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Aleksandr Kakinen,1,2 Yuhao Jiang,2 Thomas Paul Davis,2 Tambet Teesalu,3,4 Mart Saarma1 1Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland; 2Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, Australia; 3Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia; 4Materials Research Laboratory, University of California Santa Barbara, Santa Barbara, CA, USACorrespondence: Mart Saarma, Institute of Biotechnology, HiLIFE, University of Helsinki, Viikinkaari 5D, Helsinki, 00790, Finland, Tel +358505002726 ; +358294159378, Email mart.saarma@helsinki.fi Aleksandr Kakinen, Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Building 75, Cnr College Road& Cooper Road, St Lucia, QLD, 4067, Australia, Tel +61 7 344 63152, Email a.kakinen@uq.edu.auAbstract: Brain diseases are the most devastating problem among the world’s increasingly aging population, and the number of patients with neurological diseases is expected to increase in the future. Although methods for delivering drugs to the brain have advanced significantly, none of these approaches provide satisfactory results for the treatment of brain diseases. This remains a challenge due to the unique anatomy and physiology of the brain, including tight regulation and limited access of substances across the blood-brain barrier. Nanoparticles are considered an ideal drug delivery system to hard-to-reach organs such as the brain. The development of new drugs and new nanomaterial-based brain treatments has opened various opportunities for scientists to develop brain-specific delivery systems that could improve treatment outcomes for patients with brain disorders such as Alzheimer’s disease, Parkinson’s disease, stroke and brain tumors. In this review, we discuss noteworthy literature that examines recent developments in brain-targeted nanomedicines used in the treatment of neurological diseases.Keywords: brain delivery, blood-brain barrier, targeted delivery, nanoparticle, neurodegenerative diseases, stroke, cancer

Narges Bayat,1,2 Nathan McOrist,1 Nicholas Ariotti,3,4 May Lai,5 Keith CS Sia,1,2 Yuhuan Li,5 James L Grace,5 John F Quinn,5 Michael R Whittaker,5 Maria Kavallaris,2,6,7 Thomas P Davis,5,8,9,* Richard B Lock1,2,* 1Leukemia Biology Program, Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; 2School of Women’s and Children’s Health, Faculty of Medicine, University of New South Wales, Sydney, Australia; 3Electron Microscope Unit, Mark Wainwright Analytical Centre, Chemical Sciences Building, University of New South Wales, Sydney, NSW, Australia; 4School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia; 5ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, and Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia; 6Tumor Biology and Targeting Program, Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; 7Australian Centre for Nanomedicine, ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, University of New South Wales, Sydney, NSW, Australia; 8Department of Chemistry, University of Warwick, Coventry, UK; 9Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia*These authors contributed equally to this workCorrespondence: Richard B LockChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, PO Box 81, Randwick 2031, NSW, AustraliaTel +61 2 9385 2513Fax +61 2 9662 6583Email rlock@ccia.org.auPurpose: Directing nanoparticles to cancer cells without using antibodies is of great interest. Subtle changes to the surface chemistry of nanoparticles can significantly affect their biological fate, including their propensity to associate with different cell populations. For instance, nanoparticles functionalized with thiol-reactive groups can potentially enhance association with cells that over-express cell-surface thiol groups. The potential of such an approach for enhancing drug delivery for childhood acute lymphoblastic leukemia (ALL) cells has not been investigated. Herein, we investigate the impact of thiol-reactive star polymers on the cellular association and the mechanisms of uptake of the nanoparticles.Methods: We prepared fluorescently labeled star polymers functionalized with an mPEG brush corona and pyridyl disulfide to examine how reactivity to exofacial thiols impacts cellular association with ALL cells. We also studied how variations to the mPEG brush composition could potentially be used as a secondary method for controlling the extent of cell association. Specifically, we examined how the inclusion of shorter diethylene glycol brush moieties into the nanoparticle corona could be used to further influence cell association.Results: Star polymers incorporating both thiol-reactive and diethylene glycol brush moieties exhibited the highest cellular association, followed by those functionalized solely with thiol reactive groups compared to control nanoparticles in T and B pediatric ALL patient-derived xenografts harvested from the spleens and bone marrow of immunodeficient mice. Transfection of cells with an early endosomal marker and imaging with correlative light and electron microscopy confirmed cellular uptake. Endocytosis inhibitors revealed dynamin-dependent clathrin-mediated endocytosis as the main uptake pathway for all the star polymers.Conclusion: Thiol-reactive star polymers having an mPEG brush corona that includes a proportion of diethylene glycol brush moieties represent a potential strategy for improved leukemia cell delivery.Keywords: nanoparticles, targeting, endocytosis, leukemia, flow cytometry, microscopy

