Hearing loss and vestibular disorders represent major otologic disease challenges. Traditional disease models struggle to accurately mimic human otologic pathologies due to species differences and limited physiological relevance. Recent advancements in otic vitro models have provided crucial tools for related research. The core representatives include the middle ear epithelial cell model cultured at the air-liquid interface (ALI) and inner ear organoids. ALI culture of middle ear epithelial cells highly mimics middle ear tissue structure and function, finding applications in drug screening and toxicity assessment. Inner ear organoids facilitate the in vitro generation of functional three-dimensional structures containing hair cells, supporting cells, and neurons, while recapitulating both inner ear development and specific disease phenotypes. This review highlights the origins, research progress, and application prospects of these two model types, aiming to provide references for elucidating otologic disease mechanisms, personalized drug screening, and evaluating gene therapy strategies.
IntroductionThis study established finite element models of the knee incorporating radial and longitudinal meniscal tears and simulated corresponding surgical techniques to investigate the influence of different tear types, lengths, locations on stress distribution in the knee joint and evaluate the restorative effects of different surgical techniques on the biomechanical performance of the meniscus.MethodsA three-dimensional finite element model of the right knee including bone and soft tissues was developed. Stable and unstable radial and longitudinal tear models were created in the posterior horn of the meniscus across three zones (white-white, red-white, and red-red zones), together with the corresponding surgical technique models (suture repair and partial meniscectomy). Finite element analysis was performed under static loading. A cadaveric knee biomechanical experiment was also conducted to validate the finite element model.ResultsUnder static loading, the discrepancy in medial compartment contact area between the finite element model and the cadaveric experiment under intact meniscus conditions was 5.72%. The peak contact pressure was highest in the unstable radial tear model, reaching 14.88 MPa, representing an 181.82% increase compared with 5.28 MPa measured in the intact meniscus. Both repair and partial meniscectomy significantly reduced the peak contact pressure in the medial meniscus and tibial cartilage for radial tears. Repair reduced the peak pressure by 35.35% for stable radial tears, while partial meniscectomy reduced it by 49.60% for unstable radial tears. Meniscal repair reduced the peak contact pressure by 4.55% and 3.85% for stable longitudinal tears located in the red and white zones, respectively, and restored hoop stress transmission. Partial meniscectomy reduced the peak contact pressure by 7.90% (0.67 MPa) for unstable longitudinal tears located in the white zone.ConclusionStress distribution in the meniscus and its components is influenced by tear types, locations, lengths, and surgical technique. Surgical outcomes significantly depend on tear types, lengths, and locations. The extent of biomechanical restoration varies considerably among different surgical techniques, suggesting that clinical procedure selection should be based on personalized consideration of injury characteristics.
BackgroundVibrotactile stimulation (VTS) has emerged as a potential sensory-based adjunct to upper limb rehabilitation by providing additional afferent feedback and supporting sensorimotor rehabilitation. This systematic review aimed to synthesize clinical evidence on VTS for post-stroke upper-limb rehabilitation and complementary mechanistic and technological evidence from healthy participants, with emphasis on intervention characteristics, stimulation parameters, clinical outcomes, neurophysiological effects, usability and safety.MethodsThis review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and was retrospectively registered with the Open Science Framework. PubMed, PEDro, Web of Science and Google Scholar were searched for English-language full-text studies published between January 2015 and January 2026. Search terms included combinations of stroke, VTS, vibration, tactile, somatosensory, haptic, upper limb and hand.ResultsA total of 35 studies were included. Fourteen studies used direct upper-limb stimulation, six integrated VTS with robotic systems, two with virtual reality (VR), two with mirror visual feedback (MVF), seven with brain–computer interface (BCI) paradigms, and four with multimodal systems. Stimulation sites included the wrist, hand, fingers, fingertips, forearm, and upper arm, whereas reported frequencies, intensities, timing, and doses varied widely. Clinical studies suggested potential improvements in upper-limb motor function, sensory and proprioceptive function, spasticity, and affected-limb use, particularly when VTS accompanied active or task-oriented training. Mechanistic studies indicated that VTS may modulate sensorimotor rhythms, cortical activation, functional connectivity, and motor-imagery (MI)-related brain responses.ConclusionCurrent evidence suggests that VTS may support upper-limb functional recovery after stroke. However, confidence in the evidence remains limited by small samples, heterogeneous protocols, and the frequent use of multimodal interventions that do not isolate the contribution of vibration. Further adequately powered randomized controlled trials are needed to determine clinical efficacy and to identify the stimulation parameters and feedback architectures most likely to benefit people after stroke.
