The worldwide incidence of bone disorders is increasing at an alarming rate, especially among the elderly and those with increased obesity and poor physical activity. Therefore, bone tissue engineering, the process of regenerating diseased or damaged bone, is gaining increasing attention from the scientific community. One of the critical components for tissue engineering is the scaffold, an artificial extracellular matrix that promotes bone formation and regeneration activities. Due to the increasing demands for bone repair, bone tissue scaffolds have been extensively studied in state-of-the-art literature. Nevertheless, many areas related to scaffold manufacturing still offer huge scope for scientific research and development. One such area is the bioprinting of scaffolds, which combines the advantages of three-dimensional printing and biomaterials to create an ideal tissue growth support environment for bone tissue regeneration. This review highlights recent advances in the bioprinting of scaffolds for bone tissue engineering. Taking different biomaterial-based scaffolds as a starting point, the latest research progress and breakthrough points for enhancing the mechanical properties and bioactivities of scaffolds are summarized. Recent scientific breakthroughs related to the tailoring and creative design of scaffolds have been highlighted. New strategies and schemes for subsequent bone scaffold angiogenesis and osteogenesis promotion for new bone tissue regeneration are also discussed. This comprehensive review identifies the shift of research direction, where the biological requirements such as immune response and vascularization is prioritized over fabrication methods. Research gaps on vascularization bottlenecks, methodological and evaluation gaps, fabrication challenges and regulatory hurdles have been identified as well. Future direction of research includes AI assisted design, 4D printing, smart implants, organoid integration and benchmarking standardization of bone tissue implants.

Hepatocyte-like cells (HLCs) represent a promising therapeutic approach for acute liver failure (ALF), offering an alternative to primary hepatocytes, which are in short supply. Given the viscoelastic tissue properties of the liver and the growing recognition of the mechanical cues in physiology and disease, we investigated how ALF-induced changes in the liver's mechanical microenvironment might affect HLC-based cell therapy. Here, driven by specific disease-derived mechanical cues, we designed bioinspired hydrogel microspheres with tunable liver viscoelasticity to mimic the mechanical niche of healthy versus ALF liver tissue. We show that a fast-relaxation hydrogel niche mimicking the healthy liver guides the efficient differentiation of human adipose-derived mesenchymal stem cells (hADSCs) into functional HLCs by suppressing the formation of abnormal stress fibers and pathological YAP nuclear translocation through the ROCK axis. In both the carbon tetrachloride-induced and partial hepatectomy-induced ALF mouse models, these mechanically preconditioned HLCs exhibit significant therapeutic efficacy, promoting robust liver regeneration and acting as active mechanical regulators to suppress aberrant host mechanotransduction and remodel the diseased microenvironment. This disease mechanobiology-oriented strategy provides insights into the design of viscoelastic biomaterials for regenerative medicine and demonstrates a promising approach for enhancing cell therapy outcomes in liver failure.

Genetic engineering of therapeutic cells is a key strategy to enhance cell-based therapies, yet current gene delivery methods-viral vectors, electroporation, and commercial non-viral reagents-are limited by safety concerns, high cost, operational complexity, cytotoxicity, and poor scalability. We developed a safe, efficient, low-cost, and scalable non-viral gene delivery platform using a polyethylene glycol-polyethyleneimine (PEG-PEI) copolymer to engineer mesenchymal stromal cells (MSCs) for inflammatory bowel disease (IBD) treatment. The PEG-PEI copolymer was synthesized via covalent conjugation and formed stable core-shell nanocomplexes (∼130 nm, +20 mV) that completely protected DNA at N/P ≥ 10. In primary human MSCs, this platform achieved 43.8% EGFP-positive MSCs and enhanced IL-10 and bFGF secretion by approximately 2-fold and 1.6-fold, respectively, compared to Lipofectamine 3000, without compromising cell viability or multipotency. Engineered IL-10-overexpressing MSCs (PEG-PEI-IL-10-MSCs) were constructed and evaluated in a dextran sulfate sodium-induced murine acute colitis model. PEG-PEI-IL-10-MSCs restored body weight, reduced disease activity, ameliorated colon shortening and histopathological damage with efficacy comparable to the first-line drug 5-ASA, and significantly outperformed conventionally engineered or unmodified MSCs. Mechanistically, the treatment promoted epithelial proliferation and goblet cell regeneration, drove macrophage polarization toward an M2-reparative phenotype, suppressed pro-inflammatory cytokines (TNF-α and IL-6), and selectively normalized pathological angiogenesis while preserving functional vasculature. This PEG-PEI platform effectively overcomes the critical bottleneck of difficult-to-transfect primary MSCs, providing a versatile tool for cell engineering and a foundation for next-generation synergistic cell-and-gene therapies for IBD.