The T91 grade and similar 9Cr tempered-martensitic steels (also known as ferritic-martensitic) are leading candidate structural alloys for fast fission nuclear and fusion power reactors. At low temperatures (300–400 °C) neutron irradiation hardens and embrittles these steels, therefore it is important to investigate the origin of this mode of life limiting property degradation. T91 steel specimens were separately neutron irradiated to 2.14 dpa at 327 °C and 8.82 dpa at 377 °C in the Idaho National Laboratory Advanced Test Reactor. Atom probe tomography was used to investigate the segregation driven formation of Mn–Ni–Si-rich (MNSPs) and Cu-rich (CRP) co-precipitates. The precipitates increase in size and, slightly, in volume fraction at the higher irradiation temperature and dose, while their corresponding compositions were very similar, falling near the Si(Mn,Ni) phase field in the Mn–Ni–Si projection of the Fe-based quaternary phase diagram. While the structure of the precipitates has not been characterised, this composition range is distinctly different than that of the typically cited G-phase. The precipitates are composed of CRP with MNSP appendages. Such features are often observed in neutron irradiated reactor pressure vessel (RPV) steels. However, the Si, Ni, Mn, P and Cu solutes concentrations are lower in the T91 than in typical RPV steels. Thus, in T91 precipitation primarily takes place in solute segregated regions of line and loop dislocations. These results are consistent with the model for radiation induced segregation driven precipitation of MNSPs proposed by Ke et al. Cr-rich alpha prime (α’) phase formation was not observed.

The design and interpretation of chemoprevention trials are challenging tasks. Innovative methodological approaches to these investigations are in initial stages of development. Important pharmacologic issues should be addressed as early as possible in these trials to facilitate the optimal design of large, Phase III, randomized trials. These include determining the optimal dose of the compound and the toxicity profile. Other key areas involve the use of serum concentrations to monitor subject compliance, the evaluation of concentration of the chemopreventive agent in the target tissue, adequate assessment of the drug delivery systems, and the evaluation of the relationship between the dose administered and the serum or tissue concentrations achieved. Whenever possible the investigation of the relationship between serum or tissue concentrations of a chemopreventive agent vs its biologic activity should be determined. Specific examples involving the retinoids and carotenoids are presented.

Valproic acid (VPA) is an effective and widely used anti-seizure medication but is teratogenic when used during pregnancy, affecting brain and spinal cord development for reasons that remain largely unclear. Here we designed a genetic recombinase-based SOX10 reporter system in human pluripotent stem cells that enables tracking and lineage tracing of Neural Crest cells (NCCs) in a human organoid model of the developing neural tube. We found that VPA induces extensive cellular senescence and promotes mesenchymal differentiation of human NCCs. We next show that the clinically approved drug Rapamycin inhibits senescence and restores aberrant NCC differentiation trajectory after VPA exposure in human organoids and in developing zebrafish, highlighting the therapeutic promise of this approach. Finally, we identify the pioneer factor AP1 as a key element of this process. Collectively our data reveal cellular senescence as a central driver of VPA-associated neurodevelopmental teratogenicity and identifies a new pharmacological strategy for prevention. These results exemplify the power of genetically modified human stem cell-derived organoid models for drug discovery., (© 2024. The Author(s).)

Patients with brain cancers including medulloblastoma lack treatments that are effective long-term and without side effects. In this study, a multifunctional fluoropolymer-engineered iron oxide nanoparticle gene-therapeutic platform is presented to overcome these challenges. The fluoropolymers are designed and synthesized to incorporate various properties including robust anchoring moieties for efficient surface coating, cationic components to facilitate short interference RNA (siRNA) binding, and a fluorinated tail to ensure stability in serum. The blood-brain barrier (BBB) tailored system demonstrates enhanced BBB penetration, facilitates delivery of functionally active siRNA to medulloblastoma cells, and delivers a significant, almost complete block in protein expression within an in vitro extracellular acidic environment (pH 6.7) - as favored by most cancer cells. In vivo, it effectively crosses an intact BBB, provides contrast for magnetic resonance imaging (MRI), and delivers siRNA capable of slowing tumor growth without causing signs of toxicity - meaning it possesses a safe theranostic function. The pioneering methodology applied shows significant promise in the advancement of brain and tumor microenvironment-focused MRI-siRNA theranostics for the better treatment and diagnosis of medulloblastoma., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Three-dimensional (3D) printing presents a compelling alternative for fabricating microfluidic devices, circumventing certain limitations associated with traditional soft lithography methods. Microfluidics play a crucial role in the biomedical sciences, particularly in the creation of tissue spheroids and pharmaceutical research. Among the various 3D printing techniques, light-driven methods such as stereolithography (SLA), digital light processing (DLP), and photopolymer inkjet printing have gained prominence in microfluidics due to their rapid prototyping capabilities, high-resolution printing, and low processing temperatures. This review offers a comprehensive overview of light-driven 3D printing techniques used in the fabrication of advanced microfluidic devices. It explores biomedical applications for 3D-printed microfluidics and provides insights into their potential impact and functionality within the biomedical field. We further summarize three light-driven 3D printing strategies for producing biomedical microfluidic systems: direct construction of microfluidic devices for cell culture, PDMS-based microfluidic devices for tissue engineering, and a modular SLA-printed microfluidic chip to co-culture and monitor cells.

