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The objective of this study is to investigate the safety, biodistribution, and exploratory clinical outcomes of enekinragene inzadenovec (PCRX-201), a high-capacity, nonintegrating, nonreplicating adenovirus serotype 5 vector expressing interleukin-1 receptor antagonist under the control of an inflammation-inducible promoter, in patients with moderate-to-severe knee osteoarthritis. This open-label phase 1 trial (NCT04119687) enrolled participants aged 30 to 80 years with symptomatic (Western Ontario and McMaster Universities Osteoarthritis [WOMAC] pain score ≥ 5 and ≤ 9 [0-10-point scale]) and radiographic (Kellgren-Lawrence grade 2-4) knee osteoarthritis. In part 1, participants received a single intra-articular injection of PCRX-201 at 1 of 3 doses (n = 36). In part 2, participants received intra-articular methylprednisolone acetate immediately before PCRX-201 at the same dose (n = 36). Outcomes at week 104 included safety (primary endpoint), biodistribution (secondary endpoint), clinical outcomes (exploratory patient-reported endpoint), and immunogenicity. Data were analysed as observed. Transient treatment-related knee effusion was the most common adverse event and occurred less frequently in participants receiving glucocorticoid pretreatment (13/36 [36.1%]) than in those who did not (22/36 [61.1%]). Very limited biodistribution was detected outside the knee; only 2 participants had detectable PCRX-201 in plasma on days 1 and 4 postinjection. By week 104, 33/72 (45.8%) of participants had discontinued the study; however, those remaining showed sustained improvements with PCRX-201 for the exploratory outcomes of pain, stiffness, and function across doses and groups, regardless of preexisting neutralising antibody levels, with greater improvements observed in the glucocorticoid-pretreated group. A single intra-articular injection of PCRX-201 demonstrated safety and localised distribution within the knee. Exploratory patient-reported clinical outcomes suggest promise and support further investigation of PCRX-201.

Background Vascular factors have been associated with osteoarthritis (OA), but the association between popliteal artery wall morphology and symptomatic and radiographic knee OA outcomes over time remains unclear. Purpose To evaluate the associations between MRI-derived measures of popliteal artery wall morphology (localized wall thickening and global wall burden) and symptomatic and radiographic knee OA outcomes. Materials and Methods In this secondary analysis of the Osteoarthritis Initiative (February 2004 to October 2015), baseline knee MRI scans were analyzed to quantify maximum wall thickness and normalized wall index (NWI). Symptomatic OA was assessed using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores, and radiographic OA using Kellgren-Lawrence (KL) grade. Cross-sectional and longitudinal associations were assessed using linear regression and Cox proportional hazards models, respectively, adjusted for demographic and clinical covariates. Results A total of 9333 knees from 4710 participants (mean age, 61.1 years ± 9.2 [SD]; 2753 female) were included. Each 1-mm increase in maximum wall thickness was associated with higher WOMAC pain scores (β = 2.0; P < .001) and KL grades (β = 0.1; P < .001), as well as symptomatic worsening (hazard ratio = 1.10 [95% CI: 1.02, 1.19]; P = .02) and incident radiographic OA (hazard ratio = 1.21 [95% CI: 1.02, 1.44]; P = .044). Each 10% increase in NWI was associated with higher WOMAC pain scores (β = 6.7; P < .001) and symptomatic worsening (hazard ratio = 1.38 [95% CI: 1.20, 1.58]; P < .001) but was inversely associated with KL grade (β = -0.1; P = .001) and incident radiographic OA (hazard ratio = 0.60 [95% CI: 0.43, 0.83]; P = .004). Conclusion Localized popliteal arterial wall thickening was associated with symptomatic OA worsening and incident radiographic OA, whereas diffuse wall remodeling was associated with symptomatic OA worsening and was inversely associated with radiographic outcomes. Clinical trial registration no. NCT00080171 © RSNA, 2026 Supplemental material is available for this article. See also the editorial by Jarraya and Harandi in this issue.

Osteoarthritis is a complex joint disease, affecting more than 500 million people worldwide. We investigated DNA methylation profiles and integrated these with matching genotype and transcriptomics data in primary tissues of patients with knee osteoarthritis to enhance our understanding of the regulatory framework that modulates gene expression in osteoarthritis. We measured matched genotype and methylation from primary chondrocytes of macroscopically intact (low-grade) and degraded (high-grade) disease cartilage as well as synovium, infrapatellar fat pad, and blood samples, for 314 patients who underwent total knee replacement for osteoarthritis. We generated methylation quantitative trait locus (mQTL) maps in cartilage, synovium, fat pad, and blood, as well as expression quantitative trait methylation (eQTM) maps in cartilage and synovium. We integrated these results with genome-wide association studies (GWAS) to identify likely effector genes of osteoarthritis. We reported widespread associations between genetic variants and methylation as well as between methylation and gene expression. Through colocalisation, we find methylation sites with a potential causal role in osteoarthritis. By tissue-specific integration of colocalisation and eQTM results, we resolved GWAS signals and identified 50 likely effector genes. We provided the largest genome-wide mQTL maps of low- and high-grade osteoarthritis cartilage and synovium. We further presented the largest cartilage eQTM map for primary cartilage and the first eQTM map in synovium. We found methylation sites with a potential mechanistically causal role in osteoarthritis and associated these with likely effector genes. Together, the presented genome-wide eQTM and mQTL maps constitute relevant resources for osteoarthritis research and beyond.

Mechanical overloading is a key risk factor for knee osteoarthritis (OA), yet its compartment-specific effects on the mechanobiology of the osteochondral unit and its interplay with synovial inflammation remain insufficiently defined. Here, multiscale imaging of clinical specimens is applied to uncover how mechanical and inflammatory cues shape the osteochondral unit in knee OA. Medial and lateral femoral condyles from patients with primary OA and secondary OA due to rheumatoid arthritis (RA), spanning varus to valgus alignment, were analyzed. A comprehensive multiscale imaging pipeline, including micro-computed tomography, cartilage- and bone-specific histomorphometry, quantitative backscattered electron imaging, and osteocyte lacunocanalicular network analysis, is integrated with targeted proteomic profiling of synovial fluid. Mechanical alignment is strongly associated with compartment-specific cartilage degeneration and subchondral bone adaptation in OA, as reflected by robust correlations between loading and OARSI score, subchondral bone thickness, bone formation, and osteocyte lacunocanalicular network parameters. Notably, the medial compartment exhibits substantially greater susceptibility to mechanically induced osteochondral remodeling than the lateral compartment. In contrast, these structure-function relationships are attenuated in RA. Collectively, these findings indicate that osteochondral remodeling in knee OA is predominantly associated with mechanical loading and reveal disease- and compartment-specific patterns in the balance between mechanical and inflammatory contributions, supporting a more tailored approach to treating knee arthropathies by prioritizing biomechanical or anti-inflammatory strategies according to disease context and compartmental involvement. STATEMENT OF SIGNIFICANCE: There remains ongoing debate regarding the extent to which osteoarthritis (OA) is a mechanical disease. The investigation of leg axis deviations (i.e., mechanical alignment) provides an ideal model to address this question. Here, we present a comprehensive multiscale characterization of the osteochondral unit in knee OA, integrating clinical imaging, micro-CT, histomorphometry, quantitative backscattered electron imaging, and targeted synovial proteomics. Mechanical alignment emerged as the predominant factor associated with cartilage degeneration, pathological subchondral bone formation, and osteocyte lacunocanalicular network alterations. In contrast, synovial TNF-α independently predicted cartilage degeneration in an inflammatory OA subtype secondary to rheumatoid arthritis. These findings reveal disease- and compartment-specific patterns and support a tailored approach in which biomechanical and biological strategies are prioritized according to context.

Osteoarthritis (OA) is a debilitating joint disease in which early microstructural and compositional changes in articular cartilage (AC) are challenging to detect with current diagnostic tools. We hypothesized that multispectral imaging (MSI) could capture optical signatures that predict key AC properties. To test this, we developed and evaluated an MSI-based approach for estimating tissue thickness, proteoglycan (PG) content, collagen fiber orientation, and cell morphological properties (area and circularity). Reflectance images of bovine patellar AC were acquired using a custom-built MSI system operating at six wavelengths (550-970 nm), and machine learning models were trained to predict the targeted markers. The models yielded reliable estimates for AC thickness, whereas for PG content, collagen fiber orientation, and cell circularity, they achieved moderate accuracy. This work suggests that MSI holds promise as a label-free tool for characterizing AC and detecting early degenerative changes.

Cartilage extracellular matrix (ECM), a hydrated collagen II-aggrecan composite, undergoes dynamic turnover during both normal homeostasis and disease-associated remodeling. This study elucidates a crucial role for decorin in promoting the retention and stability of nascent aggrecan within this matrix. By applying bio-orthogonal click-labeling, we demonstrate that loss of decorin accelerates the release of nascent aggrecan under both physiological and inflammatory conditions, without affecting its preferential localization to the pericellular matrix. Conversely, supplementation with exogenous decorin mitigates inflammation-induced loss of nascent aggrecan, supporting its potential as a therapeutic target. At the molecular level, decorin exhibits strong binding affinity for aggrecan, and enhances aggrecan-aggrecan and aggrecan-collagen II interactions, reinforcing its direct role in integrating cartilage matrix constituents. Also, by binding to collagen II, decorin stiffens the collagen II fibril network, thereby strengthening the confinement effect that limits the diffusive loss of entrapped aggrecan. Notably, decorin does not alter chondrocyte transcriptomic profiles in vivo, emphasizing its primary role in maintaining matrix integrity through biophysical mechanisms rather than cell signaling. Together, these findings provide a mechanistic foundation for developing decorin-based biomaterials or gene therapies aimed at preserving or regenerating the cartilage matrix for improved outcomes in osteoarthritis. STATEMENT OF SIGNIFICANCE: Development of effective cartilage repair strategies is challenged by the limited understanding of molecular events that regulate the dynamic turnover and degenerative changes of cartilage extracellular matrix. This study shows that decorin, a small proteoglycan, promotes the retention and stability of nascent aggrecan within both normal and degenerative cartilage matrix by augmenting the integration between collagen II and aggrecan molecules and strengthening the collagen II fibril network. In turn, exogenous decorin mitigates the accelerated loss of nascent aggrecan instigated by inflammatory stimulation. Collectively, these findings establish decorin as a therapeutic target for preserving cartilage matrix integrity and improving osteoarthritis intervention.

