Neuroinflammatory and immune-mediated processes are increasingly recognized as important contributors to adult ischemic stroke pathobiology, contributing not only to acute neuronal injury and secondary tissue damage, but also to later phases of repair and recovery. Experimental and early clinical evidence suggests that immunotherapeutic interventions may modulate post-ischemic inflammatory cascades and immune-cell activation, thereby potentially contributing to neuroprotective and neurorestorative responses. However, the clinical efficacy, safety, and translational relevance of these approaches remain incompletely defined. This systematic review aimed to critically synthesize contemporary preclinical and clinical evidence on neuroinflammation-targeted immunotherapeutic strategies in adult ischemic stroke, while distinguishing direct immunotherapy from regenerative cell-based approaches with immunomodulatory relevance. A systematic search of PubMed/MEDLINE and Embase was conducted in October 2025 and updated in January 2026 to identify original English-language studies published between January 2020 and December 2025. Eligible studies included preclinical and clinical investigations evaluating direct immunotherapeutic interventions or regenerative cell-based therapies with immunomodulatory relevance in adult ischemic stroke, compared with placebo, standard care, or control conditions appropriate to study design. In total, 913 records were screened, of which 55 studies met all inclusion criteria and were included in the qualitative synthesis. Of these, three randomized controlled trials (N = 637) provided comparatively compatible, although methodologically heterogeneous, outcome data for an exploratory meta-analysis of excellent functional outcome at day 90. Methodological quality was assessed using validated design-specific tools for randomized controlled trials, observational studies, and preclinical animal experiments. Primary outcomes included functional recovery and infarct-related measures, while secondary outcomes encompassed neuroinflammatory biomarkers, immune modulation, and safety. Therapeutic approaches were categorized into molecular immunotherapy, biological immunotherapy, and regenerative cell-based therapies with immunomodulatory properties, according to their dominant mechanism of action and translational rationale. Molecular interventions targeting inflammatory and immunometabolic signaling pathways were associated with reductions in neuroinflammatory signaling and infarct-related measures in preclinical models in preclinical models, although corresponding human evidence remained limited. Regenerative cell-based therapies, including mesenchymal stromal/stem cells, progenitor cells, and related cellular products, demonstrated neuroregenerative, paracrine, and immunomodulatory characteristics in preclinical and early translational studies with favorable safety profiles; however, clinical functional benefits remained modest, heterogeneous, and inconsistent. Biological approaches, particularly monoclonal antibodies targeting leukocyte adhesion and immune-cell trafficking, demonstrated generally acceptable safety profiles but did not demonstrate consistent functional benefit across currently available randomized clinical trials. In the exploratory quantitative synthesis, no significant pooled clinical benefit was observed (OR = 0.87; 95% CI, 0.27-2.77), with moderate between-study heterogeneity (I2 = 46.3%). Cross-study comparability was further limited by substantial heterogeneity in intervention timing, dosing regimens, patient selection, biological targets, and outcome definitions, precluding definitive conclusions regarding efficacy. Neuroinflammation-targeted immunotherapy in adult ischemic stroke, together with selected regenerative cell-based strategies of immunomodulatory relevance, appears biologically plausible and mechanistically supported by current preclinical and early clinical evidence based on current preclinical and early clinical evidence and has demonstrated generally acceptable safety profiles in early-phase studies; however, current evidence remains insufficient to support consistent clinical benefit, and available trials may be insufficiently powered to reliably detect moderate but clinically meaningful treatment effects. Future research should prioritize mechanism-driven trial designs, standardized outcome measures, biomarker-informed patient stratification, optimized therapeutic windows, and integrative strategies combining immunomodulation with established reperfusion therapies. Well-powered, methodologically harmonized clinical trials aligned with the temporal and biological heterogeneity of post-stroke inflammation are essential to clarify translational potential and define the role of immune-targeted therapies in stroke management. Importantly, the present review supports a mechanistically differentiated framework in which direct immunotherapy and regenerative cell-based therapy should not be treated as interchangeable categories, even when both modulate post-stroke neuroinflammation. Overall, the available evidence may support further investigation of a stage-specific and mechanistically differentiated model of immune-targeted intervention in ischemic stroke.