ObjectiveThis study aims to quantify jump-landing characteristics and compare the performance of four machine learning (ML) models in classifying single- and dual-task conditions. Shapley Additive Explanations (SHAP) was used to identify key biomechanical features distinguishing the conditions and characterize multivariable biomechanical patterns associated with cognitive-motor interference, providing a quantitative basis for understanding associations between cognitive load and jump-landing biomechanics.MethodsOverall, 240 physically active young men completed single- and dual-task jump-landing tests. Kinematic and ground reaction force data were synchronously collected using a Qualisys high-speed motion capture system and an AMTI force plate. Hip, knee, ankle, and trunk angles were calculated using OpenSim inverse kinematics, and 13 kinematic and landing performance features were extracted. Four ML models were compared within the development set using participant-grouped nested cross-validation repeated five times. The selected model underwent held-out test-set evaluation; SHAP quantified feature contributions to its predictions.ResultsXGBoost achieved the highest mean outer out-of-fold AUC in the development set (0.992 ± 0.002). Corrected paired comparisons supported higher AUCs for XGBoost than for the three comparator models (all Holm-adjusted P < 0.001). XGBoost’s held-out test-set accuracy and AUC were 0.924 and 0.978, respectively. The five highest-contributing features were the normalized base-of-support ratio (BOS), hip flexion angle at initial contact (HF-IC), trunk flexion range of motion (TF-ROM), ankle dorsiflexion/plantarflexion angle at initial contact (PF-IC), and trunk flexion angle at initial contact (TF-IC). Under the dual-task condition, BOS and TF-ROM increased, whereas HF-IC, PF-IC, and TF-IC decreased, characterizing task-condition differences.ConclusionThe XGBoost-SHAP model identified and quantified key biomechanical changes during cognitive dual-task jump-landing, providing an explainable, quantitative description of dual-task landing biomechanics. These changes may be related to competition for limited attentional resources between motor control and cognitive tasks. The following five core features collectively characterize the biomechanical pattern distinguishing dual-task from single-task landing: increased BOS, decreased HF-IC, decreased PF-IC, increased TF-ROM, and decreased TF-IC. The model classified task condition only and was developed using data from physically active young men performing a laboratory mental-arithmetic task. Any injury-related interpretation requires prospective validation; generalization to other populations and task contexts requires external validation.
To date, organotypic skin models represent the gold standard for preclinical dermatological and toxicological studies. However, they are variable in quality and require long maturation times and many cells, mainly of primary origin. We propose dermal-epidermal spheroids as an alternative model that balances the physiological relevance and throughput. Alongside the corresponding full thickness skin models, three different fibroblast/keratinocyte coculture spheroids were generated. These studies used the commonly employed HaCaT cells as well as two recently immortalized keratinocyte cell lines, NHK-SV/TERT and NHK-E6/E7. To investigate their differentiation with detailed spatiotemporal resolution, a deep-learning segmentation-based pipeline capable of revealing nuclear morphology and positioning, as well as marker expression with single-cell precision, was developed and applied. Moreover, the formation of a functional barrier was assessed by live imaging of Lucifer Yellow diffusion. NHK-based coculture spheroids displayed strong evidence of functional maturation, including stratification and aspects of cornification and barrier formation, closely recapitulating the features of the corresponding full-thickness models. Furthermore, NHK-E6/E7 cells showed to be the most and HaCaT cells the least suitable alternative to primary keratinocytes in both spheroids and full thickness models. Given their scalability and compatibility with automation, micro-skin fibroblast/NHK-based 3D coculture spheroids might represent a promising new platform for pharmaceutical, cosmetic, and toxicological testing.