Cartilage degradation after joint injury often leads to post-traumatic osteoarthritis, a process accompanied by a drop in synovial pH. Traditional dynamically crosslinked hydrogels overlook how their mechanical and tribological properties change in such acidic, inflammatory environments. Here, we report an arthritis-responsive, injectable hydrogel designed to both regenerate articular cartilage and inhibit its further degradation. The hydrogel is formed via Schiff base chemistry between aldehyde groups of oxidized hyaluronic acid (OHA) and amino groups of adipic acid dihydrazide-grafted chondroitin sulfate (Chs-ADH) and carboxyethyl chitosan (CEC). Under neutral pH, the imine bonds remain stable, allowing precise defect filling and minimizing stress-induced debris; under acidic conditions, their reversible nature enhances lubrication and resists wear. The hydrogel formulation was optimized using molecular dynamics simulations to achieve excellent injectability, shear-thinning behavior, and low friction without impeding normal joint motion. In vitro, the hydrogel exhibited outstanding biocompatibility and stimulated cell migration. In vivo, it accelerated cartilage repair, prevented cartilage degradation, and restored the lubrication of newly formed tissue to levels comparable with healthy cartilage. Together, these findings demonstrate that the pH-sensitive hydrogel is a promising candidate for effective cartilage repair and prevention of cartilage degradation.

Osteoarthritis (OA) is the most common degenerative joint disease in the elderly, which sometime accompanies with bacterial infection. Hydrogen sulfide (H2S) gas delivery into cells has potential for treatment of infected OA. However, achieving controllable and sustained release of H2S for infected OA therapy continues to pose considerable challenges, attributable to the high diffusivity and exceedingly short half-life of H2S under physiological conditions. Herein, an injectable, pH-responsive, and multifunctional hydrogel (HSNP@HA) is constructed for dressing infected OA. The thioketal (TK)-linked dimeric dopamine conjugate and H₂S donor (HSD) was designed to form nanoparticles (HSNP) featuring ROS-responsibility, H2S release as well as antibacterial property. HSNPs were further incorporated into a pH-responsive hydrogel based on Schiff base cross-linking, which can gradually degrade under the acidic microenvironment of infected OA and lead to controlled and sustained release of HSNPs. Guided by this design, the hemocompatibility and cytocompatibility, H₂S release and ROS quenching, antibacterial and anti-biofilm efficacy, macrophage polarization and inflammatory signaling were synergically achieved, giving rise to attenuates inflammatory cascades, preserves collagen II/proteoglycans, and normalizes subchondral microarchitecture in a bacteria-induced OA model. This work therefore provides a unified, translational strategy for infectious OA. STATEMENT OF SIGNIFICANCE: Joint infections worsen osteoarthritis and are hard to treat because antibiotics do not stay in the joint and biofilms resist drugs. We introduce a syringeable hyaluronic-acid hydrogel that forms a local depot for nanoparticles releasing the gasotransmitter hydrogen sulfide (H₂S) only when inflammatory oxidants are present. This antibiotic-free approach couples on-demand antibacterial action with reduction of oxidative stress and immune rebalancing, protecting cartilage and subchondral bone in rats. Compared with prior hydrogels or H₂S donors, our system provides sustained intra-articular delivery, biofilm disruption, and disease modification in one material. The platform shows how smart biomaterials can locally control infection and inflammation while limiting systemic exposure and resistance.

Osteoarthritis is a debilitating disease of synovial joints affecting millions of people worldwide. Despite this, there are currently no disease modifying osteoarthritis drugs (DMOADs), mainly due to poor retention within the joint space. Previously, our group has shown that partially PEGylated cationic poly(amido amine) (PAMAM) dendrimers electrostatically bind to articular cartilage and improve therapy retention times, resulting in reduced severity of osteoarthritis symptoms. Here, we develop a greater understanding of how PEGylation influences dendrimer-cartilage interactions through systematic modulation of PEG chain length and accessible charged amines, defined as PAMAM primary amines freely accessible to the physiological environment and void of any interactions with PEG. Utilizing various models, we found that cartilage binding strength and binding kinetics increased with increasing accessible charged amines, while biocompatibility decreased, independent of PEG chain length. Conversely, decreasing accessible charged amines or increasing PEG chain length enhanced diffusion through cartilage explants. We found accessible charged amines controlled electrostatic binding strength while PEG chain length controlled reversibility of binding. When PEG-PAMAM conjugates were compared to other cationic molecules studied for their cartilage binding properties, all dendrimers tested exhibited significantly greater binding affinities and binding site densities but reduced Donnan partitioning coefficients. Finally, we found controlling binding strength and cartilage diffusion is critical to achieving extended retention within healthy joints in vivo. Future studies can use the enhanced mechanistic understanding of dendrimer-cartilage interactions established here to optimize PEG-PAMAM conjugates as a cartilage drug delivery platform.

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative disease characterized by cartilage degradation and synovial inflammation with limited therapeutic options. In our study, cell-free fat extract (CEFFE), a bioactive fraction derived from adipose tissue, is evaluated as a therapeutic strategy for TMJOA. In chondrocytes, CEFFE enhances proliferation and viability, attenuates inflammatory apoptosis, and preserves extracellular matrix homeostasis by upregulating Col2a1 and Sox9 while suppressing matrix metalloproteinases. Integrated transcriptomic and epigenomic analyses demonstrate that CEFFE reduces the activating transcription factor 3 (ATF3) binding at the promoter of actin binding LIM protein 1 (ABLIM1) via repressing ATF3-binding chromatin accessibility, thereby inhibiting nuclear factor kappa-B (NF-κB) signaling. In a rat model of TMJOA, intra-articular administration of CEFFE alleviates cartilage degeneration, subchondral bone loss, and synovitis, without systemic toxicity. CEFFE also suppresses pro-inflammatory M1 macrophage polarization and decreases interleukin-1β and tumor necrosis factor-α expression in synovial tissue. These findings identify CEFFE as a dual-target therapeutic agent that modulates both chondrocytes and macrophages through epigenetic regulation of ATF3/ABLIM1/NF-κB signaling. Our study highlights CEFFE as a safe and accessible biomaterial with potential for clinical translation as a regenerative and anti-inflammatory strategy for TMJOA.

The osteochondral junction is a specialized region ensuring the biomechanical and biological integration of the unmineralized articular cartilage with the subchondral bone through an intermediate layer of mineralized cartilage. This location is of clinical relevance, being a target of osteoarthritis. While aging is considered a risk factor for osteoarthritis, the interplay between microstructural and material changes during aging and predisposing to joint degeneration is not fully clear. This is especially true for mineralized cartilage, which remains understudied despite its critical role in load transfer from unmineralized articular cartilage to bone. We investigate age-related alterations of mineralized cartilage and subchondral bone in rat tibiae of adult and aged animals using a multimodal, high-resolution, correlative analysis. Our approach includes micro-computed tomography to measure microstructural features, second harmonic generation imaging to visualize collagen organization, quantitative backscattered electron imaging to map local mineral content, and nanoindentation to obtain mechanical properties. Mineralized cartilage and subchondral bone exhibited distinct age-related modifications. At the architectural level, the subchondral plate thickened and the trabecular network became coarser, those changes being different from those observed in the metaphysis. At the tissue level, mineralized cartilage was less mineralized than bone but exhibited a greater relative increase in mineral content with age, underlying differences in mineralization. A central observation is that aging led to an abrupt transition in mineral content and mechanical properties across the interface between unmineralized and mineralized cartilage, with a conceivable impact on stress localization. Overall, these changes may alter load transfer and contribute to age-related joint degeneration. STATEMENT OF SIGNIFICANCE: The osteochondral junction is a critical yet poorly understood determinant of joint integrity and a primary site of osteoarthritis. Despite its central biomechanical role, mineralized cartilage remains largely under investigated. Here, we use a high-resolution correlative approach to reveal distinct, age-related changes in microstructure and material properties of mineralized cartilage and subchondral bone. Aging markedly steepens the mineralization gradient at the interface between unmineralized and mineralized cartilage, leading to an abrupt change in mechanical properties that may promote stress concentration and limit energy dissipation. Concurrently, mineralized cartilage becomes more mineralized, stiffer, and more brittle, with some changes more pronounced than in subchondral bone. These findings identify a previously underappreciated mechanism by which aging alters load transfer across the osteochondral interface, with implications for joint degeneration and biomimetic interface design.

