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The impact of orthopedic scaffolds on bone defect healing, particularly the late-stage bone remodeling process, is pivotal for the therapeutic outcome. This study applies fadditively manufactured scaffolds composed of hydroxyapatite-doped poly(lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(lactide-co-glycolide) (HA-PELGA) with varying properties to treat rat calvarial defects, elucidating their significant role in bone remodeling by modulating physiological responses. We engineered two scaffolds with different polylactic acid (PLA) to polyglycolic acid (PGA) ratio (9/1 and 18/1) to vary in hydrophobicity, degradation rate, mechanical properties, and structural stability. These variations influenced physiological responses, including osteogenesis, angiogenesis, and immune reactions, thereby guiding bone remodeling. Our findings show that the HA-PELGA(18/1) scaffold, with a slower degradation rate, supported bulk bone formation due to a stable microenvironment. Conversely, the HA-PELGA(9/1) scaffold, with a faster degradation rate and more active interfaces, facilitated the formation of a thin bone layer and higher bone infiltration. This study demonstrates these degradable scaffolds help to promote bone healing and reveals how scaffold properties influence the bone remodeling process, offering a potential strategy to optimize scaffold design aiming at late-stage bone defect healing.

Proteasome activator subunit 3 (PA28γ) is a member of the proteasome activator family, which mainly regulates the degradation and stability of proteins. Studies have shown that it plays crucial roles in lipid formation, stemness maintenance, and blood vessel formation. However, few studies have clarified the association between PA28γ and bone diseases. Herein, we identified PA28γ as a previously unknown regulator of bone homeostasis that coordinates bone formation and lipid accumulation. PA28γ-knockout mice presented with the characteristics of low bone mass and accumulation of lipids. Suppressed expression of PA28γ restrained the osteogenic differentiation and enhanced the adipogenic differentiation of bone marrow stromal cells (BMSCs). Overexpression of PA28γ promoted osteogenic differentiation and inhibited adipogenic differentiation of BMSCs. Mechanistically, PA28γ interacted with Wnt5α, and the two interactors appeared to be positively correlated. PA28γ mainly activated the downstream Wnt/β-catenin signaling pathway, which affects BMSCs differentiation homeostasis. Deletion of Wnt5α significantly delayed the promotion of osteogenic differentiation and partially alleviated the inhibitory effect of adipogenic differentiation of BMSCs in the PA28γ-overexpressing group. Furthermore, we demonstrated that PA28γ-knockout mice had an inhibited rate of bone healing in a drill-hole femoral bone defect model in vivo. Therefore, our results confirm the effects of PA28γ on bone formation and bone defect repair, indicating that PA28γ mainly interacts with Wnt5α to activate the Wnt/β-catenin signaling pathway regulating BMSCs differentiation homeostasis. Our results reveal the function of PA28γ in bone diseases and provide a new theoretical basis for expanding the treatment of bone diseases. [ABSTRACT FROM AUTHOR]

The purpose of this study was to compare the effects of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine on bone defect healing. Wistar rats were randomly divided into three groups of eight animals each. The first received 0.1 ml/kg sterile saline solution, the second 5 mg/kg fluoxetine, and the third 5 mg/kg venlafaxine, daily by gastric gavage over 7 weeks. At week 3 of drug therapy, 5-mm diameter calvarial defects were created in the parietal bone of all of the animals. All rats were euthanized four weeks after surgery, micro-CT analysis and histomorphometric analysis were carried out to evaluate the following parameters: Bone volume fraction (BV/TV), bone surface (BS), bone surface density (BS/BV; bone surface/bone volume, 1/mm), trabecular number (Tb. N), trabecular thickness (Tb. Th), areas of new bone structure (positive areas), areas of mature bone structure (negative areas). Micro-CT analysis showed the presence of similar levels of bone formation within the defect site in all three groups (p >0.05). Histomorphometric analysis revealed the presence of bone-forming cells at the defect periphery, with less activity indicating bone formation at the center. No statistically significant difference was observed between the groups (p >0.05). Based on the findings of this study, it can be said that the use of both antidepressants hasn't any effect on bone defect healing. [ABSTRACT FROM AUTHOR]

