Metabolically activated energetic materials mediate cellular anabolism for bone regeneration.

The understanding of cellular energy metabolism activation by engineered scaffolds remains limited, posing challenges for therapeutic applications in tissue regeneration. This study presents biosynthesized poly(3-hydroxybutyrate-co-4-hydroxybutyrate) [P(3HB-co-4HB)] and its major degradation product, 3-hydroxybutyrate (3HB), as endogenous bioenergetic fuels that augment cellular anabolism, thereby facilitating the progression of human bone marrow-derived mesenchymal stem cells (hBMSCs) towards osteoblastogenesis. Our research demonstrated that 3HB markedly boosts in vitro ATP production, elevating mitochondrial membrane potential and capillary-like tube formation. Additionally, it raises citrate levels in the tricarboxylic acid (TCA) cycle, facilitating the synthesis of citrate-containing apatite during hBMSCs osteogenesis. Furthermore, 3HB administration significantly increased bone mass in rats with osteoporosis induced by ovariectomy. The findings also showed that P(3HB-co-4HB) scaffold substantially enhances long-term vascularized bone regeneration in rat cranial defect models. These findings reveal a previously unknown role of 3HB in promoting osteogenesis of hBMSCs and highlight the metabolic activation of P(3HB-co-4HB) scaffold for bone regeneration.

The Biocompatibility and the Effect of Titanium and PEKK on the Osseointegration of Customized Facial Implants.

The purpose of this study was to investigate the optimization of computer-aided design/computer-aided manufacturing (CAD/CAM) patient-specific implants for mandibular facial bone defects and compare the biocompatibility and osseointegration of machined titanium (Ma), Sandblasted/Large-grit/Acid-etched (SLA) titanium, and polyetherketoneketone (PEKK) facial implants. We hypothesized that the facial implants made of SLA titanium had superior osseointegration when applied to the gonial angle defect and prevented the senile atrophy of the bone. Histologic findings of the soft-tissue reaction, hard-tissue reaction, and bone-implant contact (BIC (%) of 24 Ma, SLA, and PEKK facial implants at 8 and 12 weeks were investigated. There was no statistical difference in the soft tissue reaction. Bone was formed below the periosteum in all facial implants at 12 weeks and the BIC values were significantly different at both 8 and 12 weeks (p < 0.05). Ma, SLA, and PEKK facial implants are biocompatible with osseointegration properties. SLA can enhance osseointegration and provoke minimal soft tissue reactions, making them the most suitable choice. They provide an excellent environment for bone regeneration and, over the long term, may prevent atrophy caused by an aging mandible. The bone formation between the lateral surface of the facial implant and periosteum may assist in osseointegration and stabilization.

Masquelet Technique Combined with Ilizarov External Fixator, Reamer-irrigator-aspirator, and Flap Transplantation in an Open Tibial Fracture: A Case Report.

Introduction: The induced membrane technique was initially described by Masquelet in 1986 as a treatment for tibia non-union. It then became an established method in the management of bone defects.A critical bone defect is defined by a gap larger than 25 mm, and so, has a higher probability of non-union. Many techniques have been described to resolve this problem such as segmental bone transport, free vascular fibula graft, non-vascular fibula graft, autogenous graft, or megaprothesis. Case Report: We present the case of a 37-year-old woman who presented a multi-fragmentary open fracture of the tibia and fibula bilaterally (Gustilo-Anderson III) after a high-velocity car accident. Conclusion: The aim of this article is to demonstrate that the use of a hybrid procedure combining the Masquelet technique with the Ilizarov external fixator and reamer-irrigator-aspirator can be an effective way to treat bone defect in an open tibial fracture classified as a Gustilo-Anderson III.

The Treatment of Very Large Traumatic Bone Defects of the Tibia With a Polycaprolactone-Tricalcium Phosphate 3D-Printed Cage: A Review of Three Cases.

