On-site delivery of bioactive agents facilitates enhancing the effectiveness of spinal fusion. However, the FDA-approved agents currently used in clinical practice are limited by side effects and cost issues, urging exploration of new alternatives.

This study aimed to investigate the effectiveness of KMN-159, a novel selective prostaglandin EP4 receptor agonist with osteopromotive properties, in spinal posterolateral fusion (PLF) surgery.

Various doses of KMN-159 were delivered locally using a mineralized collagen matrix (MCM) scaffold, and its efficacy results were compared with FDA-approved recombinant human bone morphogenetic protein-2 (rhBMP-2) in a rat lumbar PLF model. 192 male Wistar rats, aged 10 weeks, were randomized into 8 groups: 1) SHAM, 2) MCM, 3) MCM +10 μg rhBMP-2 (per scaffold), 4-8) MCM + 0.1, 1, 10, 100 or 1000 μg KMN-159 (per scaffold). PLF surgery was performed at the L4-5 level, and animals were euthanized after 3 and 6 weeks for spinal fusion evaluation.

KMN-159 exhibited dose-dependent osteopromotive effects on osteoblasts, osteoclasts, and vascular ingrowth within MCM carriers, resulting in new bone formation in a dose-dependent manner. The mid- and high-dose KMN-159 (10, 100, and 1000 μg) groups significantly enhanced PLF with biomechanical improvement, while low-dose (0.1 and 1 μg) groups were insufficient to achieve lumbar fusion.

KMN-159 emerges as a novel osteopromotive factor, coupled with its functionalized MCM scaffold presents a potential bioactive material for enhancing PLF surgery outcomes.

Tooth extraction is a common oral surgical procedure that often leads to delayed alveolar socket healing due to the complexity of the oral microenvironment, which can hinder the patient's aesthetic and functional recovery. Effective alveolar socket healing requires a multidisciplinary approach. Recent advancements in materials science and bioengineering have facilitated the development of innovative strategies, with hydrogels emerging as ideal restorative materials for alveolar socket repair due to their superior properties. This review provides an overview of recent advances in hydrogels for alveolar socket healing, focusing on their classification, physical properties (e.g., mechanical strength, swelling behavior, degradation rate, and injectability), biological functions, and applications in relevant animal models. Specifically, the bone-regenerative and antimicrobial properties of hydrogels are highlighted. Furthermore, this review identifies future directions and addresses challenges associated with the clinical application of hydrogels in extraction socket healing.

Fracture consolidation is a fundamental factor in understanding the biological process of bone healing in human. The objective of this study was to evaluate the effects of immunocorrection after trauma surgery on bone healing process in mandibular fracture in rabbits.

This study carried out using 24 rabbits. In all rabbits, the mandibular fracture model and osteogenesis carried out on the fracture site by titanium miniplates and screws. Blood analysis performed before and during the treatment. The animals slaughtered and fractured site removed for morphologic studies at baseline and follow-up assessments.

After surgical trauma in all animals, immunologic indicators of blood including circulating immunocomplex, complements, and lysosomes have been reduced.

General immunity and histomorphometric evaluation of the present study showed posttraumatic immunodeficiency could affects bone healing.

Osteogenesis is the process of bone formation mediated by the osteoblasts, participating in various bone-related physiological processes including bone development, bone homeostasis and fracture healing. It exhibits temporal and spatial interconnectivity with angiogenesis, constructed by multiple forms of cell communication occurring between bone and vascular endothelial cells. Molecular regulation among different cell types is crucial for coordinating osteogenesis and angiogenesis to facilitate bone remodeling, fracture healing, and other bone-related processes. The transmission of signaling molecules and the activation of their corresponding signal pathways are indispensable for various forms of cell communication. This communication acts as a "bridge" in coupling osteogenesis to angiogenesis. This article reviews the modes and processes of cell communication in osteogenesis-angiogenesis coupling over the past decade, mainly focusing on interactions among bone-related cells and vascular endothelial cells to provide insights into the mechanism of cell communication of osteogenesis-angiogenesis coupling in different bone-related contexts. Moreover, clinical relevance and applications are also introduced in this review.

Aseptic loosening is the primary cause of bone prosthesis failure, commonly attributed to inadequate osseointegration due to coatings misaligned with bone regeneration. Here, we modify the titanium surface with a mussel-inspired peptide to form a 3,4-dihydroxyphenylalanine (DOPA)-rich coating, then graft N3-K15-PVGLIG-K23 (P1) and N3-Y5-PVGLIG-K23 (P2), which are composed of anti-inflammatory (K23), angiogenic (K15), osteogenic (Y5), and inflammation-responsive (PVGLIG) sequences, onto the surface via click chemistry, forming the DOPA-P1@P2 coating. DOPA-P1@P2 promotes bone regeneration through sequential regulation. In the initial stage, the outermost K23 induces M2 macrophage polarization, establishing a pro-regenerative immune microenvironment. Subsequently, K15 and Y5, exposed by the release of K23, enhance angiogenesis and osteogenesis. In the final stage, DOPA-P1@P2 outperforms the TiO₂ control, showing a 161% increase in maximal push-out force, a 207% increase in bone volume fraction, and a 1409% increase in bone-to-implant contact. These findings show that DOPA-P1@P2 efficiently enhances interfacial osseointegration by sequentially regulating bone regeneration, providing viable insights into coating design.

The physiological functions of supersulfides, inorganic and organic sulfides with sulfur catenation, have been extensively studied. Their synthesis is mainly mediated by mitochondrial cysteinyl-tRNA synthetase (CARS2) that functions as a principal cysteine persulfide synthase. This study aimed to investigate the role of supersulfides in joint homeostasis and bone regeneration. Using Cars2AINK/+ mutant mice, in which the KIIK motif of CARS2 essential for supersulfide production was replaced with AINK, we evaluated the role of supersulfides in fracture healing and cartilage homeostasis during osteoarthritis (OA). Tibial fracture surgery was performed on the wild-type (Cars2+/+) and Cars2AINK/+ mice littermates. Bulk RNA-seq analysis for the osteochondral regeneration in the fracture model showed increased inflammatory markers and reduced osteogenic factors, indicative of impaired bone regeneration, in Cars2AINK/+ mice. Destabilization of the medial meniscus (DMM) surgery was performed to produce the mouse OA model. Histological analyses with Osteoarthritis Research Society International and synovitis scores revealed accelerated OA progression in Cars2AINK/+ mice compared with that in Cars2+/+ mice. To assess the effects of supersulfides on OA progression, glutathione trisulfide (GSSSG) or saline was periodically injected into the mouse knee joints after the DMM surgery. Thus, supersulfides derived from CARS2 and GSSSG exogenously administered significantly inhibited inflammation and lipid peroxidation of the joint cartilage, possibly through suppression of ferroptosis, during OA development. This study represents a significant advancement in understanding anti-inflammatory and anti-oxidant functions of supersulfides in skeletal tissues and may have a clinical relevance for the bone healing and OA therapeutics.