Zebrafish, in contrast to mammals, regenerate neurons after spinal cord injury, but little is known about the control mechanisms of this process. Here we use scRNA-seq and in vivo experiments to show that sema4ab, mainly expressed by lesion-reactive microglia, attenuates regenerative neurogenesis by changing the complex lesion environment. After spinal injury, disruption of sema4ab doubles the number of newly generated progenitor cells and neurons but attenuates axon regrowth and recovery of swimming function. Disruption of the plxnb1a/b receptors, selectively expressed by neural progenitor cells, increases regenerative neurogenesis. In addition, disruption of sema4ab alters activation state and cytokine expression of microglia, such that fibroblasts increase expression of the cytokine tgfb3, which strongly promotes regenerative neurogenesis. Hence, we propose that sema4ab expression in microglia attenuates regenerative neurogenesis in multiple ways, likely directly through plxnb1a/b receptors and indirectly, by controlling the inflammatory milieu and tgfb3 levels. Targeting Sema4A-dependent signaling in non-regenerating vertebrates may be a future strategy to improve regenerative outcomes.
Ischemic stroke remains a leading cause of death and long-term disability, yet effective treatments that promote recovery beyond the acute phase are lacking. Neuregulin-1 (NRG-1) has shown potent neuroprotective and anti-inflammatory properties in preclinical stroke models, with evidence of enhanced neuronal regeneration when administered after injury. To investigate the spatial mechanisms underlying its neuroregenerative therapeutic effects, we examined brain proteomic responses to post-ischemic NRG-1 treatment in mice using NanoString Digital Spatial Profiling (DSP). Adult C57BL/6 mice were subjected to photothrombotic middle cerebral artery occlusion (MCAO) and treated with NRG-1β (5 μg/kg/day) or vehicle at 24- and 48-h post-stroke. Brains were collected at 3 days post-ischemia for spatial proteomic analysis of 68 neural proteins across the ischemic core, peri-infarct tissue, and peri-infarct normal tissue (PiNT). While NRG-1 did not significantly alter overall neuronal death, it markedly reshaped the neuroregenerative milieu, upregulating myelin basic protein (MBP) and synaptophysin and attenuating inflammatory mediators (SPP1, P2RX7, and CD39). NRG-1 also enhanced expression of autophagy and mitophagy markers (ULK1, LC3B, ATG5, PINK1, and Park7), suggesting restoration of cellular clearance and mitochondrial quality control. Pathway and network analyses revealed activation of neuroregeneration, autophagy, and lysosomal biogenesis pathways, while suppressing neuroinflammatory signaling. These findings demonstrate that delayed NRG-1 therapy, even when initiated 24 h after stroke, induces early molecular programs that prime an anti-inflammatory and neuroregenerative environment. The results support further development of NRG-1 as a clinically translatable, multimodal therapy for extending the post-stroke treatment window and promoting functional recovery.
Critical limb ischemia (CLI) remains refractory to current revascularization strategies due to its complex pathology. Here, we report an injectable alginate hydrogel that orchestrates a dual-pathway regenerative cascade by simultaneously reprogramming the immune microenvironment and activating direct tissue repair. The system is rationally designed by integrating two functional modules: (i) immunomodulatory carbon dots (PNS-AA@CQDs-COS) that selectively target M1 macrophages and drive them to the M2 phenotype, and (ii) intrinsically bioactive cross-linkers (Zn2+/l-Arg) that serve as sustained-release pro-regenerative signals. Critically, this dual-component architecture enables a synergistic interplay─while the carbon dots establish an anti-inflammatory microenvironment (path 1), the liberated Zn2+ and l-Arg directly activate endothelial cells and muscle satellite cells, thereby initiating coordinated vascular and myogenic regeneration (path 2). In vitro, the hydrogel significantly amplified reparative crosstalk within macrophage-endothelial/myogenic cells' cocultures. In a murine CLI model, a single injection of the hydrogel resulted in durable recovery of hindlimb perfusion (80.4% by day 14), improved motor function, and enhanced tissue repair. Mechanistic studies revealed that these benefits stem from microenvironment remodeling (M2 polarization and IL-10 upregulation) and modulation of key signaling pathways─suppressing NF-κB while potentiating PI3K/Akt/eNOS. This work presents a material-based strategy that couples immunomodulation with direct cellular activation, offering a synergistic therapeutic platform for CLI and potentially other ischemic diseases.