Chimeric antigen receptor (CAR) T cell therapies targeting B cell maturation antigen (BCMA) have shown unprecedented success in treating multiple myeloma (MM), yet long-term relapse remains a critical challenge, possible due to the protective influence of the bone marrow (BM) microenvironment. Current in vitro models often rely on simplistic 2D cocultures of CAR T and MM cells, and fail to recapitulate the 3D structural and cellular complexity of the osteogenic niche, which is known to facilitate immune evasion. In this study, we aimed to develop a physiologically relevant 3D in vitro MM model using a perfusion bioreactor system, hydroxyapatite scaffolds, and osteogenically-differentiated human BM mesenchymal stromal cells. Our results demonstrate that this system effectively supports the engraftment and 3D clustering of MM cells while successfully mimicking the suppressive effect of the tumor on osteogenic matrix deposition. Use of the platform to assess BCMA-targeted CAR T cell activity indicated that, while CAR T cells efficiently cleared circulating tumor cells in the fluidic phase, the 3D osteogenic niche provided a protective environment that blunted cytotoxic efficacy. This resistance was not associated with T cell recruitment, suggesting that the 3D niche provides complex protection. Our study provides a proof-of-concept for a humanized, dynamic cell culture platform capturing the influence of the BM niche-MM cell crosstalk on the efficacy of immunotherapy. The model represents a promising tool for evaluating next-generation CAR T cell potencies and for investigating associated resistance mechanisms.
High-quality skin wound healing requires rapid closure, complete re-epithelialization, orderly collagen remodeling, minimal scarring, and restoration of local sensory function. Substantial evidence confirms that peripheral nerve regeneration in the skin is not a passive concomitant of repair, but a critical foundation for functional tissue regeneration. However, effective combinatorial strategies to synchronously promote nerve regeneration and wound healing via a personalized electroactive microenvironment remain an unmet clinical need, driving the development of targeted electroactive biomaterials. In this study, an electroactive polycaprolactone/carbon nanotube (PCL/CNT) nanopatch was fabricated by electrospinning. Its microstructure and electroactivity were characterized, and the biosafety and efficacy of the patch combined with exogenous electrical stimulation (ES) were evaluated. In vitro, PC12 cell proliferation, neurite outgrowth, and neural marker expression were quantified. In vivo efficacy and biosafety were assessed in a Sprague-Dawley rat full-thickness skin defect model. Compared with PCL, the PCL/CNT nanopatch exhibited uniformly aligned fibers and significantly enhanced conductivity. PCL/CNT + ES enhanced PC12 cell viability, promoted neurite outgrowth, and upregulated neural markers in vitro. In vivo, this group showed accelerated re-epithelialization, thicker granulation tissue, more organized collagen deposition, and elevated density of NF200-positive nerve fibers compared with the control, pure PCL, and PCL/CNT groups. No visceral abnormalities were detected, confirming biosafety. The “topography guidance + electrical stimulation” strategy exerted a synergistic effect on skin wound healing by enhancing peripheral nerve regeneration, coordinating tissue repair, and improving healing quality. This study presents a promising therapeutic approach for high-quality wound healing and supports the rational design of electroactive biomaterials targeting synchronous nerve regeneration and wound repair.
