The marriage of immunomodulatory,angiogenic,and osteogenic capabilities in a piezoelectric hydrogel tissue engineering scafold for military medicine

Background:Most bone-related injuries to grassroots troops are caused by training or accidental injuries.To establish preventive measures to reduce all kinds of trauma and improve the combat effectiveness of grassroots troops,it is imperative to develop new strategies and scafolds to promote bone regeneration.Methods:In this study,a porous piezoelectric hydrogel bone scafold was fabricated by incorporating polydopamine(PDA)-modified ceramic hydroxyapatite(PDA-hydroxyapatite,PHA)and PDA-modified barium titanate(PDABaTiO_(3),PBT)nanoparticles into a chitosan/gelatin(Cs/Gel)matrix.The physical and chemical properties of the Cs/Gel/PHA scafold with 0–10 wt%PBT were analyzed.Cell and animal experiments were performed to characterize the immunomodulatory,angiogenic,and osteogenic capabilities of the piezoelectric hydrogel scafold in vitro and in vivo.Results:The incorporation of BaTiO_(3) into the scafold improved its mechanical properties and increased self-generated electricity.Due to their endogenous piezoelectric stimulation and bioactive constituents,the prepared Cs/Gel/PHA/PBT hydrogels exhibited cytocompatibility as well as immunomodulatory,angiogenic,and osteogenic capabilities;they not only effectively induced macrophage polarization to M2 phenotype but also promoted the migration,tube formation,and angiogenic differentiation of human umbilical vein endothelial cells(HUVECs)and facilitated the migration,osteodifferentiation,and extracellular matrix(ECM)mineralization of MC3T3-E1 cells.The in vivo evaluations showed that these piezoelectric hydrogels with versatile capabilities significantly facilitated new bone formation in a rat large-sized cranial injury model.The underlying molecular mechanism can be partly attributed to the immunomodulation of the Cs/Gel/PHA/PBT hydrogels as shown via transcriptome sequencing analysis,and the PI3K/Akt signaling axis plays an important role in regulating macrophage M2 polarization.Conclusion:The piezoelectric Cs/Gel/PHA/PBT hydrogels developed here with favorable immunomodulation,angiogenesis,and osteogenesis functions may be used as a substitute in periosteum injuries,thereby offering the novel strategy of applying piezoelectric stimulation in bone tissue engineering for the enhancement of combat efectiveness in grassroots troops.

Self‑Healing Dynamic Hydrogel Microparticles with Structural Color for Wound Management

Chronic diabetic wounds confront a significant medical challenge because of increasing prevalence and difficult-healing circumstances.It is vital to develop multifunctional hydrogel dressings,with well-designed morphology and structure to enhance flexibility and effectiveness in wound management.To achieve these,we propose a self-healing hydrogel dressing based on structural color microspheres for wound management.The microsphere comprised a photothermal-responsive inverse opal framework,which was constructed by hyaluronic acid methacryloyl,silk fibroin methacryloyl and black phosphorus quantum dots(BPQDs),and was further re-filled with a dynamic hydrogel.The dynamic hydrogel filler was formed by Knoevenagel condensation reaction between cyanoacetate and benzaldehyde-functionalized dextran(DEX-CA and DEX-BA).Notably,the composite microspheres can be applied arbitrarily,and they can adhere together upon near-infrared irradiation by leveraging the BPQDs-mediated photothermal effect and the thermoreversible stiffness change of dynamic hydrogel.Additionally,eumenitin and vascular endothelial growth factor were co-loaded in the microspheres and their release behavior can be regulated by the same mechanism.Moreover,effective monitoring of the drug release process can be achieved through visual color variations.The microsphere system has demonstrated desired capabilities of controllable drug release and efficient wound management.These characteristics suggest broad prospects for the proposed composite microspheres in clinical applications.