This review explores gels that assemble from low-molecular-weight gelator (LMWG) building blocks for use in cell culture, with a focus on fibroblasts and stem cells. These LMWG hydrogels have unique potential for controlling and directing cell growth. We provide an overview of gel tunability and how careful molecular design can direct biological outcomes. The LMWG hydrogel approach to cell growth is based on reversible assembly, potentially enabling cells to be encapsulated and subsequently released. It is possible to easily formulate multiple active ingredients into LMWG hydrogels by co-assembly - a powerful strategy to create multi-functional hybrid hydrogels. Rheological properties can be tuned over orders of magnitude, with stiffness helping control properties like cell invasion or stem cell differentiation. Furthermore, gel dynamics at both molecular and network levels can control factors such as cell adhesion. By developing strategies to shape and pattern these gels, it is possible to create structured assemblies of cells or direct the growth of multi-functional biological tissues. The dynamic characteristics of these gels enables them to evolve, potentially facilitating 4D tissue engineering or the creation of materials that are both bio-instructive and bio-responsive. LMWG hydrogels have been applied both in vitro and in vivo and some are in commercial use. This critical review provides an overview of progress to date, emphasising the unique advantages of the LMWG hydrogel approach, and highlighting concepts that might unlock untapped potential, hence transforming next-generation regenerative medicine.
The age-related decline in liver regenerative capacity worsens outcomes for elderly patients with liver disease or undergoing liver surgery, and therapeutic options are limited. The RNA modification N4-acetylcytidine (ac4C), catalyzed by N-acetyltransferase 10 (Nat10), is implicated in regeneration; however, its role in the aged liver remains unknown. We quantified Nat10/ac4C levels in human and murine livers across ages and correlated them with regenerative capacity. Function was assessed via hepatocyte-specific knockout, adeno-associated virus (AAV)-mediated gene manipulation, and pharmacological inhibition. Mechanisms were defined using integrated ac4C-specific immunoprecipitation sequencing (ac4C-seq), ribosome profiling (Ribo-seq), and RNA sequencing (RNA-seq). Hepatic Nat10 and ac4C levels decreased with age. Disruption of Nat10/ac4C impaired liver regeneration, whereas their augmentation enhanced it. Multi-omics integration linked ac4C to coordinated changes in mRNA abundance, stability, and translation. Mechanistically, Nat10 installed ac4C on Parp10 mRNA to enhance its stability and translational efficiency. Upregulated Parp10 inhibited GSK3β, thereby activating pro-regenerative β-catenin signaling. Furthermore, we identified the age-related decline in Nat10 was attributed to loss of its transcriptional driver, ATF3. Pharmacological induction of ATF3 restored Nat10 expression and rescued regeneration in aged liver. Our study highlights the critical role of Nat10 in liver regeneration via mRNA ac4C-manner and identifies its age-related decline as a reversible impairment. Targeting this presents a promising therapeutic strategy for stimulating regeneration in the aged liver.
Eggshell membrane (ESM) is a naturally derived biomaterial with potential applications in bone regeneration and guided bone regeneration (GBR) because of its extracellular matrix-like structure and bioactive composition. This scoping review aimed to map the current evidence regarding the use of ESM and its derivatives in bone regeneration and regenerative dentistry. This review followed the PRISMA-ScR guidelines. PubMed, EBSCOhost, and Web of Science were searched for English-language studies published between January 2019 and August 2025. Studies investigating ESM in in vitro, in vivo, or clinical regenerative models were included. Data extraction and methodological quality overview were performed independently by two reviewers. Results were synthesized descriptively. Of 280 identified records, 13 studies met the inclusion criteria, including 9 in vivo studies, 3 in vitro studies, and 1 clinical study. Various ESM formulations were evaluated, including native, modified, mineralized, soluble, and composite systems. Overall, ESM-based materials demonstrated favorable biocompatibility, osteogenic potential, angiogenic activity, and support for bone healing and osseointegration. Modified ESM systems generally showed superior regenerative performance compared with native ESM. The only clinical study reported improved socket healing, increased bone density, and reduced postoperative pain when ESM was combined with advanced platelet-rich fibrin (A-PRF). Methodological limitations included heterogeneity of study designs, limited standardization, and scarcity of clinical evidence. Current evidence suggests that ESM is a promising biomaterial for bone regeneration and GBR applications. However, further standardized and well-designed clinical studies are necessary to confirm its long-term safety, efficacy, and clinical applicability.