Ischemic stroke is one of the leading causes of death and disability. Occlusion and reperfusion of cerebral blood vessels (i.e., ischemia/reperfusion (I/R) injury) generates reactive oxygen species (ROS) that contribute to brain cell death and dysfunction of the blood-brain barrier (BBB) via oxidative stress. BBB disruption influences the pathogenesis of ischemic stroke by contributing to cerebral edema, hemorrhagic transformation, and extravasation of circulating neurotoxic proteins. An improved understanding of mechanisms for ROS-associated alterations in BBB function during ischemia/reperfusion (I/R) injury can lead to improved treatment paradigms for ischemic stroke. Unfortunately, progress in developing ROS targeted therapeutics that are effective for stroke treatment has been slow. Here, we review how ROS are produced in response to I/R injury, their effects on BBB integrity (i.e., tight junction protein complexes, transporters), and the utilization of antioxidant treatments in ischemic stroke clinical trials. Overall, knowledge in this area provides a strong translational framework for discovery of novel drugs for stroke and/or improved strategies to mitigate I/R injury in stroke patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Actinobacteriophage Djungelskog was isolated from a sample of degraded organic material in Poughkeepsie, NY, using Arthrobacter globiformis B-2979 . Its genome is 54,512 bp and encodes 86 putative protein-coding genes. Djungelskog has a siphovirus morphology and is assigned to cluster AW based on gene content similarity to actinobacteriophages., Competing Interests: The authors declare no conflict of interest.

The purpose of this study is to compare outcomes in patients undergoing buried and non-buried free flaps for breast reconstruction, in addition to evaluating the safety and reliability of venous flow couplers. A retrospective review was performed of all patients undergoing free flap breast reconstruction between 2013 and 2023. The primary outcomes were free flap failure, complications and the number of procedures required to complete the reconstructive journey. A total of 322 flaps were performed in 254 consecutive patients, with 47.5% ( n = 153) being buried and 52.0% ( n = 169) being non-buried reconstructions. The most common flap of choice being deep inferior epigastric artery perforator flaps (81.9%) followed by profunda artery perforator flaps (14.3%). There was no significant difference between the two groups in complications, including flap failure (buried 2.0% vs. non-buried 1.8% p = 0.902). There was a significant reduction in the number of procedures required to complete the reconstructive journey, with 52.2% ( n = 59) of patients undergoing single-stage breast reconstruction in the buried group compared with only 25.5% ( n = 36) in the non-buried group ( p < 0.001). Two (0.6%) patients experienced a false negative in which the signal of the flow coupler was lost but the flap was perfused during re-exploration. No flap losses occurred without being identified in advance by a loss of audible venous flow signal. Buried free flap breast reconstruction is safe and requires fewer operations to complete patients' reconstructive journey. Flow couplers are a safe and effective method of monitoring buried free flaps in breast reconstruction.