The need for an artificial scaffold in very large bone defects is clear, not only to limit the risk of graft harvesting but also to improve clinical success. The use of custom osteoconductive scaffolds made from biodegradable polyester and ceramics can be a valuable patient-friendly option, especially in case of a concomitant infection. Multiple types of scaffolds for the Masquelet procedure (MP) are available. However, these frequently demonstrate central graft involution when defects exceed a certain size and the complication rates remain high. This paper describes three infected tibial defect nonunions with a segmental defect over 10 centimeters long treated with a three-dimensional (3D)-printed polycaprolactone-tricalcium phosphate (PCL-TCP) cage in combination with biological adjuncts. Three male patients, between the ages of 37 and 47, were treated for an infected tibial defect nonunion after sustaining Gustilo grade 3 open fractures. All had a segmental midshaft bone defect of more than 10 centimeters (range 11-15cm). First-stage MPs consisted of extensive debridement, external fixation, and placement of anterior lateral thigh flaps. Positive cultures were obtained from all patients during this first stage, which were treated with specific systemic antibiotics for 12 weeks. The second-stage MP was carried out at least two months after the first stage. CT scans were obtained after the first stage to manufacture defect-specific cages. In the final procedure, a custom 3D-printed PCL-TCP cage (Osteopore, Singapore) was placed in the defect in combination with biological adjuncts (BMAC, RIA-derived autograft, iFactor, and BioActive Glass). Bridging of the defect, assessed at six months by CT, was achieved in all cases. SPECT scans six months post-operatively demonstrated active bone regeneration, also involving the central part of the scaffold. All three patients regained function and reported less pain with full weight bearing. This case report shows that 3D-printed PCL-TCP cages in combination with biological adjuncts are a novel addition to the surgical treatment of very large bone defects in (infected) post-traumatic nonunion of the tibia. This combination could overcome some of the current drawbacks in this challenging indication.

Experimental research of different forms of autolyzed antigen-extracted allogeneic bone combined with vascular endothelial growth factor for the repair of bone defects.

OBJECTIVE: To investigate the effect of different forms of autolyzed antigen-extracted allogeneic(AAA) bone combined with vascular endothelial growth factor (VEGF) on bone reconstruction. METHOD: The AAA bone was made into a block and a granule shape, and mixed with VEGF to prepare VEGF bone. Establishment of rat calvarium defect animal model, it is divided into 5 groups. With block bone, granular bone, block VEGF bone, granular VEGF bone was implanted in the bone defect for repair as the experimental group. The defect area was evaluated by histological and CBCT analysis 4 weeks postoperatively. RESULTS: Postoperative 4 weeks imaging results showed that there was no high-density shadow in the bone defect area of the blank group and the volume of high-density shadow in the bone defect area of the experimental group was different. Histological results showed that no osteoblasts were found in the blank group, and new bone was formed in the experimental group. The effect of bone formation in the granular bone was better than that in the block bone, and the amount of new bone formation in the VEGF bone group was higher than that of the single bone group. CONCLUSION: Granular bone has a better osteogenesis effect than block bone. The effect of allogeneic bone combined with VEGF in promoting new bone formation in the area of the bone defect is better than that of allogeneic bone alone. These results provide a theoretical and practical basis for its further clinical application.

Exploring the application of piezoelectric ceramics in bone regeneration.

Piezoelectric ceramics are piezoelectric materials with polycrystalline structure and have been widely used in many fields such as medical imaging and sound sensors. As knowledge about this kind of material develops, researchers find piezoelectric ceramics possess favorable piezoelectricity, biocompatibility, mechanical properties, porous structure and antibacterial effect and endeavor to apply piezoelectric ceramics to the field of bone tissue engineering. However, clinically no piezoelectric ceramics have been exercised so far. Therefore, in this paper we present a comprehensive review of the research and development of various piezoelectric ceramics including barium titanate, potassium sodium niobate and zinc oxide ceramics and aims to explore the application of piezoelectric ceramics in bone regeneration by providing a detailed overview of the current knowledge and research of piezoelectric ceramics in bone tissue regeneration.

Efficacy and Safety of Stem Cell Therapy for Orthopedic Conditions, Including Osteoarthritis and Bone Defects.