Plasticity transitions during carcinoma progression generate fetal-like progenitor states with metastatic capacity. How these progenitors emerge and persist during tumor progression remains unclear. Here, we elucidate a process that drives the emergence of SOX2+ metastatic progenitors in lung adenocarcinomas (LUAD). LUAD cells at the tumor invasive front and distant metastases express the cell adhesion molecule L1CAM, a marker of regenerative epithelial progenitors and a mediator of cell-basement membrane and cell-cell interactions, as well as the proliferation of extravasated micrometastatic cells. We now identify a distinct and broader role of L1CAM as promoter of the SOX2+ LUAD progenitor state. We show that L1CAM at cell-cell interfaces promotes the assembly of the planar cell polarity (PCP) complex in metastatic LUAD progenitors. L1CAM-dependent PCP acting through a non-canonical WNT signaling activates c-Jun, which cooperates with the chromatin remodeling factor CHD1 to drive SOX2 expression and metastatic activity. This axis sustains the tumor-initiating and regenerative capacity of LUAD progenitor cells. By illuminating the role of L1CAM and PCP signaling in the generation of SOX2+ LUAD progenitors, our findings identify potential new targets to treat metastatic cancer.
Musculoskeletal tissue regeneration remains a major clinical challenge due to the limited intrinsic healing capacity of cartilage, bone and interface tissues, as well as the complexity of recreating their hierarchical structure and mechanical properties. In recent years, costal cartilage (CC) has emerged as a promising and versatile resource for regenerative applications, owing to its hyaline cartilage composition, biological plasticity and relative surgical accessibility. This systematic review aims to critically evaluate in vivo and clinical evidence published over the last decade regarding the use of CC-derived cells and matrices for musculoskeletal tissue regeneration. A systematic search of PubMed, Scopus and Web of Science databases was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, identifying 26 eligible studies, including 18 in vivo and 8 clinical investigations. CC was employed either as a source of costal chondrocytes or cartilage-derived stem cells, or as decellularized or particulate extracellular matrix scaffolds. Preclinical studies demonstrated consistent regenerative potential across cartilage, osteochondral, bone and enthesis models, with outcomes showing hyaline-like tissue formation, improved biomechanical properties, enhanced integration with host tissue and coordinated chondrogenic and osteogenic responses. Clinical studies, primarily focused on cartilage and osteochondral defects, reported significant improvements in patient-reported outcomes, imaging-based repair quality and functional recovery, with follow-up periods extending up to 5 years and a favourable safety profile. Cell-based CC approaches showed robust biological efficacy but were associated with greater regulatory and translational complexity due to substantial manipulation requirements. In contrast, matrix-based CC strategies offered a more readily translatable option, leveraging the intrinsic bioactivity of the extracellular matrix while reducing regulatory burden. CC could be considered a highly promising and adaptable platform for musculoskeletal regeneration. However, heterogeneity in study design, limited sample sizes and variable methodological quality highlight the need for standardized protocols and well-designed, long-term randomized clinical trials to definitively establish clinical indications and optimize therapeutic strategies. N/A.
These case reports describe traumatic dental injuries affecting maxillary permanent central incisors in young children, which may lead to pulp necrosis with or without apical periodontitis. Immature teeth with necrotic pulp are very challenging to treat because of their short and thin dentinal walls, open apices, and broad root canals that make them weak and prone to fracture, which can ultimately render the tooth unrestorable and require extraction. Apexification has traditionally been the treatment of choice for such cases; however, recently, regenerative and revascularization procedures have shown encouraging results, including improved radicular dentin thickness and increased root length. The primary aim of this case report was to describe Regenerative endodontic procedures (REPs) performed on three post-trauma immature permanent maxillary central incisors with necrotic pulp. Each tooth was treated using a different biocompatible material, all of which resulted in favorable clinical and radiographic outcomes. This report includes two patients aged 8-10 years, presenting with three maxillary central incisors diagnosed with pulp necrosis. All teeth were managed following the established REPs guidelines. Blood clot revascularization (BCR) was performed in two teeth, followed by placement of white, putty consistency mineral trioxide aggregate (MTA) in one tooth and capsule Biodentine in the other. In the third tooth, platelet-rich fibrin (PRF) was used as the scaffold, followed by white putty consistency MTA placement. At the 12-month follow-up, both cases were clinically asymptomatic and radiographic evaluation showed advancing root development. The PRF treated tooth also exhibited a positive response to sensibility testing using an electric pulp tester. These case reports suggest that, with appropriate case selection, REPs can regenerate and revitalize post-trauma immature permanent teeth with necrotic pulps and act as a beneficial alternative to apexification.