Early diagnosis of non-union fractures is vital for treatment planning, yet studies using bone morphometric parameters for this purpose are scarce. This study aims to create a fracture micro-CT image dataset, design a deep learning algorithm for fracture segmentation, and develop an early diagnosis model for fracture non-union.

Using fracture animal models, micro-CT images from 12 rats at various healing stages (days 1, 7, 14, 21, 28, and 35) were analyzed. Fracture lesion frames were annotated to create a high-resolution dataset. We proposed the Vision Mamba Triplet Attention and Edge Feature Decoupling Module UNet (VM-TE-UNet) for fracture area segmentation. And we extracted bone morphometric parameters to establish an early diagnostic evaluation system for the non-union of fractures.

A dataset comprising 2,448 micro-CT images of the rat fracture lesions with fracture Region of Interest (ROI), bone callus and healing characteristics was established and used to train and test the proposed VM-TE-UNet which achieved a Dice Similarity Coefficient of 0.809, an improvement over the baseline's 0.765, and reduced the 95th Hausdorff Distance to 13.1. Through ablation studies, comparative experiments, and result analysis, the algorithm's effectiveness and superiority were validated. Significant differences (p < 0.05) were observed between the fracture and fracture non-union groups during the inflammatory and repair phases. Key indices, such as the average CT values of hematoma and cartilage tissues, BS/TS and BS/TV of mineralized cartilage, BS/TV of osteogenic tissue, and BV/TV of osteogenic tissue, align with clinical methods for diagnosing fracture non-union by assessing callus presence and local soft tissue swelling. On day 14, the early diagnosis model achieved an AUC of 0.995, demonstrating its ability to diagnose fracture non-union during the soft-callus phase.

This study proposed the VM-TE-UNet for fracture areas segmentation, extracted micro-CT indices, and established an early diagnostic model for fracture non-union. We believe that the prediction model can effectively screen out samples of poor fracture rehabilitation caused by blood supply limitations in rats 14 days after fracture, rather than the widely accepted 35 or 40 days. This provides important reference for the clinical prediction of fracture non-union and early intervention treatment.

Replicating the complex mechanical forces of muscle movement and fluid flow in in vitro cell culture systems is crucial for understanding cell differentiation and development. However, previous research focused on cell differentiation on static micro/nanotextures without a force field or flat 2-dimensional substrates under a continuous in-plane mechanical force. In this study, cell differentiation is reported using a spatial geometric platform that can periodically modulate complex mechanical forces through a custom-made soft pneumatic device (SPD) to mimic the interfaces between periosteum and interstitial fluid. To elucidate fluidic dynamics and cell fates relevant to bone physiology, the platform exhibited distinct functional responses based on mechanical force levels: low mechanotransduction induced mesenchymal stem/progenitor cells differentiation into osteoprogenitor cells (≈1.5-fold increase in osteo-differentiation), while high mechanotransduction resulted in structural disruptions resembling cell detachment without protein degradation (≈2-fold increase in effective cell detachment). Numerical simulations of SPD elucidated the principal mechanical components for programmable cell differentiation and detachment by deconvoluting the in-plane and out-of-plane mechanical forces of the SPD complex mode. This study offers comprehensive and novel insights into the correlation between mechanical forces and cell differentiation, recovery, and injury in organisms.

Delayed bone healing is common in orthopaedic clinical care. Agents that alter cell function to enhance healing would change treatment paradigms. 4-aminopyridine (4-AP) is a U.S. Food and Drug Administration (FDA)-approved drug shown to improve walking in patients with chronic neurological disorders. We recently showed 4-AP's positive effects in the setting of nerve, wound, and even combined multi-tissue limb injury. Here, we directly investigated the effects of 4-AP on bone fracture healing, where differentiation of mesenchymal stem cells into osteoblasts is crucial.

All animal experiments conformed to the protocols approved by the Institutional Animal Care and Use Committee at the University of Arizona and Pennsylvania State University. Ten-week-old C57BL/6J male mice (22 to 28 g), following midshaft tibial fracture, were assigned to 4-AP (1.6 mg/kg/day, intraperitoneal [IP]) and saline solution (0.1 mL/mouse/day, IP) treatment groups. Tibiae were harvested on day 21 for micro-computed tomography (CT), 3-point bending tests, and histomorphological analyses. 4-AP's effect on human bone marrow mesenchymal stem cell (hBMSC) and human osteoblast (hOB) cell viability, migration, and proliferation; collagen deposition; matrix mineralization; and bone-forming gene/protein expression analyses was assessed.

4-AP significantly upregulated BMP2 gene and protein expression and gene expression of RUNX2, OSX, BSP, OCN, and OPN in hBMSCs and hOBs. 4-AP significantly enhanced osteoblast migration and proliferation, collagen deposition, and matrix mineralization. Radiographic and micro-CT imaging confirmed 4-AP's benefit versus saline solution treatment in mouse tibial fracture healing (bone mineral density, 687.12 versus 488.29 mg hydroxyapatite/cm3 [p ≤ 0.0021]; bone volume/tissue volume, 0.87 versus 0.72 [p ≤ 0.05]; trabecular number, 7.50 versus 5.78/mm [p ≤ 0.05]; and trabecular thickness, 0.08 versus 0.06 mm [p ≤ 0.05]). Three-point bending tests demonstrated 4-AP's improvement of tibial fracture biomechanical properties versus saline solution (stiffness, 27.93 versus 14.30 N/mm; p ≤ 0.05). 4-AP also increased endogenous BMP2 expression and matrix components in healing callus.

4-AP increased the healing rate, biomechanical properties, and endogenous BMP2 expression of tibiae following fracture.

Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Bone tissue engineering (BTE) has emerged as a promising approach to address large bone defects caused by trauma, infections, congenital malformations, and tumors. This review focuses on scaffold design, cell sources, growth factors, and vascularization strategies, highlighting their roles in developing effective treatments. We explore the complexities of balancing mechanical properties, porosity, and biocompatibility in scaffold materials, alongside optimizing mesenchymal stem cell delivery methods. The critical role of growth factors in bone regeneration and the need for controlled release systems are discussed. Vascularization remains a significant hurdle, with strategies such as angiogenic factors, co-culture systems, and bioprinting under investigation. Mechanical challenges, tissue responses, and inflammation management are examined, alongside gene therapy's potential for enhancing osteogenesis and angiogenesis via both viral and non-viral delivery methods. The review emphasizes the impact of patient-specific factors on bone healing outcomes and the importance of personalized approaches. Future directions are described, emphasizing the necessity of interdisciplinary cooperation to advance the field of BTE and convert laboratory results into clinically feasible solutions.

Effective treatment of bone diseases is quite tricky due to the unique nature of bone tissue and the complexity of the bone repair process. In combination with biological materials, cells and biological factors can provide a highly effective and safe treatment strategy for bone repair and regeneration, especially based on these multifunctional hydrogel interface materials. However, itis still a challenge to formulate hydrogel materials with fascinating properties (e.g., biological activity, controllable biodegradability, mechanical strength, excellent cell/tissue adhesion, and controllable release properties) for their clinical applications in complex bone repair processes. In this review, we will highlight recent advances in developing functional interface hydrogels. We then discuss the barriers to  producing of functional hydrogel materials without sacrificing their inherent properties, and potential applications in cartilage and bone repair are discussed. Multifunctional hydrogel interface materials can serve as a fundamental building block for bone tissue engineering.

Mandibular fractures are one of the most common sites of injuries and are difficult to restore in establishing preinjury occlusion and it is influenced by biomechanical principles. Open Reduction and Internal Fixation remain the gold standard in treating mandibular fractures to achieve pre-injury occlusion though it was limited toward expensive cost. As an option, closed reduction using an arch bar, wire, and elastic combination was preferred to establish functional preinjury occlusion.

Patients came to University Hospital with chief complaints of pain and difficulties in mouth opening and mastication. From clinical and radiographic examination the first case with history of assault injury during martial arts was found unilateral left mandibular angle and right mandibular body fracture. In the second case with the history of motorcycle injury 11 days ago was found displaced right parasimphysis mandibular fracture.

All cases was treated with close reduction using dynamic elastic for gradual reposition and followed with wire fixation until occlusion was established. After the evaluation, functional occlusion and normal mouth opening was achieved.

The selection of the therapy on multiple site fractures can be handled in a closed reduction with Intermaxillary Fixation which minimally invasive, low risk of nerve injury and give a good bone remodeling process and can restore mandibular function according to anatomy.

Despite advancements in biomimetic mineralization techniques, the repair of large-scale bone defects remains a significant challenge. Inspired by the bone formation process, a multidimensional biomimetic cascade strategy is developed by replicating the biomineralization cascade, emulating the hierarchical structure of bone, and biomimicking its biological functions for efficient bone regeneration. This strategy involves the photocrosslinking of sodium methacrylate carboxymethyl cellulose-stabilized amorphous magnesium-calcium phosphate with methacrylate-modified type I collagen to create a self-mineralizing hydrogel. The hydrogel is then integrated with either naturally derived or synthetic oriented bulk scaffolds. The resulting composite, named Osteomimix, provides excellent mechanical support and can be customized for irregular bone defects using CAD/CAM technology. Through in vitro and in vivo studies, this work finds that Osteomimix exhibits spontaneous in situ biomimetic mineralization in a cell-free environment, while modulating immune responses and promoting vascularized bone formation in a cell-dependent manner. Built on bone-specific insights, this strategy achieves biomimicry across temporal, spatial, and functional dimensions, facilitating the seamless integration of artificial constructs with the natural tissue repair dynamics.

Acute pain levels following orthopaedic injury (eg, fracture) are a predictor of the onset of chronic pain, which affects nearly 50% of fracture patients and impairs functional recovery. Among current pharmacological treatments for acute pain, non-steroidal anti-inflammatory drugs have been associated with delayed bone healing, while opioids inhibit effective bone remodelling, increase the risk of pseudarthrosis and carry a high risk of addiction. In light of this, the development of new pain treatments is essential. Cannabidiol (CBD), a non-addictive and non-psychotropic cannabis component stands out as a potential therapeutic agent, given its analgesic and anti-inflammatory properties as well as its potential benefits for bone healing. This randomised controlled trial aims to investigate the effect of acute CBD treatment, compared with placebo, on patients' self-reported pain, inflammation and well-being following a fracture injury.

This is a triple-blind, randomised, placebo-controlled clinical trial. A total of 225 adults aged 18-70 years, who have suffered a long bone fracture and were treated at the Hôpital du Sacré-Coeur de Montréal, will be randomly assigned within 1 week to one of three treatment arms (25 mg or 50 mg of CBD or placebo) for 1 month. The primary outcome will be the difference in the pain score between groups at 1-month follow-up. Secondary outcomes will include measures of persistent pain, inflammation, opioid usage, quality of life, sleep quality, depression, anxiety, cognition and orthopaedic function. Data will be collected at baseline, 1-month and 3-month follow-ups.

This study obtained a Health Canada licence for use of cannabis products. It has also been approved by Health Canada and the Research Ethics Board of the CIUSSS du Nord-de-l'Île-de-Montréal (Project ID 2025-2105). The findings will be published in a peer-reviewed journal and presented at local, national and international conferences. The trial's results will be made publicly available on the ClinicalTrials.gov database.

NCT06448923.

Muscle regeneration is a vital biological process that is crucial for maintaining muscle function and integrity, particularly for the treatment of muscle diseases such as sarcopenia and muscular dystrophy. Generally, muscular tissues can self-repair and regenerate under various conditions, including acute or chronic injuries, aging, and genetic mutation. However, regeneration becomes challenging beyond a certain threshold, particularly in severe muscle injuries or progressive diseases. In recent years, liposome-based nanotechnologies have shown potential as promising therapeutic strategies for muscle regeneration. Liposomes offer an adaptable platform for targeted drug delivery due to their cell membrane-like structure and excellent biocompatibility. They can enhance drug solubility, stability, and targeted delivery while minimizing systemic side effects by different mechanisms. This review summarizes recent advancements, discusses current applications and mechanisms, and highlights challenges and future directions for possible clinical translation of liposome-based nanomaterials in the treatment of muscle diseases. It is hoped this review offers new insights into the development of liposome-enabled nanomedicine to address current limitations.

