Targeting capabilities of engineered extracellular vesicles for the treatment of neurological diseases

Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–brain barrier,extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions,including ischemic stroke,traumatic brain injury,neurodegenerative diseases,glioma,and psychosis.However,the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body.To address these limitations,multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles,thereby enabling the delivery of therapeutic contents to specific tissues or cells.Therefore,this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles,exploring their applications in treating traumatic brain injury,ischemic stroke,Parkinson's disease,Alzheimer's disease,amyotrophic lateral sclerosis,glioma,and psychosis.Additionally,we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases.This review offers new insights for developing highly targeted therapies in this field.

Utilizing engineered extracellular vesicles as delivery vectors in the management of ischemic stroke:a special outlook on mitochondrial delivery

Ischemic stroke is a secondary cause of mortality worldwide,imposing considerable medical and economic burdens on society.Extracellular vesicles,serving as natural nanocarriers for drug delivery,exhibit excellent biocompatibility in vivo and have significant advantages in the management of ischemic stroke.However,the uncertain distribution and rapid clearance of extracellular vesicles impede their delivery efficiency.By utilizing membrane decoration or by encapsulating therapeutic cargo within extracellular vesicles,their delivery efficacy may be greatly improved.Furthermore,previous studies have indicated that microvesicles,a subset of large-sized extracellular vesicles,can transport mitochondria to neighboring cells,thereby aiding in the restoration of mitochondrial function post-ischemic stroke.Small extracellular vesicles have also demonstrated the capability to transfer mitochondrial components,such as proteins or deoxyribonucleic acid,or their sub-components,for extracellular vesicle-based ischemic stroke therapy.In this review,we undertake a comparative analysis of the isolation techniques employed for extracellular vesicles and present an overview of the current dominant extracellular vesicle modification methodologies.Given the complex facets of treating ischemic stroke,we also delineate various extracellular vesicle modification approaches which are suited to different facets of the treatment process.Moreover,given the burgeoning interest in mitochondrial delivery,we delved into the feasibility and existing research findings on the transportation of mitochondrial fractions or intact mitochondria through small extracellular vesicles and microvesicles to offer a fresh perspective on ischemic stroke therapy.

Experimental investigation of engineered geopolymer composite for structural strengthening against blast loads

The recent increase in blast/bombing incidents all over the world has pushed the development of effective strengthening approaches to enhance the blast resistance of existing civil infrastructures.Engineered geopolymer composite(EGC)is a promising material featured by eco-friendly,fast-setting and strain-hardening characteristics for emergent strengthening and construction.However,the fiber optimization for preparing EGC and its protective effect on structural elements under blast scenarios are uncertain.In this study,laboratory tests were firstly conducted to evaluate the effects of fiber types on the properties of EGC in terms of workability,dry shrinkage,and mechanical properties in compression,tension and flexure.The experimental results showed that EGC containing PE fiber exhibited suitable workability,acceptable dry shrinkage and superior mechanical properties compared with other types of fibers.After that,a series of field tests were carried out to evaluate the effectiveness of EGC retrofitting layer on the enhancement of blast performance of typical elements.The tests include autoclaved aerated concrete(AAC)masonry walls subjected to vented gas explosion,reinforced AAC panels subjected to TNT explosion and plain concrete slabs subjected to contact explosion.It was found that EGC could effectively enhance the blast resistance of structural elements in different scenarios.For AAC masonry walls and panels,with the existence of EGC,the integrity of specimens could be maintained,and their deflections and damage were significantly reduced.For plain concrete slabs,the EGC overlay could reduce the diameter and depth of the crater and spallation of specimens.