Stimuli-Responsive Gene Delivery Nanocarriers for Cancer Therapy

Gene therapy provides a promising approach in treating cancers with high efficacy and selectivity and few adverse effects.Currently,the development of functional vectors with safety and effectiveness is the intense focus for improving the delivery of nucleic acid drugs for gene therapy.For this purpose,stimuli-responsive nanocarriers displayed strong potential in improving the overall efficiencies of gene therapy and reducing adverse effects via effective protection,prolonged blood circulation,specific tumor accumulation,and controlled release profile of nucleic acid drugs.Besides,synergistic therapy could be achieved when combined with other therapeutic regimens.This review summarizes recent advances in various stimuliresponsive nanocarriers for gene delivery.Particularly,the nanocarriers responding to endogenous stimuli including pH,reactive oxygen species,glutathione,and enzyme,etc.,and exogenous stimuli including light,thermo,ultrasound,magnetic field,etc.,are introduced.Finally,the future challenges and prospects of stimuli-responsive gene delivery nanocarriers toward potential clinical translation are well discussed.The major objective of this review is to present the biomedical potential of stimuli-responsive gene delivery nanocarriers for cancer therapy and provide guidance for developing novel nanoplatforms that are clinically applicable.

HuR-mediated nucleocytoplasmic translocation of HOTAIR relieves its inhibition of osteogenic differentiation and promotes bone formation

Bone marrow mesenchymal stem cell(BMSC)osteogenic differentiation and osteoblast function play critical roles in bone formation,which is a highly regulated process.Long noncoding RNAs(lncRNAs)perform diverse functions in a variety of biological processes,including BMSC osteogenic differentiation.Although several studies have reported that HOX transcript antisense RNA(HOTAIR)is involved in BMSC osteogenic differentiation,its effect on bone formation in vivo remains unclear.Here,by constructing transgenic mice with BMSC(Prx1-HOTAIR)-and osteoblast(Bglap-HOTAIR)-specific overexpression of HOTAIR,we found that Prx1-HOTAIR and Bglap-HOTAIR transgenic mice show different bone phenotypes in vivo.Specifically,Prx1-HOTAIR mice showed delayed bone formation,while Bglap-HOTAIR mice showed increased bone formation.HOTAIR inhibits BMSC osteogenic differentiation but promotes osteoblast function in vitro.Furthermore,we identified that HOTAIR is mainly located in the nucleus of BMSCs and in the cytoplasm of osteoblasts.HOTAIR displays a nucleocytoplasmic translocation pattern during BMSC osteogenic differentiation.We first identified that the RNA-binding protein human antigen R(HuR)is responsible for HOTAIR nucleocytoplasmic translocation.HOTAIR is essential for osteoblast function,and cytoplasmic HOTAIR binds to miR-214 and acts as a ceRNA to increase Atf4 protein levels and osteoblast function.BglapHOTAIR mice,but not Prx1-HOTAIR mice,showed alleviation of bone loss induced by unloading.This study reveals the importance of temporal and spatial regulation of HOTAIR in BMSC osteogenic differentiation and bone formation,which provides new insights into precise regulation as a target for bone loss.

3D Bioprinting for Biomedical Applications

Three-dimensional(3D)printing,referring to a type of additive manufacturing,has emerged as a promising fabrication technique in the past decades since it can create 3D objects with desired architecture by precise control over the deposition of successive layers of various materials.Benefiting from these advantages,3D printing has been extensively applied in varied areas of science and engineering.

Mesenchymal stem cell-derived extracellular vesicles in skin wound healing:roles,opportunities and challenges

Skin wounds are characterized by injury to the skin due to trauma,tearing,cuts,or contusions.As such injuries are common to all human groups,they may at times represent a serious socioeconomic burden.Currently,increasing numbers of studies have focused on the role of mesenchymal stem cell(MSC)-derived extracellular vesicles(EVs)in skin wound repair.As a cell-free therapy,MSC-derived EVs have shown significant application potential in the field of wound repair as a more stable and safer option than conventional cell therapy.Treatment based on MSC-derived EVs can significantly promote the repair of damaged substructures,including the regeneration of vessels,nerves,and hair follicles.In addition,MSC-derived EVs can inhibit scar formation by affecting angiogenesis-related and antifibrotic pathways in promoting macrophage polarization,wound angiogenesis,cell proliferation,and cell migration,and by inhibiting excessive extracellular matrix production.Additionally,these structures can serve as a scaffold for components used in wound repair,and they can be developed into bioengineered EVs to support trauma repair.Through the formulation of standardized culture,isolation,purification,and drug delivery strategies,exploration of the detailed mechanism of EVs will allow them to be used as clinical treatments for wound repair.In conclusion,MSCderived EV-based therapies have important application prospects in wound repair.Here we provide a comprehensive overview of their current status,application potential,and associated drawbacks.