INTRODUCTION: Orthopedic conditions like osteoarthritis and bone defects pose significant challenges due to their impact on individuals' quality of life. Traditional treatments often provide only symptomatic relief, necessitating alternative therapies for long-term management. Stem cell therapy has grabbed attention for its regenerative and immunomodulatory properties, offering potential for tissue repair and functional restoration. OBJECTIVE: This study aims to assess the efficacy and safety of stem cell therapy for orthopedic conditions, specifically osteoarthritis and bone defects. MATERIALS AND METHODS: A retrospective cross-sectional study analyzed data from patients who underwent stem cell therapy for osteoarthritis or bone defects between January and September 2023. Outcome measures focused on pain and function improvements using tools such as Visual Analog Scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), alongside radiographic assessments. Adverse events, range of motion, quality of life, and demographic factors were also examined. Data were collected from electronic medical records while maintaining patient confidentiality. Descriptive statistics using SPSS (IBM Corp., Armonk, NY, USA) were employed to analyze patient characteristics, treatment variables, and outcomes, with statistical significance determined using Chi-square test and Independent t-test. RESULTS: Out of 50 individuals, the majority, i.e., 35 (or 70%), were diagnosed with osteoarthritis, while the remaining 15 (30%) had bone defects. Treatment outcomes showed significant improvements in pain and function, with a decrease in mean VAS and WOMAC scores at the six-month follow-up. Seven participants (28%) reported adverse events, and two participants (8%) experienced serious adverse events. CONCLUSION: Stem cell therapy shows promise for treating orthopedic conditions like osteoarthritis and bone defects. While demonstrating efficacy in pain management and functional improvement, safety considerations warrant further investigation and optimization of treatment protocols. Future research should focus on refining stem cell therapy techniques and addressing safety concerns to maximize its therapeutic potential in orthopedic practice.

[Direct anterior bone block grafting for treatment of bone defects and dysplasia of the coronoid process]. / Direkte anteriore Knochenblocktransplantation zur Behandlung von Knochendefekten und Dysplasie des Processus coronoideus.

OBJECTIVE: The aim of the surgery was to treat an elbow instability caused by critical coronoid bone loss (CCBL), lateral ulnar collateral ligament (LUCL) insufficiency,and general hyperlaxity by performing a direct anterior coronoid bone graft (CBG) and LUCL reconstruction in the same setting. INDICATIONS: In cases with CCBL isolated ligament reconstruction harbors a high failure rate, necessitating supplementary bony procedures. The diagnosis of CCBL is confirmed through lateral radiographs and further quantified through computed tomography (CT) imaging. Objective assessment of instability is conducted with standardized arthroscopic tests. Performing an anterior approach for CBG offers distinct advantages, notably in terms of achieving precise positioning of plates and screws and providing access to the proximal radioulnar joint. CONTRAINDICATIONS: Usual contraindications to surgery, coronoid bone loss less than 40%. SURGICAL TECHNIQUE: The surgical procedure is thoroughly illustrated with a video of the operation that can be accessed online: reconstruction of the LUCL with a semitendinosus allograft, harvesting of the graft from the iliac crest, exposure of the coronoid process with a direct anterior approach, freshening up of the graft bed. Temporary fixation of the graft with a Kirschner wire. Assessment of joint congruency, stability and range of motion (ROM) prior to definitive fixation with a 2.4 mm buttress plate and screws. FOLLOW-UP: Nonsteroidal anti-inflammatory drugs (NSAID) to prevent heterotopic ossification. Elbow mobilization in pronation from day 1 with an overhead motion protocol. Removable splint for 4 weeks, free mobilization at 6 weeks, return to sport at 3 months. RESULTS: Durable elbow stability was achieved along with free ROM and high patient satisfaction.

[Modified Masquelet technique : Technique of the induced membrane in the course of time]. / Modifizierte Masquelet-Plastik : Technik der induzierten Membran im Wandel der Zeit.

The reconstruction of long bone defects as a result of primary traumatic, secondary infection or tumor-related loss of substance continues to represent a surgical challenge. Callus distraction via segment transport, vascularized bone transfer and the induced membrane technique (IMT) are established methods of reconstruction. In recent decades IMT has experienced increasing popularity due to its practicability, reproducibility and reliability. At the same time, the original technique has undergone numerous modifications. The results are correspondingly heterogeneous. This overview is intended to explain the basic principles of IMT and to provide an overview of the various modifications and their complications.