Mycoplasma bovis is one of the most important pathogens in animal husbandry, and the current infection and morbidity rates are increasing year by year, causing great losses to the farming industry and seriously affecting animal welfare. In this study, we took tracheal tissues from calves infected with M. bovis to make pathological tissue sections for observation, and selected tracheal tissues for transcriptome sequencing to screen differentially expressed genes based on the threshold |log2FoldChange| > 1 and Padjust < 0.05 and functional enrichment, to explore in depth the potential mechanisms of bovine tracheal damage caused by bovine tracheitis. Experiments were conducted to observe the changes in tracheal tissues after M. bovis infection through pathological sections of the trachea of M. bovis-infected calves. From the transcriptome sequencing results, we mined the main differential genes and important metabolic pathways of M. bovis causing damage to the trachea of calves. It was found that the cricoid cartilage tissue of the trachea was congested and hemorrhagic after M. bovis infection in calves, and the pathological sections showed localized necrosis of epithelial cells, disorganization, high inflammatory cell infiltration in the interepithelial and lamina propria, and some epithelial cell detachment. Transcriptome sequencing identified 4199 DEGs, including 1378 up-regulated genes and 2821 down-regulated genes. KEGG enrichment analysis indicated that the differential genes were enriched to 59 significantly differing signaling pathways, and a number of important metabolic pathways related to tracheitis induced by M. bovis-infected calves were unearthed. The major ones included IL-17, the Toll-like receptor, JAK/STAT, the PI3K-Akt signaling pathway, etc. In this study, we found that M. bovis infection of calves caused inflammatory damage to the trachea, and transcriptome sequencing results also showed significant differences in the expression of key genes such as IL-6 inflammatory factor, CASP8, and APOA1.

The distinction between prolonged bone healing and nonunion in long bone fracture remains a historical challenge in the field of orthopedics. Despite numerous proposed definitions and scoring systems, a consensus remains elusive, thereby complicating both diagnosis and treatment. An accurate diagnosis is necessary, facilitated by a range of imaging modalities. Bone nonunion management encompasses surgical and non-surgical options, including external or internal fixation, and bone grafting, tailored to the nonunion type. This review discusses the pathophysiology of nonunion, risk factors, diagnosis and treatment. It particularly addresses early detection and the impacts of nonunion on the patient. The aim of this review is to obtain a global and updated point of view regarding nonunion of the bone as well as to reflect on the potential use of untraditional methods in their treatment such as orthobiologics, along with emerging and non-invasive technologies including shockwave therapy, gene therapy, tissue engineering, regenerative medicine and 3D printing.

Endothelial cells coat blood vessels and release molecular signals to affect the fate of other cells. Endothelial cells can adjust their behavior in response to the changing microenvironmental conditions. During bone regeneration, bone tissue cells release factors that promote blood vessel growth. Notch is a key signaling that regulates cell fate decisions in many tissues and plays an important role in bone tissue development and homeostasis. Understanding the interplay between angiogenesis and osteogenesis is currently a focus of research efforts in order to facilitate and improve osteogenesis when needed. Our review explores the cellular and molecular mechanisms including Notch-dependent endothelial-MSC communication that drive osteogenesis-angiogenesis processes and their effects on bone remodeling and repair.

Bioaerogels represent a type of three-dimensional porous materials fabricated from natural biopolymers, and show a significant potential for medical application due to their characteristics of extremely low density, high specific surface area, excellent biocompatibility and biodegradability. The preparation method and parameters of bioaerogels are focused on, and their influence on the structure and properties of bioaerogels are discussed in detail. Then, to match the properties of bioaerogels with the medical applications, this work emphasizes the main properties (including biocompatibility, degradability, and mechanical properties), structural parameters (such as suitable porosity, pore size and high specific surface area), and further summarizes the influence of single-component and composite bioaerogels on their properties. Moreover, according to the different applications (wound healing, drug delivery, and tissue engineering and other fields), the function method, mechanism and practical effect of bioaerogels are comprehensively analyzed. Finally, the challenges, future research directions, and solutions for the practical application of bioaerogels in medicine are discussed.

Bone implant-associated infections and inflammations, primarily caused by bacteria colonization, frequently result in unsuccessful procedures and pose significant health risks to patients. To mitigate these challenges, the development of engineered implants with spatiotemporal regulation capabilities, designed to inhibit bacterial survival and modulate immune responses in the early stage, while promoting bone defect healing in the late stage is proposed. The implants are functionalized with ε-poly-l-lysine-phenylboronic acid (PP) via dynamic boronic ester bonds, which facilitate its release through a reactive oxygen species (ROS) and pH-responsive strategy, thereby establishing an antibacterial microenvironment on and around the implants. Additionally, the dynamic metal coordination interaction facilitates the loading and sustained release of Sr2+ under an acidic environment, providing immunomodulatory and osteogenic effects. The ROS/pH-responsive feature, coupled with the implant-bone tissue integration process, affords precise spatiotemporal regulation of the Ti-TA-Sr-PP implants. This strategy represents a promising approach for the preparation of advanced bone implants.

With the ongoing development of osteoimmunology, increasing evidence indicates that the local immune microenvironment plays a critical role in various stages of bone formation. Consequently, modulating the immune inflammatory response triggered by biomaterials to foster a more favorable immune microenvironment for bone regeneration has emerged as a novel strategy in bone tissue engineering. This review first examines the roles of various immune cells in bone tissue injury and repair. Then, the contributions of different biomaterials, including metals, bioceramics, and polymers, in promoting osteogenesis through immune regulation, as well as their future development directions, are discussed. Finally, various design strategies, such as modifying the physicochemical properties of biomaterials and integrating bioactive substances, to optimize material design and create an immune environment conducive to bone formation, are explored. In summary, this review comprehensively covers strategies and approaches for promoting bone tissue regeneration through immune modulation. It offers a thorough understanding of current research trends in biomaterial-based immune regulation, serving as a theoretical reference for the further development and clinical application of biomaterials in bone tissue engineering.