Restoring load-bearing connective tissues (bone, cartilage, tendon, and ligament) remains a central challenge in regenerative medicine. While autografts and synthetic grafts provide temporary solutions, they are hampered by donor-site morbidity, immune complications, and poor long-term stability. Hydrogels, with their extracellular matrix-like architecture and biocompatibility, have emerged as versatile scaffolds for regeneration. Yet their intrinsic mechanical fragility has limited clinical use in mechanically demanding environments. Recently, both intrinsic and biomimetic reinforcement strategies have advanced hydrogel mechanics, while composition-structure designs incorporating bio-functional components and tailored architectures have expanded their therapeutic scope. However, the complexity of native tissues renders single-strategy solutions insufficient to simultaneously achieve robust mechanics, functional bioactivity, and physiological adaptability. This review uniquely consolidates mechanical reinforcement and bio-functional design strategies for biomass-derived hydrogels, emphasizing integrative concepts that couple macroscopic architecture, dynamic bonding, interfacial engineering, and multiphase doping. By framing hydrogel development through a cross-strategy and systems perspective, this article addresses a critical gap in the field and highlights a rational pathway toward next-generation scaffolds. Looking forward, stimuli-responsive hydrogels with adaptability, gradient, and multiphasic architectures, and AI-guided optimization are set to redefine design. Integrating materials science, biomechanics, and computational intelligence will yield patient-specific, translatable hydrogels with strong mechanics and regenerative efficacy.
Delayed wound healing is a serious issue in diabetes, which is driven by metabolic and non-metabolic factors. Dysfunction and decreased lifespan of fibroblast cells play a key role in this condition. Lawsone (2-hydroxy-1,4-naphthoquinone), the main active component of Lawsonia inermis, is well known for its anticancer and regenerative effects, although these effects vary depending on concentration and experimental conditions. Regarding the importance of Diabetic wound treatment, this study examines how lawsone affects fibroblast behavior under high-glucose conditions, focusing on cell viability, apoptosis, intracellular Reactive Oxygen Species (ROS) levels, migration, and the expression of repair-related genes Nerve Growth Factor (NGF) and Transforming Growth Factor-beta (TGF-β). Human dermal fibroblasts were cultured under high-glucose (85-140mM) conditions, in the presence or absence of lawsone (10µg/mL). The MTT assay assessed cell viability, migration by the scratch assay, apoptosis by Annexin V- Fluorescein Isothiocyanate/Propidium Iodide (FITC/PI) flow cytometry, and ROS levels by 2',7'-dichlorodihydrofluorescein diacetate (H₂DCFDA) staining. quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) was used to quantify NGF and TGF-β mRNA expression. High glucose significantly impaired fibroblast viability and migration, increased apoptosis and ROS production, and downregulated TGF-β expression. Co-treatment with lawsone markedly restored cell viability and migration, suppressed oxidative stress and apoptosis, and enhanced NGF and TGF-β transcription, indicating reactivation of reparative pathways (p ≤ 0.05). Lawsone exhibits potent cytoprotective and pro-regenerative effects in human dermal fibroblasts under hyperglycemic stress, independent of its known anticancer activity. These findings highlight lawsone as a natural candidate for promoting diabetic wound healing and warrant further mechanistic and in vivo investigations.