Accelerated Bone Healing via Electrical Stimulation.

Piezoelectric effect produces an electrical signal when stress is applied to the bone. When the integrity of the bone is destroyed, the biopotential within the defect site is reduced and several physiological responses are initiated to facilitate healing. During the healing of the bone defect, the bioelectric potential returns to normal levels. Treatment of fractures that exceed innate regenerative capacity or exhibit delayed healing requires surgical intervention for bone reconstruction. For bone defects that cannot heal on their own, exogenous electric fields are used to assist in treatment. This paper reviews the effects of exogenous electrical stimulation on bone healing, including osteogenesis, angiogenesis, reduction in inflammation and effects on the peripheral nervous system. This paper also reviews novel electrical stimulation methods, such as small power supplies and nanogenerators, that have emerged in recent years. Finally, the challenges and future trends of using electrical stimulation therapy for accelerating bone healing are discussed.

Arthroscopic Autologous Iliac Crest Grafting with an Adjustable Loop Suspensory Device Yields Favorable Outcomes for Anterior Shoulder Instability with Glenoid Defects.

PURPOSE: This study aims to evaluate the clinical and radiological outcomes of the arthroscopic autologous iliac crest grafting (AICG) procedure with an adjustable-loop suspensory fixation device in the treatment of anterior shoulder instability (ASI) with glenoid bone defects. METHODS: A retrospective review was conducted on the patients who underwent arthroscopic AICG with an adjustable-loop suspensory fixation device from January 2017 to December 2020. Patients with traumatic ASI, significant glenoid bone defects, and a minimum follow-up of 24 months were included. Patient-reported outcomes (PROs), including the Oxford Shoulder Instability Score (OSIS), the Rowe score, the Walch-Duplay score, the Constant score, and the Visual Analogue Score (VAS), were compared preoperatively and postoperatively. Radiological assessments using computed tomography (CT) were performed before and after the procedure. Additional data on active range of motion, recurrence events, and complications were recorded. RESULTS: A total of 42 patients were included in the study, with a mean follow-up time of 35.2 months ranging from 25.1 to 55.9 months. Mean preoperative OSIS, Rowe score, Walch-Duplay score, and Constant score significantly improved from 24.4±7.2, 25.0±9.0, 25.2±9.8, 87.5±7.1 to 42.4±4.9, 92.4±8.1, 87.9±8.3, 93.6±4.5 at the last follow-up, respectively. All patients exceeded the minimal clinically important difference (MCID) for OSIS, Rowe, and Walch-Duplay scores. The graft union rate was 100%, and the glenoid area increased significantly from 82.5% preoperatively to 100.1% at the final follow-up. No patient experienced a recurrence of instability. Two recorded complications included one case of dysesthesia around the donor site and one case of postoperative shoulder stiffness. CONCLUSIONS: The outcomes of the arthroscopic AICG procedure, which utilizes an adjustable-loop suspensory fixation device, demonstrated stable bone graft fixation, high rates of graft integration, favorable clinical results, and a low incidence of complications. Moreover, the remodeling of the graft during the follow-up period significantly restored the width and concavity of the inferior glenoid, contributing to the overall recovery. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Treatment of Intrabony Defects with Non-Surgical Subgingival Debridement: A Radiographic Evaluation of Bone Gain Using an Experimental Digital Software "Bone Defect Analysis (BDA)".

Background: The aim of this study was to retrospectively evaluate the 3-year radiographic outcomes of periodontal intrabony defects treated with non-surgical subgingival therapy (NST), assessing radiographic bone gain (RBG) through experimental digital software, named "Bone Defect Analysis (BDA)". Methods: The study included 17 intrabony defects in 14 patients. BDA software (version 1) was used on radiographs to calculate RBG (in %) and variations in defect angle (in °) between baseline (T0) and 3-year follow-up (T1). Soft tissue conditions were registered, reporting bleeding on probing (BOP), probing pocket depth (PPD), and clinical attachment level (CAL). Defects were analyzed according to angles less (group A) or greater (group B) than 30°. Results: Nine and eight defects were, respectively, analyzed in groups A and B. Three years after treatment, an average RBG of 12.28% was found overall, with 13.25% and 10.11% for groups A and B, respectively (p = 0.28). Clinically, a mean CAL of 6.05 mm at T1 (from 10.94 mm at T0) was found, with 6.88 mm and 5.12 mm in groups A and B, respectively (p = 0.07). Conclusions: BDA software demonstrated predictability in the evaluation of bone variations after NST, revealing better clinical findings for intrabony defects with an initial smaller angle.