Advancements in tissue regeneration, particularly bone regeneration is key area of research due to potential of novel therapeutic approaches. Efforts to reduce reliance on autologous and allogeneic bone grafts have led to the development of biomaterials that promote synchronized and controlled bone healing. However, the use of growth factors is limited by their short half-life, slow tissue penetration, large molecular size and potential toxicity. These factors suggest that traditional delivery methods may be inadequate hence, to address these challenges, new strategies are being explored. These novel approaches include the use of bioactive substances within advanced delivery systems that enable precise spatiotemporal control. Dual-release composite scaffolds offer a promising solution by reducing the need for multiple surgical interventions and simplifying the treatment process. These scaffolds allow for sustained and controlled drug release, enhancing bone repair while minimizing the drawbacks of conventional methods. This review explores various dual-drug release systems, discussing their modes of action, types of drugs used and release mechanisms to improve bone regeneration.

Infected alveolar bone defects pose challenging clinical issues due to disrupted intrinsic healing mechanisms. Thus, the employment of advanced biomaterials enabling the modulation of several aspects of bone regeneration is necessary. This study investigated the effect of multi-functional nanoparticles on anti-inflammatory/osteoconductive characteristics and bone repair in the context of inflamed bone abnormalities. Tannic-acid mineral nanoparticles (TMPs) were prepared by the supramolecular assembly of tannic acid with bioactive calcium and phosphate ions, which were subsequently incorporated into collagen plugs via molecular interactions. Under physiological conditions, in vitro analysis confirmed that tannic acid was dissociated and released, which significantly reduced the expression of pro-inflammatory genes in lipopolysaccharide (LPS)-activated RAW264.7 cells. Meanwhile, the bioactive ions of Ca2+ and PO43- synergistically increased the gene and protein expressions of osteogenic markers of bone marrow-derived stem cells. For in vivo studies, combined endodontic-periodontal lesions were induced in beagle dogs where the plugs were readily implanted. After 2 months of the implantation, analysis of micro-computed tomography and histomorphometry revealed that groups of dogs implanted with the plug incorporating TMPs exhibited a significant decrease in bone surface density as well as structural model index, and significant increase in the mineralized bone content, respectively, with positive OPN expression being observed in reversal lines. Notably, the profound improvement in bone regeneration relied on the concentration of TMPs in the implants, underscoring the promise of multi-functional nanoparticles for treating infected alveolar bones.

The management of segmental bone defects presents a complex reconstruction challenge for orthopedic surgeons. Current treatment options are limited by efficacy across the spectrum of injury, morbidity, and cost. Regional gene therapy is a promising tissue engineering strategy for bone repair, as it allows for local implantation of nucleic acids or genetically modified cells to direct specific protein expression. In cell-based gene therapy approaches, a variety of different cell types have been described including mesenchymal stem cells (MSCs) derived from multiple sources-bone marrow, adipose, skeletal muscle, and umbilical cord tissue, among others. MSCs, in particular, have been well studied, as they serve as a source of osteoprogenitor cells in addition to providing a vehicle for transgene delivery. Furthermore, MSCs possess immunomodulatory properties, which may support the development of an allogeneic "off-the-shelf" gene therapy product. Identifying an optimal cell type is paramount to the successful clinical translation of cell-based gene therapy approaches. Here, we review current strategies for the management of segmental bone loss in orthopedic surgery, including bone grafting, bone graft substitutes, and operative techniques. We also highlight regional gene therapy as a tissue engineering strategy for bone repair, with a focus on cell types and cell sources suitable for this application.

To summarize complication rates, reoperation rates, length-of-stay (LOS), patient-reported outcome measures (PROMs), and range of motion following total shoulder arthroplasty (TSA) in patients with preexisting psychiatric disorders (PDs) compared to controls.

Three databases (MEDLINE, PubMed, and EMBASE) were searched from inception to 4 March 2024 to identify studies comparing outcomes between patients undergoing anatomic (aTSA) or reverse TSA (rTSA) with or without a preexisting psychiatric condition. The authors adhered to the preferred reporting items for systematic reviews and meta-analyses and revised assessment of multiple systematic review guidelines. Data on demographics, as well as postoperative complication rates, reoperation rates, LOS, PROMs, and range of motion were extracted from included studies. PROMs included the American Shoulder and Elbow Surgeons (ASESs) score, and visual analogue scale (VAS) pain score. Meta-analyses were conducted for outcomes reported by multiple studies, with odds ratios (ORs) and mean differences (MDs) as effect measures for continuous and dichotomous outcomes, respectively.

Thirteen studies were included in this review, comprising a total of 820,831 TSA patients. The PD group (71.0% female) consisted of 150,432 patients (mean age: 67.6 ± 9.9) with a mean follow-up time of 34.1 ± 30.1 months. The control group (58.1% female) consisted of 670,399 patients (mean age: 69.4 ± 10.7) with a mean follow-up time of 39.1 ± 36.0 months. The PD group had significantly higher rates of complications and reoperation. The PD group also reported significantly lower postoperative ASES scores, higher postoperative VAS scores, and inferior postoperative abduction. There were no significant differences in postoperative LOS, forward flexion, internal rotation, or external rotation.

Patients with preexisting PDs may have a one-and-a-half times higher odds of postoperative complication or reoperation, as well as significantly worse postoperative pain and PROMs. Identification of at-risk individuals with preexisting psychiatric conditions and preoperative referral to a mental health specialist to optimize psychiatric conditions may benefit this patient cohort ahead of their shoulder arthroplasty procedure.

IV.

Bone fractures are a leading cause of morbidity and healthcare expenditure globally. The complex healing process involves inflammation, cartilage formation, mineralization, and bone remodeling. Current treatments like immobilization, surgery, and bone grafting, though effective, pose significant challenges, such as prolonged recovery and high costs. Emerging therapies such as biological agents, pharmacological treatments, and physical stimulation techniques are also associated with high costs, side effects, and practical applicability limitations. There is a critical need for alternative therapies that are cost-effective, safe, and easy to use. Recent studies suggest the potential of β-caryophyllene (BCP) and statins in promoting bone healing. BCP, a naturally occurring anti-inflammatory and antioxidant compound found in essential oils, enhances osteoblast activity and inhibits osteoclastogenesis. Statins, known for their cholesterol-lowering effects, also promote bone formation and reduce bone resorption through multiple biochemical pathways. Both BCP and statins have shown promising results in preclinical studies, enhancing bone density and promoting fracture healing. This review explores the individual and potential synergistic effects of BCP and statins on bone fracture healing. It highlights the complementary mechanisms of these agents: BCP's anti-inflammatory and osteogenic properties and statins' ability to inhibit osteoclast activity and promote angiogenesis. Combining BCP and statins could offer a multifaceted approach to enhance fracture healing, reduce complications, and improve patient outcomes. While individual effects are supported preclinically, further studies investigating synergies, formulations, and clinical translation are needed to develop this promising novel therapeutic approach for improving fracture repair outcomes.