Spatial transcriptomics:recent developments and insights in respiratory research

The respiratory system's complex cellular heterogeneity presents unique challenges to researchers in this field.Although bulk RNA sequencing and single-cell RNA sequencing(scRNA-seq)have provided insights into cell types and heterogeneity in the respiratory system,the relevant specific spatial localization and cellular interactions have not been clearly elucidated.Spatial transcriptomics(ST)has filled this gap and has been widely used in respiratory studies.This review focuses on the latest iterative technology of ST in recent years,summarizing how ST can be applied to the physiological and pathological processes of the respiratory system,with emphasis on the lungs.Finally,the current challenges and potential development directions are proposed,including high-throughput full-length transcriptome,integration of multi-omics,temporal and spatial omics,bioinformatics analysis,etc.These viewpoints are expected to advance the study of systematic mechanisms,including respiratory studies.

SIL1 improves cognitive impairment in APP23/PS45 mice by regulating amyloid precursor protein processing and Aβ generation

SIL1,an endoplasmic reticulum(ER)-resident protein,is reported to play a protective role in Alzheimer’s disease(AD).However,the effect of SIL1 on amyloid precursor protein(APP)processing remains unclear.In this study,the role of SIL1 in APP processing was explored both in vitro and in vivo.In the in vitro experiment,SIL1 was either overexpressed or knocked down in cells stably expressing the human Swedish mutant APP695.In the in vivo experiment,AAV-SIL1-EGFP or AAV-EGFP was microinjected into APP23/PS45 mice and their wild-type littermates.Western blotting(WB),immunohistochemistry,RNA sequencing(RNA-seq),and behavioral experiments were performed to evaluate the relevant parameters.Results indicated that SIL1 expression decreased in APP23/PS45 mice.Overexpression of SIL1 significantly decreased the protein levels of APP,presenilin-1(PS1),and C-terminal fragments(CTFs)of APP in vivo and in vitro.Conversely,knockdown of SIL1 increased the protein levels of APP,β-site APP cleavage enzyme 1(BACE1),PS1,and CTFs,as well as APP mRNA expression in 2EB2 cells.Furthermore,SIL1 overexpression reduced the number of senile plaques in APP23/PS45 mice.Importantly,Y-maze and Morris Water maze tests demonstrated that SIL1 overexpression improved cognitive impairment in APP23/PS45 mice.These findings indicate that SIL1 improves cognitive impairment in APP23/PS45 mice by inhibiting APP amyloidogenic processing and suggest that SIL1 is a potential therapeutic target for AD by modulating APP processing.

Biomass Microcapsules with Stem Cell Encapsulation for Bone Repair

Bone defects caused by trauma,tumor,or osteoarthritis remain challenging due to the lack of effective treatments in clinic.Stem cell transplantation has emerged as an alternative approach for bone repair and attracted widespread attention owing to its excellent biological activities and therapy effect.The attempts to develop this therapeutic approach focus on the generation of effective cell delivery vehicles,since the shortcomings of direct injection of stem cells into target tissues.Here,we developed a novel core-shell microcapsule with a stem cell-laden core and a biomass shell by using all-aqueous phase microfluidic electrospray technology.The designed core-shell microcapsules showed a high cell viability during the culture procedure.In addition,the animal experiments exhibited that stem cell-laden core-shell microcapsules have good biocompatibility and therapeutic effect for bone defects.This study indicated that the core-shell biomass microcapsules generated by microfluidic electrospray have promising potential in tissue engineering and regenerative medicine.