Unanticipated change-of-direction (COD) maneuvers represent a key scenario for non-contact lower-limb injury exposure in sport. This study investigated how anticipation modulates lower-limb mechanics across varying cutting angles (45°, 90°, and 180°) to identify phase-specific dynamic joint vulnerabilities. Twenty-three high-level male soccer players performed anticipated (ANT) and unanticipated (UNA) COD tasks. Kinematics, kinetics, and muscle activation were analyzed using two-way repeated-measures ANOVA and Statistical Parametric Mapping (SPM1D). Significant angle effects occurred for temporal and force variables (p < 0.05). At 45°, ANT showed higher impact forces and stiffness (p < 0.01). Condition × Angle interaction effects emerged for medial gastrocnemius preactivation (p = 0.004) and vastus medialis cushion (p = 0.007). SPM1D revealed interactions for CoM velocity (p < 0.005), early-cushion knee angles (p = 0.034), and mid-cushion moments (p = 0.024). UNA-45 exhibited greater negative knee power during mid-cushion (p < 0.001), while trunk lateral bending interaction occurred during early preactivation (p = 0.039). Anticipation effects were maximal at 45°, whereas 90° and 180° mechanics were primarily angle-driven (p < 0.001). While 90° and 180° maneuvers provide a temporal buffer for movement reorientation, the 45° task forces athletes to process extreme loads within a compressed timeframe. Under unanticipated conditions, altered feedforward neuromuscular preparation combined with an upright landing posture was accompanied by greater eccentric power absorption, indicating increased multi-planar mechanical demands. These findings suggest that 45° UNA cutting may serve as a challenging biomechanical paradigm for examining biomechanical characteristics relevant to ACL injury mechanisms, revealing potential neuromuscular control adaptations under constrained preparation conditions that may remain less evident during larger-angle or pre-planned maneuvers.
IntroductionIntervertebral disc disease (IVDD) leads to chronic lumbosacral radiculopathy (LSR) with nerve root compression resulting in numbness and low back pain. The aim was to evaluate therapeutic and immunomodulatory potential of multi-protein platelet and plasma-derived biologic (C-1101) to alter inflammatory mediators and gene expression in IVDD.MethodsIn aim 1, intervertebral discs and dorsal root ganglia (DRG) were harvested from female ovine lumbar spines (n = 6). Annulus fibrosus (AF), nucleus pulposus (NP) and DRG were dissociated to form single-cell suspensions. Cells were plated (100,000 cells/well, 24-well plates) and subjected to 4 treatments, 24 h (non-stimulated, IL-1β+TNF-α, IL-1β+TNF-α+C-1101, IL-1β+TNF-α+vehicle). Cells were washed, cultured 24 h, and media evaluated for cytokine secretion (n = 14) by ovine multiplex immunoassay. mRNA was collected from cells and sequencing performed via Illumina-based platform. In aim 2, peripheral neuropathy was induced (paclitaxel) in male C57Bl6/J mice who were treated intravenously with C-1101 or vehicle. Mice were assessed via acetone cooling for allodynia and plasma evaluated for cytokines.ResultsC-1101 elicited cytokine release from ovine AF and NP cells but not DRG. Gene expression analyses revealed upregulation of cell replication and translation pathways but downregulation of inflammatory (namely, interferons), extracellular matrix and cell signaling pathways in AF/NP, with upregulation of translation and ribosome activity in DRG. C-1101 reduced allodynia and transiently induced elevated plasma IL-1β in murine peripheral neuropathy.DiscussionFunctional reduction in pain sensation with C-1101 was observed in murine peripheral neuropathy, indicating potential therapeutic efficacy. C-1101 induced a mixed inflammatory response in cultured cells, warranting further investigation of mechanism.