Dental socket repair theoretically involves a constructive inflammatory immune response, which evolves from an initial M1 prevalence to a subsequent M2 dominance. In this scenario, the MEK1/2 signaling pathway is allegedly involved in M2 polarization. This study aimed to evaluate the impact of MEK1/2 pharmacological inhibition in the local host response and repair outcome. C57Bl/6-WT 8-week-old male mice were submitted to the extraction of the right upper incisor and treated (or not, control group) with MEK1/2 inhibitor PD0325901 (10 mg/kg/24 h/IP, MEK1/2i group) and analyzed at 0, 3, 7, and 14 days using microcomputed tomography, histomorphometry, birefringence, immunohistochemistry, and PCR array analysis. The results demonstrate that MEK1/2 inhibition limits the development of M2 response over time, being associated with lower expression of M2, MSCs, and bone markers, lower levels of growth and osteogenic factors, along with a higher expression of iNOS, IL-1b, IL-6, and TNF-α, as well inflammatory chemokines, indicating a predominantly M1 pro-inflammatory environment. This modulation of local inflammatory immune response is associated with impaired bone formation as demonstrated by microtomographic and histomorphometric data. The results show that MEK1/2 inhibition delays bone repair after tooth extraction, supporting the concept that M2 macrophages are essential elements for host response regulation and proper repair.

Background: Bone regeneration remains a challenging issue in tissue engineering. The use of hydrogels as scaffolds for bone tissue repair has gained attention due to their biocompatibility and ability to mimic the extracellular matrix. This study aims to develop a functionalized GelMA/CMCS composite hydrogel incorporating magnesium phosphate cement (MPC) for enhanced bone regeneration. Methods: These composites were developed by incorporating potassium magnesium phosphate hexahydrate (KMgPO4·6H2O, MPC) powders into methacrylated gelatin/carboxymethyl chitosan (GelMA-C) hydrogels. The material's mechanical properties, antibacterial performance, and cytocompatibility were evaluated. In vitro experiments involved cell viability and osteogenic differentiation assays using rBMSCs as well as angiogenic potential assays using HUVECs. The hydrogel was also assessed for its potential in promoting bone repair in a rat (Sprague-Dawley) model of bone defect. Results: The developed GelMA-CM composite demonstrated improved mechanical properties, biocompatibility, and osteogenic potential compared to individual GelMA or CMCS hydrogels. Incorporation of MPC facilitated the sustained release of ions which promoted osteogenic differentiation of pre-osteoblasts. In vivo results indicated accelerated bone healing in the rat bone defect model. Conclusions: The functionalized GelMA-CM composite could be a viable candidate for clinical applications in bone regeneration therapies.

In the musculoskeletal system, lymphatic vessels (LVs), which are interdigitated with blood vessels, travel and form an extensive transport network. Blood vessels in bone regulate osteogenesis and hematopoiesis, however, whether LVs in bone affect fracture healing is unclear. Here, we investigate the lymphatic draining function at the tibial fracture sites using near-infrared indocyanine green lymphatic imaging (NIR-ICG) and discover that lymphatic drainage insufficiency (LDI) starts on day one and persists for up to two weeks following the fracture in male mice. Sufficient lymphatic drainage facilitates fracture healing in male mice. Furthermore, we identify that lymphatic platelet thrombosis (LPT) blocks the draining lymphoid sinus and LVs, causes LDI, and inhibits fracture healing in male mice, which can be rescued by a blood thinner. Moreover, unblocked lymphatic drainage decreases neutrophils and increases M2-type macrophages of the hematoma niche to support osteoblast (OB) survival and bone marrow-derived mesenchymal stem cell (BMSC) proliferation via transporting damage-associated molecular patterns (DAMPs) in male rats. Lymphatic platelet thrombolysis also benefits senile fracture healing in female mice. These findings demonstrate that LPT limits bone regeneration by impeding lymphatic transporting DAMPs. Together, these findings represent a way forward in the treatment of bone repair.

To compare the clinical efficacy of the minimally invasive lateral shoulder approach and deltopectoral space approach in the treatment of proximal humerus fractures.

The clinical data of 95 patients with proximal humerus fractures admitted to the hospital from June 2018 to June 2023 were retrospectively collected. Forty-four patients were treated with a minimally invasive lateral shoulder approach (study group), and 51 patients were treated with a deltopectoral space approach (control group). The baseline data (age, sex, mechanism of injury, preoperative Neer classification, and time from injury to surgery), operation time, intraoperative blood loss, incision length, fracture healing time, and postoperative complications were compared between these two groups. The VAS score, shoulder range of motion (ROM) score, and Constant-Murley score were used to evaluate the shoulder joint function of the two groups one year after surgery.

There were no significant differences in operation time, blood loss, incision length or fracture healing time between the two groups (P > 0.05). The incidence of postoperative complications in the study group was significantly lower than that in the control group, and the difference between the groups was statistically significant (P < 0.05). There was no significant difference in shoulder joint function or VAS score between the two groups one year after surgery (P > 0.05).

The treatment of proximal humerus fractures via the lateral shoulder approach is minimally invasive and can reduce the occurrence of complications such as ischemic necrosis of the humerus head, relieve shoulder pain in the short term, and restore good shoulder function. Therefore, given the strict grasp of indications and familiarity with surgical operations, the minimally invasive lateral shoulder approach for the treatment of proximal humeral fractures is safe and effective and is worth promoting and applying in clinical practice.