Assessment of the application of a novel three-dimension printing individualized titanium mesh in alveolar bone augmentation: A retrospective study.

OBJECTIVE: To assess the clinical and radiographic outcomes of alveolar ridge augmentation using a novel three-dimensional printed individualized titanium mesh (3D-PITM) for guided bone regeneration (GBR). MATERIALS AND METHODS: Preoperative cone-beam computed tomography (CBCT) was used to evaluate alveolar ridge defects, followed by augmentation with high-porosity 3D-PITM featuring circular and spindle-shaped pores. Postoperative CBCT scans were taken immediately and after 6 months of healing. These scans were compared with preoperative scans to calculate changes in bone volume, height, and width, along with the corresponding resorption rates. A statistical analysis of the results was then conducted. RESULTS: A total of 21 patients participated in the study, involving alveolar ridge augmentation at 38 implant sites. After 6 months of healing, the average bone augmentation volume of 21 patients remained at 489.71 ± 252.53 mm3, with a resorption rate of 16.05% ± 8.07%. For 38 implant sites, the average vertical bone increment was 3.63 ± 2.29 mm, with a resorption rate of 17.55% ± 15.10%. The horizontal bone increment at the designed implant platform was 4.43 ± 1.85 mm, with a resorption rate of 25.26% ± 15.73%. The horizontal bone increment 2 mm below the platform was 5.50 ± 2.48 mm, with a resorption rate of 16.03% ± 9.57%. The main complication was exposure to 3D-PITM, which occurred at a rate of 15.79%. CONCLUSION: The novel 3D-PITM used in GBR resulted in predictable bone augmentation. Moderate over-augmentation in the design, proper soft tissue management, and rigorous follow-ups are beneficial for reducing the graft resorption and the incidence of exposure.

Bone Grafts and Flaps in the Management of Complex Upper-Extremity Defects: Indications and Outcomes.

Reconstruction of bony defects is challenging. Most cases can be solved by means of nonvascularized bone grafts, either corticocancellous or cancellous. However, when the defect is long, there is a combined soft tissue defect, infection, a poor scarred bed, and when a piece of cartilage needs to be included, a vascularized bone graft is preferred. This article features a review of the most useful flaps for small and long defects in the hand and upper limb.

GAPDH-Silence Microsphere via Reprogramming Macrophage Metabolism and eradicating Bacteria for Diabetic infection bone regeneration.

Macrophage metabolism dysregulation, which is exacerbated by persistent stimulation in infectious and inflammatory diseases, such as diabetic infectious bone defects (DIBD), eventually leads to the failure of bone repair. Here, we have developed an injectable, macrophage-modulated GAPDH-Silence drug delivery system. This microsphere comprises chondroitin sulfate methacrylate (CM) and methacrylated gelatin (GM), while the dimethyl fumarate (DMF)-loaded liposome (D-lip) is encapsulated within the microsphere (CM@GM), named D-lip/CM@GM. Triggered by the over-expressed collagenase in DIBD, the microspheres degrade and release the encapsulated D-lip. D-lip could modulate metabolism by inhibiting GAPDH, which suppresses the over-activation of glycolysis, thus preventing the inflammatory response of macrophages in vitro. While beneficial for macrophages, D-lip/CM@GM is harmful to bacteria. GAPDH, while crucial for glycolysis of staphylococcal species (S. aureus), can be effectively countered by D-lip/CM@GM. We are utilizing existing drugs in innovative ways to target central metabolism for effective eradication of bacteria. In the DIBD model, our results confirmed that the D-lip/CM@GM enhanced bacteria clearance and reprogrammed dysregulated metabolism, thereby significantly improving bone regeneration. In conclusion, this GAPDH-Silence microsphere system may provide a viable strategy to promote diabetic infection bone regeneration.