Tensile Strain Capacity Prediction of Engineered Cementitious Composites (ECC) Using Soft Computing Techniques

Plain concrete is strong in compression but brittle in tension,having a low tensile strain capacity that can significantly degrade the long-term performance of concrete structures,even when steel reinforcing is present.In order to address these challenges,short polymer fibers are randomly dispersed in a cement-based matrix to forma highly ductile engineered cementitious composite(ECC).Thismaterial exhibits high ductility under tensile forces,with its tensile strain being several hundred times greater than conventional concrete.Since concrete is inherently weak in tension,the tensile strain capacity(TSC)has become one of the most extensively researched properties.As a result,developing a model to predict the TSC of the ECC and to optimize the mixture proportions becomes challenging.Meanwhile,the effort required for laboratory trial batches to determine the TSC is reduced.To achieve the research objectives,five distinct models,artificial neural network(ANN),nonlinear model(NLR),linear relationship model(LR),multi-logistic model(MLR),and M5P-tree model(M5P),are investigated and employed to predict the TSCof ECCmixtures containing fly ash.Data from115 mixtures are gathered and analyzed to develop a new model.The input variables include mixture proportions,fiber length and diameter,and the time required for curing the various mixtures.The model’s effectiveness is evaluated and verified based on statistical parameters such as R2,mean absolute error(MAE),scatter index(SI),root mean squared error(RMSE),and objective function(OBJ)value.Consequently,the ANN model outperforms the others in predicting the TSC of the ECC,with RMSE,MAE,OBJ,SI,and R2 values of 0.42%,0.3%,0.33%,0.135%,and 0.98,respectively.

Decade Milestone Advancement of Defect-Engineered g-C_(3)N_(4) for Solar Catalytic Applications

Over the past decade, graphitic carbon nitride(g-C_(3)N_(4)) has emerged as a universal photocatalyst toward various sustainable carbo-neutral technologies. Despite solar applications discrepancy, g-C_(3)N_(4) is still confronted with a general fatal issue of insufficient supply of thermodynamically active photocarriers due to its inferior solar harvesting ability and sluggish charge transfer dynamics. Fortunately, this could be significantly alleviated by the “all-in-one” defect engineering strategy, which enables a simultaneous amelioration of both textural uniqueness and intrinsic electronic band structures. To this end, we have summarized an unprecedently comprehensive discussion on defect controls including the vacancy/non-metallic dopant creation with optimized electronic band structure and electronic density, metallic doping with ultraactive coordinated environment(M–N_(x), M–C_(2)N_(2), M–O bonding), functional group grafting with optimized band structure, and promoted crystallinity with extended conjugation π system with weakened interlayered van der Waals interaction. Among them, the defect states induced by various defect types such as N vacancy, P/S/halogen dopants, and cyano group in boosting solar harvesting and accelerating photocarrier transfer have also been emphasized. More importantly, the shallow defect traps identified by femtosecond transient absorption spectra(fs-TAS) have also been highlighted. It is believed that this review would pave the way for future readers with a unique insight into a more precise defective g-C_(3)N_(4) “customization”, motivating more profound thinking and flourishing research outputs on g-C_(3)N_(4)-based photocatalysis.

Bioengineered skin organoids:from development to applications

Signifcant advancements have been made in recent years in the development of highly sophisticated skin organoids.Serving as three-dimensional(3D)models that mimic human skin,these organoids have evolved into complex structures and are increasingly recognized as efective alternatives to traditional culture models and human skin due to their ability to overcome the limitations of two-dimensional(2D)systems and ethical concerns.The inherent plasticity of skin organoids allows for their construction into physiological and pathological models,enabling the study of skin development and dynamic changes.This review provides an overview of the pivotal work in the progression from 3D layered epidermis to cyst-like skin organoids with appendages.Furthermore,it highlights the latest advancements in organoid construction facilitated by state-of-the-art engineering techniques,such as 3D printing and microfuidic devices.The review also summarizes and discusses the diverse applications of skin organoids in developmental biology,disease modelling,regenerative medicine,and personalized medicine,while considering their prospects and limitations.