Therapeutic peptides are a major class of pharmaceutical drugs owing to their target-binding specificity as well as their versatility in inhibiting aberrant protein-protein interactions associated with human pathologies. Within the realm of amyloid diseases, the use of peptides and peptidomimetics tailor-designed to overcome amyloidogenesis has been an active research endeavor since the late 90s. In more recent years, incorporating nanoparticles for enhancing the biocirculation and delivery of peptide drugs has emerged as a frontier in nanomedicine, and nanoparticles have further demonstrated a potency against amyloid aggregation and cellular inflammation to rival strategies employing small molecules, peptides, and antibodies. Despite these efforts, however, a fundamental understanding of the chemistry, characteristics and function of peptido-nanocomposites is lacking, and a systematic analysis of such strategy for combating a range of amyloid pathogeneses is missing. Here we review the history, principles and evolving chemistry of constructing peptido-nanocomposites from bottom up and discuss their future application against amyloid diseases that debilitate a significant portion of the global population., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Alzheimer's disease (AD) is a major cause of dementia debilitating the global ageing population. Current understanding of the AD pathophysiology implicates the aggregation of amyloid beta (Aβ) as causative to neurodegeneration, with tauopathies, apolipoprotein E and neuroinflammation considered as other major culprits. Curiously, vascular endothelial barrier dysfunction is strongly associated with Aβ deposition and 80-90% AD subjects also experience cerebral amyloid angiopathy. Here we show amyloid protein-induced endothelial leakiness (APEL) in human microvascular endothelial monolayers as well as in mouse cerebral vasculature. Using signaling pathway assays and discrete molecular dynamics, we revealed that the angiopathy first arose from a disruption to vascular endothelial (VE)-cadherin junctions exposed to the nanoparticulates of Aβ oligomers and seeds, preceding the earlier implicated proinflammatory and pro-oxidative stressors to endothelial leakiness. These findings were analogous to nanomaterials-induced endothelial leakiness (NanoEL), a major phenomenon in nanomedicine depicting the paracellular transport of anionic inorganic nanoparticles in the vasculature. As APEL also occurred in vitro with the oligomers and seeds of alpha synuclein, this study proposes a paradigm for elucidating the vascular permeation, systemic spread, and cross-seeding of amyloid proteins that underlie the pathogeneses of AD and Parkinson's disease., (© 2024. The Author(s).)

Droplet-based microfluidics represents a disruptive technology in the field of chemistry and biology through the generation and manipulation of sub-microlitre droplets. To avoid droplet coalescence, fluoropolymer-based surfactants are commonly used to reduce the interfacial tension between two immiscible phases to stabilize droplet interfaces. However, the conventional preparation of fluorosurfactants involves multiple steps of conjugation reactions between fluorinated and hydrophilic segments to form multiple-block copolymers. In addition, synthesis of customized surfactants with tailored properties is challenging due to the complex synthesis process. Here, we report a highly efficient synthetic method that utilizes living radical polymerization (LRP) to produce fluorosurfactants with tailored functionalities. Compared to the commercialized surfactant, our surfactants outperform in thermal cycling for polymerase chain reaction (PCR) testing, and exhibit exceptional biocompatibility for cell and yeast culturing in a double-emulsion system. This breakthrough synthetic approach has the potential to revolutionize the field of droplet-based microfluidics by enabling the development of novel designs that generate droplets with superior stability and functionality for a wide range of applications., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The ability to target specific tissues and to be internalized by cells is critical for successful nanoparticle-based targeted drug delivery. Here, we combined "stealthy" rod-shaped poly(2-oxazoline) (POx) nanoparticles of different lengths with a cancer marker targeting nanobody and a fluorescent cell internalization sensor via a heat-induced living crystallization-driven self-assembly (CDSA) strategy. A significant increase in association and uptake driven by nanobody-receptor interactions was observed alongside nanorod-length-dependent kinetics. Importantly, the incorporation of the internalization sensor allowed for quantitative differentiation between cell surface association and internalization of the targeted nanorods, revealing unprecedented length-dependent cellular interactions of CDSA nanorods. This study highlights the modularity and versatility of the heat-induced CDSA process and further demonstrates the potential of POx nanorods as a modular nanomedicine platform.

Aim: To investigate the influence of fluorine in reducing the adsorption of immune-reactive proteins onto PEGylated gold nanoparticles. Methods: Reversible addition fragmentation chain transfer polymerization, the Turkevich method and ligand exchange were used to prepare polymer-coated gold nanoparticles. Subsequent in vitro physicochemical and biological characterizations and proteomic analysis were performed. Results: Fluorine-modified polymers reduced the adsorption of complement and other immune-reactive proteins while potentially improving circulatory times and modulating liver toxicity by reducing apolipoprotein E adsorption. Fluorine actively discouraged phagocytosis while encouraging the adsorption of therapeutic targets, CD209 and signaling molecule calreticulin. Conclusion: This study suggests that the addition of fluorine in the surface coating of nanoparticles could lead to improved performance in nanomedicine designed for the intravenous delivery of cargos.