Senescence is broadly considered an age-related phenomenon; however, it also been implicated in normal tissue repair and wound healing. Skeletal muscle repair is a complex process that requires the coordination of several different cell populations but the role of senescence in skeletal muscle repair has yet to be fully elucidated. We hypothesize that senescence serves as a control mechanism throughout the regenerative process and the removal of senescent cells through senolytics will negatively impact the repair process in young mice. Briefly, young mice were exposed to either (a) vehicle (VEH), receiving only a cardiotoxin (CTx) injection in one hindlimb or (b) 7 days of senolytic treatment (SEN) pre-CTx and 3x/week for 4 weeks post-CTx. Dasatinib + Quercetin (D+Q) was used to selectively eliminate senescent cells. There were no significant differences between groups in functional measures such as hindlimb grip strength and cross-sectional area. eMHC+ fibers remained elevated at D28 in the SEN group. Macrophage infiltration was twice as high in the SEN group compared to VEH at D7. Satellite cell quantity and fibrotic area were significantly increased at D14 in the SEN group compared to VEH. We conclude that reducing senescent cells during muscle repair in young mice significantly altered the kinetics of muscle repair. Therefore, senescent cells may act as a regulatory mechanism in skeletal muscle to orchestrate the activity of the different cell populations involved in repair and regeneration such as immune cells, satellite cells, and fibrotic cells.
Hematopoietic stem and progenitor cells (HSPCs) respond to infections, inflammation, and regenerative challenges using emergency myelopoiesis (EM) pathways to amplify myeloid cell production. However, it remains unclear how various EM inducers regulate HSPCs using shared or distinct molecular mechanisms. Here, we generate a comprehensive and generalizable cell annotation method (HemaScribe) and a refined quantitative model of hematopoietic differentiation (HemaScape) using single-cell RNA sequencing (scRNA-seq) of murine HSPCs, which we apply to a broad range of EM modalities. We uncover multiple strategies for enhancing myelopoiesis that act at different levels of the HSPC hierarchy and are associated with both unique and shared transcriptional response modules. In particular, we identify a myeloid progenitor-based EM activation module across diverse inflammatory challenges that is conserved in humans and informs outcomes in adult and pediatric acute myeloid leukemia. Our work illuminates fundamental regulatory mechanisms in hematopoietic regeneration that have direct translational applications in disease contexts.
Periodontitis is a widespread chronic inflammatory disease driven by host-microbial interactions and immune dysregulation, often resulting in alveolar bone loss and systemic complications. Exosomes, small extracellular vesicles enriched with microRNAs (miRNAs), have emerged as central modulators of these processes, mediated intercellular communication, and influenced inflammation, immunity, tissue homeostasis, and host-pathogen interactions in the periodontal microenvironment. Existing literature has identified their diagnostic relevance; however, a comprehensive framework connecting molecular mechanisms to clinical applications remains lacking. This narrative review proposes an integrative conceptual framework that illustrates the progression from exosomal miRNA biogenesis to their regulatory roles in periodontal disease, linking microbial triggers, immune modulation, and their emerging clinical relevance. We trace the molecular footprints of these exosomal miRNAs, particularly miR-146a, miR-155, and miR-223, and assess their dynamic roles as both biomarkers and regulatory agents in inflammation and tissue remodeling. Recent analytical advances, including systems biology, multiomics integration, and network modeling, are examined for their potential to decode complex miRNA-mediated pathways. Integration of transcriptomic, proteomic, and exosomal data is highlighted as a promising approach to enhance mechanistic insights and predictive accuracy. We also evaluate emerging diagnostic and therapeutic applications of exosomal miRNAs, particularly their potential in noninvasive biomarker development and targeted regenerative strategies. Key translational challenges are addressed, including the lack of standardized isolation protocols, interindividual biological variability, and the need for in vivo validation. Future directions should prioritize the development of engineered exosomes for targeted miRNA and anti-inflammatory delivery, alongside exosomal miRNA-based biosensors for real-time, minimally invasive disease monitoring. By bridging molecular footprints with emerging analytical approaches, this review offers a forward-looking perspective on the translational potential of exosomal miRNAs in periodontology, demonstrating their potential in advancing precision diagnostics and targeted therapeutics.