Boosting overall saline water splitting by constructing a strain-engineered high-entropy electrocatalyst

High-entropy materials(HEMs),which are newly manufactured compounds that contain five or more metal cations,can be a platform with desired properties,including improved electrocatalytic performance owing to the inherent complexity.Here,a strain engineering methodology is proposed to design transition-metal-based HEM by Li manipulation(LiTM)with tunable lattice strain,thus tailoring the electronic structure and boosting electrocatalytic performance.As confirmed by the experiments and calculation results,tensile strain in the LiTM after Li manipulation can optimize the d-band center and increase the electrical conductivity.Accordingly,the asprepared LiTM-25 demonstrates optimized oxygen evolution reaction and hydrogen evolution reaction activity in alkaline saline water,requiring ultralow overpotentials of 265 and 42 mV at 10 mA cm−2,respectively.More strikingly,LiTM-25 retains 94.6%activity after 80 h of a durability test when assembled as an anion-exchange membrane water electrolyzer.Finally,in order to show the general efficacy of strain engineering,we incorporate Li into electrocatalysts with higher entropies as well.

Generation of broadband polarization-orthogonal photon pairs via the dispersion-engineered thin-film lithium niobate waveguide

Broadband photon pairs are highly desirable for quantum metrology,quantum sensing,and quantum communication.Such sources are usually designed through type-0 phase-matching spontaneous parametric down-conversion(SPDC)that makes the photon pairs hard to separate in the frequency-degenerate case and thus limits their applications.In this paper,we design a broadband frequency-degenerate telecom-band photon pair source via the type-II SPDC in a dispersion-engineered thin-film lithium niobate waveguide,where the polarization modes of photon pairs are orthogonal and thus are easily separated deterministically.With a 5-mm-long waveguide,our design can achieve a bandwidth of 5.56 THz(44.8 nm),which is 8.6 times larger than that of the bulk lithium niobate,and the central wavelength can be flexibly adjusted.Our design is a promising approach towards high-quality integrated photon sources and may have wide applications in photonic quantum technologies.

Experimental and numerical study on flexural behaviors of steel reinforced engineered cementitious composite beams

To investigate the flexural behaviors of steel reinforced engineered cementitious composite （ECC） beams, the behaviors of the steel reinforced ECC beam and the conventional steel reinforced concrete beam subjected to flexural load are experimentally compared. The experimental results show that the flexural strength and ductility of the steel reinforced ECC beam are 24.8% and 187.67% times larger than those of the steel reinforced concrete beam, and the substitution of concrete with ECC can significantly delay the propagation of cracks. Additionally, a simplified constitutive model of the ECC material is used to simulate the flexural behaviors of beams by the finite element analysis （FEA）. The results show a good agreement between the simulation and test results. The crack width of the steel reinforced ECC beam can be limited to 0.4 mm under the service load conditions. The application of ductile ECC can significantly increase the flexural performance in terms of flexural strength, deformation capacity and ductility of the beams.

Development of engineered cementitious composites with local ingredients

In order to reduce the cost of high performance polyvinyl alcohol（PVA） fiber reinforced cementitious material（called engineered cementitious composites,ECC）,a ductile ECC material is developed using domestic PVA fibers along with other local ingredients,such as fly ash,cement and sand.In addition to the economic analysis of ECC,the four-point bending test and the optical microscope are employed to investigate the deflection capacity of ECC,its crack width and the occurrence of the self-healing phenomenon.The experimental results suggest that ECC made with domestic ingredients exhibits larger deformability and the average crack width is controlled around 60 μm.Furthermore,the self-healing behavior is observed in cracks of the specimens after cycles of wet and dry curing.The economic analysis shows that the cost of ECC can be greatly reduced via employing domestic PVA fibers.It is,therefore,feasible to produce low cost ECC material employing domestic PVA fibers,while simultaneously retaining high material ductility.

Impact Properties of Engineered Cementitious Composites with High Volume Fly Ash Using SHPB Test

The split Hopkinson pressure bar （SHPB） testing with diameter 40 mm was used to investigate the dynamic mechanical properties of engineered cementitious composites （ECCs） with different fly ash content. The basic properties including deformation, energy absorption capacity, strain-stress relationship and failure patterns were discussed. The ECCs showed strain-rate dependency and kept better plastic flow during impact process compared with reactive powder concrete （RPC） and concrete, but the critical compressive strength was lower than that of RPC and concrete. The bridging effect of PVA fiber and addition of fly ash can significantly improve the deformation and energy absorption capacities of ECCs. With the increase of fly ash content in ECCs, the static and dynamic compressive strength lowered and the dynamic increase factor enhanced. Therefore, to meet different engineering needs, the content of fly ash can be an important index to control the static and dynamic mechanical properties of ECCs.