Musculoskeletal regenerative medicine has traditionally been guided by a product-centered model in which therapeutic outcomes are primarily attributed to the biological characteristics of the administered orthobiologic. However, the marked variability in clinical response suggests that treatment efficacy may also depend on the biological condition of the patient and the receptivity of the target tissue. This integrative review proposes a translational seed–soil framework in which therapeutic response is interpreted through the interaction among the biologic product (seed), systemic host biological readiness (systemic soil), and target tissue receptivity (local tissue soil), with knee osteoarthritis as the primary clinical and evidence context. A structured literature search was conducted in PubMed/MEDLINE, Embase, Scopus, and Web of Science, complemented by citation tracking. Evidence from clinical trials, systematic reviews, observational, imaging, biomarker, mechanistic, and conceptual studies was integrated according to prespecified framework domains. Our synthesis suggests that heterogeneity in orthobiologic outcomes can be more coherently interpreted when three interacting biological layers are considered together: product composition and potency, systemic host factors, and local joint and tissue characteristics. Although several orthobiologic classes demonstrate meaningful clinical signals in knee osteoarthritis, treatment effects remain inconsistent because of variability in product processing and composition, contextual and placebo effects, the strength of active comparators, differences in pain phenotypes, and the multicomponent nature of osteoarthritic joint disease. Importantly, symptomatic improvement should be distinguished from structural regeneration, which remains inconsistently demonstrated across orthobiologic studies. Rigorous product characterization remains essential, but the proposed seed–soil framework extends this perspective by integrating product characteristics with systemic host biology and local tissue receptivity. Although optimization of systemic and local soil conditions has not yet been definitively validated in randomized trials, the proposed framework provides a biologically grounded structure for explaining response heterogeneity, improving patient stratification, and guiding the design of future translational and clinical studies.
Tissue engineering and regenerative medicine (TERM) has advanced by leveraging innovations in biomaterials, cell biology, and drug delivery, but its potential remains to be fully realized due to limitations in manufacturing complex cellular constructs. The complexity of cellular and extracellular matrix (ECM) organization poses a formidable challenge to replicate using conventional fabrication methods. Additive manufacturing (AM) enables the translation of design intent into controlled three-dimensional (3D) constructs with defined geometry, internal architecture, and spatially organized components. Beyond merely fabricating complex structures, its value lies in addressing structural, spatial, reproducibility, personalization, and translational limitations. However, printability does not guarantee biological function. By exploring AM of soft matter (hydrogels) as a practical manufacturing framework for TERM, this review first identifies the core manufacturing bottlenecks in classical TERM (Section 2), then evaluates how AM addresses structural fidelity, spatial patterning, digital reproducibility, and personalization (Section 3). Using osteochondral units, skin, and vascular grafts as representative testbeds (Section 4), we critically analyze current limitations—including bioink tradeoffs, resolution-scale constraints, and regulatory barriers (Section 5)—and outline the functional validation, standardization, and digital-AI integration needed for clinical implementation (Section 6). The review concludes that AM’s translational impact will depend less on geometric complexity than on demonstrating tissue maturation, host integration, and regulatory compliance within viable clinical workflows.
Cardiovascular diseases remain a leading cause of morbidity and mortality worldwide and impose a substantial clinical and socioeconomic burden. Despite advances in medical, interventional, and surgical treatments, considerable residual cardiovascular risk persists, highlighting the need for effective and sustainable therapeutic approaches. Milk-derived extracellular vesicles (MDEVs) are heterogeneous lipid-bilayer vesicles present in human and bovine milk and have attracted increasing interest as potential orally administered biological nanocarriers. MDEVs carry diverse bioactive cargo, including proteins, lipids, messenger RNAs, microRNAs, and long non-coding RNAs, while their membrane-associated components may contribute to gastrointestinal stability, cargo protection, and interactions with intestinal cells. Emerging preclinical evidence suggests that MDEVs may influence inflammatory responses, oxidative stress, myocardial fibrosis, angiogenesis, and gut–heart axis signaling. However, direct evidence from cardiovascular disease models remains limited, and several proposed mechanisms are supported primarily by studies conducted in intestinal, metabolic, oncological, or other non-cardiovascular settings. MDEVs can also be engineered to carry nucleic acids, peptides, proteins, and small-molecule drugs or to introduce tissue-targeting properties. Nevertheless, their systemic absorption, biodistribution, cardiovascular tissue accumulation, and long-term safety after oral administration remain insufficiently defined. Moreover, milk source, processing conditions, isolation methods, co-isolated non-vesicular components, cargo composition, dose metrics, administration routes, and disease models may substantially affect the reported biological effects. Continued advances in purification, standardized characterization, rigorous biodistribution analysis, safety assessment, and scalable manufacturing are therefore required to determine the translational potential of MDEVs in cardiovascular therapy.