Diabetic wounds are characterized by delayed healing due to impaired angiogenesis and dysregulated immune-inflammatory responses. In this study, we developed a novel therapeutic approach utilizing a 4ArmPEG-NHS/4ArmPEG-NH2 cross-linked hydrogel for the sustained delivery of exosomes (Exos) derived from genetically engineered human adipose-derived mesenchymal stem cells (ADSCs) overexpressing Brain and Muscle Arnt-Like 1 (BMAL1). The efficacy of this system was evaluated both in vitro and in vivo. The hydrogel exhibited excellent injectability, tissue adhesiveness, and rapid hemostatic properties, enabling prolonged release of BMAL1-overexpressing exosomes (BMAL1-Exos). In a diabetic mouse wound model, treatment with BMAL1-Exos@Gel significantly accelerated wound closure, enhanced re-epithelialization, increased microvascular density (as indicated by CD31 and α-SMA immunostaining), improved blood perfusion, and promoted deposition of type I and type III collagen. Mechanistic investigations demonstrated that BMAL1-Exos effectively ameliorated high glucose-induced dysfunction in HUVECs, NIH/3T3 fibroblasts, and HaCaT keratinocytes, while promoting macrophage polarization toward the pro-reparative M2 phenotype and stimulating angiogenesis. These effects were mediated through modulation of the MAPK signaling pathway—specifically activation of JNK, ERK, and p38 kinases—along with upregulation of VEGFb and downregulation of TNF-α. In summary, our research findings indicate that hydrogel loaded with BMAL1-Exos hold promise as a diabetic wound repair strategy by enhancing angiogenesis, modulating immune responses, and remodeling the extracellular matrix.

The core of bio-3D printing technology lies in the development and optimization of bio-inks. For a long time, researchers have been looking for bio-inks that can balance printability and cell function. However, traditional bio-inks often have limitations in meeting this balance, limiting the complexity and scale of printable structures. In recent years, the emergence of sacrificial inks has brought a major breakthrough in this field, allowing bio-inks that were originally not very suitable for printing to accurately construct larger and more complex structures. This ink is unique in that it is used to support and position the bio-ink but is removed after printing is complete, not as part of the final printed structure. The mild nature of the state transition and removal conditions allows for minimal damage to cell viability and print structure when the ink is "sacrificed." This review will focus on the types of sacrificial inks and their two key applications in bioprinting: building intracranial vascular networks and improving bioink performance. We will summarize the current status, advantages, and challenges of these applications, aiming to provide readers with a comprehensive overview of the latest advances in the use of sacrificial inks in bioprinting. By sacrificing the application of ink, bioprinting technology can not only produce more realistic and complex tissue structures but also is expected to provide broader application prospects for clinical treatment and regenerative medicine in the future.