Hierarchically Inverse Opal Porous Scaffolds from Droplet Microfluidics for Biomimetic 3D Cell Co-Culture

With the advantages of better mimicking the specificity of natural tissues,three-dimensional(3D)cell culture plays a major role in drug development,toxicity testing,and tissue engineering.However,existing scaffolds or microcarriers for 3D cell culture are often limited in size and show suboptimal performance in simulating the vascular complexes of living organisms.Therefore,we present a novel hierarchically inverse opal porous scaffold made via a simple microfluidic approach for promoting 3D cell co-culture techniques.The designed scaffold is constructed using a combined concept involving an emulsion droplet template and inert polymer polymerization.This work demonstrates that the resultant scaffolds ensure a sufficient supply of nutrients during cell culture,so as to achieve large-volume cell culture.In addition,by serially planting different cells in the scaffold,a 3D co-culture system of endothelial-cellencapsulated hepatocytes can be developed for constructing certain functional tissues.It is also demonstrated that the use of the proposed scaffold for a co-culture system helps hepatocytes to maintain specific in vivo functions.These hierarchically inverse opal scaffolds lay the foundation for 3D cell culture and even the construction of biomimetic tissues.

Enhanced photonic nanojets for submicron patterning

Photonic nanojets(PNJs) have a wide range of applications in laser processing, nanolithography, optical highdensity storage, super-resolution microscopy, and other fields due to their processing capacity to overcome the diffraction limit. Herein, we control static microsphere be developed into the motion state to fabricate vector graphics nano-grooves.The microspheres roll on the substrate while the laser is kept synchronously irradiated, and the overlapping PNJ ablated craters form patterned grooves on the indium-tin oxide(ITO) substrate. Thus, PNJ has been expanded from “point”processing to “line” processing. The fabricated nano grooves have high continuity and consistency. Whereas, the precise customization of critical groove dimension can be achieved via modulation in diameter and kinetics of dielectric microshperes. Furthermore, by etching vectographs on an ITO conductive glass substrate, we demonstrated the advantages and potential of the proposed method in nanopatterning. The proposed method effectively reduces the cost and complexity of photonic nanojets applied in nanopatterning. The proposed nanopatterning methodology will play a vital role in the fabrication of semiconductor materials, sensors, microfluidic devices, surface-enhanced Raman scattering(SERS), biomedicine, nanoscience and nanoengineering.

Developing natural polymers for skin wound healing

Natural polymers are complex organic molecules that occur in the natural environment and have not been subjected to artificial synthesis.They are frequently encountered in various creatures,including mammals,plants,and microbes.The aforementioned polymers are commonly derived from renewable sources,possess a notable level of compatibility with living organisms,and have a limited adverse effect on the environment.As a result,they hold considerable significance in the development of sustainable and environmentally friendly goods.In recent times,there has been notable advancement in the investigation of the potential uses of natural polymers in the field of biomedicine,specifically in relation to natural biomaterials that exhibit antibacterial and antioxidant characteristics.This review provides a comprehensive overview of prevalent natural polymers utilized in the biomedical domain throughout the preceding two decades.In this paper,we present a comprehensive examination of the components and typical methods for the preparation of biomaterials based on natural polymers.Furthermore,we summarize the application of natural polymer materials in each stage of skin wound repair.Finally,we present key findings and insights into the limitations of current natural polymers and elucidate the prospects for their future development in this field.

基于脱细胞后鱼皮细胞外基质的生物打印水凝胶纺织品用于创面修复

创面修复具有普遍性、治疗困难、患者众多和医疗负担沉重的特点,一直是临床研究的热点。为了满足特定需求,研究者投入了大量科研力量,致力于开发各种个性化需求和功能的伤口敷料。在这方面,我们提出了一种基于鱼皮脱细胞的细胞外基质(d ECM)水凝胶纺织品用于创面修复。鱼源的d ECM具有理想的生物相容性,并且通过生物打印技术制备的纺织品在细胞黏附和增殖方面表现出卓越的性能。此外,基于d ECM的水凝胶纺织品采用生物打印技术生成,因此具有可调节的多孔结构,使整个纺织品具备良好的透气性。而且,水凝胶骨架上的多孔结构高比表面积使其能够负载多种活性分子,从而提高创面愈合效果。通过体内研究结果,我们证明了这种制备的纺织品负载活性药物分子姜黄素(Cur)和碱性成纤维细胞生长因子(b FGF)能够显著加速慢性创面的修复过程。这些结果表明鱼皮d ECM纺织品在创面修复和生物医学工程领域具有潜在的价值。