Adipose tissue is a vital component in both regenerative medicine and cultivated meat, yet the selection of the cellular starting material remains an underexplored determinant of adipose construct performance in bioprinting. This mini-review explores next-generation adipose tissue engineering, emphasizing bioprinting functional fat with adipocytes at the intersection of these two fields. While current adipose bioprinting strategies predominantly rely on adipose-derived stem or stromal cells for their expandability and manufacturability, mature adipocytes (ACs) and microfat emerge as alternative cell sources with distinct advantages in functional fidelity, metabolic relevance, and immediate tissue-like behavior. However, these approaches impose fundamentally different biological and engineering constraints that directly influence biofabrication strategy, biomaterial design, and translational potential. This mini review offers a structured comparison of mature adipocyte-, progenitor-, and microtissue-based strategies, highlighting features that influence biofabrication and applicability. Scalability is identified as a major bottleneck in translation, with a focus on process robustness, batch-to-batch reproducibility, and manufacturing concepts relevant to preclinical test systems, clinical applications, and large-scale cultivated meat (CM) production. By proposing a cell-source-guided framework for adipose bioprinting, this mini review aims to provide a practical decision-making perspective for developing next-generation adipose constructs.
The Notch signaling pathway is pivotal in joint homeostasis and the pathogenesis of osteoarthritis (OA). Under physiological conditions, transient or physiological Notch signaling maintains cartilage matrix synthesis to preserve joint function. Under pathological conditions, persistent or excessive activation of Notch signaling suppresses the expression of chondrogenic genes and induces the production of catabolic factors, thereby driving OA progression. From a cellular perspective, the Notch signaling pathway exerts crucial regulatory role in the functions of various resident cell types within the joint. For instance, it regulates the differentiation and maturation of chondrocytes, influences the chondrogenic differentiation process of mesenchymal stem cells (MSCs), and modulates the phenotype of fibroblast-like synoviocytes (FLSs). At the level of the extracellular cartilage microenvironment, the Notch signaling pathway participates in extracellular matrix (ECM) homeostasis imbalance and inflammatory factor activation in OA by regulating the expression of downstream genes. Furthermore, Notch controls chondrocyte hypertrophic degeneration through extensive molecular crosstalk with the TGF-β/BMP, Wnt/β-catenin, NF-κB, and Hippo-YAP pathways. Beyond cartilage, Notch plays a crucial role in promoting neurovascular invasion at the osteochondral junction and abnormal subchondral bone remodeling, which directly contributes to joint pain and structural failure. Many Notch-targeted approaches, such as pharmacological inhibitors, RNA-based therapies, and molecular interventions targeting ligands and downstream effectors, have been investigated because existing treatments are unable to stop the progression of OA. Simultaneously, stem cell-based approaches use precise Notch modulation to improve cartilage repair and chondrogenic differentiation. However, systemic administration of small-molecule inhibitors raises concerns about off-target effects and delivery inefficiency in avascular cartilage, while conventional stem cell injections frequently encounter problems like phenotypic instability and limited durability. In conclusion, in-depth studies on the Notch signaling pathway in OA not only clarify the pathogenesis of OA but also lay a theoretical and experimental foundation for the development of innovative therapeutic strategies.
