Biomaterials research最新文献

Photodynamic immunotherapy, which combines photodynamic therapy (PDT) with immunotherapy, has become an important and effective treatment for cancer. However, most photodynamic immunotherapy systems for cancer do not allow for the precise release of immunomodulators, leading to systemic side effects and poor patient prognosis. This study reports a dual-activatable nanoimmunomodulator (CPPM), whose photodynamic effect and agonist release are both activated in response to specific stimuli, which can be used for precise photodynamic immunotherapy of cancer. CPPM has a half-life of 119 min in circulation and accumulates in tumor tissue 4 h after injection (23.8%). In addition, CPPM is able to achieve tumor localization of nanomedicines through PD-L1-targeting peptides, blocking the specific binding of PD-L1 to PD-1, exposing tumor surface antigens, and reinvigorating the activity of T cells in combination with macitentan to promote T-cell proliferation. Meanwhile, under laser irradiation, CPPM was able to increase intracellular oxidative stress, inhibit cell proliferation through PDT, and trigger immunogenic cell death, further enhancing tumor immunogenicity through synergistic treatment. Ultimately, CPPM enhanced the immunotherapeutic efficiency against tumors by improving the tumor immunosuppressive microenvironment, synergistically inhibiting the growth of primary and distant tumors while activating systemic antitumor immunity to eliminate lung metastases without obvious side effects. This study presents an uncomplicated and multifunctional strategy for the precise modulation of tumor photodynamic immunotherapy with a dual-activatable smart nanoimmunomodulator that can improve the efficacy of PDT, enhance systemic antitumor immunity, and potentially extend it to a wide range of cancers.

Each year, 1 in every 700 babies is born with an orofacial cleft in the USA. Despite a well-established protocol for early cleft repair, the alveolar cleft persists during craniofacial growth. Current surgical treatments with bone grafts for alveolar cleft often provide inadequate nasal base support and insufficient alveolar bone volume for permanent tooth eruption. Here, we developed 3-dimensionally printed polycaprolactone scaffolds with controlled delivery of icariin (ICA) to facilitate bone reconstruction. After establishing a reliable fabrication process, we determined the optimal loading dose and release kinetics of ICA for induced osteogenic differentiation of bone marrow mesenchymal stem/progenitor cells and mineralized tissue formation in vitro. Then, the ICA-releasing polycaprolactone scaffolds with the preoptimized dose were implanted into rats with full-thickness maxillary defects. Up to 8 weeks, micro-computed tomography analyses demonstrated significantly accelerated bone healing and defect closure with an ICA-releasing scaffold compared to scaffold alone and defect controls. Histology consistently confirmed the formation of dense woven bone with ICA-releasing scaffolds in contrast to unclosed gaps and soft tissue infiltration in controls. Our findings suggest the significant potential of ICA-releasing 3-dimensionally printed scaffolds to serve as a patient-focused and custom-built bone graft to improve the clinical outcome of alveolar cleft reconstruction.

Silencing NOP2/Sun RNA methyltransferase family member 2 (NSUN2) effectively inhibits gastric cancer (GC) progression but is limited by RNase degradation, rapid renal clearance, and low uptake. Based on the characteristic high levels of reactive oxygen species (ROS) in the tumor microenvironment, this study designed and synthesized a novel ROS-responsive ferrocene nanoparticle loaded with siNSUN2 (PRPFc@siNSUN2). Under ROS conditions, the nanoparticle disintegrates to release siNSUN2. Characterization by proton nuclear magnetic resonance, transmission electron microscopy, dynamic light scattering, and ultraviolet-visible spectrophotometry revealed that PRPFc@siNSUN2 is spherical, with an average diameter of 88.79 ± 1.14 nm, an encapsulation efficiency of 83.10%, and a drug loading capacity of 13.85%. Moreover, these nanoparticles demonstrated excellent stability and, under hydrogen peroxide conditions, exhibited structural disruption leading to the release of siNSUN2, thereby confirming their high ROS responsiveness. In vitro, PRPFc@siNSUN2 markedly enhanced the inhibition of GC cell proliferation, migration, and invasion, and promoted apoptosis, accompanied by increased intracellular ROS and improved siNSUN2 uptake. In vivo studies further confirmed that PRPFc@siNSUN2 markedly enhanced the therapeutic efficacy of siNSUN2 against GC, while exhibiting low cytotoxicity and good biocompatibility. Overall, our findings indicate that PRPFc@siNSUN2, with its favorable morphology, stability, and ROS-triggered release, substantially improves the anti-GC effects of siNSUN2 by inhibiting GC cell proliferation, migration, and invasion, as well as by promoting apoptosis. These results support NSUN2 as a promising therapeutic target and underscore the potential of PRPFc@siNSUN2 nanoparticles in drug delivery, offering a novel strategy to improve clinical outcomes for GC patients.