To gain insight into higher fracture risk in individuals with type 2 diabetes, we determined the association of type 2 diabetes glycemic status and severity with longitudinal changes in peripheral bone density and microarchitecture. We conducted a longitudinal study of 769 participants from the Framingham Study who underwent high-resolution, peripheral, quantitative computed tomography (HR-pQCT) at the tibia and radius, in 2012-2016 and 2021-2023 (mean 8-year follow-up). Linear regression models estimated mean 8-year percent changes in bone measures, across indicators of diabetes severity, adjusting for age, sex, weight, and height. The mean age was 67 ± 7 years, and 59% of participants were women. More than half (57%) were normoglycemic (fasting plasma glucose [FPG] <100 mg/dL, not on any treatment), 31% had prediabetes (100 ≤ FPG ≤125 mg/dL), and 12% had type 2 diabetes (FPG >125 mg/dL or on treatment). Adjusted mean percent changes in HR-pQCT bone measures were similar across diabetes severity, including glycemic status, use of diabetes medications, duration of diabetes, and HbA1c. For example, cortical volumetric bone mineral density at the radius changed by -1.50% (95% CI -2.43, -0.56) in type 2 diabetes and -1.96% (-2.53, -1.39), in prediabetes, compared with -2.42% (-2.86, -1.97) in normoglycemia (reference group; all P > 0.05). The magnitude of peripheral bone loss over 8 years did not differ between individuals with type 2 diabetes and those with normoglycemia, suggesting that bone deterioration alone does not explain the higher fracture risk in older adults with type 2 diabetes. Future studies should address other contributors to skeletal fragility.

Puberty is a critical window for bone mass acquisition, determining lifelong fracture risk. Gonadotropin-releasing hormone agonist (GnRHa)-based pubertal suppression followed by gender-affirming hormone therapy (GAHT) is increasingly used in transgender and gender-diverse (TGD) adolescents, raising concerns about peak bone mass. To quantify changes in bone mineral density (BMD), bone mineral apparent density (BMAD), and z scores in TGD adolescents undergoing GnRHa with or without GAHT, and to identify predictors of skeletal outcomes. PubMed, Scopus, Web of Science, and Cochrane Library, from inception through September 2025. Longitudinal cohorts assessing BMD, BMAD, or z scores at the lumbar spine, total hip, or femoral neck in TGD adolescents treated with GnRHa with or without GAHT. Ten studies met the inclusion criteria. Data were extracted in duplicate; study quality was assessed using the Newcastle-Ottawa Scale. Random-effects models pooled mean changes across baseline (time 0 [T0]), after GnRHa (T1), and after GAHT (T2), stratified by skeletal site and sex assigned at birth. Metaregressions examined body mass index, age, Tanner stage, and treatment duration. Dual-energy x-ray absorptiometry-derived BMD, BMAD, and z scores. Ten cohorts comprising 751 adolescents (427 assigned female at birth [AFAB]; 324 assigned male at birth [AMAB]) were included. Lumbar spine z scores declined during GnRHa (AFAB: z-score change, -0.97 [95% CI, -1.09 to -0.85]; AMAB: z-score change, -0.73 [95% CI, -0.93 to -0.53]) despite stable BMD. z Scores used sex-assigned-at-birth normative references. After GAHT, BMD increased (AFAB: BMD mean difference, 0.09 g/cm2 [95% CI, 0.07-0.10 g/cm2]; AMAB: BMD mean difference, 0.13 g/cm2 [95% CI, 0.10-0.16 g/cm2]), with partial z-score recovery; values remained below baseline at T2 (AFAB: z-score change, -0.51 [95% CI, -0.69 to -0.34]; AMAB: z-score change, -0.52 [95% CI, -0.82 to -0.21]) but were not consistently statistically different across skeletal sites. Recovery at the total hip and femoral neck was smaller and more heterogeneous. Higher body mass index, shorter GnRHa duration, and longer GAHT exposure were associated with more favorable outcomes. This systematic review and meta-analysis found that pubertal suppression followed by GAHT was associated with transient z-score reductions and subsequent BMD increases. At T2, z scores remained numerically below baseline but were not consistently statistically different, suggesting an uncertain rather than demonstrated persistent deficit. Timely GAHT initiation is recommended.

Osteoporosis (OP) poses a significant challenge in regenerative medicine due to the lack of therapeutic strategies that can intelligently respond to the local pathological microenvironment for precise intervention. To address this issue, we developed a multifunction-integrated acid-responsive bone-affinitive nanoplatform (Asp6-PSO@MSNs, APS-M) for spatiotemporally coordinated bone regeneration. Hollow mesoporous silica nanoparticles (MSNs) were engineered to encapsulate the osteogenic bioactive Psoralen (PSO), surface-gated by a bone-targeting peptide (Asp6). This sophisticated design serves a dual function: the Asp6 gatekeeper ensures spatial accumulation at hydroxyapatite-rich lesion sites and remains closed at physiological pH, while the acidic microenvironment of osteoclasts triggers "temporal" gate opening for on-demand drug release. Mechanistically, transcriptomics and molecular assays unveiled a dual-mode therapeutic mechanism: the nanoplatform not only ensures high intracellular PSO concentration but also provides bioactive silicon ions from carrier degradation, which collectively robustly activate the PI3K-Akt signaling axis. This activation orchestrates a regenerative microenvironment by coupling osteogenesis (via RUNX2 stabilization) with angiogenesis (via VEGF upregulation), significantly outperforming free drug administration. Consequently, APS-M effectively reversed bone loss, restored microarchitecture, and enhanced biomechanical strength in osteoporotic mice. This work presents a sophisticated "seek-and-treat" nanoplatform that harmonizes the intrinsic bioactivity of silicate materials with targeted pharmacotherapy, offering an effective solution for precision osteoporosis management. STATEMENT OF SIGNIFICANCE: Herein, we report the rational design and synthesis of a new class of acid-responsive nanoreactors by integrating hollow mesoporous silica nanoparticles (MSNs) with surface-adaptive bone-targeting peptides (Asp6). Characterization studies demonstrated an optimal construct (APS-M) with a sophisticated "gatekeeping" capability, showing robust stability at physiological pH and rapid responsiveness to the acidic osteoporotic microenvironment. This optimized nanocarrier was subsequently encapsulated with the osteogenic drug psoralen (PSO). The resulting APS-M system was adequately investigated and shown to effectively synergize osteogenesis and angiogenesis via the activation of the PI3K-Akt signaling pathway. Our work provides new insights into nanoreactor engineering strategies for precision osteoporosis management.

Psoralea corylifolia L. (PCL) has been widely used to improve osteoporosis for thousands of years, whereas the anti-osteoporosis activity of its polysaccharides has not been systematically reported. Here, we firstly proved that PCLP80 crude polysaccharides exhibited significant improvement effects (p < 0.05) about femur bone mineral density, bone trabecula, and muscle function performances including grip strengths, and forced swimming times in glucocorticoid-induced osteoporosis (GIOP) mice. Subsequently, a novel acidic (PCLP80-1) and a neutral (PCLP80-2) polysaccharides were purified from PCLP80 fraction, with molecular weights of 20.07 and 53.39 kDa, respectively. PCLP80-1 was proposed to mainly consist of →3,6)-β-D-Galp-(1→, →6)-β-D-Galp-(1→, β-D-Galp-(1→, →4)-α-D-GalpA-(1→, →3,4)-β-D-Glcp-(1→, and α-L-Araf-(1 → moieties. PCLP80-2 was mainly characterized by →4)-β-D-Manp-(1→, →4,6)-β-D-Manp-(1→, α-D-Manp-(1→, →4)-β-D-Glcp-(1→, α-D-Galp-(1 → together with a small amount of →3,6)-β-D-Galp-(1 → residues. Their advanced structures were further characterized. Moreover, PCLP80-1 and PCLP80-2 both showed obvious anti-osteoporosis activity and improvement of muscle function in GIOP mice. The mechanism about increasing osteoblastogenesis mainly involved in PI3K/AKT/mTOR pathway in MG63 cells, Wnt and Hippo pathways in MC3T3-E1 cells. Taken together, this would benefit to develop high efficacy and low toxicity agents from PCL for the prevention and treatment of osteoporosis.

Osteoporotic bone defects (OBD) present a major clinical challenge, largely due to a pathological bone microenvironment that severely compromises regenerative capacity. Moving beyond conventional classification schemes that often fail to capture this pathological complexity, our review establishes a conceptual framework that categorizes emerging biomaterials by mirroring the intrinsic functional components of the bone microenvironment itself-namely, ion-releasing, metabolite-based, extracellular matrix (ECM)-mimetic, and cytokine-loaded systems. The component-centric taxonomy not only systematizes a disparate field but also directly links material design to underlying pathological mechanisms. Accordingly, these materials are engineered not merely as structural replacements but as active modulators designed to reprogram the pathological niche by concurrently targeting key mechanisms such as cellular dysfunction and immune-metabolic dysregulation. Furthermore, we explore the emerging roles of bone organoids and artificial intelligence (AI) in refining preclinical models. By integrating a deep biological understanding of the niche with engineering innovation, our work aims to provide a cohesive framework and forward-looking perspective to guide the development of effective, microenvironment-targeted regenerative strategies.

Calcium pyrophosphate deposition (CPPD) disease is a common form of arthritis affecting older individuals. This disease is characterised by high levels of pyrophosphate in articular cartilage, resulting in calcium pyrophosphate crystal formation in humans and inflammatory and degenerative arthritis. A loss-of-function mutation in the TNFRSF11B locus (also known as CCAL1), which encodes osteoprotegerin (OPG) causes familial CPPD. OPG acts as a decoy receptor for RANKL, thereby inhibiting osteoclast differentiation and activity. CPPD currently lacks any animal models. The goal of this study was to develop a murine model of early CPPD by incorporating the TNFRSF11B gene mutation in mice and determining its effects on bones, joints and CPPD biomarkers. We used CRISPR/Cas9 editing to generate mice carrying the TNFRSF11B mutation (Opgmt). Joint and bone phenotypes, bone remodelling biomarkers and key CPPD biomarkers were assessed in wild type (WT; Opgwt/wt), Opgwt/mt and Opgmt/mt mice at 6 and 12 months of age. Male and female mice carrying Opgmt displayed osteopenia and high bone remodelling markers at 6 and 12 months of age. This phenotype was concurrent with increased osteoclast numbers and activity. Female Opgmt/mt mice also displayed significant osteoarthritis features by 12 months of age, including articular cartilage loss in the lateral compartment of the knee based on Mankin structural damage scores. Additionally, biomarkers pathognomonic of CPPD disease, such as pyrophosphate, transforming growth factor (TGF)-β1 levels and ENPP1 activity, were significantly elevated in the joints of both 6- and 12-month-old female mice with OPGmt. Mice carrying Opgmt display bone and joint phenotypes characteristic of early-stage CPPD disease in humans. Opgmt mice represent a novel preclinical model of early CPPD, ideal for exploring potential therapies targeting the disease prior to the development of major joint damage.