An update–tissue engineered nerve grafts for the repair of peripheral nerve injuries

Peripheral nerve injuries（PNI） are caused by a range of etiologies and result in a broad spectrum of disability. While nerve autografts are the current gold standard for the reconstruction of extensive nerve damage, the limited supply of autologous nerve and complications associated with harvesting nerve from a second surgical site has driven groups from multiple disciplines, including biomedical engineering, neurosurgery, plastic surgery, and orthopedic surgery, to develop a suitable or superior alternative to autografting. Over the last couple of decades, various types of scaffolds, such as acellular nerve grafts（ANGs）, nerve guidance conduits, and non-nervous tissues, have been filled with Schwann cells, stem cells, and/or neurotrophic factors to develop tissue engineered nerve grafts（TENGs）. Although these have shown promising effects on peripheral nerve regeneration in experimental models, the autograft has remained the gold standard for large nerve gaps. This review provides a discussion of recent advances in the development of TENGs and their efficacy in experimental models. Specifically, TENGs have been enhanced via incorporation of genetically engineered cells, methods to improve stem cell survival and differentiation, optimized delivery of neurotrophic factors via drug delivery systems（DDS）, co-administration of platelet-rich plasma（PRP）, and pretreatment with chondroitinase ABC（Ch-ABC）. Other notable advancements include conduits that have been bioengineered to mimic native nerve structure via cell-derived extracellular matrix（ECM） deposition, and the development of transplantable living nervous tissue constructs from rat and human dorsal root ganglia（DRG） neurons. Grafts composed of non-nervous tissues, such as vein, artery, and muscle, will be briefly discussed.

Safety of engineered structures against blast vibrations： A case study

Blasting used for rock excavation is associated with ground vibrations having potential damage to surrounding structures.The extent of damage produced in a structure depends largely on ground motion characteristics,dynamic characteristics of structure and the type of geological strata on which it is founded.The safety of surrounding structures against blast vibrations is a cause of concern.However,use of a systematic approach to rock blasting helps to complete the excavation safely in time without endangering the safety of surrounding structures.Various steps are commonly adopted at construction sites to ensure safety of engineered structures against blast vibrations,e.g.adopting a suitable safe vibration level,developing site-specific attenuation relation,estimating safe charges for different distances,designing blasting pattern,and monitoring vibrations during actual blasting.The paper describes the details of studies conducted for ensuring safety of an 85 years old masonry dam and green concrete of varying ages during excavation of about 30,000 m;of hard rock in Maharashtra,India.The studies helped to complete the rock excavation safely in time and the safety of the dam was ensured by monitoring blast vibrations during actual rock excavation.

Nonphytate Phosphorus Requirement and Efficacy of a Genetically Engineered Yeast Phytase for Yellow Broilers at 22- to 42-d-Old Age

An experiment was conducted to investigate the requirement of nonphytate phosphorus（nPP） and efficacy of a genetically engineered yeast phytase（PHY A） for Lingnan yellow broilers from 22-to 42-d-old age.A total of 1 320 1-d-old male chicks were randomly divided into 11 dietary treatment groups,which consisted of 4 replicate floor pens with 30 birds per pen.The control group（treatment 1） was fed with basal diet of nPP 0.08% without dicalcium phosphate or phytase supplementation.Dietary levels of nPP were 0.16,0.24,0.32,0.40,0.48,and 0.56%,respectively,for treatments 2 to 7,through addition of dicalcium phosphate（chemistry grade） to the basal diet.Diets of treatments 8 to 11 were supplemented with PHY A at 200,400 and 600 U kg-1,a commercial phytase product（PHY B） at 400 U kg-1 level,respectively.The birds in 0.32-0.56% nPP groups gained more than those of the other groups（P0.05）.The nPP supplementation significantly improved feed intake（P0.05）.The feed gain ratio was significantly decreased by 0.40% nPP diet compared to the control birds（P0.05）.The level of 0.48% nPP was required for optimum tibia development.The additions of PHY A at 400 and 600 U kg-1 level and PHY B all significantly improved ADG（P0.05）,ADFI（P0.05）,and dry defatted tibia weight（P0.05）.Similarly,the percentage of tibia ash was increased by 600 U kg-1 PHY A supplementation（P0.05）.The requirement of nPP for maximal ADG and highest percentage tibia ash both was 0.40%.The phosphorus equivalency value of PHY A was estimated as 685 U kg-1 for male yellow broilers of 22-to 42-d-old age.