Introduction: Successful neuropharmacology requires optimization of CNS drug delivery and, by extension, free drug concentrations at brain molecular targets. Detailed assessment of blood-brain barrier (BBB) physiological characteristics is necessary to achieve this goal. The 'next frontier' in CNS drug delivery is targeting BBB uptake transporters, an approach that requires evaluation of brain endothelial cell transport processes so that effective drug accumulation and improved therapeutic efficacy can occur., Areas Covered: BBB permeability of drugs is governed by tight junction protein complexes (i.e., physical barrier) and transporters/enzymes (i.e., biochemical barrier). For most therapeutics, a component of blood-to-brain transport involves passive transcellular diffusion. Small molecule drugs that do not possess acceptable physicochemical characteristics for passive permeability may utilize putative membrane transporters for CNS uptake. While both uptake and efflux transport mechanisms are expressed at the brain microvascular endothelium, uptake transporters can be targeted for optimization of brain drug delivery and improved treatment of neurological disease states., Expert Opinion: Uptake transporters represent a unique opportunity to optimize brain drug delivery by leveraging the endogenous biology of the BBB. A rigorous understanding of these transporters is required to improve translation from the bench to clinical trials and stimulate the development of new treatment paradigms for neurological diseases.

Drug development for ischemic stroke is challenging as evidenced by the paucity of therapeutics that have advanced beyond a phase III trial. There are many reasons for this lack of clinical translation including factors related to the experimental design of preclinical studies. Often overlooked in therapeutic development for ischemic stroke is the requirement of effective drug delivery to the brain, which is critical for neuroprotective efficacy of several small and large molecule drugs. Advancing central nervous system drug delivery technologies implies a need for detailed comprehension of the blood-brain barrier (BBB) and neurovascular unit. Such knowledge will permit the innate biology of the BBB/neurovascular unit to be leveraged for improved bench-to-bedside translation of novel stroke therapeutics. In this review, we will highlight key aspects of BBB/neurovascular unit pathophysiology and describe state-of-the-art approaches for optimization of central nervous system drug delivery (ie, passive diffusion, mechanical opening of the BBB, liposomes/nanoparticles, transcytosis, intranasal drug administration). Additionally, we will discuss how endogenous BBB transporters represent the next frontier of drug delivery strategies for stroke. Overall, this review will provide cutting edge perspective on how central nervous system drug delivery must be considered for the advancement of new stroke drugs toward human trials., Competing Interests: Disclosures Dr Ronaldson receives research funding from the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Drug Abuse (NIDA), and the National Institute on Aging. Dr Davis receives research funding from the NINDS and NIDA. The other authors report no conflicts.

Background: Cerebral edema is a secondary complication of acute ischemic stroke, but its time course and imaging markers are not fully understood. Recently, net water uptake (NWU) has been proposed as a novel marker of edema., Aims: Studying the RHAPSODY trial cohort, we sought to characterize the time course of edema and test the hypothesis that NWU provides distinct information when added to traditional markers of cerebral edema after stroke by examining its association with other markers., Methods: A total of 65 patients had measurable supratentorial ischemic lesions. Patients underwent head computed tomography (CT), brain magnetic resonance imaging (MRI) scans, or both at the baseline visit and after 2, 7, 30, and 90 days following enrollment. CT and MRI scans were used to measure four imaging markers of edema: midline shift (MLS), hemisphere volume ratio (HVR), cerebrospinal fluid (CSF) volume, and NWU using semi-quantitative threshold analysis. Trajectories of the markers were summarized, as available. Correlations of the markers of edema were computed and the markers compared by clinical outcome. Regression models were used to examine the effect of 3K3A-activated protein C (APC) treatment., Results: Two measures of mass effect, MLS and HVR, could be measured on all imaging modalities, and had values available across all time points. Accordingly, mass effect reached a maximum level by day 7, normalized by day 30, and then reversed by day 90 for both measures. In the first 2 days after stroke, the change in CSF volume was associated with MLS (ρ = -0.57, p  = 0.0001) and HVR (ρ = -0.66, p  < 0.0001). In contrast, the change in NWU was not associated with the other imaging markers (all p  ⩾ 0.49). While being directionally consistent, we did not observe a difference in the edema markers by clinical outcome. In addition, baseline stroke volume was associated with all markers (MLS ( p  < 0.001), HVR ( p  < 0.001), change in CSF volume ( p  = 0.003)) with the exception of NWU ( p  = 0.5). Exploratory analysis did not reveal a difference in cerebral edema markers by treatment arm., Conclusions: Existing cerebral edema imaging markers potentially describe two distinct processes, including lesional water concentration (i.e. NWU) and mass effect (MLS, HVR, and CSF volume). These two types of imaging markers may represent distinct aspects of cerebral edema, which could be useful for future trials targeting this process., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: TPD and JHG are consultants to ZZ Biotech, LLC. BVZ is scientific founder of ZZ Biotech LLC and chairs its Scientific Advisory Board. WTK reports research grants from Biogen, consulting fees from NControl Therapeutics, and equity in Woolsey Pharmaceuticals. All other authors report no conflicts of interest.