Intervertebral disc degeneration (IVDD) is the primary cause of low back pain, and patients with severe degeneration usually require lumbar fusion or total disc arthroplasty. Lumbar fusion carries the risk of accelerated degeneration of the adjacent intervertebral disc (IVD), and total disc arthroplasty could reduce the risk. However, the clinical application of artificial IVD whose nondegradable properties make it difficult to restore the biological function of the IVD. Therefore, we intend to fabricate a novel biomimetic microchannel integrated silk fibroin scaffold (BMI-SF scaffold) containing annulus fibrosus with oriented cross-microchannels and nucleus pulposus with interconnected porous structure. The BMI-SF scaffold exhibits controllable microchannels as well as excellent biocompatibility and biodegradability. In vitro and in vivo studies have demonstrated that microchannels can direct cells into the BMI-SF scaffold and enhance neovascularization, supplying adequate nutritional support for tissue regeneration. The IVD replacement model showed that the BMI-SF scaffold has superior regenerative effects, such as restoring IVD height and providing motion segments with dynamic mechanical properties akin to the natural IVD. In this study, the BMI-SF scaffold developed using controlled microchannels provides a new strategy for patients with severe IVDD and has broad clinical application prospects.

While fluorescent labeling has been the standard for visualizing fibers within fibrillar scaffold models of the extracellular matrix (ECM), the use of fluorescent dyes can compromise cell viability and photobleach prematurely. The intricate fibrillar composition of ECM is crucial for its viscoelastic properties, which regulate intracellular signaling and provide structural support for cells. Naturally derived biomaterials such as fibrin and collagen replicate these fibrillar structures, but longitudinal confocal imaging of fibers using fluorescent dyes may impact cell function and photobleach the sample long before termination of the experiment. An alternative technique is reflection confocal microscopy (RCM) that provides high-resolution images of fibers. However, RCM is sensitive to fiber orientation relative to the optical axis, and consequently, many fibers are not detected. We aim to recover these fibers. Here, we propose a deep learning tool for predicting fluorescently labeled optical sections from unlabeled image stacks. Specifically, our model is conditioned to reproduce fluorescent labeling using RCM images at 3 laser wavelengths and a single laser transmission image. The model is implemented using a fully convolutional image-to-image mapping architecture with a hybrid loss function that includes both low-dimensional statistical and high-dimensional structural components. Upon convergence, the proposed method accurately recovers 3-dimensional fibrous architecture without substantial differences in fiber length or fiber count. However, the predicted fibers were slightly wider than original fluorescent labels (0.213 ± 0.009 μm). The model can be implemented on any commercial laser scanning microscope, providing wide use in the study of ECM biology.

Energy storage and conversion extensively use MXenes, a class of 2-dimensional transition metals. Research is currently exploring MXenes in areas such as biomedical imaging, positioning them as a substantial contender in biomedical applications. Even though these biocompatible MXenes have many uses, it is challenging to make nanoparticles that are all the same size. This has made it harder to use them in the biomedical field. Herein, we meticulously crafted nano-sized MXene particles, achieving exceptional uniformity and amplified photothermal conversion efficiency compared to those of their bulkier micro-sized counterparts. To make these nanoparticles better at finding tumors, we added ARGD peptides to their surfaces. These are biomolecules that are known to bind to integrin α_vβ₃, a protein that is highly expressed in cancerous cells. Our research showed that these RGD-MXene nanoconjugates have excellent targeting accuracy and can eradicate tumors very effectively. This targeted photothermal therapy platform promises to redefine cancer treatment by selectively eradicating malignant cells while safeguarding healthy tissue. Also, MXene's natural ability to change surfaces opens up a world of possibilities for a wide range of uses in nanomedicine, bringing about a new era of sophisticated therapeutic interventions.

The industrialization of mesenchymal stem cells for regenerative medicine faces substantial challenges, particularly in large-scale production. Conventional 2-dimensional (2D) culture systems demonstrate limitations in meeting clinical requirements, such as inadequate cell yield, and poor cell-cell and cell-matrix interactions. These challenges can potentially be addressed by employing a 3D culture platform, which offers higher cell yields and enhanced efficacy. Moreover, it is essential to conduct a systematic and rigorous evaluation of cells produced in 3D culture systems to ensure their successful clinical translation. In this study, we cultured human umbilical cord mesenchymal stem cells (hUCMSCs) using an automated, scalable, and enclosed 3D microcarrier-bioreactor system, and comprehensively investigated their biological characteristics and potential therapeutic effects for diabetic wound repair. Our findings revealed that hUCMSCs harvested from this 3D microcarrier-bioreactor system are genetically stable and maintain the trilineage differentiation potential. Compared to hUCMSCs expanded under 2D conditions, those cultured in 3D exhibited reduced senescence and enhanced capabilities in migration, angiogenesis, and anti-inflammatory responses across different passages in vitro. RNA-sequencing analysis showed higher expression levels of genes related to angiogenesis and anti-inflammatory pathways in hUCMSCs cultured in 3D compared to those in 2D, which was further validated using quantitative real-time polymerase chain reaction and Western blot analysis. Additionally, 3D-cultured hUCMSCs demonstrated superior therapeutic effects for diabetic wound repair in mice, potentially due to their enhanced angiogenetic and anti-inflammatory effects. Collectively, our finding showcases the high quality of hUCMSCs cultured using an automated and enclosed 3D microcarrier-bioreactor system and their promising potential for diabetic wound repair.