There is a strong need to quantify skin mechanical properties for flap design in plastic surgery, such as syndactyly reconstruction. Quantitative measurement of skin mechanical properties enables more accurate surgical planning, thereby improving surgical outcomes and reducing complications. Although a large number of methods and devices have been proposed, nearly none of them have been applied in surgical practice. We therefore conducted a comprehensive narrative review of the literature published from 1969 to the present on in vivo skin mechanical property measurement. To identify the factors limiting clinical application, studies using suction, indentation, torsion, stretching, non-contact, and computational approaches were screened and categorized based on their underlying mechanical assumptions and boundary conditions. Three fundamental paradoxes limiting clinical translation were identified: (1) conventional engineering characterization requires destructive testing, which is incompatible with preserving intact skin for surgery; (2) in vivo measurements inevitably capture surrounding tissue boundary constraints rather than intrinsic skin mechanics; and (3) engineering analyses depend on stress-based parameters and skin thickness, whereas thickness is rarely considered in clinical flap planning. Furthermore, inverse numerical models, such as finite element analysis, rely on idealized assumptions that may not fully reflect complex, patient-specific surgical conditions. Rather than attempting to identify a universally accurate conventional measurement device, this review proposes a novel paradigm shift: combining non-invasive microstructural imaging with computer vision and machine learning to predict mechanical transition thresholds (e.g., collagen alignment and tangent modulus) directly from unstretched tissue, with the goal of enabling patient-specific, computational surgical flap planning.
IntroductionInvestigating the stress distribution generated by orthodontic forces within the periodontal ligament (PDL) is critical for quantifying mechanical stimuli, correlating them with subsequent histological responses, and ultimately identifying evidence-based optimal force levels. This study aimed to evaluate the combined biomechanical effects of alveolar bone height loss, tooth movement type, and alveolar bone density on the initial retraction of the maxillary central incisor, and to quantify the weighting of each factor on PDL stress.MethodsA three-dimensional (3D) finite element model of the maxilla, dentition, PDL, and orthodontic appliances was constructed based on cone-beam computed tomography (CBCT) data. Eighty experimental conditions were established by combining five levels of alveolar bone height loss (0–4 mm), four tooth movement types, and four alveolar bone density levels (simulated via cortical bone Young’s modulus: 12,500–27,500 MPa). A 1 N bilateral retraction force was applied. The initial displacements of the crown and root and the maximum PDL von Mises stress were calculated. Multiple linear regression was used to quantify the factor contributions.ResultsAlveolar bone height loss significantly increased both tooth displacement and PDL stress. Uncontrolled and controlled tipping resulted in greater sagittal retraction and root intrusion, whereas bodily and controlled root movements were associated with more distolingual rotation. However, bone density affected displacement but had no significant effect on PDL stress. The regression model (R2 = 0.80) revealed that tooth movement types exerted the strongest influence on PDL stress, followed by alveolar bone height loss (β = 0.535, p < 0.05). All conditions, except for 4 mm bone loss combined with uncontrolled tipping, exhibited PDL stresses below the 0.026 MPa safety threshold.ConclusionThese findings provided novel quantitative biomechanical evidence regarding the combined effects of these variables and could guide individualized force control strategies and the development of AI-assisted orthodontic decision-making systems.