Postmenopausal osteoporosis (PMOP) stems from estrogen deficiency, which leads to reduced central serotonin (5-HT) levels, induces depressive-like behaviors, enhances sympathetic nervous system (SNS) activity, and disrupts bone homeostasis. However, the underlying mechanisms and potential therapeutic strategies targeting this pathway remain incompletely understood. To test whether phytoestrogens diosgenin (DG) can inhibit bone loss in PMOP by restoring the 5-HT-SNS-bone metabolism circuit. Ovariectomized (OVX) mice and a pharmacological 5-HT-depletion model were used to quantify the DG's impact on brain 5-HT synthesis, SNS output, and skeletal integrity. PC12 cells were probed to determine whether DG activation of estrogen receptor-alpha (ERα) and its downstream PI3K/AKT/GSK3β cascade regulated the 5-HT synthase tryptophan hydroxylase-2 (TPH2) and the catabolic enzyme monoamine oxidase A (MAOA). DG triggers activation of PI3K/AKT/GSK3β via binding to membrane ERα, leading to increased central 5-HT levels, reduced SNS hyperactivity, and preservation of bone mass in OVX mice. In vitro, DG increased neuronal 5-HT supply by upregulating TPH2 and downregulating MAOA, mediated through the ERα-PI3K/AKT/GSK3β pathway. DG stabilizes the 5-HT-SNS-bone formation loop by repairing estrogen deficiency-induced 5-HT reduction, thereby preventing bone loss in PMOP. These findings highlight DG as a promising therapeutic candidate for mitigating central 5-HT deficiency and protecting skeletal health in postmenopausal women.

Bone marrow mesenchymal stem cells (BMSCs) are a critical cell type for stem cell-based bone regenerative therapy. Promoting osteogenic differentiation of BMSCs is important for the promotion of bone formation. Interferon regulatory factor 1 (IRF1) was discovered as an essential factor in immune responses and the differentiation of several cell lines. Nevertheless, the potential of IRF1 as a therapeutic target for the modulation of BMSCs in the context of bone regeneration strategies remains unexplored. Here, we investigated the role of IRF1 in BMSC fate determination and demonstrated IRF1 as a promising target for osteoporosis. Irf1-overexpressing and Irf1-knockdown murine BMSCs (mBMSCs) were established by plasmid and lentivirus transfection, and the expression efficiency was verified. The role of IRF1 in regulating the proliferation, migration, apoptosis, and osteogenic differentiation of mBMSCs in vitro was investigated using gain- and loss-of-function experiments. In addition, Irf1-overexpressing mBMSCs were implanted subcutaneously with scaffold material into the backs of nude mice to evaluate the ectopic osteogenesis capability in vivo. Irf1-overexpressing mBMSCs were injected into the tail vein of ovariectomized and aging-related osteoporosis mouse models to evaluate their therapeutic effects. In addition, the underlying mechanisms were explored by RNA sequencing and validated through real-time reverse transcription-polymerase chain reaction (RT-PCR) and western blotting (WB) analysis. Overexpression of Irf1 promoted the proliferation, migration, and osteogenic differentiation of mBMSCs, and suppressed apoptosis in vitro, while Irf1 knockdown had the opposite effects. Irf1-overexpressing mBMSCs also promoted ectopic bone formation and alleviated osteoporosis compared to controls in vivo. IRF1 may regulate the fate of mBMSCs through activation of the PI3K/AKT signaling pathway. This study suggested that overexpression of Irf1 promotes osteogenic differentiation of BMSCs and has a therapeutic effect on osteoporosis. IRF1 could play dual roles as a biomarker for bone formation and a potential target for osteoporosis treatment.

Current osteoporosis treatments fail to balance bone resorption and formation. Here we show that engineered 2-N,6-O-sulfated chitosan (26SCS), a synthetic pentasaccharide, restores 115% bone mass (therapeutic) and prevents 66% bone loss, surpassing bisphosphonates by simultaneously suppressing osteoclastogenesis and promoting vascularized osteogenesis. Mechanistically, 26SCS targets K97 in receptor activator of nuclear factor-κB (RANK) through geometrically matched sulfate pairs, blocking RANK ligand (RANKL) signalling to arrest preosteoclast fusion while enhancing platelet-derived growth factor-BB (PDGF-BB) secretion via preserved preosteoclast viability to drive angiogenesis-coupled mineralization. Structural and functional analyses reveal that carboxyl groups in natural glycosaminoglycans such as heparin competitively bind K97, disrupting therapeutic specificity-a limitation overcome by 26SCS's carboxyl-free design and sequence-controlled sulfation. Unlike monosulfated analogues (2SCS/6SCS) that oversuppress osteoclastogenesis or lack pro-osteogenic effects, 26SCS's dual sulfation balances inhibition with trophic support. Thus, this work redefines glycosaminoglycan therapeutics via sulfation-patterned, topology-engineered biomaterials harmonizing bone metabolism.

Signaling downstream of the receptor of parathyroid hormone (PTH1R) exerts two major skeletal effects: increases bone remodeling and, when stimulated intermittently, induces bone anabolism. Osteocytes express the PTH1R and are critical for the action of teriparatide/parathyroid hormone 1-34 (PTH). However, it is unknown whether they also mediate the effects of abaloparatide (a 34 amino acid synthetic analog of human parathyroid hormone-related protein, ABL), and whether actions on osteocytes are required for the increase in remodeling and/or the bone gain induced by PTH/ABL in diabetes. We addressed these questions by treating with PTH or ABL control or diabetic (DM) mice lacking the PTH1R in DMP1-Cre expressing cells that targets all osteocytes (cKO). Both PTH and ABL increased bone mass and improved or corrected cortical and trabecular bone microarchitecture only in fl/fl littermates but not in cKO, control or DM mice. Further, PTH/ABL increased bone strength and microindentation resistance only in control or DM fl/fl mice. In contrast, PTH/ABL increased serum P1NP and bone formation on cancellous, periosteal and endocortical surfaces, in control or DM mice of both genotypes. Moreover, serum CTX and osteoclast surface were increased by PTH/ABL in fl/fl and cKO, control or DM mice. Thus, actions on DMP1-Cre expressing cells are required for bone gain, microarchitecture restoration, strength and resistance to fracture, exerted by PTH and ABL under physiological and DM conditions, but not for the increase in bone remodeling. These findings demonstrate the dissociation of bone gain from bone remodeling and reveal that actions on DMP1-Cre expressing cells drive the gain in bone mass and strength induced by PTH and ABL.

The high stability of storage and high mineralization efficiency are pivotal for the restoration of acid-etched dental enamel, yet these demands are mutually exclusive and difficult to be met. Herein, we propose a bioinspired "dormancy-to-activation" mineralization strategy by synthesizing "dormant" adenosine 5'-triphosphate (ATP)-stabilized amorphous calcium phosphate (ACP) nanoparticles as the precursor that can be activated and accelerated by saliva for rapid crystallization to form hierarchically ordered crystalline hydroxyapatite nanorods (mineralization). To realize this goal, we have designed and constructed a bioinspired dormant-ATP-stabilized ACP nanoparticle system with high stability and controllable mineralization ability using ATP biomolecules as the stabilizer. The ACP-ATP nanoparticles can maintain the dormancy for mineralization in vitro, which can stabilize the amorphous structure of ACP nanoparticles for 25 days in water. In the oral environment, the alkaline phosphatase (ALP) in saliva acts as a biological signal to activate and accelerate the mineralization of ACP-ATP amorphous nanoparticles. More importantly, the coating of ACP-ATP amorphous nanoparticles on the acid-etched dental enamel can effectively restore the hierarchically ordered structure, recover mechanical properties, and replicate fracture-resistance behaviors of natural dental enamel.

Zn-based materials degrade in vitro at rates of <0.1 mm·y-1, which is slower than the clinical window required for barrier membranes. However, effective strategies to accelerate degradation remain limited, and increased degradation rates often result in premature perforation. Here, we introduce a 100 µm-thick Zn-based layered composite membrane that exploits chemical and potential gradients to simultaneously accelerate degradation and prevent through-thickness perforation. The membrane is sequentially stacked in ascending potential: Zn, Zn-2Cu, Zn-4Cu, and Zn-8Cu, establishing an interlayer potential gradient of 5.03 mV·µm-1. This gradient transforms corrosion from pitting-dominated penetration to a laterally propagated mode, yielding a degradation rate of 0.17 ± 0.03 mm·y-1 (3.4 times that of pure Zn) without perforation. The membrane exhibits an antibacterial rate exceeding 90% while reducing Cu content by 56%. Overall, the potential-gradient reprogramming enables safe accelerated degradation of biodegradable metals. STATEMENT OF SIGNIFICANCE: Current zinc-based biodegradable membranes degrade too slowly (<0.1 mm·y-1) for clinical barrier applications, while conventional acceleration strategies inevitably cause premature perforation. This work addresses this critical limitation through a 100 µm-thick layered composite membrane with an engineered interlayer potential gradient. By redirecting corrosion from pitting-dominated penetration to lateral propagation, the membrane achieves a 3.4-fold accelerated degradation rate without through-thickness perforation-the first biodegradable metallic barrier membrane to satisfy clinical requirements. Furthermore, this strategy of establishing electrochemical gradients via compositional layering is readily extendable to other biodegradable metal systems.