Aging is a major risk factor for neurodegenerative diseases, and coronavirus disease 2019 (COVID-19) is linked to severe neurological manifestations. Senescent cells contribute to brain aging, but the impact of virus-induced senescence on neuropathologies is unknown. Here we show that senescent cells accumulate in aged human brain organoids and that senolytics reduce age-related inflammation and rejuvenate transcriptomic aging clocks. In postmortem brains of patients with severe COVID-19 we observed increased senescent cell accumulation compared with age-matched controls. Exposure of human brain organoids to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induced cellular senescence, and transcriptomic analysis revealed a unique SARS-CoV-2 inflammatory signature. Senolytic treatment of infected brain organoids blocked viral replication and prevented senescence in distinct neuronal populations. In human-ACE2-overexpressing mice, senolytics improved COVID-19 clinical outcomes, promoted dopaminergic neuron survival and alleviated viral and proinflammatory gene expression. Collectively our results demonstrate an important role for cellular senescence in driving brain aging and SARS-CoV-2-induced neuropathology, and a therapeutic benefit of senolytic treatments., (© 2023. The Author(s).)

4D printing combines 3D printing with nanomaterials to create shape-morphing materials that exhibit stimuli-responsive functionalities. In this study, reversible addition-fragmentation chain transfer polymerization agents grafted onto liquid metal nanoparticles are successfully employed in ultraviolet light-mediated stereolithographic 3D printing and near-infrared light-responsive 4D printing. Spherical liquid metal nanoparticles are directly prepared in 3D-printed resins via a one-pot approach, providing a simple and efficient strategy for fabricating liquid metal-polymer composites. Unlike rigid nanoparticles, the soft and liquid nature of nanoparticles reduces glass transition temperature, tensile stress, and modulus of 3D-printed materials. This approach enables the photothermal-induced 4D printing of composites, as demonstrated by the programmed shape memory of 3D-printed composites rapidly recovering to their original shape in 60 s under light irradiation. This work provides a perspective on the use of liquid metal-polymer composites in 4D printing, showcasing their potential for application in the field of soft robots., (© 2023. The Author(s).)

Metal-on-metal (MoM) total hip arthroplasty has been widely used since the end of the 20 th century, although rates have now decreased due to concerns regarding adverse reactions and failure rates. The MoM implant has been replaced with other materials, such as ceramic-on-ceramic (CoC) and metal-on-polyethylene (MoP). This literature review looks at the past and present use of MoM prostheses to assess whether the turn away from MoM use is justified. Online literature searches were performed on PubMed, Ovid Medical Literature Analysis and Retrieval System Online (MEDLINE), and Web of Science online databases using the search terms "MoM and (ARMD and ALVAL)" (ARMD: adverse reaction to metal debris; ALVAL: aseptic lymphocyte-dominant vasculitis-associated lesion). A total of 64 relevant titles were included in the review. Although risk factors for adverse reactions and the causes of ARMD are generally agreed upon, more work is required to further understand the specific thresholds of blood metal ion levels that can be used to consistently identify ARMD and excessive metal wear-debris in patients who have not had their MoM implants revised. Metal-on-metal devices are not an acceptable option for total hip arthroplasties (THAs) in their current formulation due to the high rate and risk of ARMD. Some MoM hip resurfacing operations are appropriate for very carefully selected patients who are fully aware of the risks posed by the implant. It is recommended that device-specific thresholds for metal ion levels be developed to identify patients at risk of ARMD locally and systemically while using auxiliary tools to assist diagnosis, such as metal artefact reduction sequences (MARS)-MRI and hip scoring tools. Further work should investigate device-specific blood metal ion levels, the systemic effects of raised metal ion concentrations secondary to MoM arthroprosthetic wear, and the potential risks of ARMD caused by wear from tapered stems (including the implications this has for patients with CoC and MoP prostheses)., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Davis et al.)