Precision pore structure optimization of additive manufacturing porous tantalum scaffolds for bone regeneration: A proof-of-concept study.

Currently, the treatment of bone defects in arthroplasty is a challenge in clinical practice. Nonetheless, commercially available orthopaedic scaffolds have shown limited therapeutic effects for large bone defects, especially for massiveand irregular defects. Additively manufactured porous tantalum, in particular, has emerged as a promising material for such scaffolds and is widely used in orthopaedics for its exceptional biocompatibility, osteoinduction, and mechanical properties. Porous tantalum has also exhibited unique advantages in personalised rapid manufacturing, which allows for the creation of customised scaffolds with complex geometric shapes for clinical applications at a low cost and high efficiency. However, studies on the effect of the pore structure of additively manufactured porous tantalum on bone regeneration have been rare. In this study, our group designed and fabricated a batch of precision porous tantalum scaffolds via laser powder bed fusion (LPBF) with pore sizes of 250 µm (Ta 250), 450 µm (Ta 450), 650 µm (Ta 650), and 850 µm (Ta 850). We then performed a series of in vitro experiments and observed that all four groups showed good biocompatibility. In particular, Ta 450 demonstrated the best osteogenic performance. Afterwards, our team used a rat bone defect model to determine the in vivo osteogenic effects. Based on micro-computed tomography and histology, we identified that Ta 450 exhibited the best bone ingrowth performance. Subsequently, sheep femur and hip defect models were used to further confirm the osteogenic effects of Ta 450 scaffolds. Finally, we verified the aforementioned in vitro and in vivo results via clinical application (seven patients waiting for revision total hip arthroplasty) of the Ta 450 scaffold. The clinical results confirmed that Ta 450 had satisfactory clinical outcomes up to the 12-month follow-up. In summary, our findings indicate that 450 µm is the suitable pore size for porous tantalum scaffolds. This study may provide a new therapeutic strategy for the treatment of massive, irreparable, and protracted bone defects in arthroplasty.

3D Bioprinted Tissue-Engineered Bone with Enhanced Mechanical Strength and Bioactivities: Accelerating Bone Defect Repair through Sequential Immunomodulatory Properties.

In this study, a new-generation tissue-engineered bone capable of temporally regulating the immune response, balancing proinflammatory and anti-inflammatory activities, and facilitating bone regeneration and repair to address the challenges of delayed healing and nonunion in large-sized bone defects, is innovatively developed. Using the innovative techniques including multiphysics-assisted combined decellularization, side-chain biochemical modification, and sterile freeze-drying, a novel photocurable extracellular matrix hydrogel, methacrylated bone-derived decellularized extracellular matrix (bdECM-MA), is synthesized. After incorporating the bdECM-MA with silicon-substituted calcium phosphate and bone marrow mesenchymal stem cells, the tissue-engineered bone is fabricated through digital light processing 3D bioprinting. This study provides in vitro confirmation that the engineered bone maintains high cellular viability while achieving MPa-level mechanical strength. Moreover, this engineered bone exhibits excellent osteogenesis, angiogenesis, and immunomodulatory functions. One of the molecular mechanisms of the immunomodulatory function involves the inhibition of the p38-MAPK pathway. A pioneering in vivo discovery is that the natural biomaterial-based tissue-engineered bone demonstrates sequential immunomodulatory properties that activate proinflammatory and anti-inflammatory responses in succession, significantly accelerating the repair of bone defects. This study provides a new research basis and an effective method for developing autogenous bone substitute materials and treating large-sized bone defects.

A Novel Approach to Total Ankle Arthroplasty with Simultaneous Structural Tibial Cut Autograft for Anterior Tibial Bone Defects.

Severe bone defects pose a clinical challenge in total ankle arthroplasty (TAA) and are frequently considered contraindicated. We introduce an innovative approach that utilizes a structural tibial cut autograft to address anterior distal tibia bone defects during TAA. This technique is a viable alternative to employing revision TAA systems or resorting to excessively high tibial cuts. Furthermore, it facilitates achieving favorable sagittal alignment and ensures adequate fixation strength of the tibial component.