Biodegradation of azo dyes by genetically engineered azoreductase

A azoreductase gene with 537 bp was obtained by PCR amplification from Rhodobacter sphaeroides AS1 1737 The enzyme, with a molecular weight of 18 7 kD, was efficiently expressed in Escherichia coli and its biodegradation characteristics for azo dyes were investigated. Furthermore, the reaction kinetics and mechanism of azo dyes catalyzed by the genetically engineered azoreductase were studied in detail. The presence of a hydrazo-intermediate was identified, which provided a convincing evidence for the assumption that azo dyes were degraded via an incomplete reduction stage.

Mechanical properties of polyvinyl alcohol-basalt hybrid fiber engineered cementitious composites with impact of elevated temperatures

In the present study,the mechanical properties of polyvinyl alcohol(PVA)-basalt hybrid fiber reinforced engineered cementitious composites(ECC)after exposure to elevated temperatures were experimentally investigated.Five temperatures of 20,50,100,200 and 400℃ were set to evaluate the residual compressive,tensile and flexural behaviors of hybrid and mono fiber ECC.It was shown that partial replacement of PVA fibers with basalt fibers endowed ECC with improved residual compressive toughness,compared to brittle failure of mono fiber ECC heated to 400℃.The tension tests indicated that the presence of basalt fibers benefited the tensile strength up to 200℃,and delayed the sharp reduction of strength to 400℃.Under flexural load,the peak deflections corresponding to flexural strengths of hybrid fiber ECC were found to be less vulnerable ranging from 20 to 100℃.Further,the scanning electron microscopy(SEM)results uncovered that the rupture of basalt fiber at moderate temperature and its pullout mechanism at high temperature was responsible for the mechanical evolution of hybrid fiber ECC.This work develops a better understanding of elevated temperature and basalt fiber impact on the residual mechanical properties and further provides guideline for tailoring ECC for improved fire resistance.

Differentiation of mesenchymal stem cells into neuronal cells on fetal bovine acellular dermal matrix as a tissue engineered nerve scaffold

The purpose of this study was to assess fetal bovine acellular dermal matrix as a scaffold for supporting the differentiation of bone marrow mesenchymal stem cells into neural cells fol-lowing induction with neural differentiation medium. We performed long-term, continuous observation of cell morphology, growth, differentiation, and neuronal development using several microscopy techniques in conjunction with immunohistochemistry. We examined speciifc neu-ronal proteins and Nissl bodies involved in the differentiation process in order to determine the neuronal differentiation of bone marrow mesenchymal stem cells. The results show that bone marrow mesenchymal stem cells that differentiate on fetal bovine acellular dermal matrix display neuronal morphology with unipolar and bi/multipolar neurite elongations that express neuro-nal-speciifc proteins, includingβIII tubulin. The bone marrow mesenchymal stem cells grown on fetal bovine acellular dermal matrix and induced for long periods of time with neural differen-tiation medium differentiated into a multilayered neural network-like structure with long nerve ifbers that was composed of several parallel microifbers and neuronal cells, forming a complete neural circuit with dendrite-dendrite to axon-dendrite to dendrite-axon synapses. In addition, growth cones with filopodia were observed using scanning electron microscopy. Paraffin sec-tioning showed differentiated bone marrow mesenchymal stem cells with the typical features of neuronal phenotype, such as a large, round nucleus and a cytoplasm full of Nissl bodies. The data suggest that the biological scaffold fetal bovine acellular dermal matrix is capable of supporting human bone marrow mesenchymal stem cell differentiation into functional neurons and the subsequent formation of tissue engineered nerve.