Impairment or irreversible loss of bone tissue function remains a prevalent clinical challenge, frequently compounded by donor scarcity, perioperative infection, and immune-mediated rejection, which collectively constrain therapeutic success rates. Novel functional nanomaterials based on nucleic acids-endowed with superior biocompatibility, predictable biodegradability, negligible systemic toxicity, and an abundance of programmable modification sites-have emerged as versatile platforms in bone tissue engineering. Currently, these materials are principally exploited across four interrelated domains: sustained release, bone targeting, scaffold materials for bone regeneration, and bioimaging, all aimed at orchestrating efficient bone regeneration. Recent mechanistic investigations into nano-bio interactions reveal that autophagy, a conserved catabolic pathway in eukaryotes that maintains energetic and metabolic homeostasis, critically governs skeletal repair by directing the timely degradation of intracellular cargo and the turnover of damaged organelles. Through direct modulation of osteoclast and osteoblast differentiation, autophagy fine-tunes the coupled process of bone remodeling. Concurrently, it shapes the regenerative milieu by reprogramming immune cell responses. Consequently, targeted modulation of autophagy represents a rational and promising strategy through which nucleic acid nanomaterials can accelerate bone regeneration. This review synthesizes current knowledge on the contributions of nucleic acid nanomaterials to bone healing, delineates the regulatory functions of autophagy in skeletal regeneration, and explains how these nanomaterials exploit autophagy as a mechanistic lever to enhance bone repair.
Alzheimer's disease (AD) is a severe neurodegenerative disorder that progressively worsens with age. Medicinal plants have demonstrated potential for the management of AD. Cassytha filiformis, a native plant of the Indian subcontinent, has been reported to exhibit antioxidant activity, which could be beneficial in neurodegenerative disorders. This study evaluates the anti-neurodegenerative effect and possible mechanism of action of a methanolic extract of Cassytha filiformis (MECF). Two compounds, AC-2 and AC-4, were isolated from the extract and assessed for cognitive behavior using the Morris water maze and probe test, followed by evaluation of antioxidant, neurochemical, and anti-inflammatory parameters, as well as in silico studies. Neurochemical abnormalities (acetylcholinesterase (AChE), NMDA (N-methyl-Daspartate), dopamine (DA)), neuro-inflammatory markers (TNF-α, IL-6), and antioxidant parameters (superoxide dismutase (SOD), lipid peroxidation (LPO), nitric oxide (NO)) were evaluated. Histological examination of brain cells assessed the regenerative impact of the isolated compounds. Antioxidant levels and neuroinflammation were significantly reduced (p < 0.05) in the MECF-, AC-2-, and AC-4-treated groups. Additionally, superoxide dismutase and catalase levels were significantly increased in the treated groups. Acetylcholine, NMDA, and dopamine levels showed marked improvement. Histopathological analysis revealed neuroregeneration in the test groups, and hematological evaluations supported these findings by demonstrating normalization of elevated blood profiles observed in the scopolamine-induced groups. MECF and its isolated compounds, AC-2 and AC-4, exhibited notable antioxidant and neuro-anti-inflammatory properties, enhancing cognitive function, learning, and memory. The observed neuroprotective effects suggest a potential therapeutic role for these compounds in the management of AD. Phenolic compounds present in AC-2 and AC-4 may be integral to the mechanism of action of MECF. Further investigations, including clinical validation, are necessary to explore the therapeutic potential of MECF, AC-2, and AC-4 in AD treatment.
Corneal endothelial cells (CECs) play a vital role in maintaining corneal transparency and function, with their hexagonal morphology being a hallmark of proper cellular packing and barrier integrity. This study investigates the functional role of miR-196a in regulating key cellular processes, including viability, cell cycle progression, stemness, mitochondrial function, and senescence. Human CECs were cultured and transfected with miR-196a mimics or inhibitors. Cell viability, proliferation, and cell cycle progression were assessed using the CCK-8 assay and flow cytometry. Gene expression was analyzed through real-time polymerase chain reaction and Western blotting. Mitochondrial function was evaluated using JC-1 staining and by measuring mitophagy markers. Senescence was induced using transforming growth factor β (TGF-β) and detected by senescence-associated β-galactosidase staining. Cytoskeletal changes were visualized through immunofluorescence staining. Signaling pathway activation was assessed using Western blotting and immunofluorescence. miR-196a overexpression enhanced cell viability, promoted cell cycle progression, and upregulated stemness markers, while its inhibition had opposite effects. It increased mitochondrial membrane potential and suppressed mitophagy markers. miR-196a modulated autophagy, cytoskeletal dynamics, and inflammation-related pathways by regulating ROCK1, ROCK2, and PAD4. It activated prosurvival pathways (YAP, MAPK) and reduced p53 levels. Importantly, miR-196a mitigated TGF-β-induced senescence by improving mitochondrial function, suppressing autophagy, and modulating TGF-β signaling components. These results showed the protective role of miR-196a in maintaining cellular function and suggest its therapeutic potential for addressing aging-related diseases, fibrotic disorders, and mitochondrial dysfunction. This study underscores miR-196a as a promising target for therapies aimed at counteracting cellular senescence and promoting regenerative capacities. miR-196a may serve as a novel therapeutic target for preserving corneal endothelial function and preventing age-related degeneration.
