ACS Biomaterials Science & Engineering最新文献

Neuroinflammation induced by the accumulation of amyloid beta plaques expedites the progression of Alzheimer's disease (AD). Reducing Aβ plaques and associated neuroinflammation could potentially help to delay the progression of AD. Cannabidiol (CBD) is well-known for its antioxidant, anti-inflammatory, and neuroprotective nature, and the ApoE2 is effective in binding and clearing Aβ plaques in the brain. Therefore, codelivery of CBD and pApoE2 to the brain would be a promising therapeutic approach in developing effective therapeutics against AD. This research aims to design a nonviral delivery agent that delivers both drugs and genes to the brain through a noninvasive intranasal route. We have developed mPEG-PLGA nanoparticles coated with mannose, a brain-targeting ligand, to deliver CBD and pApoE2. The designed CBD-loaded coated nanoparticles showed an average diameter of 179.3 ± 4.57 nm and a zeta potential of 30.3 ± 6.45 mV. The coated nanoparticles prolonged the CBD release and showed a 93% release of its payload in 30 days. CBD-loaded nanoparticles, as compared to the free CBD, significantly reduced lipopolysaccharide and amyloid beta-induced inflammation in immortalized microglia cells. Cytotoxicity of the designed nanoparticles was assessed against brain endothelial cells (bEND.3) and found to be nontoxic in nature. The mannose-conjugated chitosan-coated nanoparticles were cationic and able to bind with the pApoE2, protecting the encapsulated pApoE2 from enzymatic degradation. Quantitative in vitro transfection efficiency study in primary astrocytes and primary neurons revealed that the ApoE2 expression level is significantly (P < 0.0001) higher for mPLGA-CBD-MC/pApoE2 than the control. The ApoE2 expression level in the brain of C57BL6/J mice was significantly (P < 0.0001) increased after intranasal administration of mPLGA-CBD-MC/pApoE2. Henceforth, the mannose-conjugated chitosan-coated mPLGA nanoparticles could serve as a nonviral delivery system to deliver both drugs and genes to the brain through the intranasal route for the management of AD.

The glycocalyx (GCX), a multicomponent coating on endothelial cells (ECs), plays a critical role in various cellular behaviors, including barrier formation, vasodilation, and mechanotransduction. Mechanical perturbations in the vascular environment, such as blood vessel stiffness, are sensed and transduced by ECs via the GCX. Hypertension-induced stiffness disrupts GCX-mediated mechanotransduction, leading to EC dysfunction and atherosclerotic cardiovascular diseases. Understanding GCX-regulated mechanotransduction necessitates an in vitro model that closely mimics in vivo conditions. Existing models are insufficient, prompting the development of the system described in this manuscript. Here, we report on a new system to model varying EC substrate stiffness under sustained physiological fluid shear stress, providing a realistic environment for comprehensive examination of EC function. Gelatin methacrylate (GelMA) substrates with stiffnesses of 5 kPa (physiological) and 10 kPa (pathological) were seeded with human umbilical vein ECs (HUVECs) and subjected to constant physiological shear stress (12 dyn/cm²) for 6 h. Analysis focused on heparan sulfate (HS), sialic acid (SA), hyaluronic acid (HA), syndecan-1 (SDC1), cluster of differentiation 44 (CD44), and Yes-associated protein (YAP). Compared to the 5 kPa conditions, HS coverage and thickness decreased at 10 kPa, indicating impaired barrier function and increased susceptibility to inflammatory agents. SA density increased despite decreased coverage, suggesting enhanced binding site availability for inflammatory recruitment. HA expression remained unchanged, but the amount of the HA core receptor, CD44, was found to be increased at 10 kPa. Consistent with previously published interactions between CD44 and YAP, we observed increased YAP activation at 10 kPa, as evidenced by increased nuclear translocation and decreased phosphorylation. These findings, bridging biomaterials and mechanobiology approaches, deepen our understanding of how mechanical stimuli influence the EC GCX function. The results underscore the potential of mechanotherapeutic strategies aimed at preserving vascular health by modulating the endothelial function.

Stem cells have a considerable role to play in future biomedical breakthroughs due to their therapeutic potential. As stem cells may be studied in a variety of different applications, a "one size fits all" approach to the stem cell culture substrate is not appropriate. Different biomaterial formulations may be necessary in different contexts. Screening can help identify biomaterials for specific applications to harness stem cells' full potential. In this review, we cover experimental setups appropriate for screening applications, as well as data collection tools for both material and cell characterization. Finally, we cover high throughput data processing techniques, emphasizing the potential of introducing machine learning (ML) techniques into the analytical process. With increased use of ML-based analytical techniques, biomaterial screening has the potential to contribute to the rapid development of biomaterials for targeted stem cell applications.