Magnesium alloys are emerging as promising candidates for biomedical applications due to their biodegradability, biocompatibility, and appropriate mechanical properties. However, achieving a balance between high strength and corrosion resistance remains a critical challenge. This study presents the development of a low-alloy Mg-1.2Zn-0.32Ca-0.25Sn (ZXT100) alloy aimed at overcoming the trade-off between high strength and high corrosion resistance. Comprehensive microstructural, mechanical, and electrochemical analyses were performed to elucidate the alloy's performance and underlying mechanisms. The ZXT100 alloy demonstrates the promising tensile yield strength (∼345 ± 13 MPa) and degradation rate (∼0.209 ± 0.012 mm/y), surpassing most commercially available and recently reported medical magnesium alloys. Grain boundary strengthening was found to be the primary mechanism for the improved yield strength, contributing approximately 65.8%. The modification of heterogeneous fiber structure facilitates balance between elasticity and strength. In vitro cytocompatibility and osteogenic differentiation assays confirmed favorable biocompatibility and enhanced cell migration compared to high-purity Mg. In vivo studies in rats and rabbits demonstrated controlled degradation, minimal gas formation, and favorable osteointegration with no systemic toxicity. This work provides a feasible strategy for designing high-performance biodegradable Mg alloys for load-bearing orthopedic implants. STATEMENT OF SIGNIFICANCE: Biodegradable magnesium alloys offer a promising alternative to permanent metallic implants, eliminating the need for secondary removal surgery. However, achieving both high strength and controlled degradation-essential for load-bearing orthopedic applications-remains a major challenge. Building on our previous compositional optimization, this study demonstrates that precise control of extrusion temperature enables microstructural design that simultaneously achieves exceptional yield strength (349 ± 13 MPa) and a low degradation rate (0.209 ± 0.012 mm/y) in a low-alloyed Mg-Zn-Ca-Sn system. The alloy also exhibits favorable biocompatibility in vitro and in vivo, positioning it as a strong candidate for next-generation biodegradable orthopedic implants.

The development of protein-based orthopedic biomaterials that integrate high performance with robust bioactivity for bone regeneration remains challenging. Here, inspired by ion-mediated natural silk spinning and calcium-mediated bone regeneration, we develop a calcium ion-mediated silk (CaIMS) bulk material via a scalable thermal moulding strategy. By engineering ion-associated protein-water interactions, the molecular structures and mechanical properties of bulk silk materials can be tailored. Mechanistic investigations reveal that Ca2+ exhibits a strong interaction with the silk fibroin backbone, increasing the glass transition temperature (Tg) and suppressing β-sheet crystallization during thermal processing. Meanwhile, water molecules preferentially coordinated by Ca2+ act as dynamic plasticizers, enabling effective thermoplastic processability while preserving structural integrity. Through coordinated regulation of calcium chloride content and environmental humidity, CaIMS bulk materials exhibit adaptable mechanical properties. The incorporated Ca2+ acts as an intrinsic mineralization reservoir, enabling in situ apatite formation and creating a pro-osteogenic microenvironment that significantly enhances osteogenic differentiation in vitro and bone regeneration in vivo. This work demonstrates CaIMS bulk materials as a promising platform for bone repair and highlights the critical role of ion-associated protein-water interactions in the development of functional regenerative biomaterials. STATEMENT OF SIGNIFICANCE: Inspired by ion-mediated natural silk spinning and calcium-mediated bone regeneration, we develop calcium ion-mediated silk (CaIMS) bulk materials for bone repair. Using a thermal moulding process, calcium ions simultaneously control the material's stiffness, toughness, and ability to form bone‑like mineral. Unlike conventional implants that trade strength for bioactivity, our silk retains adaptable mechanics while actively promoting new bone growth. The embedded calcium acts as a built‑in reservoir for mineralization, creating a pro‑healing environment that enhances cell differentiation and accelerates bone regeneration in rats. This work introduces ion‑protein interactions as a powerful design strategy for next‑generation, load‑bearing biomaterials that are both mechanically robust and biologically active.

Hydrogels have garnered considerable attention in wearable devices due to their tunable mechanical properties. However, their applications are constrained by limited conductivity and inadequate freeze-resistance. In this study, we develop a physical-chemical dual network eutectogel (PECA/CMCX) through a synergistic enhancement strategy combining the multiple hydrogen bonds of carboxymethyl cellulose sodium (CMC) with metal-ion coordination within a deep eutectic solvent (DES). The eutectogel incorporates a physically cross-linked CMC network with a chemically cross-linked polyacrylamide (PAM) network via multiple non-covalent interactions (e. g., hydrogen bonds) and covalent bonds formed through free-radical polymerization. PECA/CMC1.35 eutectogel exhibits superior mechanical properties, a fracture toughness (29.22 kJ·m-3) and a high tensile stress (23.8 kPa). Owing to the carboxyl-metal ions coordination and the freezing-point depression effect of DES, the eutectogel maintains a high conductivity of 0.35 S·m-1 at -20 °C. When employed as an electrolyte in a supercapacitor, it exhibits stable cycling performance, retaining 79.4% of its initial capacitance and a Coulombic efficiency of 92.3% after 2000 cycles. As a strain sensor, the eutectogel achieves a gauge factor (GF) of 1.06 over a range of 40-200%. This work introduces a sustainable synergistic design strategy for multifunctional eutectogel suitable for flexible electronic devices under extreme conditions.

The application of hydrogels in flexible electronics and strain sensors devices is severely constrained by their intrinsic mechanical weaknesses. Conventional uniaxial orientation strategies enhance strength along one direction but inevitably result in mechanical anisotropy within the plane, making them susceptible to failure under complex loads. This study presents a "Cooperative Ordered Arrangement" strategy to fabricate sodium alginate/polyacrylamide (SA/PAM) hydrogels with exceptional and uniform in-plane mechanical properties due to the alignment of SA parallel to the plane. The obtained hydrogel exhibits outstanding comprehensive properties with quasi-isotropic and uniformly reinforced in-plane performance. It delivers a tensile strength of 6.06 ± 0.15 MPa, a Young's modulus of 24.79 ± 0.86 MPa, a fracture toughness of 10.20 ± 0.55 MJ m-3, and a fracture strain of 226.88 ± 10.71%, consistently achieved along all in-plane directions. Meanwhile, the hydrogel also shows direction-insensitive strain-sensing behavior, exhibiting a high conductivity of 81.18 ± 1.91mS m-1 and nearly identical relative resistance change (ΔR/R₀) trend under deformation regardless of the loading directions. This work provides an efficient manufacturing strategy for developing high-performance hydrogels with uniform in-plane characteristics, demonstrating their significant potential for use in demanding mechanical and sensing applications.

Implant-associated infections and loosening remain formidable clinical challenges. Conventional strategies such as incorporating antibiotics and metal ions can result in drug resistance and systemic toxicity, ultimately compromising tissue regeneration. Herein, we propose an immune-driven strategy for safe and effective anti-infection and pro-osseointegration, in which early immune activation promotes bacterial clearance, followed by timely resolution of inflammation to support angiogenesis and osteogenesis. As proof of the principle, gradient phase-transited lysozyme (PTL) on fixed size sodium titanate nanowires (PTL/nanowire composite coating) was constructed on Ti surface, creating a multifunctional platform for high-throughput screening (HTS) of optimal PTL dosages to support macrophage-driven bacterial clearance and osseointegration. The results revealed that PTL markedly enhanced bacterial clearance of macrophages (MΦs) through activating their Toll-like receptor 4 (TLR4) signaling pathway, while the nanowires beneath the PTL could promptly convert MΦs into pro-healing M2 phenotype, creating favorable macrophage-mediated immune microenvironment that promoted angiogenesis and osteogenesis. Among the tested formulations, moderate PTL dosage (PTL-3) achieved optimal balance of bacterial clearance and bone regeneration. In vivo experiments further corroborated the efficacy of PTL/nanowire composite coating in promoting infectious bone regeneration. This study underscores the potential of PTL/nanowire composite coatings for safely and effectively macrophage-driven bacterial clearance and osseointegration, paving the way for clinical translation in orthopedic and dental applications.

Achieving both robust mechanical and osteogenic properties of bone adhesives remains challenging. Here, we developed a novel polyurethane-based bone adhesive (PCLU-g-nHA) by covalently incorporating aminated nanohydroxyapatite (nHA-NH2) into a biodegradable poly (ε-caprolactone) urethane (PCLU) network. This design promoted uniform nHA dispersion and strong organic-inorganic integration through urea linkages, significantly enhancing compressive modulus (4.91 ± 0.10 MPa) and adhesive strength (3.41 ± 0.24 MPa in lap-shear). The adhesive cured rapidly under mild conditions with minimal heat release. PCLU-g-nHA showed improved biocompatibility and stimulated bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation in vitro. Transcriptomics revealed upregulation of extracellular matrix remodeling and collagen synthesis pathways. In vivo, PCLU-g-nHA enhanced bone regeneration and osseointegration in rabbit femoral condyle defect and tibial fracture models, outperforming a commercial PMMA bone cement. This study offers a scalable strategy for developing highly bioactive and tough bone adhesives with clinical translational potential.