Background: Periosteum plays a significant role in bone formation and regeneration by storing progenitor cells, and also acts as a source of local growth factors and a scaffold for recruiting cells and other growth factors. Recently, tissue-engineered periosteum has been studied extensively and shown to be important for osteogenesis and chondrogenesis. Using biomimetic methods for artificial periosteum synthesis, membranous tissues with similar function and structure to native periosteum are produced that significantly improve the efficacy of bone grafting and scaffold engineering, and can serve as direct replacements for native periosteum. Many problems involving bone defects can be solved by preparation of idealized periosteum from materials with different properties using various techniques. Methods: This review summarizes the significance of periosteum for osteogenesis and chondrogenesis from the aspects of periosteum tissue structure, osteogenesis performance, clinical application, and development of periosteum tissue engineering. The advantages and disadvantages of different tissue engineering methods are also summarized. Results: The fast-developing field of periosteum tissue engineering is aimed toward synthesis of bionic periosteum that can ensure or accelerate the repair of bone defects. Artificial periosteum materials can be similar to natural periosteum in both structure and function, and have good therapeutic potential. Induction of periosteum tissue regeneration and bone regeneration by biomimetic periosteum is the ideal process for bone repair. Conclusions: Periosteum is essential for bone formation and regeneration, and it is indispensable in bone repair. Achieving personalized structure and composition in the construction of tissue engineering periosteum is in accordance with the design concept of both universality and emphasis on individual differences and ensures the combination of commonness and individuality, which are expected to meet the clinical needs of bone repair more effectively. The translational potential of this article: To better understand the role of periosteum in bone repair, clarify the present research situation of periosteum and tissue engineering periosteum, and determine the development and optimization direction of tissue engineering periosteum in the future. It is hoped that periosteum tissue engineering will play a greater role in meeting the clinical needs of bone repair in the future, and makes it possible to achieve optimization of bone tissue therapy.

The impact of orthopedic scaffolds on bone defect healing, particularly the late-stage bone remodeling process, is pivotal for the therapeutic outcome. This study applies fadditively manufactured scaffolds composed of hydroxyapatite-doped poly(lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(lactide-co-glycolide) (HA-PELGA) with varying properties to treat rat calvarial defects, elucidating their significant role in bone remodeling by modulating physiological responses. We engineered two scaffolds with different polylactic acid (PLA) to polyglycolic acid (PGA) ratio (9/1 and 18/1) to vary in hydrophobicity, degradation rate, mechanical properties, and structural stability. These variations influenced physiological responses, including osteogenesis, angiogenesis, and immune reactions, thereby guiding bone remodeling. Our findings show that the HA-PELGA(18/1) scaffold, with a slower degradation rate, supported bulk bone formation due to a stable microenvironment. Conversely, the HA-PELGA(9/1) scaffold, with a faster degradation rate and more active interfaces, facilitated the formation of a thin bone layer and higher bone infiltration. This study demonstrates these degradable scaffolds help to promote bone healing and reveals how scaffold properties influence the bone remodeling process, offering a potential strategy to optimize scaffold design aiming at late-stage bone defect healing., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Donghui Zhu reports equipment, drugs, or supplies was provided by Stony Brook University. Donghui Zhu reports a relationship with Summit Life Science Research Institute that includes: consulting or advisory. Donghui Zhu is an editorial board member for Bioactive Materials and was not involved in the editorial review or the decision to publish this article. Cunjiang Yu is an associate editor for Bioactive Materials and was not involved in the editorial review or the decision to publish this article. Other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

The treatment of large bone defects represents a major clinical challenge. 3D printed scaffolds appear as a promising strategy to support bone defect regeneration. The 3D design of such scaffolds impacts the healing path and thus defect regeneration potential. Among others, scaffold architecture has been shown to influence the healing outcome. Gyroid architecture, characterized by a zero mean surface curvature, has been discussed as a promising scaffold design for bone regeneration. However, whether gyroid scaffolds are favourable for bone regeneration in large bone defects over traditional strut-like architecture scaffolds remains unknown. Therefore, the aim of this study was to investigate whether gyroid scaffolds present advantages over more traditional strut-like scaffolds in terms of their bone regeneration potential. Validated bone defect regeneration principles were applied in an in silico modeling approach that allows to predict bone formation in defect regeneration. Towards this aim, the mechano-biological bone regeneration principles were adapted to allow simulating bone regeneration within both gyroid and strut-like scaffolds. We found that the large surface curvatures of the gyroid scaffold led to a slower tissue formation dynamic and conclusively reduced bone regeneration. The initial claim, that an overall reduced zero mean surface curvature would enhance bone formation, could not be confirmed. The here presented approach illustrates the potential of in silico tools to evaluate in pre-clinical studies scaffold designs and eventually lead to optimized architectures of 3D printed implants for bone regeneration.