The use of natural killer (NK) cell-based immunotherapy has been extensively explored in clinical trials for multiple types of tumors and has surfaced as a promising approach in tumor immunotherapy. Interleukins (ILs), a vital class of cytokines, play a crucial role in regulating several functions of NK cells, thereby becoming a focal point in the advancement of NK cell-based therapies. Nonetheless, the use of ILs as single agents is significantly constrained by their short half-life, limited efficacy, and adverse reactions. Currently, nanomaterials are being progressively employed in the delivery of ILs to enhance NK cell-based immunotherapy. However, there is currently a lack of comprehensive reviews summarizing the design of NK-cell-targeted nanomaterials and related systems for delivery of ILs. Furthermore, certain nanomaterials, either alone or in conjunction with other therapeutics, can also promote the secretion of ILs, representing a promising avenue for further exploration. Accordingly, this review begins by outlining various types of ILs and subsequently discusses the advancements in applying nanomaterials for IL delivery. It also examines the potential of nanomaterials to enhance IL secretion from other immune cells, thereby influencing the NK cell functionality. Lastly, this review addresses the challenges associated with using nanomaterials in these contexts and offers perspectives for future research. This study aims to provide valuable insights into the development of NK cell immunotherapy and innovative nanomaterial-based drug delivery systems.

Bacterial endophthalmitis (BE) is a severe ocular infection that can lead to irreversible blinding ocular disease. When diagnosed with BE, the main treatment approach is empirically administering intravitreal antibiotic injections. However, the excessive use of antibiotics leads to increased drug resistance in pathogens, and the retinal dose-limiting toxicities greatly limit its application in clinic. In this work, we present a series of polylysine derivatives (PLL-n) for the treatment of bacterial endophthalmitis. By precisely adjusting the balance of hydrophilic/hydrophobic, the optimal polymer, PLL-2, demonstrates high efficacy against Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), and various clinically isolated drug-resistant bacteria. The antibacterial mechanism showed that PLL-2 could effectively destroy the bacterial membrane and lead to bacterial death. Due to its unique antibacterial mechanism, PLL-2 exhibits rapid bactericidal kinetics and does not induce bacterial resistance up to 16 generations. More importantly, PLL-2 showed a significant therapeutic effect on a methicillin-resistant S. aureus-induced rat endophthalmitis model, which presents a promising therapeutic approach for managing endophthalmitis.

Complex wound management remains a significant global challenge, and the development of multifunctional wound dressings that can effectively promote wound healing remains an urgent clinical need. Herein, a kind of multifunctional hydrogel wound dressing that combines bacteriostasis, self-healing capability, growth factor release, electrical stimulation, and photothermal stimulation is developed. This kind of wound dressing is generated by adding protocatechualdehyde (protocatechuic aldehyde (PA)), short core-shell fibers loading with platelet-rich-plasma (platelet-rich plasma fibers), and polydopamine-coated carbon nanotubes (PDA@CNTs) into quaternary ammonium chitosan (QCS) solution to form a shear-reversibly cross-linked QCS/PA/PDA@CNTs-PRP hydrogel. The obtained hydrogels possess impressive properties, including high swelling capacity (445-852%), strong adhesion ability (16.4-36.7 kPa), self-healing ability, injectability, conductivity (0.24-0.46 S/m), and photothermal properties. Notably, under near-infrared irradiation, the hydrogel exhibits a highly efficient bactericidal activity. In vitro experiments demonstrated that the hydrogel exhibits excellent biocompatibility and anti-inflammatory capability as well as its ability to stimulate cell proliferation, migration, and tubule formation. Moreover, the in vivo studies further confirmed that with the additional assistance of near-infrared light and electrical stimulation, the hydrogel further promotes wound epithelization, angiogenesis, and collagen deposition. Consequently, this hydrogel provides a promising therapeutic strategy for complex wound healing.

Cell culture for tissue engineering is a global and flexible research method that relies heavily on plastic consumables, which generates millions of tons of plastic waste annually. Here, we develop an innovative sustainable method for scaffold production by repurposing spent tissue culture polystyrene into biocompatible microfiber scaffolds, while using environmentally friendly solvents. Our new green electrospinning approach utilizes two green, biodegradable and low-toxicity solvents, dihydrolevoglucosenone (Cyrene) and dimethyl carbonate (DMC) to process laboratory cell culture petri dishes into polymer dopes for electrospinning. Scaffolds produced from these spinning dopes, produced both aligned and non-aligned microfiber configurations, were examined in detail. The scaffolds exhibited mechanical properties comparable to cancellous bones whereby aligned scaffolds achieved an ultimate tensile strength (UTS) of 4.58 ± 0.34 MPa and a Young's modulus of 11.87 ± 0.54 MPa, while the non-aligned scaffolds exhibited a UTS of 4.27 ± 0.92 MPa and a Young's modulus of 20.37 ± 4.85. To evaluate their potential for cell-culture, MG63 osteoblast-like cells were seeded onto aligned and non-aligned scaffolds to assess their biocompatibility, cell adhesion, and differentiation, where the cell viability, DNA content, and proliferation were monitored over 14 days. DNA quantification demonstrated an eight-fold increase from 0.195 μg/mL (day 1) to 1.55 μg/mL (day 14), with a significant rise in cell metabolic activity over 7 days, and no observed cytotoxic effects. Confocal microscopy revealed elongated cell alignment on aligned fiber scaffolds, while rounded, disoriented cells were observed on non-aligned fiber scaffolds. Alizarin Red staining and calcium quantification confirmed osteogenic differentiation, as evidenced by mineral deposition on the scaffolds. This research therefore demonstrates the feasibility of this new method to repurpose laboratory polystyrene waste into sustainable cell culture tissue engineering scaffolds using eco-friendly solvents. Such an approach provides a route for cell culture for tissue engineering related activities to transition towards more sustainable and environmentally conscious scientific practices, thereby aligning with the principles of a circular economy.