Diabetic wounds pose considerable healing challenges due to factors such as impaired angiogenesis, persistent inflammation, elevated levels of reactive oxygen species, and bacterial infections. In this study, we synthesized copper sulfide nanoparticles (NPs) using sericin as a biotemplate and functionalized them with tannic acid-Fe (TA-Fe) metal-phenolic network coatings to create CuS-based nanoenzymes (CuS-Se@TA-Fe NPs). These NPs were integrated into a composite hydrogel formed from polyvinyl alcohol, carboxymethyl chitosan, and borax. The hydrogen bonding between polyvinyl alcohol and carboxymethyl chitosan, combined with the borate ester bonds from borax and the electrostatic interactions with CuS-Se@TA-Fe NPs, resulted in a hydrogel with remarkable adhesion, self-healing capabilities, and shape retention (PCCuT hydrogel). Additionally, the PCCuT hydrogel demonstrated superoxide dismutase and catalase mimetic activities to eliminate excess free radicals, along with excellent photothermal conversion and antimicrobial properties due to the photothermal effect. Both in vitro and in vivo investigations indicated that the PCCuT hydrogel could enhance angiogenesis and promote the transformation of macrophages into the M2 anti-inflammatory phenotype. Notably, in a rat model of diabetic wound infection, the hydrogel exhibited substantial wound-healing benefits. In summary, the PCCuT hydrogel holds promise for advancing the treatment of diabetic wounds complicated by infection.

Stem-cell-derived extracellular vesicles (EVs) have emerged as a promising therapeutic option, addressing the limitations of conventional stem cell therapies. However, the variability and poorly defined therapeutic contents of EVs produced under standard 2-dimensional culture conditions present challenges for their clinical application. In this study, we investigated how the therapeutic properties of mesenchymal stem cell (MSC)-derived EVs can be enhanced by culturing MSCs within 3-dimensional hydrogels that have tunable mechanical properties. Our results demonstrate that different mechanical cues from the culture environment can induce specific gene expression changes in MSCs without compromising their inherent characteristics. Furthermore, EVs derived from these MSCs exhibited distinct angiogenic and immunomodulatory activities, which were dependent on the mechanical properties of the hydrogels used. A comprehensive analysis of the cytokines and microRNAs present in the EVs provided additional validation of these findings. By utilizing a noninvasive culture method that eliminates the need for genetic modification or exogenous biochemical supplementation, our approach presents a novel platform for the tailored production of EVs, thereby enhancing their therapeutic potential in regenerative medicine.

Hepatic ischemia-reperfusion injury (HIRI) is a common perioperative complication occurring after liver transplantation and can lead to further problems such as early allograft dysfunction (EAD). Currently, the treatment options for HIRI are extremely limited. In this study, we used bioinformatics analysis to elucidate the critical role of neutrophil chemokines (CXC chemokines) in HIRI. By analyzing sequencing data from the hepatic tissue of posttransplant patients with EAD and the reperfused animal model, we discovered that hepatocytes and macrophages are the primary cells secreting CXC chemokines, and the activation of the nuclear factor kappa B (NF-κB) signaling pathway is the main driver of their secretion. Melatonin (MT) can protect cells from oxidative harm while also inhibiting NF-κB signaling, suggesting its potential to ameliorate HIRI. Accordingly, we designed a nanoparticle platform coated with genetically engineered macrophage membranes-called CXCR2-MM@PLGA/MT-to target the cells secreting CXC chemokines. CXCR2 overexpression on the macrophage membranes not only enhanced the targeting capacity of the nanoparticles but also prevented neutrophil infiltration via the scavenging of CXC chemokines. Meanwhile, the MT delivered to the site of injury successfully attenuated CXC chemokine release after macrophage polarization and hepatocyte necrosis by inhibiting NF-κB phosphorylation and inducing antioxidant effects. Through the synergistic effects of MT and the CXCL/CXCR axis-blocking function of the engineered nanoparticles, CXCR2-MM@PLGA/MT attenuated the aggregation of neutrophils at the site of injury, markedly reducing local inflammation and cellular damage following HIRI. This engineered cellular nanoparticle-based therapy could thus serve as a safe, effective, and cost-efficient strategy for treating HIRI.