A Rapid Trace Analysis of GBS using the Specific Spectral Absorption of Chromogenic Culture Media

Group B streptococcus(GBS)is a Gram-positive,encapsulated bacterium that belongs to the group of pyogenic streptococci,and it is an asymptomatic colonizer of the digestive and genitourinary tracts of healthy human adults.However,it can cause severe invasive infections in neonates and immunocompromised adults.In the 1960s,GBS was identified as a leading cause of life-threatening neonatal infections[1,2].

CHIT1-positive microglia act as culprits for spinal motor neuron aging

Aging is one of the primary factors in spinal cord-associated disorders(Roberts,1990).However,the effects of aging on the spinal cord and the age-specific mechanisms underlying this relationship remain unclear.Motor neurons(MNs)are essential for regulating motor,autonomic,and sensory modalities(Arber,2012).

Gold nanoclusters encapsulated microneedle patches with antibacterial and self-monitoring capacities for wound management

The management of infected wounds is always of great significance and urgency in clinical and biomedicalfields.Recent efforts in this area are focusing on the development of functional wound patches with effective antibacterial,drug delivery,and sensor properties.Here,we present novel hyaluronic acid(HA)microneedle patches with these features by encapsulating aminobenzeneboronic acid-modified gold nanoclusters(A-GNCs)for infected wound management.The A-GNCs loaded microneedle patches were derived from negative-mold replication and showed high mechanical strength to penetrate the skin.The release of the A-GNCs was realized by the degradation of HA,and the self-monitor of the released actives was based on the dynamic bright orangefluorescence emitted from A-GNCs under ultravio-let radiation.As the A-GNCs could destroy bacteria membranes,the microneedle patches were with excellent in vitro antibiosis ability.Based on these features,we have demonstrated the bacteria inhibition,residual drug self-monitoring,and wound healing promotion abilities of the microneedle patches in Escherichia coli-or Staphylococcus aureus-infected wound management.These results indicated the great potential of such A-GNCs loaded microneedle patches for clinical applications.

De novo design of highly efficient type-Ⅰphotosensitizer based onπ-conjugated oligomer for photodynamic eradication of multidrug-resistant bacterial infections

Traditional photosensitizers show limited singlet oxygen generation in hypoxic infection lesions,which greatly suppress their performance in antibacterial therapy.Meanwhile,there still is lack of feasible design strategy for developing hypoxia-overcoming photosensitizers agents.Herein,radical generation ofπ-conjugated small molecules is efficiently manipulated by an individual selenium(Se)substituent.With this strategy,the first proof-of-concept study of a Se-anchored oligo(thienyl ethynylene)(OT-Se)with high-performance superoxide radical(O_(2)^(·-))and hydroxyl radical(·OH)generation capability is present,and achieves efficient antibacterial activities towards the clinically extracted multidrug-resistant bacteria methicillin-resistant S.aureus(MRSA)and carbapenem-resistant E.coli(CREC)at sub-micromolar concentration under a low white light irradiation(30 mW/cm^(2)).The water-dispersible OT-Se shows a good bacteria-anchoring capability,biocompatibility,and complete elimination of multidrug-resistant bacteria wound infection in vivo.This work offers a strategy to boost type-I photodynamic therapy(PDT)performance for efficient antibacterial treatments,advancing the development of antibacterial agents.