Proliferative diabetic retinopathy (PDR) is a leading cause of severe visual loss in working-age adults and represents the end stage of chronic neurovascular injury in diabetes. Despite advances in screening and treatment, including panretinal photocoagulation (PRP), intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents and pars plana vitrectomy (PPV), outcomes remain heterogeneous: many eyes stabilise, whereas others progress to vitreous hemorrhage, tractional retinal detachment or neovascular glaucoma despite apparently adequate therapy. This review synthesises current knowledge on the pathophysiology, morphological phenotypes and treatment paradigms of PDR, with a specific focus on predictors of onset, progression, and recurrence. PDR is contextualised as a multifactorial neurovascular and inflammatory disease, integrating data on hypoxia-driven angiogenesis, glial activation, microvascular rarefaction, neurodegeneration, and vitreoretinal interface remodelling. Histopathological and multimodal imaging characteristics of neovascular complexes and the vitreoretinal interface are described, highlighting how phenotypes on colour fundus photography, widefield fluorescein angiography, optical coherence tomography (OCT), and OCT angiography relate to ischemic burden and clinical behaviour. Systemic, ocular, imaging, biomarker, and genetic factors associated with progression from non-proliferative diabetic retinopathy to PDR and with progression within established PDR after PRP, anti-VEGF therapy, and PPV are critically appraised. Across modalities, younger age, diabetes duration, poor glycaemic control, renal disease, extensive non-perfusion, high neovascular burden, complex fibrovascular proliferation, and incomplete or unsustained treatment consistently emerge as determinants of guarded outcomes. Outstanding gaps in mechanistic understanding, risk stratification, regenerative therapy, and implementation are identified, alongside a proposed research agenda aimed at delivering mechanistically grounded risk-prediction tools and disease-modifying interventions for PDR.
Hollow-fiber bioreactors (HFBs) have emerged as promising platforms for tissue engineering because their capillary-like architecture can improve perfusion, molecular exchange, and three-dimensional cell organization. Their high surface-area-to-volume ratio and compartmentalized design help reduce the diffusion limitations commonly observed in static cultures, particularly in large or metabolically active tissue constructs. This review discusses recent advances in hollow-fiber-based systems for bone, liver, and pancreatic tissue engineering from experimental, computational, and materials-engineering perspectives. Particular attention is given to membrane composition, scaffold architecture, perfusion strategy, cell source, and organ-specific functional requirements. The reviewed studies show that hollow-fiber systems support different biological functions depending on the target tissue. In bone tissue engineering, hollow and hollow-channel scaffolds mainly contribute to vascular-like transport, osteogenic differentiation, and structurally guided tissue formation. In bioartificial liver systems, stable semipermeable membranes support compartmentalized hepatocyte culture, controlled solute exchange, and partial metabolic function. In bioartificial pancreas systems, hollow-fiber and encapsulation-based membranes are primarily designed to balance immunoprotection with rapid glucose sensing and insulin release. Across these applications, material selection is a critical determinant of performance, as biodegradable, bioactive, or mechanically stable polymers are required depending on the intended organ-specific function. Hollow-fiber-based platforms offer a versatile framework for engineering complex tissue constructs, but their clinical translation remains limited by challenges in scale-up, long-term cell functionality, oxygen supply, immune compatibility, and standardized evaluation. Future progress will require integrated optimization of membrane properties, dynamic perfusion, biomaterial design, and multicellular culture systems to improve the translational potential of hollow-fiber technologies in regenerative medicine.