Periodontitis is a chronic inflammatory oral disease characterized by irreversible alveolar bone resorption, which severely impairs oral health and even leads to tooth loss. Clinical bone augmentation therapy for alveolar bone defects mainly relies on exogenous bone substitute materials. However, traditional materials are prone to implantation failure due to the persistent inflammatory microenvironment and bacterial infection in the periodontal area. The addition of antibiotics to improve antibacterial properties not only induces bacterial resistance but also causes systemic toxic and side effects, making it difficult to meet clinical treatment needs. This review focuses on the core demand for bone substitute materials in periodontitis treatment to simultaneously achieve antibacterial, anti-inflammatory, and osteogenic functions—an essential characteristic that distinguishes such materials from conventional antibacterial drugs and single-function bone graft materials. We systematically elaborate on multiple interrelated inflammatory signaling pathways (e.g., RANKL/RANK/OPG, cGAS-STING, NF-κB, JAK-STAT, MAPK, PI3K/AKT, HIF-1, TGF-β/SMAD, Wnt/β-catenin, Hippo) and inflammasome mechanisms involved in periodontitis-associated alveolar bone resorption, exploring potential targets for screening excellent anti-inflammatory and osteogenic active molecules. On this basis, we summarize modification strategies for bioceramic bone tissue-engineered substitutes, including incorporating metal ions (Ag, Cu, Sr, Mn, Mg, Zn, etc.) and natural anti-inflammatory molecules into the material matrix to enhance their multifunctional properties while maintaining favorable physical and biological characteristics. We also discuss structural and functional optimization of composites via surface morphology modification, photothermal, and photodynamic coating construction to improve adaptability to the periodontal inflammatory microenvironment. These reconstructed multifunctional composite bioceramic materials integrate antibacterial, anti-inflammatory, and osteogenic functions, eliminating periodontal bacterial infection, alleviating local chronic inflammation, and actively promoting osteoblast differentiation and alveolar bone defect repair, thereby perfectly matching the pathological characteristics of periodontitis. This review clarifies the core design concept of multifunctional integration for bioceramic bone tissue-engineered substitutes in periodontitis treatment and provides a theoretical basis and technical reference for developing novel bone graft materials with clinical transformation potential.
Terpenoids (isoprenoids) constitute one of the largest and most structurally diverse families of natural products with application ranging from flavors, pharmaceuticals to biofuels. Conventional extraction from plants is often limited by low yields, seasonal variability, and environmental constraints; whereas, chemical synthesis requires toxic chemicals and energy-intensive processes. Consequently, microbial cell factories have emerged as sustainable and industrially scalable alternatives for terpenoid biosynthesis. Different microorganisms possess distinct physiological and metabolic advantages, including efficient precursor supply, tolerance to toxic products, internal storage for hydrophobic compounds, utilization of renewable carbon sources, and compatibility with complex biosynthetic pathways. Furthermore, several microbial hosts have strains with Generally Recognized as Safe (GRAS) status, making them attractive candidates for food and nutraceutical applications, although their regulatory acceptance ultimately depends on the production strain, genetic modifications, manufacturing process, product, and intended use. In addition, photosynthetic cyanobacteria offer a promising platform for direct conversion of CO2 into terpenoids, providing opportunities for more resource-efficient and sustainable biomanufacturing. Therefore, strategic host selection is a crucial step in designing efficient microbial platforms for terpenoid production. The present review provides a host-centric perspective by comparing conventional and emerging microbial cell factories, highlighting their physiological strengths, product spectrum, industrial applicability, and strategic considerations for sustainable and application-specific terpenoid biomanufacturing.
Biopharmaceuticals are the originating products of biotechnology, an area of increased focus for strategic U.S. leadership. The discovery, development, and manufacturing of biopharmaceuticals create large amounts of data, which is then managed and preserved for business and regulatory purposes. In accordance with the resource-based view management framework, this data is a resource which, when combined with the right capabilities, is foundational to building a company’s competitive market advantage. Big Data Capabilities to acquire, analyze, curate, store, and use data for targeted purposes across the entire biopharmaceutical manufacturing lifecycle are key to realizing business value from big data collections. This paper describes these capabilities in relation to recent advances in biopharmaceutical manufacturing and the benefits these capabilities can help realize. We argue that developing shared capabilities benefits both individual businesses, who can adopt and adapt them to establish their own strategy and competitive advantage, as well as the entire industry, which advances biopharmaceutical science through shared knowledge and collaboration. This paper was derived from extensive material collected from biopharmaceutical manufacturing industry subject matter experts gathered by the Big Data Program of the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL).