The impaired bone healing and osseointegration in diabetes are largely driven by hyperglycemia-induced mitochondrial dysfunction in bone marrow mesenchymal stem cells (BMSCs). To rescue this cellular deficit and enhance bone repair, this study aimed to develop an adhesive, self-healing, mitochondrial coenzyme-based hydrogel coating for titanium (T) implants. We synthesized p(LA-AcAln) hydrogel through the copolymerization of α-lipoic acid (LA) and acrylated alendronate sodium (AcAln). This coating achieved robust "interface-welding" adhesion by forming a stable covalent "surface-S-S-gel" interface through dynamic thiol-disulfide exchange between the disulfide bonds (-S-S-) in p(LA) and the thiolated titanium surface. In vitro experiments demonstrated that the released LA monomers from the coating activate the Keap1/Nrf2 signaling pathway, suppress oxidative stress, restore the mitochondrial membrane potential of BMSCs, and significantly inhibit cell apoptosis in a hyperglycemic environment. Moreover, Ti/p(LA-AcAln) regulated mitochondrial dynamics by promoting fusion and inhibiting fission, thereby restoring ATP production and compensating for the energy deficit in bone formation. In vivo evaluations using a diabetic rat femoral defect model revealed that this coating can significantly improve bone osseointegration. This study not only developed a promising surface modification strategy for orthopedic implants but also provided a viable approach for the treatment of diabetic bone defects and mitochondrial-related orthopedic diseases.

Zinc (Zn)-based biodegradable implants hold great promise for orthopedic applications, yet their clinical translation is hampered by uncontrollable corrosion leading to Zn2+ release at potentially toxic levels in the early stage and insufficient osteogenic stimulation later. Herein, a near-infrared (NIR)-responsive hybrid coating composed of indocyanine green-loaded zeolitic imidazolate framework-8 (ICG@ZIF-8) and polycaprolactone (PCL) is engineered on a Zn-Li-Mg alloy to achieve stage-adaptive corrosion regulation. Initially, the PCL barrier effectively slows down corrosion (∼3.84 μm yr-1) and Zn2+ release, ensuring initial biocompatibility. Upon NIR irradiation, photothermal conversion of ICG@ZIF-8 induces localized heating and PCL deformation, on-demand partially restoring corrosion (∼8.53 μm yr-1) and enabling sustained Zn2+ release to leverage its osteogenic effect. In vitro studies demonstrate enhanced osteogenic differentiation and mineralization, mechanistically attributed to the activation of the Wnt/β-catenin/TCF pathway. In vivo, the NIR-triggered platform promotes critical-sized femoral defect regeneration with 26% higher new bone formation. This work provides a smart material strategy for spatiotemporal control of biodegradable Zn implants, offering a promising strategy toward bone repair.

Rheumatoid arthritis (RA) remains a challenging autoimmune disease with variable treatment responses to tumor necrosis factor-α (TNF-α) inhibitors. This study investigates the clinical significance of PD-1hiCXCR5-CD4+T peripheral helper (Tph) cells in RA and their potential utility as biomarkers for predicting etanercept (ETN) therapy response. We enrolled 58 RA patients, 12 age- and sex-matched osteoarthritis patients, and 15 healthy controls, with Tph cells quantified by flow cytometry. Among 25 RA patients with inadequate response to conventional synthetic disease-modifying antirheumatic drugs receiving ETN therapy, treatment outcomes were stratified by ACR20 response criteria. Tph cell frequency was significantly elevated in RA patients and correlated positively with multiple disease activity indicators. At baseline, ETN nonresponders exhibited higher Tph proportions than responders (13.23 ± 2.60% vs. 10.82 ± 3.08%, p = 0.0467). Following ETN treatment, responders demonstrated significant Tph reduction (10.82% decreased to 7.97%, p = 0.0105), paralleling serum IL‑21 dynamics. In an exploratory analysis, baseline Tph levels showed an association with ETN response. These findings suggest that circulating Tph cells may serve as a candidate biomarker for RA disease activity and therapeutic response monitoring, warranting further validation in larger prospective cohorts.

Tough adhesives require efficient bulk energy dissipation, yet the molecular design principles for achieving this without sacrificing adhesion strength remain a challenge. Here, we report a chain-length regulation strategy for UV-curable acrylate adhesives, in which long polymer strands between cross-linking points generate effective entanglements, thereby promoting bulk energy dissipation during debonding. The resulting adhesives achieve exceptional adhesion strength (23.13 MPa) and ultrahigh adhesion toughness (36.77 kJ m-2). Fracture measurements and digital image correlation show that the long-chain entangled network markedly increases bulk fracture energy by delocalizing crack-tip strain into an enlarged deformation process zone and retarding crack propagation. Chain-dynamics and chain-conformation analyses further confirm the role of entanglement by revealing a broader relaxation spectrum and a much larger releasable conformational length in the long-chain network that enhances bulk energy dissipation. We further demonstrate its application potential and excellent long-term environmental stability, together with a physics-informed prediction of long-term adhesion retention across practical service temperatures. These results establish chain-length regulation as an effective molecular design strategy for strong and tough adhesives.

MXenes combine rich surface chemistry, mechanical strength, and high conductivity for a multitude of emerging applications. Predictive modeling supports accelerated materials designs and has been limited by the absence of validated and transferable force fields. Here, we introduce an interpretable, reactive INTERFACE force field (IFF and IFF-R) for Ti3C2Tx MXenes that is trained based on chemical knowledge and achieves quantitative agreement with experiments across lattice parameters (<0.5%), density (<0.2%), liquid contact angles, Raman spectra, and the in-plane elastic modulus (∼320 GPa). The models cover surface terminations from hydroxyl (-OH) to fluorine (-F) groups and are extensible to other chemistries. We introduce pH-resolved surface chemistry and identify dopamine adsorption mechanisms at MXene-aqueous interfaces supported by QCM-D and UV-Vis experiments. The data reveal coplanar and perpendicular binding modes and concentration-dependent multilayer assembly. We predict previously inaccessible properties, including termination-dependent cleavage energies, interlayer shear moduli and dynamic shear failure, nanoindentation and brittle fracture, anisotropic in-plane and out-of-plane thermal conductivities, including the role of defects. Agreement with available experimental data is consistently close and exceeds DFT accuracy across the benchmark properties examined. The IFF/IFF-R model is compatible with CHARMM, AMBER, OPLS, and CVFF force fields for simulations of MXenes with diverse surface terminations, electrolyte interfaces, biointerfaces, and polymer composites without additional parameters. Parameter sets, 3D models, and analysis scripts are provided for community use. The validated, reactive, and transferable IFF framework facilitates predictive design of MXene-based films, membranes, sensing interfaces, and composites.

A system was developed and demonstrated that uses solid sorbents to capture CO2 passively from ambient air and to subsequently release CO2 when immersed in an alkaline medium. The system was used to cultivate the cyanobacterium Synechocystis sp. PCC 6803 at the flask (50 mL) and bench (12 L) scales. A small pilot-scale system installed in a 4.2-m2 outdoor raceway pond (840 L) was evaluated for over 300 days of outdoor wet/dry cycling and in cultivation trials over four seasons. Sorbent CO2-release capacity and kinetics were reduced due to competitive binding of nitrate and biofouling, and sorbent performance could be partially restored using a wash protocol. Over time, the sorbent beads showed significant reduction in the force needed to induce mechanical failure (i.e., fracture) and loss of quaternary ammonium functional groups necessary for CO2 capture, which may have been due to cumulative UV-induced damage to the polymer. Under the assumption that sorbent performance can be retained during cultivation, preliminary techno-economic analyses showed the potential for the viability of a small biorefinery producing 7.6 million gasoline gallon equivalents of biofuel per year ($3.62/GGE) by offsetting the cultivation costs by first extracting bulk protein as a supplement ($6 kg-1) and phycocyanin as a natural food and beverage dye ($50 kg-1).

Secondary aluminum dross (SAD) contains soluble halide salts, reactive Al/AlN, and multi-metal impurities that jointly drive high ionic releases and heavy metal mobilization. While MgAl₂O₄-based ceramics offer a promising stabilization route, conventional MgO blending and reactive sintering often form impurity-enriched intergranular phases that can become highly connected through the microstructure, degrading strength and increasing leaching vulnerability. Here we identify a MgAl₂O₄ connectivity‑control mechanism by transforming Mg delivery from stochastic mixing to interface‑directed enrichment. Mg was introduced as MgCl₂·6H₂O and converted by pH‑controlled in situ precipitation (pH ≈ 9) into nanoscale Mg(OH)₂ shells on mechanically activated SAD particles, followed by filtration and washing for desalination before identical forming and sintering. Thermal and microstructural analyses indicate that the Mg(OH)₂-derived MgO preferentially reacts at particle contacts, accelerating interparticle spinel necking to build a spinel-rich load-bearing framework while reducing the connectivity of impurity-rich intergranular phases. Consequently, at 1400 °C the ceramics achieved 3.12 g cm⁻³ density, 6.7% open porosity, 86 MPa flexural strength, and 1.58 MPa·m¹ ᐟ² fracture toughness, with markedly lower salt and metal releases in TCLP including crushed-sample leaching (<200 mesh) (e.g., Cl: 3.4→0.01 mg L⁻¹; Zn: 1.2→0.02 mg L⁻¹). A washed mixed-powder control confirmed that desalination improves performance, but the additional gains arise from interface-directed Mg delivery and phase-connectivity regulation. These findings identify connectivity programming at the precursor/interface level as a general lever for converting complex hazardous residues into mechanically reliable and environmentally robust ceramics.