Flexural behavior of steel reinforced engineered cementitious composite beams

In order to enhance the durability of steel encased concrete beams, a new type of steel reinforced engineered cementitious composite(SRECC) beam composed of steel shapes, steel bars and ECC is proposed. The theoretical analyses of the SRECC beam including crack propagation and stress-strain distributions along the depth of the composite beam in different loading stages are conducted. A theoretical model and simplified design method are proposed to calculate the load carrying capacity. Based on the proposed theoretical model, the relationship between the moment and corresponding curvature is derived. The theoretical results are verified with the finite element analysis. Finally, an extensive parametric study is performed to study the effect of the matrix type, steel shape ratio, reinforced bar ratio, ECC compressive strength and ECC tensile ductility on the mechanical behavior of SRECC beams. The results show that substitution concrete with ECC can effectively improve the bearing capacity and ductility of composite beams. The steel shape and longitudinal reinforcement can enhance the loading carrying capacity, while the ductility decreases with the increase of steel shape ratio. ECC compressive strength has significant effects on both load carrying capacity and ductility, and changing the ultimate strain of ECC results in a very limited variation in the mechanical behavior of SRECC beams.

Effects of Water/Binder Ratio on the Properties of Engineered Cementitious Composites

The effects of water/binder ratio （w/b） on the toughness behavior, compressive strength and flexural strength of engineered cementitious composites （ECC） were investigated. The w/b ratios of 0.25, 0.31, 0.33 and 0.37 were selected and the specimens were tested at the ages of 7 d and 28 d. The experimental results showed that there was a corresponding increase in first cracking strength, modulus of rupture, compressive strength and flexural strength with the decrease of w/b. Within the w/b range of 0.25-0.37, higher w/b was found to have improved effects on deflection, strain hardening index and toughness index of ECC. In the permission of meeting the requirement of compressive strength grade, selecting higher w/b in mix design will help to obtain robust ECC.

Swelling ability and behaviour of bentonite-based materials for deep repository engineered barrier systems:Influence of physical,chemical and thermal factors

Compacted bentonite-sand(B/S)mixtures have been used as a barrier material in engineered barrier systems(EBSs)of deep geological repositories(DGR)to store nuclear wastes.This study investigates the individual and combined effects of different chemical compositions of deep groundwaters(chemical factor)at potential repository sites in Canada(the Trenton and Guelph regions in Ontario),heat generated in DGRs(thermal factor),dry densities and mass ratios of bentonite and sand mixtures(physical factors)on the swelling behavior and ability of bentonite-based materials.In this study,swelling tests are conducted on B/S mixtures with different B/S mix ratios(20/80 to 70/30),compacted at different dry densities(ρd=1.6-2 g/cm^(3)),saturated with different types of water(distilled water and simulated deep groundwater of Trenton and Guelph)and exposed to different temperatures(20℃-80℃).Moreover,scanning electron microscopy(SEM)analyses,mercury intrusion porosimetry(MIP)tests and X-ray diffractometry(XRD)analyses are carried out to evaluate the morphological,microstructural and mineralogical characteristics of the B/S mixtures.The test results indicate that the swelling potential of the B/S mixtures is significantly affected by these physical and chemical factors as well as the combined effects of the chemical and thermal factors.A significant decrease in the swelling capacity is observed when the B/S materials are exposed to the aforementioned groundwaters.A large decrease in the swelling capacity is observed for higher bentonite content in the mixtures.Moreover,higher temperatures intensify the chemically-induced reduction of the swelling capacity of the B/S barrier materials.This decrease in the swelling capacity is caused by the chemical and/or microstructural changes of the materials.The results from this research will help engineers to design and build EBSs for DGRs with similar groundwater and thermal conditions.