Targeting the adenosine A2A receptor for neuroprotection and cognitive improvement in traumatic brain injury and Parkinson's disease

Adenosine exerts its dual functions of homeostasis and neuromodulation in the brain by acting at mainly 2 G-protein coupled receptors,called A1 and A2A receptors.The adenosine A2A receptor(A2AR)antagonists have been clinically pursued for the last 2 decades,leading to final approval of the istradefylline,an A2AR antagonist,for the treatment of OFF-Parkinson's disease(PD)patients.The approval paves the way to develop novel therapeutic methods for A2AR antagonists to address 2 major unmet medical needs in PD and traumatic brain injury(TBI),namely neuroprotection or improving cognition.In this review,we first consider the evidence for aberrantly increased adenosine signaling in PD and TBI and the sufficiency of the increased A2AR signaling to trigger neurotoxicity and cognitive impairment.We further discuss the increasing preclinical data on the reversal of cognitive deficits in PD and TBI by A2AR antagonists through control of degenerative proteins and synaptotoxicity,and on protection against TBI and PD pathologies by A2AR antagonists through control of neuroinflammation.Moreover,we provide the supporting evidence from multiple human prospective epidemiological studies which revealed an inverse relation between the consumption of caffeine and the risk of developing PD and cognitive decline in aging population and Alzheimer's disease patients.Collectively,the convergence of clinical,epidemiological and experimental evidence supports the validity of A2AR as a new therapeutic target and facilitates the design of A2AR antagonists in clinical trials for disease-modifying and cognitive benefit in PD and TBI patients.

Integrated photothermal microcarriers for precise exosome-secreted microRNA profiling in breast cancer diagnosis

Breast cancer constitutes a significant global health burden,while conventional diagnosis approaches may lack precision and can be discomforting for patients.Exosomes have emerged as promising biomarkers for breast cancer due to their participation in diverse pathological processes,and a convenient analysis platform is believed to greatly promote its application.In this study,we propose a novel digital PCR approach utilizing near-infrared(NIR)photo-responsive thermosensitive microcarriers integrated with black phosphorus for quantifying microRNA(miRNA)biomarkers within exosomes.Petal-like biomimetic nanomaterials were firstly assembled for nonspecific exosome capture based on the affinity effect of avidin and biotin.Photothermal-responsive microcarriers,fabricated using gelatin-based substrates blended with photothermal nanocomposite,exhibited NIRinduced heating and reversible phase transition properties.We optimized synthesis parameters on thermal response and established a programmable and controllable NIR light source module.The results indicated a significant elevation in the levels of biomarkers miRNA-1246 and miRNA-122,with fold increases ranging from 6.2 to 23.6 and 5.9 to 13.0,respectively,in breast cancer cell lines MCF-7 and MDA-MB-231 compared to healthy control cells HUVEC.This study offers broad prospects for utilizing exosomes to resolve predictive biomarkers.

Hierarchical Spinning of Janus Textiles with Anisotropic Wettability for Wound Healing

Wound healing and tissue repair are recognized as basic human health problems worldwide.Attempts to accelerate the reparative process are focused on developing functional wound dressings.Herein,we present novel Janus textiles with anisotropic wettability from hierarchical microfluidic spinning for wound healing.The hydrophilic hydrogel microfibers from microfluidics are woven into textiles for freeze-drying treatment,followed by the deposition of electrostatic spinning nanofibers composed of hydrophobic polylactic acid(PLA)and silver nanoparticles.The electrospun nanofiber layer can be well coupled with the hydrogel microfiber layer to generate Janus textiles with anisotropic wettability due to the roughness of the hydrogel textile surface and the incomplete evaporation of PLA solution when reaching the surface.For wound treatment with the hydrophobic PLA side contacting the wound surface,the wound exudate can be pumped from the hydrophobic to the hydrophilic side based on the wettability differential derived drainage force.During this process,the hydrophobic side of the Janus textile can prevent excess fluid from infiltrating the wound again,preventing excessive moisture and preserving the breathability of the wound.In addition,the silver nanoparticles contained in the hydrophobic nanofibers could impart the textiles with good antibacterial effect,which further promote the wound healing efficiency.These features indicate that the described Janus fiber textile has great application potential in the field of wound treatment.