Mesenchymal stem cells (MSCs) have shown significant potential in bone regeneration and regenerative medicine in recent years. With the advancement of tissue engineering, MSCs have been increasingly applied in bone repair and regeneration, and their clinical application potential has grown through interdisciplinary approaches involving biomaterials and genetic engineering. However, there is a lack of systematic reviews summarizing their applications in bone regeneration. To address this gap, we analyzed the latest research on MSCs for bone regeneration published from 2013 to 2023. Using the Web of Science Core Collection, we conducted a literature search in December 2024 and employed bibliometric tools like CiteSpace and VOSviewer for a comprehensive analysis of the key research trends. Our findings focus on the development of cell engineering, highlighting the advantages, limitations, and future prospects of MSC applications in bone regeneration. These insights aim to enhance understanding of MSC-based bone regeneration, inspire new research directions, and facilitate the clinical translation of MSC research.

This study evaluated the impact of different doses of gabapentin and pregabalin on fracture healing in a rat femoral shaft model, with histological, radiological, and biomechanical assessments.

Seventy male Wistar albino rats were divided into five groups: control, low-dose gabapentin (GBP-L, 300 mg/day), high-dose gabapentin (GBP-H, 3600 mg/day), low-dose pregabalin (PRG-L, 150 mg/day), and high-dose pregabalin (PRG-H, 600 mg/day), based on human equivalent doses. Bilateral femoral fractures were induced; the right femurs were prepared for radiological examination using microtomography, followed by histological analysis, whereas the left femurs were allocated for biomechanical testing. Drug administration began three weeks preoperatively and continued until sacrifice at either two or four weeks. Histological assessments included inflammation and transformation scoring and microtomography-measured callus volume. Biomechanical testing assessed maximum force and stiffness.

At the fourth week, inflammation levels were significantly higher in the GBP-H, PRG-L, and PRG-H groups compared to control (p<0.01, p<0.05, and p<0.01), while transformation scores were significantly lower in these groups (p<0.01, p<0.05, and p<0.001). Low-dose pregabalin showed a borderline transformation difference (p=0.051). Microtomography analysis showed that the GBP-H group had significantly reduced callus volume versus control by the second week (p<0.01), persisting at a lower significance by week four (p<0.05). By the fourth week, PRG-H also had reduced callus volume (p<0.05). Maximum force values by the fourth week were significantly lower in the GBP-L, GBP-H, and PRG-H groups compared to control (p<0.05 for GBP-L; p<0.01 for GBP-H and PRG-H).

These findings suggest that these drugs, particularly with their high-dose applications, may lead to prolonged inflammation and hinder fracture healing by reducing callus volume and biomechanical integrity, potentially disrupting the transition from the inflammatory to reparative phases of healing.

Ex vivo regional gene therapy is a promising tissue-engineering strategy for bone regeneration: osteogenic mesenchymal stem cells (MSCs) can be genetically modified to express an osteoinductive stimulus (e.g., bone morphogenetic protein-2), seeded onto an osteoconductive scaffold, and then implanted into a bone defect to exert a therapeutic effect. Compared to recombinant human BMP-2 (rhBMP-2), which is approved for clinical use, regional gene therapy may have unique benefits related to the addition of MSCs and the sustained release of BMP-2. However, the cellular and transcriptional mechanisms regulating the response to these two strategies for BMP-2 mediated bone regeneration are largely unknown. Here, for the first time, we performed single-cell RNA sequencing (10x Genomics) of hematoma tissue in six rats with critical-sized femoral defects that were treated with either regional gene therapy or rhBMP-2. Our unbiased bioinformatic analysis of 2393 filtered cells in each group revealed treatment-specific differences in their cellular composition, transcriptional profiles, and cellular communication patterns. Gene therapy treatment induced a more robust chondrogenic response, as well as a decrease in the proportion of fibroblasts and the expression of profibrotic pathways. Additionally, gene therapy was associated with an anti-inflammatory microenvironment; macrophages expressing canonical anti-inflammatory markers were more common in the gene therapy group. In contrast, pro-inflammatory markers were more highly expressed in the rhBMP-2 group. Collectively, the results of our study may offer insights into the unique pathways through which ex vivo regional gene therapy can augment bone regeneration compared to rhBMP-2. Furthermore, an improved understanding of the cellular pathways involved in segmental bone defect healing may allow for the further optimization of regional gene therapy or other bone repair strategies.

The field of osteoimmunology has primarily focused on fracture healing in isolated musculoskeletal injuries. The innate immune system is the initial response to fracture, with inflammatory macrophages, cytokines, and neutrophils arriving first at the fracture hematoma, followed by an anti-inflammatory phase to begin the process of new bone formation. This review aims to first discuss the current literature and knowledge gaps on the immune responses governing single fracture healing by encompassing the individual role of macrophages, neutrophils, cytokines, mesenchymal stem cells, bone cells, and other immune cells. This paper discusses the interactive effects of these cellular responses underscoring the field of osteoimmunology. The critical role of the metabolic environment in guiding the immune system properties will be highlighted along with some effective therapeutics for fracture healing in the context of osteoimmunology. However, compared to isolated fractures, which frequently heal well, long bone fractures in over 30 % of polytrauma patients exhibit impaired healing. Clinical evidence suggests there may be distinct physiologic and inflammatory pathways altered in polytrauma resulting in nonunion. Nonunion is associated with worse patient outcomes and increased societal healthcare costs. The dysregulated immunomodulatory/inflammatory response seen in polytrauma may lead to this increased nonunion rate. This paper will investigate the differences in immune response between isolated and polytrauma fractures. Finally, future directions for fracture studies are explored with consideration of the emerging roles of newly discovered immune cell functions in fracture healing, the existing challenges and conflicting results in the field, the translational potential of these studies in clinic, and the more complex nature of polytrauma fractures that can alter cell functions in different tissues.