Background: Drug discovery for stroke is challenging as indicated by poor clinical translatability. In contrast, HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (ie, statins) improve poststroke neurological outcomes. This property requires transport across the blood-brain barrier via an endogenous uptake transporter (ie, Oatp1a4 [organic anion transporting polypeptide 1a4]). Our goal was to study Oatp1a4 as a drug delivery mechanism because the blood-brain barrier cannot be assumed to be completely open for all drugs in ischemic stroke., Methods: Male Sprague-Dawley rats (200-250 g) were subjected to middle cerebral artery occlusion (90 minutes) followed by reperfusion for up to 7 days. Atorvastatin (20 mg/kg, IV) was administered 2 hours following intraluminal suture removal. Involvement of Oatp-mediated transport was determined using fexofenadine (3.2 mg/kg, IV), a competitive Oatp inhibitor. Oatp1a4 transport activity was measured by in situ brain perfusion. Infarction volumes/brain edema ratios and neuronal nuclei expression were determined using 2,3,5-triphenyltetrazolium chloride-stained brain tissue slices and confocal microscopy, respectively. Poststroke functional outcomes were assessed via neurological deficit scores and rotarod analysis., Results: At 2-hour post-middle cerebral artery occlusion, [ 3 H]atorvastatin uptake was increased in ischemic brain tissue. A single dose of atorvastatin significantly reduced post-middle cerebral artery occlusion infarction volume, decreased brain edema ratio, increased caudoputamen neuronal nuclei expression, and improved functional neurological outcomes. All middle cerebral artery occlusion positive effects of atorvastatin were attenuated by fexofenadine coadministration (ie, an Oatp transport inhibitor)., Conclusions: Our data demonstrate that neuroprotective effects of atorvastatin may require central nervous system delivery by Oatp-mediated transport at the blood-brain barrier, a mechanism that persists despite increased cerebrovascular permeability in ischemic stroke. These novel and translational findings support utility of blood-brain barrier transporters in drug delivery for neuroprotective agents., Competing Interests: Disclosures Dr Ronaldson is funded by grants from the National Institute of Neurological Disorders and Stroke (NINDS), National Institute on Drug Abuse (NIDA), and the National Institute on Aging (NIA). Dr Davis is funded by grants from the National Institutes of Neurological Disorders and Stroke (NINDS) and the National Institute on Drug Abuse (NIDA). The other authors report no conflicts.

