricted severity range; (2) only male participants, unrestricted severity; (3) all genders, higher severity only; and (4) only male participants, higher severity. Each set consisted of 200 participants per group (ASD, TD; matched on age and head motion): 160 for training and 40 for validation. FMRI time series from 237 regions of interest (ROIs) were Pearson correlated in a 237 × 237 FC matrix, and classifiers were built using random forest in training samples. Classification accuracies in validation samples were 62.5%, 65%, 70%, and 73.75%, respectively, for samples 1–4. Connectivity within cingulo-opercular task control (COTC) network, and between COTC ROIs and default mode and dorsal attention network contributed overall most informative features, but features differed across sets. Findings suggest that diagnostic classifiers vary depending on ASD sample composition. Specifically, greater homogeneity of samples regarding gender and symptom severity enhances classifier performance. However, given the true heterogeneity of ASDs, performance metrics alone may not adequately reflect classifier utility.

Degradation and fragmentation of plastics in the environment are still poorly understood. This is partly caused by the lack of long-term studies and methods that determine weathering duration. We here present a novel study object that preserves information on plastic age: microplastic (MP) resin pellets from the wreck of the SS Hamada, a ship that foundered twenty-nine years ago at the coast of Wadi el Gemal national park, Egypt. Its sinking date enabled us to precisely determine how long MP rested in the wreck and a nearby beach, on which part of the load was washed off. Pellets from both sampling sites were analyzed by microscopy, X-ray tomography, spectroscopy, calorimetry, gel permeation chromatography, and rheology. Most pellets were made of low-density polyethylene, but a minor proportion also consisted of high-density polyethylene. MP from inside the wreck showed no signs of degradation compared to pristine reference samples. Contrary, beached plastics exhibited changes on all structural levels, which sometimes caused fragmentation. These findings provide further evidence that plastic degradation under saltwater conditions is comparatively slow, whereas UV radiation and high temperatures on beaches are major drivers of that process. Future long-term studies should focus on underlying mechanisms and timescales of plastic degradation.

Tissue injury and the healing response lead to the release of endogenous danger signals including Toll-like receptor (TLR) and interleukin-1 receptor, type 1 (IL-1R1) ligands, which modulate the immune microenvironment. Because TLRs and IL-1R1 have been shown to influence the repair process of various tissues, we explored their role during bone regeneration, seeking to design regenerative strategies integrating a control of their signalling. Here we show that IL-1R1/MyD88 signalling negatively regulates bone regeneration, in the mouse. Furthermore, IL-1β which is released at the bone injury site, inhibits the regenerative capacities of mesenchymal stem cells (MSCs). Mechanistically, IL-1R1/MyD88 signalling impairs MSC proliferation, migration and differentiation by inhibiting the Akt/GSK-3β/β-catenin pathway. Lastly, as a proof of concept, we engineer a MSC delivery system integrating inhibitors of IL-1R1/MyD88 signalling. Using this strategy, we considerably improve MSC-based bone regeneration in the mouse, demonstrating that this approach may be useful in regenerative medicine applications. TLR and IL-1R1 ligands are danger signals released following tissue injury and during the healing response. Here, the authors show that IL-1β signalling via IL-1R1/MyD88 inhibits the Akt/GSK-3β/β-catenin pathway in mesenchymal stem cells, which suppresses their mobilization, proliferation, and differentiation into osteoblasts, processes necessary for bone regeneration.

Bone is able to react to changing mechanical demands by adapting its internal microstructure through bone forming and resorbing cells. This process is called bone modeling and remodeling. It is evident that changes in mechanical demands at the organ level must be interpreted at the tissue level where bone (re)modeling takes place. Although assumed for a long time, the relationship between the locations of bone formation and resorption and the local mechanical environment is still under debate. The lack of suitable imaging modalities for measuring bone formation and resorption in vivo has made it difficult to assess the mechanoregulation of bone three-dimensionally by experiment. Using in vivo micro-computed tomography and high resolution finite element analysis in living mice, we show that bone formation most likely occurs at sites of high local mechanical strain (p<0.0001) and resorption at sites of low local mechanical strain (p<0.0001). Furthermore, the probability of bone resorption decreases exponentially with increasing mechanical stimulus (R(2) = 0.99) whereas the probability of bone formation follows an exponential growth function to a maximum value (R(2) = 0.99). Moreover, resorption is more strictly controlled than formation in loaded animals, and ovariectomy increases the amount of non-targeted resorption. Our experimental assessment of mechanoregulation at the tissue level does not show any evidence of a lazy zone and suggests that around 80% of all (re)modeling can be linked to the mechanical micro-environment. These findings disclose how mechanical stimuli at the tissue level contribute to the regulation of bone adaptation at the organ level.