Regenerating the missing periodontium represents a difficult task during clinical management of periodontitis given that alveolar bone, periodontal ligament and cementum possess poor regeneration potential. The significant contribution of the inflammatory response to periodontitis occurrence and development has been extensively documented. Although the efficacy of treatments based on mesenchymal stromal cells (MSCs) has been proved, that of naïve MSCs treatment remains suboptimal. Herein, human MSCs stably expressing interleukin-10 (IL-10-MSCs) were established and evaluated for their performance in treating ligature-induced periodontitis rats. Utilising the electroporation method, a recombinant plasmid containing the human IL10 gene was introduced into human MSCs derived from umbilical cord to generate IL-10-MSCs. These IL-10-MSCs and blank vector transfected MSCs were transplanted into rat ligature-induced periodontitis models by repeated injections via the periodontal and tail veins. Following MSCs transplantation, their therapeutic effects on the rat model and the underlying mechanisms were explored. IL-10-MSCs injections markedly promoted periodontal tissue regeneration, decreased bone resorption, and inhibited inflammation at the lesion area, relative to transplantation with unmodified MSCs as a control. Additionally, treatment with IL-10-MSCs respectively enhanced and decreased the proportions of macrophages undergoing alternative (M2) and classical (M1) activation at the lesion site. IL-10-MSCs exhibited more promising therapeutic efficacy against periodontitis in rats than naive MSCs and might represent a novel periodontitis treatment option.

Three-dimensional (3D) culture systems have been shown to enhance cellular secretion of small extracellular vesicles (sEVs) compared to two-dimensional (2D) culture. However, the molecular mechanisms driving sEV secretion and influencing their potential for disease treatment have not been elucidated. In this study, we discovered the depolymerisation of cortical actin as a new mechanism that leads to increased sEV release, and that in 3D cultured mesenchymal stem cells (MSCs), this process was modulated by the downregulation of integrin-α1 (ITGA1) and subsequent inhibition of the RhoA/cofilin signalling pathway. Interestingly, the knockdown of Rab27A and Rab27B significantly reduced sEV secretion by MSCs to 0.5- and 0.1-fold, respectively. However, there was no difference in expression levels of Rab27A/B between MSCs cultured in 2D and 3D environments. In addition, sEVs derived from 3D cultured MSCs demonstrated enhanced therapeutic function both in vitro and in rat models of osteoarthritis (OA) and wound healing. Collectively, this study illustrates a new mechanism for enhanced secretion of sEVs, involving RhoA/cofilin pathway-dependent cortical actin depolymerisation, which is independent of Rab27A/B. These findings provide novel insights for optimising the yield of stem cell-derived sEVs, as well as their therapeutic efficacy for treating chronic diseases.

Sanggenon F is a flavanone-type natural product with different bioactivities, but its total synthesis has never been reported. In the present study, the first total synthesis of (±)-sanggenon F was accomplished in ten steps and 2.4% overall yield, involving two key reactions of the Aldol condensation and oxa-Michael addition. The promoting activity of (±)-sanggenon F on the osteogenic differentiation of human umbilical cord-derived mesenchymal stem cells (MSC) and human adipose-derived MSC was assessed via alkaline phosphatase staining and alizarin red S staining. Excitingly, (±)-sanggenon F displayed significant osteogenic differentiation promoting effect towards both cell lines and it might be used as a template molecule for the future design and development of adjuvant drugs in MSC therapy.

[This corrects the article DOI: 10.1016/j.mtbio.2025.101585.].

Liver fibrosis/cirrhosis, characterized by excessive deposition of extracellular matrix (ECM) and formation of fibrous scars, arises from chronic liver injury and poses a significant global health burden. Although liver transplantation remains the sole curative option, its application is limited by donor scarcity, immune rejection risks, and high costs. Cellular therapies, particularly those based on mesenchymal stromal cells (MSCs), have emerged as a promising alternative. This review comprehensively examines the therapeutic mechanisms and clinical efficacy of diverse cell therapies for liver cirrhosis, with a focus on MSC-based approaches. MSCs demonstrate multifaceted advantages, including immunomodulatory properties, anti-fibrotic effects (via hepatic stellate cell inhibition and ECM remodeling), promotion of hepatocyte regeneration, and mitigation of oxidative stress. Their low immunogenicity facilitates allogeneic transplantation, while their availability from multiple sources (e.g., bone marrow, umbilical cord, adipose tissue) supports scalable clinical application. We analyze 95 registered clinical trials (73 MSC-focused), highlighting consistent safety profiles but variable efficacy, influenced by factors such as cell source, preparation protocols, administration route, and patient heterogeneity. Key challenges include standardizing MSC production (donor selection, culture conditions, cryopreservation), optimizing delivery methods (intravenous vs. intrahepatic routes), and defining dosing regimens. Strategies to enhance MSC efficacy—such as genetic modification, biomaterial engineering, combinatorial therapies (e.g., with endothelial progenitor cells or macrophages), and MSC-derived extracellular vesicles—are critically evaluated. Future perspectives emphasize the need for large-scale randomized trials, single-cell technologies to resolve MSC heterogeneity, and organoid models to refine therapeutic protocols.