Alzheimer's disease (AD) is a leading form of dementia where the presence of extra-neuronal plaques of Amyloid-β (Aβ) is a pathological hallmark. However, Aβ peptide is also observed in the intestinal tissues of AD patients and animal models. In this study, it is reported that Aβ monomers can target and disintegrate microbial amyloids of FapC and CsgA formed by opportunistic gut pathogens, Pseudomonas aeruginosa and Escherichia coli, explaining a potential role of Aβ in the gut-brain axis. Employing a zebrafish-based transparent in vivo system and whole-mount live-imaging, Aβ is observed to diffuse into the vasculature and subsequently localize with FapC or CsgA fibrils that were injected into the tail muscles of the fish. FapC aggregates, produced after Aβ treatment (Faβ), present selective toxicity to SH-SY5Y neuronal cells while the intestinal Caco-2 cells are shown to phagocytose Faβ in a non-toxic cellular process. After remodeling by Aβ, microbial fibrils lose their native function of cell adhesion with intestinal Caco-2 cells and Aβ dissolves and detaches the microbial fibrils already attached to the cell membrane. Taken together, this study strongly indicates an anti-biofilm role for Aβ monomers that can help aid in the future development of selective anti-Alzheimer's and anti-infective medicine., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background and Aim: While early detection and timely treatments can prevent diabetic retinopathy (DR) related blindness, barriers to receiving these DR services may cause permanent sight loss. Despite having similar prevalence to diabetes and DR, women are less likely than men to perform these behaviors due to multi-faced barriers in screening and receiving follow-up treatments for DR. This study, therefore, aimed at identifying the barriers to - and enablers of - screening and follow-up treatments behaviors for DR among women aged more than 40 years with diabetes from the behavioral perspectives in Bangladesh., Methods: This Barrier Analysis study interviewed 360 women (180 "Doers" and 180 "Non-doers") to explore twelve behavioral determinants of four DR behaviors including screening, injection of anti-vascular endothelial growth factor (anti-VEGF medication), laser therapy and vitro-retinal surgery. The data analysis was performed to calculate estimated relative risk to identify the degree of association between the determinants and behaviors, and to find statistically significant differences (at p < 0.05) in the responses between the Doers and Non-doers., Results: Access to healthcare facilities was the major barrier impeding women from performing DR behaviors. Difficulty in locating DR service centers, the need to travel long distances, the inability to travel alone and during illness, challenges of paying for transportation and managing workload significantly affected women's ability to perform the behaviors. Other determinants included women's perceived self-efficacy, perceived negative consequences (e.g. fear and discomfort associated with injections or laser treatment), and cues for action. Significant perceived enablers included low cost of DR treatments, supportive attitudes by healthcare providers, government policy, and perceived social norms., Conclusion: The study found a host of determinants related to the barriers to and enablers of DR screening and treatment behaviors. These determinants included perceived self-efficacy (and agency), positive and negative consequences, perceived access, perceived social norms, culture, and perceived risk. Further investments are required to enhance the availability of DR services within primary and secondary health institutions along with health behavior promotion to dispel misconceptions and fears related to DR treatments., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Brain pathologies are considered one of the greatest contributors of death and disability worldwide. Neurodegenerative Alzheimer's disease is the second leading cause of death in adults, whilst brain cancers including glioblastoma multiforme in adults, and pediatric-type high-grade gliomas in children remain largely untreatable. A further compounding issue for patients with brain pathologies is that of long-term neuropsychiatric sequela - as a symptom or arising from high dose therapeutic intervention. The major challenge to effective, low dose treatment is finding therapeutics that successfully cross the blood-brain barrier and target aberrant cellular processes, while having minimum effect on essential cellular processes, and healthy bystander cells. Following over 30 years of research, CRISPR technology has emerged as a biomedical tour de force with the potential to revolutionise the treatment of both neurological and cancer related brain pathologies. The aim of this review is to take stock of the progress made in CRISPR technology in relation to treating brain pathologies. Specifically, we will describe studies which look beyond design, synthesis, and theoretical application; and focus instead on in vivo studies with translation potential. Along with discussing the latest breakthrough techniques being applied within the CRISPR field, we aim to provide a prospective on the knowledge gaps that exist and challenges that still lay ahead for CRISPR technology prior to successful application in the brain disease treatment field., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Employing monoclonal antibodies to target vaccine antigens to different immune cells within lymph nodes where adaptive immunity is initiated can provide a mechanism to fine-tune the magnitude or the quality of immune responses. However, studying the effects of different targeting antibodies head-to-head is challenging due to the lack of a feasible method that allows rapid screening of multiple antibodies for their impact on immunogenicity. Here self-assembling ferritin nanoparticles are prepared that co-display vaccine antigens and the Fc-binding domain of Staphylococcal protein A, allowing rapid attachment of soluble antibodies to the nanoparticle surface. Using this tunable system, ten antibodies targeting different immune cell subsets are screened, with targeting to Clec9a associated with higher serum antibody titers after immunization. Immune cell targeting using ferritin nanoparticles with anti-Clec9a antibodies drives concentrated deposition of antigens within germinal centers, boosting germinal center formation and robust antibody responses. However, the capacity to augment humoral immunity is antigen-dependent, with significant boosting observed for prototypic ovalbumin immunogens but reduced effectiveness with the SARS-CoV-2 RBD. This work provides a rapid platform for screening targeting antibodies, which will accelerate mechanistic insights into optimal delivery strategies for nanoparticle-based vaccines to maximize protective immunity., (© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

In this perspective, we outline a new opportunity for exploiting nanoparticle delivery of antagonists to target G-protein coupled receptors localized in intracellular compartments. We discuss the specific example of antagonizing endosomal receptors involved in pain to develop long-lasting analgesics but also outline the broader application potential of this delivery approach. We discuss the materials used to target endosomal receptors and indicate the design requirements for future successful applications.

Central nervous system (CNS) disorders affect as many as 1.5 billion people globally. The limited delivery of most imaging and therapeutic agents into the brain is a major challenge for treatment of CNS disorders. With the advent of nanotechnologies, controlled delivery of drugs with nanoparticles holds great promise in CNS disorders for overcoming the blood-brain barrier (BBB) and improving delivery efficacy. In recent years, magnetic iron oxide nanoparticles (MIONPs) have stood out as a promising theranostic nanoplatform for brain imaging and drug delivery as they possess unique physical properties and biodegradable characteristics. In this review, we summarize the recent advances in MIONP-based platforms as imaging and drug delivery agents for brain diseases. We firstly introduce the methods of synthesis and surface functionalization of MIONPs with emphasis on the inclusion of biocompatible polymers that allow for the addition of tailored physicochemical properties. We then discuss the recent advances in in vivo imaging and drug delivery applications using MIONPs. Finally, we present a perspective on the remaining challenges and possible future directions for MIONP-based brain delivery systems., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)