Fibrin-konjac glucomannan-black phosphorus hydrogel scaffolds loaded with nasal ectodermal mesenchymal stem cells accelerated alveolar bone regeneration.

BACKGROUND: Effective treatments for the alveolar bone defect remain a major concern in dental therapy. The objectives of this study were to develop a fibrin and konjac glucomannan (KGM) composite hydrogel as scaffolds for the osteogenesis of nasal mucosa-derived ectodermal mesenchymal stem cells (EMSCs) for the regeneration of alveolar bone defect, and to investigate the osteogenesis-accelerating effects of black phosphorus nanoparticles (BPNs) embedded in the hydrogels. METHODS: Primary EMSCs were isolated from rat nasal mucosa and used for the alveolar bone recovery. Fibrin and KGM were prepared in different ratios for osteomimetic hydrogel scaffolds, and the optimal ratio was determined by mechanical properties and biocompatibility analysis. Then, the optimal hydrogels were integrated with BPNs to obtain BPNs/fibrin-KGM hydrogels, and the effects on osteogenic EMSCs in vitro were evaluated. To explore the osteogenesis-enhancing effects of hydrogels in vivo, the BPNs/fibrin-KGM scaffolds combined with EMSCs were implanted to a rat model of alveolar bone defect. Micro-computed tomography (CT), histological examination, real-time quantitative polymerase chain reaction (RT-qPCR) and western blot were conducted to evaluate the bone morphology and expression of osteogenesis-related genes of the bone regeneration. RESULTS: The addition of KGM improved the mechanical properties and biodegradation characteristics of the fibrin hydrogels. In vitro, the BPNs-containing compound hydrogel was proved to be biocompatible and capable of enhancing the osteogenesis of EMSCs by upregulating the mineralization and the activity of alkaline phosphatase. In vivo, the micro-CT analysis and histological evaluation demonstrated that rats implanted EMSCs-BPNs/fibrin-KGM hydrogels exhibited the best bone reconstruction. And compared to the model group, the expression of osteogenesis genes including osteopontin (Opn, p < 0.0001), osteocalcin (Ocn, p < 0.0001), type collagen (Col , p < 0.0001), bone morphogenetic protein-2 (Bmp2, p < 0.0001), Smad1 (p = 0.0006), and runt-related transcription factor 2 (Runx2, p < 0.0001) were all significantly upregulated. CONCLUSIONS: EMSCs/BPNs-containing fibrin-KGM hydrogels accelerated the recovery of the alveolar bone defect in rats by effectively up-regulating the expression of osteogenesis-related genes, promoting the formation and mineralisation of bone matrix.

Macrophage metabolic reprogramming-based diabetic infected bone defect/bone reconstruction though multi-function silk hydrogel with exosome release.

Diabetic infected bone defects (DIBD) with abnormal immune metabolism are prone to the hard-to-treat bacterial infections and delayed bone regeneration, which present significant challenges in clinic. Control of immune metabolism is believed to be important in regulating fundamental immunological processes. Here, we developed a macrophage metabolic reprogramming hydrogel composed of modified silk fibroin (Silk-6) and poly-l-lysine (ε-PL) and further integrated with M2 Macrophage-derived Exo (M2-Exo), named Silk-6/ε-PL@Exo. This degradable hydrogel showed a broad-spectrum antibacterial performance against both Gram-positive and -negative bacteria. More importantly, the release of M2-Exo from Silk-6/ε-PL@Exo could target M1 macrophages, modulating the activity of the key enzyme hexokinase II (HK2) to control the inflammation-related NF-κB pathway, alleviate lactate accumulation, and inhibit glycolysis to normalize the cycle, thereby promoting M1-to-M2 balance. Using a rat model of DIBD, Silk-6/ε-PL@Exo hydrogel promoted infection control, balanced immune responses and accelerated the bone defect healing. Overall, this study demonstrates that this Silk-6/ε-PL @Exo is a promising filler biomaterial with multi-function to treat DIBD and emphasizes the importance of metabolic reprogramming in bone regeneration.