Background: Hip fracture (HF) is one of the most prevalent orthopedic conditions among the elderly, with falls being the primary risk factor for HF. With the surge of aged population, China is facing great challenges from HF and falls. However, a comprehensive long-term observation of risk factors affecting HF and falls and their association are little reported at a national level. Methods: The longitudinal cohort was established using the China Health and Retirement Longitudinal Study (CHARLS) data from 2011 to 2018. The incidence density and multi-risk-stratified lifetime risk (up to 90 years of age) of falls and HF were studied at index ages of 50, 60, and 70, as well as the lifetime risk stratified by six regions in China, based on the modified Kaplan-Meier method with Statistical Analysis System (SAS). Results: This study identified 17 705 subjects aged 50-89. The incidence density of falls was 65.07 and 47.53 per 1000 person-years in women and men, respectively. The incidence density of HF was also higher in women at 5.58 per 1000 person-years than in men at 4.88. By age 50, the lifetime risk of experiencing a HF was 18.58% for women and 13.72 % for men. Vision and hearing abilities were significantly related to the lifetime risk of both falls and HF. Obesity-related factors presented age-relevant relationships with lifelong risks. Lack of naps, poor lower limb strength, and physical capabilities were indicative of HF risk. The north-western region of China had the lowest lifetime risk of falls but highest risk of HF, while other regions showed a consistent trend between falls and HF. Conclusion: The aging population worldwide faces a considerable risk of falls and HF. Several risk factors were identified in this study using a Chinese population, relating to disease history, lifestyle habits, health status and physical function, and the risks differed among six regions in China. Future precautionary management programs, as well as patient self-awareness are necessary for improving the prevention of falls and HF to reduce their incidence in the aging population. The translational potential of this article: With the greatest aged population worldwide, China faces the unparalleled challenge on public health. The study poses the lifetime risk of hip fracture and falls stratified by multiple risk factors in people from 45 to 90 in a national scale, which would shed a light on the early and continuous prevention of such injury.

Background Osteoporosis is a progressive skeletal disorder influenced by multiple clinical and lifestyle factors. Early identification of individuals at high risk is essential for prevention and personalized management. This study aimed to identify key determinants of osteoporosis and to establish a bone density–based aging model to evaluate accelerated skeletal aging. Methods We analyzed data from a large cohort with dual-energy X-ray absorptiometry (DXA) measurements of the lumbar spine and proximal femur. Univariate and multivariate regression models were applied to assess the associations between clinical and lifestyle factors and osteoporosis risk. A bone density aging model was developed using support vector regression to estimate bone density age, and bone density age acceleration (BDAA) was calculated as the residual from chronological age. Results The bone density aging model showed good predictive performance (mean absolute error = 5.716 years, R² = 0.145). Higher BDAA was positively correlated with osteoporosis risk across bone health categories, including individuals without clinical diagnosis. In addition, BDAA differed significantly by exercise level, dietary pattern, body mass index, blood pressure, and metabolic comorbidities, providing insights into skeletal aging beyond chronological age. Conclusions Bone density based biological aging models can improve early identification and personalized risk stratification of osteoporosis. This approach may facilitate and support the development of precision medicine strategies in osteoporosis prevention and management. Trial registration Not applicable.