Wound healing is a dynamic and complex process that demands substantial energy expenditure and a biomimetic microenvironment. Developing a simple and effective biological hydrogel to enhance mitochondrial energy metabolism could effectively promote wound healing. To this end, we developed a hybrid biological hydrogel based on Escherichia coli lipoate protein ligase A (LplA), which combines its catalytic and self-assembling properties to promote wound healing. In murine fibroblast L929 cell models, LplA significantly enhances cellular activity and intracellular metabolism, promoting cell proliferation and energy supply. However, cells aggregated into spherical clusters on the pure LplA hydrogel. To address this issue, we integrated glutaraldehyde (GA) as a cross-linker into the LplA hydrogel. The GA-LplA hydrogel enhances cell adhesion and proliferation and, unexpectedly, exhibits higher catalytic activity compared with the pure LplA hydrogel. Furthermore, LplA was observed to decompose H₂O₂, and the GA-LplA hybrid hydrogel significantly reduced reactive oxygen species (ROS) production. The promise of this hybrid hydrogel is successfully demonstrated in a male mice full-thickness skin defect model with accelerated re-epithelialization and cell proliferation while reducing inflammation.

RNA therapeutics represent a pivotal advancement in contemporary medicine, pioneering innovative treatments in oncology and vaccine production. The inherent instability of RNA and its delivery challenges necessitate the use of lipid-based nanoparticles as crucial transport vehicles. This research focuses on the design, simulation, and optimization of various microfluidic channel configurations for fabricating poly(dimethylsiloxane) (PDMS) microfluidic chips, aimed at producing lipid nanoparticles (LNPs) encapsulating green fluorescent protein mRNA (GFP mRNA). Aiming for high mixing efficiency and acceptable pressure drop suitable for scale-up, we designed and improved multiple microfluidic channels featuring flow focusing and diverse tilted rectangular baffle structures via computational fluid dynamics (CFD). Simulation results indicated that baffle angles ranging from 70 to 90° exhibited similar mixing efficiencies at different total flow rates, with pressure drops increasing alongside the baffle angle. Additionally, increasing the baffle length at a fixed angle of 70° not only improved mixing efficiency but also increased the pressure drop. To validate these findings, PDMS microfluidic chips were fabricated for all designs to prepare empty LNPs. The baffle structure with a 70° angle and 150 μm length was identified as the best configuration based on both simulation and experimental results. This optimal design was then used to prepare LNPs with varying GFP mRNA concentrations, demonstrating that an N/P ratio of 5.6 yielded the highest transfection efficiency from in vitro experiments. This work not only advances the production of lipid-based nanoparticles through microfluidics but also provides a scalable and reproducible method that can potentially enhance the clinical translation of RNA therapeutics.

Recently, mRNA/lipid nanoparticle (LNP)-based vaccines have been successfully applied to prevent infectious diseases, and several types of neoantigen-encoding mRNA cancer vaccines are currently under clinical trials. While mRNA vaccines effectively induce adaptive immune responses to antigens, mRNA vaccine-induced immunity is shortly maintained, and the longevity of the immune memory, especially improving the CD8⁺ T cell memory potential, could be even more important. Previously, microbiome metabolites have shown T cell memory potential-augmenting effects via regulating the immunometabolism. Herein, we develop microbiome metabolite-incorporated LNPs (mmi-LNPs) and evaluate their potential to enhance T cell memory responses following mRNA vaccination. In various ionizable LNP formulations, mmi-LNPs elicited more stem cell-like memory T cells (T-SCMs) and augmented central and effector memory T cell responses, which indicates the general applicability of mmi-LNPs. Notably, butyrate-incorporated mmi-LNP exhibited the strongest effects. In conclusion, we suggest microbiome metabolite-incorporated LNP as a next-generation delivery vehicle for mRNA vaccines.