Viper fangs represent one of the most mechanically sophisticated biological penetration devices found in nature. Despite extensive interest in their venom-delivery function, a comprehensive characterization of the structure, composition, and biomechanics of neotropical viper fangs remains lacking. This study presents the first integrated analysis of the tubular fangs of three Latin American viper species - Lachesis acrochorda, Crotalus durissus cumanensis, and Bothrops asper - combining optical microscopy, scanning electron microscopy, high-resolution X-ray computed tomography, attenuated total reflectance Fourier-transform infrared spectroscopy, Vickers microindentation, compression testing, and high-speed strike kinematics. All three species exhibited fangs composed of aprismatic enamel concentrated at the tip and a dentinal body organized around a fused venom-conducting canal, producing three distinct regions: an outer C-region, an inner C-region, and a suture line. Dentinal tubules were significantly branched throughout the fang length. The chemical composition, dominated by biological apatite and an organic collagen matrix, was consistent across species and comparable to crocodilian and chondrichthyan teeth. Vickers hardness in dentin ranged from approximately 0.4 to 0.6 GPa and varied along the fang axis. Hydrated fangs withstood compressive loads up to 30 N and stresses up to 110 MPa before failure near the tip, with a radial fracture mode distinct from that of dried specimens. Strike velocities ranged from 2.0 to 2.6 m/s during defensive strikes, with kinetic energies of approximately 2.5 to 3.0 J, neither differing significantly among species. These results demonstrate that neotropical vipers share a conserved fang design with implications for bioinspired penetration devices and functionally graded hard-tissue biomaterials. STATEMENT OF SIGNIFICANCE: Viper fangs integrate controlled compositional gradients, hierarchical microstructure, and macro-scale curvature into a biological penetration system capable of repeated high-energy tissue puncture. This study provides the first integrated, fully hydrated characterization of the tubular fangs of three neotropical viper species - Lachesis acrochorda, Crotalus durissus cumanensis, and Bothrops asper - spanning microstructural imaging, compositional spectroscopy, mechanical testing, and high-speed strike kinematics. The findings reveal conserved structural solutions across species differing markedly in body size: an enamel gradient at the tip, branched dentinal tubules in three morphologically distinct regions, suture lines potentially contributing to impact-energy absorption, and dentin hardness comparable to human and crocodilian teeth. These results offer design principles for bioinspired penetration devices and functionally graded hard-tissue biomaterials.

Many natural and biological materials exhibit intricate hierarchical architectures to effectively manage crack propagation and fracture. This enables them to overcome the critical trade-off between strength and toughness that plagues modern ceramics and ceramic composites. This study investigates the microstructure of enamel from five different mammalian species to inform the synthesis of strong, fracture-resistant bioinspired materials. Dental enamel, the hard, outer surface layer of teeth, is renowned for its exceptional damage tolerance and high strength. Enamel can withstand cracks and other forms of structural damage without leading to catastrophic failure, a property that conventional ceramics often lack. The primary factor contributing to enamel's crack resistance, often attributed to its complex hierarchical microstructure, is the decussation of enamel rods. In this study, synchrotron micro X-ray tomography was performed to elucidate the microstructural assembly of the rods and to characterize the decussation bands. This analysis was conducted across samples taken from different teeth (molar, premolar, canine), tooth regions (cervical, mid-cervical, cusp, intercuspal), and species (lion, wolf, wild African dog, snow leopard, and black bear). Microtomography images were reconstructed and analyzed using a particle image velocimetry technique to offer detailed insights into the decussation bands and the orientation of rods within these bands. Overall, the decussation patterns exhibit branching of the decussation bands reminiscent of Turing patterns, and these organizational motifs within enamel architecture provide a mechanistic perspective on hierarchical structure and its role in damage tolerance. STATEMENT OF SIGNIFICANCE: This study explores the intricate microstructure of dental enamel from various mammalian species using synchrotron X-ray nano- and microtomography. Through a detailed examination of the enamel rods and their distinct Turing patterns, this new insight offers the potential to unlock the secrets behind enamel's extraordinary strength and unparalleled fracture resistance. Our findings suggest that these patterns help distribute stress and prevent catastrophic failure, offering insights that could inspire the design of advanced, damage-resistant ceramics. This research bridges biology and materials science, potentially leading to the development of innovative materials with applications in extreme environments, such as aerospace and nuclear reactors.

To investigate the impact of diabetes on incidence rates (IRs), incidence rate ratios (IRRs), and site-specific fracture susceptibility of subtrochanteric/femoral shaft (ST/FS) and hip fractures. Using Danish registries, we estimated IRs, IRRs, and fracture site associations of ST/FS and hip fracture (1997-2021) in adults ≥65 years old with type 1 diabetes, with type 2 diabetes, and without diabetes. IRRs were significantly higher in those with type 1 diabetes (ST/FS 2.53, P < 0.001; hip 2.17, P < 0.001) and type 2 diabetes (ST/FS 1.08, P = 0.002; hip 1.06, P = 0.008) compared with no diabetes. After age adjustment, only type 1 diabetes remained significantly increased. Adjusted analysis found both type 1 (odds ratio 1.14, P = 0.002) and type 2 (odds ratio 1.05, P = 0.008) diabetes to be significantly associated with higher odds of ST/FS compared with hip fractures. Type 1 diabetes was associated with increased incidence of femoral fractures and slightly higher odds of ST/FS than hip fractures after adjustment.

Zn-based biodegradable alloys hold promise for fracture suture-line applications, but are often limited by insufficient mechanical performance. In this study, alloying and extrusion were employed to regulate the microstructure of Zn-5Cu alloys, thereby synergistically optimizing their mechanical properties, corrosion behavior, and biological functions. Samples extruded at 200 °C exhibited the most favorable comprehensive mechanical performance, achieving a tensile yield strength of 191.5 MPa, an ultimate tensile strength of 208.3 MPa, and an elongation of 39.2%. After 28 days of immersion in simulated body fluid, the samples extruded at 200 °C showed the slowest degradation rate of 31.8 μm·y-1. Notably, the extruded Zn-5Cu alloys exhibit better antibacterial performance than that of pure Zn due to the release of Cu2+. In vitro biological evaluations confirmed suitable cytocompatibility with negligible cytotoxicity. The extruded Zn-5Cu alloys also exhibited a pronounced ability to induce M2 macrophage polarization, thereby promoting osteogenesis and inhibiting osteoclast differentiation in vitro. In vivo studies confirmed the alloy's osteoimmunomodulatory and anti-osteolytic functions. Collectively, these findings indicate that these extruded Zn-5Cu alloys with suitable degradation rates, enhanced mechanical properties, and integrated antibacterial, immunomodulatory, and osteogenic capabilities represent a promising material for fracture suture lines. STATEMENT OF SIGNIFICANCE: Biodegradable zinc alloys have shown promise for fracture fixation, yet their clinical translation remains hindered by insufficient ductility, uncontrolled degradation, and limited biological functionality. Here, we demonstrate that low-temperature extrusion of a Zn-5Cu alloy uniquely orchestrates immunomodulatory, antibacterial, and anti-osteolytic functions within a single material platform-a triad rarely achieved together. Through microstructure tailoring at 200 °C, our alloy achieves clinically suitable mechanical strength (191.5 MPa) and degradation rate (0.032 mm/y) while harnessing Cu2+ release to promote M2 macrophage polarization, enhance osteogenesis, and suppress osteoclast differentiation. For readers, this work establishes a processing‑microstructure‑function paradigm for designing bioactive biodegradable metals that transcend passive fixation toward actively orchestrating bone regeneration.

Critical segmental bone defects (CSBDs) heal poorly in the aging microenvironment, leading to high complication rates. This study developed a novel periosteum with epigenetic reprogramming capability to address this challenge. The material combines a three-layer structure with bone fracture-derived extracellular vesicles (BFVs) from juvenile mice. It demonstrated stable BFV release over 14 days and favorable tensile properties (modulus ∼0.22 MPa, elongation ∼200%). In vitro, extracts from BFV-loaded periosteum significantly reduced senescence markers (β-gal, γH2A.x, p16, p21) in aging bone marrow stromal cells (BMSCs) while enhancing osteogenesis. The material also modulated macrophage polarization toward the anti-inflammatory M2 phenotype and inhibited osteoclast formation. In senior mice with femoral CSBDs, the BFV-loaded periosteum combined with 3D-printed scaffolds maintained structural integrity and substantially enhanced bone regeneration, achieving repair levels comparable to mature mice. Reduced representation bisulfite sequencing revealed that the material reprogrammed the aging bone microenvironment by promoting DNA methylation in genebody regions. The Forkhead Box O3 (Foxo3) gene emerged as a key regulator in this process. This periosteum effectively bridges mechanical compatibility between 3D-printed scaffolds and host bone while rejuvenating the aged bone microenvironment through epigenetic regulation, offering a promising strategy for treating skeletal injuries in the elderly.

Effective postoperative pain management remains a significant clinical challenge in orthopaedic surgery, necessitating alternatives to systemic opioid administration. This study investigated an in-situ polymerizable hydrogel system for the simultaneous local delivery of the analgesic bupivacaine and the nonsteroidal anti-inflammatory drug (NSAID) ketorolac in a rat model of tibia fracture/osteotomy and plate fixation. Two hydrogel formulations, slow-degrading (MAPLAPEG) and fast-degrading (MAPGAPEG), were synthesized and characterized. Functional recovery was assessed via static weight-bearing, gait analysis, and mechanical sensitivity (Von Frey tests). Local inflammation was evaluated by measuring serum alpha-2 macroglobulin (α2M) levels and local matrix metalloproteinase-9 (MMP-9) activity, along with histological and immunofluorescence analyses. Static weight-bearing analysis demonstrated a ∼80% improvement toward symmetric hind-limb loading in the MAPGAPEG treatment group compared with control at postoperative day 42 (p < 0.05). At POD 3, 2-4 toe spread demonstrated ∼80% normalization toward symmetric limb use in the MAPGAPEG treatment group compared with control. Minimal inflammation and no negative impact on bone healing were observed. This dual drug-loaded hydrogel system offers a promising strategy for postoperative pain management in orthopaedics, potentially reducing reliance on systemic opioids and enhancing patient recovery.