Currently, there is no longer any doubt that the use of artificial intelligence models has exceptional potential in many areas of our life, including medicine. It brings medical research to a fundamentally new qualitative level due to a high degree of accuracy in the analysis of growing volumes of medical data, avoiding the influence of the human factor and related medical mistakes. Despite the rapid development of neural networks, their practical application in modern scientific research is extremely rare. In the articles of scientists, there are no works in which neural networks used for analytics of morphological images. The methods of mathematical statistics currently used for this purpose are very complex and, in most cases, difficult for medical scientists to apply. This leads to many errors and, in some cases, to unscientific and absurd conclusions. Therefore, the authors of this work have developed methodology of creation the mathematical model based on GoogLeNet architecture, which is used for investigation of morphological healing process of a bone defect. The expert pathologist confirms results of morphological investigation conducted by mathematical model created based on a convolutional artificial neural network. The reliability of the results of a qualitative and quantitative morphological study—image analysis using the neural network developed by the authors of the article—significantly exceeds the reliability of the processing of the results by a specialist performed in the traditional way. The mathematical model makes it possible to exclude the random sampling, as well as the human factor in evaluating research results. [ABSTRACT FROM AUTHOR]

Abstract Background Hypoxia in the vicinity of bone defects triggers the osteogenic differentiation of precursor cells and promotes healing. The activation of STAT3 signaling in mesenchymal stem cells (MSCs) has similarly been reported to mediate bone regeneration. However, the interaction between hypoxia and STAT3 signaling in the osteogenic differentiation of precursor cells during bone defect healing is still unknown. Methods In this study, we assessed the impact of different durations of CoCl2-induced cellular hypoxia on the osteogenic differentiation of MSCs. Role of STAT3 signaling on hypoxia induced osteogenic differentiation was analyzed both in vitro and in vivo. The interaction between cellular hypoxia and STAT3 signaling in vivo was investigated in a mouse femoral bone defect model. Results The peak osteogenic differentiation and expression of vascular endothelial growth factor (VEGF) occurred after 3 days of hypoxia. Inhibiting STAT3 reversed this effect. Hypoxia enhanced the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and STAT3 phosphorylation in MSCs. Histology and μ-CT results showed that CoCl2 treatment enhanced bone defect healing. Inhibiting STAT3 reduced this effect. Immunohistochemistry results showed that CoCl2 treatment enhanced Hif-1α, ALP and pSTAT3 expression in cells present in the bone defect area and that inhibiting STAT3 reduced this effect. Conclusions The in vitro study revealed that the duration of hypoxia is crucial for osteogenic differentiation of precursor cells. The results from both the in vitro and in vivo studies show the role of STAT3 signaling in hypoxia-induced osteogenic differentiation of precursor cells and bone defect healing.

Objective: To investigate the role of high-mobility group AT-hook 2 (HMGA2) in osteogenic differentiation of adipose-derived mesenchymal stem cells (ADSCs) and the effect of Hmga2 knockdown for promoting bone defect repair., Methods: Bioinformatics studies using the GEO database and Rstudio software identified HMGA2 as a key factor in adipogenic-osteogenic differentiation balance of ADSCs. The protein-protein interaction network of HMGA2 in osteogenic differentiation was mapped using String and visualized with Cytoscape to predict the downstream targets of HMGA2. Primary mouse ADSCs (mADSCs) were transfected with Hmga2 siRNA, and the changes in osteogenic differentiation of the cells were evaluated using alkaline phosphatase staining and Alizarin red S staining. The expressions of osteogenic markers Runt-related transcription factor 2 (RUNX2), osteopontin (OPN), and osteocalcein (OCN) in the transfected cells were detected using RT-qPCR and Western blotting. In a mouse model of critical-sized calvarial defects, mADSCs with Hmga2- knockdown were transplanted into the defect, and bone repair was evaluated 6 weeks later using micro-CT scanning and histological staining., Results: GEO database analysis showed that HMGA2 expression was upregulated during adipogenic differentiation of ADSCs. Protein-protein interaction network analysis suggested that the potential HMGA2 targets in osteogenic differentiation of ADSCs included SMAD7, CDH1, CDH2, SNAI1, SMAD9, IGF2BP3, and ALDH1A1. In mADSCs, Hmga2 knockdown significantly upregulated the expressions of RUNX2, OPN, and OCN and increased cellular alkaline phosphatase activity and calcium deposition. In a critical-sized calvarial defect model, transplantation of mADSCs with Hmga2 knockdown significantly promoted new bone formation., Conclusion: HMGA2 is a crucial regulator of osteogenic differentiation in ADSCs, and Hmga2 knockdown significantly promotes osteogenic differentiation of ADSCs and accelerates ADSCs-mediated bone defect repair in mice.