Zinc (Zn)-based composites are promising biodegradable bone-implant materials because of their good biocompatibility, processability, and biodegradability. Nevertheless, the low interfacial bonding strength, coordinated deformation capacity, and mechanical strength of current Zn-based composites hinder their clinical application. In this study, we developed a biodegradable in situ 4Mg2Ge/Zn-0.3Cu-0.05P composite (denoted ZMGCP) via phosphorus (P) modification and hot-rolling for bone-implant applications. The mechanical properties, corrosion behavior, biotribological performance, in vitro cytocompatibility and osteogenic differentiation, and in vivo osteogenesis and osteointegration of the as-cast (AC) and hot-rolled (HR) ZMGCP samples were systematically evaluated and compared to those of 4Mg2Ge/Zn-0.3Cu (denoted ZMGC). The primary and eutectic reinforcement Mg2Ge phases formed during solidification were refined after P modification and hot-rolling. The HR ZMGCP exhibited the best tensile properties among all the samples with an ultimate tensile strength of 288.9 MPa, a yield strength of 194.5 MPa, and an elongation of 17.7 %. The HR ZMGCP showed the lowest corrosion rate of 336 μm/a, 186 μm/a, and 61.7 μm/a as measured by potentiodynamic polarization, electrochemical impedance spectroscopy, and immersion testing, respectively, among all the samples in Hanks' solution. The HR ZMGCP also showed higher biotribological resistance than its ZMGC counterpart. The HR ZMGCP exhibited the highest in vitro cytocompatibility, the best osteogenesis capability and angiogenesis property among the HR samples of pure Zn, ZMGC, and ZMGCP. Furthermore, the HR ZMGCP displayed complete in vivo biocompatibility, osteogenesis, osteointegration capability, and an appropriate degradation rate, showing significant potential for a biodegradable bone-implant material.

Bone-related diseases like osteoarthritis and osteoporosis impact millions globally, affecting quality of life. Osteoporosis considerably enhances the probability of bone fractures of the wrist, hip, and spine. Enhancement and acceleration of functional bone development can be achieved through the sustained delivery of growth factors (GFs) and cells in biomaterial carriers. The delivery of bioactive compounds in a targeted, spatiotemporal way that most closely resembles the natural defect repair process can be achieved by designing the carrier system with established release kinetics. Furthermore, the carrier can serve as a substrate that mimics the extracellular matrix, facilitating osteoprogenitor cell infiltration and growth for integrative tissue healing. In this report, we explore the significance of GFs within the realm of bone and cartilage tissue engineering, encompassing their encapsulation and delivery methodologies, the kinetics of release, and their amalgamation with biomaterials and stem cells (SCs) to facilitate the mending of bone fractures. Moreover, the significance of GFs in evaluating the microenvironment of bone tissue through reciprocal signaling with cells and biomaterial scaffolds is emphasized which will serve as the foundation for prospective advances in bone and cartilage tissue engineering as well as therapeutic equipment. Nanoparticles are being used in regenerative medicine to promote bone regeneration and repair by delivering osteoinductive growth factors like BMP-2, VEGF, TGF-β. These nanocarriers allow controlled release, minimizing adverse effects and ensuring growth factors are concentrated at the injury site. They are also mixed with mesenchymal stem cells (MSCs) to improve their engraftment, differentiation, and survival. This approach is a key step in developing multi-model systems that more efficiently facilitate bone regeneration. Researchers are exploring smart nanoparticles with immunomodulatory qualities to improve bonre regeneration and reduce inflammation in injury site. Despite promising preclinical results, challenges include cost management, regulatory approval, and long term safety. However, incorporating stem cell transport and growth factors in nanoparticles could revolutionize bone regeneration and offer more personalized therapies for complex bone disorders and accidents.

Stem cell transport and growth factors encapsulated in nanoparticles are becoming revolutionary methods for bone regeneration and repair. By encouraging stem cells to develop into osteoblasts, osteoinductive GFs like BMP-2, VEGF, and TGF-β can be delivered under control due to nanomaterials like nanoparticles, nanofibers, and nanotubes. By ensuring sustained release, these nanocarriers lessen adverse effects and enhance therapeutic results. In order to prove their survival and development, MCSs, which are essential for bone regeneration, are mixed with nanoparticles, frequently using scaffolds that resemble the ECM of bone. Furthermore, by adjusting to the injured environment and lowering inflammation, immunomodulatory nanostructures and stimuli-responsive nanomaterials can further maximize. While there are still shotcomings to overcome, including managing expenses, negotiating regulatory processes, and guaranteeing long-term safety, this method promises to outperform traditional bone grafting by providing quicker, more individualized, and more efficient treatments. Nano-embedded growth factors and stem cell technologies have the potential to revolutionize orthopedic therapy and significantly enhance patient outcomes with further research.

The growing annual demand for bone grafts and artificial implants emphasizes the need for effective solutions to repair or replace injured bones. Additive manufacturing technology offers unique merits for advancing bone tissue engineering (BTE), enabling the creation of scaffolds and implants with customized shapes and designs, interconnected architecture, controlled mechanical properties and compositions, and broadening its range of applications. It overcomes the limitations of traditional manufacturing methods such as electrospinning, salt leaching, freeze drying, solvent casting etc. This review highlights additive manufacturing technologies and their applications in BTE, as well as materials and scaffold architectures to widen the potential of the biomedical sector. The selection of optimal printing methods for BTE requires careful consideration of the advantages and disadvantages against the needs for degradation, strength, and biocompatibility. Material extrusion and powder bed fusion techniques are the most widely used additive manufacturing processes in BTE. The comprehensive review also revealed that parametric designs such as triply periodic minimal surface (TPMS) and Voronoi hold better characteristics for their application in BTE. Voronoi designs exhibit exceptional randomness whereas TPMS structures feature high permeability with continuous surfaces. Topology optimized and gradient models exhibited superior physical and mechanical properties compared to uniform lattices. Future research should focus on the development of novel biomaterials, multi-material printing, assessing long-term impacts, and enhancing 3D printing technologies.

Aging is marked by a decline in tissue regeneration, posing significant challenges to an increasingly older population. Here, we investigate age-related impairments in calvarial bone healing and introduce a novel two-part rejuvenation strategy to restore youthful repair. We demonstrate that aging negatively impacts the calvarial bone structure and its osteogenic tissues, diminishing osteoprogenitor number and function and severely impairing bone formation. Notably, increasing osteogenic cell numbers locally fails to rescue repair in aged mice, identifying the presence of intrinsic cellular deficits. Our strategy combines Wnt-mediated osteoprogenitor expansion with intermittent fasting, which leads to a striking restoration of youthful levels of bone healing. We find that intermittent fasting improves osteoprogenitor function, benefits that can be recapitulated by modulating NAD+-dependent pathways or the gut microbiota, underscoring the multifaceted nature of this intervention. Mechanistically, we identify mitochondrial dysfunction as a key component in age-related decline in osteoprogenitor function and show that both cyclical nutrient deprivation and Nicotinamide mononucleotide rejuvenate mitochondrial health, enhancing osteogenesis. These findings offer a promising therapeutic avenue for restoring youthful bone repair in aged individuals, with potential implications for rejuvenating other tissues.