Composite lower extremity injuries, characterized by open bone fractures with soft tissue damage, frequently result in delayed or failed fracture union, chronic pain and long-term disability. Standard clinical care overlooks the muscle as a critical driver of composite tissue healing, and current regenerative approaches fail to fully restore physical function. This study explores a muscle-driven approach to promote coordinated regeneration across both muscle and bone tissue. An engineered muscle (EM) composed of cell-laden nanofibrillar patterned scaffolds, was transplanted into the injured muscle in a mouse model of composite injury. EM constructs of either primary myoblasts or differentiated myotubes significantly improved healing outcomes and functional recovery compared to untreated controls. Myoblast-EM treatment led to accelerated tibial union, increased early bone mineral density, and faster restoration of symmetrical limb loading, along with enhanced single muscle fiber contractile power and velocity. Myotube-EM treatment yielded complimentary gains, including increased muscle cross-sectional area and whole-muscle force production. Importantly, all EM-treated animals exhibited higher survival rates and reduced limb morbidity. Notably, the superior functional outcomes observed with Myoblast EMs may be attributed to greater engraftment and in vivo differentiation of transplanted myogenic cells into mature myofibers. These findings introduce a paradigm-shifting regenerative strategy in which targeted muscle therapy drives systemic musculoskeletal repair, challenging conventional compartmentalized treatment models.

Accurate Cobb angle measurement is essential for scoliosis assessment but remains labor-intensive and observer-dependent. We introduce DGPDT (Detection-Guided Prompt-driven Transformer), a unified transformer-based framework that integrates vertebra detection and foundation-model segmentation for generalizable spinal analysis. A Roboflow Detection Transformer (RF-DETR) with a DINOv2 backbone localizes vertebrae, followed by post-processing to ensure anatomical continuity. The resulting bounding boxes serve as automatic prompts for a fine-tuned Segment Anything Model 2.1 (SAM 2.1), which generates high-resolution vertebral masks. Cobb angles are then computed from vertebral masks, enabling estimation of both main and compensatory curves. Evaluations on the in-house (TVGH-SpineXR) and external (SpineWeb-16) datasets demonstrate encouraging performance on both internal and external datasets, achieving mean Dice coefficients of 0.944 and 0.781, respectively, and mean absolute Cobb angle errors of approximately 2-3° in-domain and 4.93° under cross-domain evaluation. Despite being trained solely on TVGH-SpineXR, DGPDT maintains accuracy comparable to models trained directly on the benchmark dataset. By coupling detection-guided prompting with transformer-based segmentation, DGPDT achieves a clinically acceptable mean absolute error ( $\lt 5^{\circ }\text {)}$ , suggesting good reproducibility and potential applicability beyond the training dataset.

Conservative treatment of scoliosis relies on physiotherapy and bracing, yet both approaches lack tools for quantitative, real-time monitoring of corrective forces. Here, we introduce a hemispherical latitude-gradient (HS-LG) sensor as a previously unknown sensing paradigm for soft, curved-body interfaces, using scoliosis as a clinical exemplar. Leveraging a nonzero Gaussian curvature ([Formula: see text]) geometry, the device acts as a spatiotemporal mechanical filter, converting normal pressure into in-plane tensile forces to overcome shear and stress artifacts limiting conventional sensors. Integrated into a wireless platform, the HS-LG sensor enables immediate visualization of spatiotemporal pressure dynamics during therapy. In physiotherapy, bilateral deployment established the first quantitative, closed-loop Schroth regimen. Real-time visual feedback amplified targeted asymmetric breathing by ∼40% and decoupled nontargeted regional effort, transforming subjective instruction into data-driven neuromuscular internalization. In bracing, embedded sensors mapped pressures during daily activities, uncovering highly dynamic, posture-specific force redistributions, including transient pressure gradient reversals during ambulation, that challenge conventional static orthotic paradigms. Furthermore, age ([Formula: see text]) and body mass index (BMI; [Formula: see text]) emerged as strong predictors of daily wear compliance in the lumbar cohort, while BMI consistently drove interfacial mechanical loading across both spinal regions (lumbar [Formula: see text]; thoracic [Formula: see text]). Together, these results establish the HS-LG sensor design as a versatile, patient-ready platform that links geometry-driven sensing design to personalized, data-informed scoliosis management, while broadly advancing the development of wearable mechanosensing technologies for soft, curved biological surfaces.

Fatty infiltration and fibrosis drive poor outcomes after chronic muscle injury. Here, we characterized fibroadipogenic progenitor cell (FAP) subpopulations from healthy and injured human rotator cuff muscle by single-cell RNA sequencing, full-spectrum flow cytometry, and functional assays and found distinct subpopulations, including a preadipogenic population that expresses delta-like noncanonical notch ligand 1 (DLK1+) and a prefibrogenic population that expresses decay-accelerating factor (CD55+). We used in vitro and flow cytometry experiments to show that human FAP lineages displayed unique surface marker expression across adipogenic and fibrogenic differentiation. In chronic human rotator cuff injury, expression of DLK1 RNA and DLK1 protein was decreased compared with that in healthy muscle. Overexpression of DLK1 in primary human FAPs suppressed differentiation into adipocytes in vitro, whereas DLK1 knockdown increased adipogenesis. In an immunodeficient murine model of glycerol-induced acute muscle injury, xenotransplantation of DLK1-overexpressing human FAPs into the injured murine muscle resulted in reduced fatty infiltration after 14 days by histological assessment, supporting a functional role for DLK1 in restraining adipogenesis. Together, we defined molecularly distinct, clinically relevant human FAP subpopulations, established DLK1 as a regulator of adipogenic potential in vivo, and provided a framework to identify pathogenic FAP states that may be used in the pursuit to prevent maladaptive muscle remodeling.

Infectious jawbone defects, arising from open fractures, surgical contamination, or hematogenous pathogen spread, represent severe orthopedic complications characterized by concurrent bone loss and chronic infection. Precise control of pathogen colonization, effective modulation of local immune microenvironment, and activation of osteogenesis are spatiotemporal phases that pose significant clinical challenges. Here, we construct a multifunctional platform of copper-zinc bimetallic metal-organic nanosheets encapsulated in a polyvinylpyrrolidone-polyvinyl alcohol hydrogel (CuZn-MON@gel). Upon ultrasound irradiation, CuZn-MON produces singlet oxygen, achieving antibacterial efficiencies of 99.93% against Staphylococcus aureus and 99.78% against Porphyromonas gingivalis. In the absence of ultrasound, the nanozyme switches to SOD- and CAT-like activities, scavenging excess reactive oxygen species and downregulating pro-inflammatory pathways, including chemokine and NF-κB signaling pathway. Simultaneously, controlled release of osteogenic Cu2+ and Zn2+ ions activates AMPK and PI3K/Akt pathways, enhancing the expression of osteogenic markers Runx2, ALP, OCN, and OPN. This system promotes osteogenic differentiation and accelerates bone regeneration in an infected rat model, achieving robust repair of jawbone defects. By dynamically balancing bactericidal ROS generation and antioxidant protection, CuZn-MON@gel offers a spatiotemporal therapeutic strategy for reconstructing infectious bone defects.

The intracellular survival of Staphylococcus aureus (S. aureus) within immune cells poses a significant clinical challenge, driving recurrent infections and antibiotic resistance in orthopaedic practice. Specific identification and precise eradication of intracellular S. aureus are therefore crucial for effective infection management. However, specific visualization of intracellular S. aureus remains challenging due to interference from extracellular bacteria and low intracellular pathogen abundance in vivo, complicating efforts to eliminate them in situ. Herein, we developed a micrococcal nuclease (MNase)-activatable multifunctional theranostic probe, AuTPC@AB, for specific imaging and targeted photothermal eradication of intracellular S. aureus in joints in vivo. The probe operates through a dynamic three-step process: (1) apoptotic body (AB)-mediated targeting to immune cells; (2) activation by S. aureus-secreted MNase, which triggers near-infrared Cy5.5 fluorescence for specific bacterial visualization; and (3) targeted photothermal ablation by target peptide-modified gold nanorods (AuNRs) under laser irradiation. Administration of the AuTPC@AB probe yielded strong fluorescence signals exclusively in S. aureus-infected joints, achieving the differentiation of intracellular S. aureus infection from other bacterial strains. And the subsequent AuNRs-based photothermal therapy effectively eliminated the targeted bacteria in joints. These findings demonstrated that the selective activation of fluorescence imaging and targeted photothermal ablation of intracellular S. aureus, highlighting the clinical potential of the AuTPC@AB for precise diagnosis and treatment of intracellular S. aureus infections.

The tissues spanning from tendon to bone exhibit a highly specialized extracellular matrix (ECM) architecture, characterized by hierarchical collagen alignment and a gradient mineral composition, which together enable efficient force transfer and guide spatially organized cellular phenotypes. However, recapitulating such complex multi-scale organization and compositional gradients to achieve integrated soft-hard tissue remains challenging. Here, we report the de novo construction of biomimetic collagen-mineral matrices that mimic both the hierarchical organization and mineral gradient distribution of the native tendon-to-bone ECM. Through synergistic electro-assembly and post-treatment, collagen molecules self-organized into aligned fibrillar matrices with multi-scale architecture, replicating tendon-side morphology while providing robust tensile mechanics. At the opposing end, intrafibrillar and interfibrillar minerals were spatially patterned to emulate the mineral gradient from tendon to bone. This structural and compositional continuum enables smooth mechanical transition across the soft-hard tissue interface and promotes region-specific regeneration of aligned tendon-like tissue, fibrocartilage and bone. In vivo studies in rabbit models confirm that these de novo constructed matrices support histological reconstruction of multiple tissues from tendon to bone at the rotator cuff, and significantly improve functional recovery. This work presents a bottom-up biomimetic strategy for engineering multiscale collagen-based scaffolds and demonstrates the therapeutic potential of de novo constructed matrices for multiple tissue regeneration.