BACKGROUND:Postmenopausal osteoporosis (PMOP) is a critical bone metabolic disorder marked by progressive bone loss and compromised bone microstructure. Empirical clinical observations suggest that Fu Fang Sheng Mai Capsules (FFSM) can effectively alleviate symptoms of osteoporosis; however, their underlying molecular mechanisms remain insufficiently defined. The present study was designed to investigate the regulatory effects of FFSM on osteoclast differentiation and to evaluate its therapeutic potential in PMOP. METHODS:Bone marrow-derived macrophages (BMMs) were isolated and induced to differentiate into osteoclasts in vitro. The impact of FFSM on osteoclastogenesis was assessed by tartrate-resistant acid phosphatase (TRAP) staining and F-ACTIN ring fluorescence staining. Subsequently, quantitative real-time PCR (qRT-PCR) and Western blot analyses were performed to evaluate the expression of osteoclast-specific genes, with further mechanistic investigations. For in vivo validation, a bilateral ovariectomy model was established in C57BL/6 mice, and bone quality was examined using micro-CT and histological analysis. RESULTS AND CONCLUSION:FFSM significantly suppressed osteoclast formation and F-ACTIN ring assembly, with notable downregulation of osteoclast differentiation markers NFATc1 and Acp5 observed at days 3-5. Mechanistically, FFSM reduced intracellular ROS levels within osteoclasts, and specifically inhibited the phosphorylation of key signaling proteins, p-P65 in the NF-κB pathway and p-JNK in the MAPK pathway, thus interfering with pathways critical for osteoclastogenesis. Consistent with in vitro findings, in vivo studies revealed that FFSM reduced osteoclastogenesis and effectively rescued bone mass loss.

Artificial enzymes mimicking natural processes offer promising solutions for treating infections, but their development faces challenges in synthesis complexity and therapeutic performance. We present a modular-assembly strategy to construct hierarchical MOF@COF heterostructures through covalent interface engineering, bypassing the need for function-specific monomer synthesis while amplifying functionality. By growing porphyrin-based COF shell on amino-functionalized Fe-MIL-88A MOF core, we achieved a morphology-controlled core-shell architecture with well-defined heterojunctions. This hybrid integrates the MOF's dual peroxidase- and catalase-like activities with the COF's photoactivity, enabling cascade therapeutic effects. MOF@COF selectively converts endogenous H2O2 into bactericidal ⋅OH and O2 within infected tissues, enhancing photodynamic therapy through improved light harvesting and charge separation while alleviating hypoxia-induced resistance. As a broad-spectrum antimicrobial agent, MOF@COF simultaneously utilizes and remodels the infectious microenvironment, significantly accelerating wound healing. This work demonstrates a rational design approach for biocompatible artificial enzymes with synergistic catalytic sites, advancing self-reinforcing therapeutic strategies for infection treatment.

Aims: To optimize the culture process of Mesenchymal Stem Cells (MSCs) and enhance their biological functions. Background: MSCs have shown great potential in treating various diseases due to their low immunogenicity and potent paracrine effects. However, the inherent heterogeneity of MSC populations, which can vary depending on the culture conditions, may challenge large-scale clinical application. Objective: This study investigates the inconsistency of MSCs cultured in different media, from the transcriptional level to biological functions. Method: RNA sequencing was used to identify different expressed genes of MSCs separated and expanded in three media, which were then validated with qPCR. In vitro assays, including proliferation, tube formation, wound healing, multilineage differentiation, paracrine secretome and injured hepatocyte protection assay, were performed to verify the potential differences among three groups. Result: MSCs cultured in platelet lysate-containing medium exhibited high expression of genes involved in extracellular matrix regulation, collagen metabolic processes, and angiogenesis, whereas those cultured in serum-free medium demonstrated high expression of genes associated with DNA replication and chromosome segregation. MSCs cultured under serum-containing medium indicated high levels of genes associated with extracellular matrix regulation, cartilage development, and chemotaxis. The results of functional comparative experiments were consistent with the differences in their gene expression patterns. Notably, MSCs cultured in the serum- containing system exhibited greater protective effect against hepatocyte activity. Conclusion: Different culture conditions affect the biological functions of MSCs. Optimal conditions should be investigated for applications. Next, an in vivo model should be established to evaluate differences in MSC tissue repair function under various culture conditions. .