Critical-sized bone defects are critical healing conditions that, if left untreated, often lead to non-unions. To reduce the risk, critical-sized bone defects are often treated with recombinant human BMP-2. Although enhanced bone tissue formation is observed when BMP-2 is administered locally to the defect, spatial and temporal distribution of callus tissue often differs from that found during regular bone healing or in defects treated differently. How this altered tissue patterning due to BMP-2 treatment is linked to mechano-biological principles at the cellular scale remains largely unknown. In this study, the mechano-biological regulation of BMP-2-treated critical-sized bone defect healing was investigated using a multiphysics multiscale in silico approach. Finite element and agent-based modeling techniques were combined to simulate healing within a critical-sized bone defect (5 mm) in a rat femur. Computer model predictions were compared to in vivo microCT data outcome of bone tissue patterning at 2, 4, and 6 weeks postoperation. In vivo, BMP-2 treatment led to complete healing through periosteal bone bridging already after 2 weeks postoperation. Computer model simulations showed that the BMP-2 specific tissue patterning can be explained by the migration of mesenchymal stromal cells to regions with a specific concentration of BMP-2 (chemotaxis). This study shows how computational modeling can help us to further understand the mechanisms behind treatment effects on compromised healing conditions as well as to optimize future treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Bone grafts are in high demand due to the increase in the cases of bone defects mainly caused by trauma, old age, and disease-related bone damages. Tissue-engineered calcium phosphate (CaP) biomaterials match the major inorganic contents of bone, thereby could be the potential bone graft substitute. However, CaP-bone grafts lack the osteoinductivity that is vital for effective bone regeneration. In this study, we aimed to test the bone defect healing potential of biomimetically fabricated low dose BMP2-doped CaP (BMP2.BioCaP) grafts in a large animal model.Methods: Low dose BMP2 was doped internally (BMP2-int.BioCaP) or on the surface of CaP (BMP2-sur.BioCaP) grafts during the fabrication process. Our previous study showed the robust bone regenerative potential of BMP2-int.BioCaP and BMP2-sur.BioCaP grafts in the rat ectopic model. In this study, we investigated the bone defect healing potential of BMP2.BioCaP grafts in sheep humerus/femoral defects, as well as compared with that of autologous bone graft and clinically used deproteinized bovine bone (DBB) xenograft.Results: Different ways of BMP2 doping did not affect the surface morphology and degradation properties of the graft materials. Micro-CT and histology results showed robustly higher bone defect-healing potential of the BMP2.BioCaP grafts compared to clinically used DBB grafts. The bone defect healing potential of BMP2.BioCaP grafts was as effective as that of the autologous bone graft. Although, BMP2-int.BioCaP doped half the amount of BMP2 compared to BMP2-sur.BioCaP, its' bone defect healing potential was even robust. The BMP2.BioCaP grafts showed less immunogenicity compared to BioCaP or DBB grafts. The volume density of blood vessel-like and bone marrow-like structures in both BMP2.BioCaP graft groups were in a similar extent to the autologous group. Meticulous observation of higher magnification histological images showed active bone regeneration and remodeling during bone defect healing in BMP2.BioCaP graft groups.Conclusion: The robust bone regenerative potential of BMP2.BioCaP grafts in the ectopic model and in-situ bone defects in small and large animals warrant the pre-clinical studies on large animal critical-sized segmental bone defects.

To evaluate the effect of a high-fat diet (HFD) on bone mineral density and bone repair in osteoporotic rats and explore the possible mechanisms. Methods Female SD rats were randomly divided into three groups: sham surgical ovariectomy group (Sham), surgical ovariectomy model group (OVX), surgical ovariectomy model + HFD (OVX + HFD), all rats were subsequently ovarian removed on both sides Bilateral femoral shafts were created on the basis of 12 weeks after surgery or sham operation to establish a bone defect model. OVX + HFD rats received HFD intervention on the femur for 4 weeks. Imaging, serology, bone biomechanics, and genetic level testing were then used to evaluate the effect of bone repair. Results Compared with the Sham group, serum E2 and ALP levels in the OVX and OVX + HFD groups were significantly reduced (P <0. 05), while TRAP levels were significantly increased (P

Large segmental bone defects represent a clinical challenge for which current treatment procedures have many drawbacks. 3D-printed scaffolds may help to support healing, but their design process relies mainly on trial and error due to a lack of understanding of which scaffold features support bone regeneration. The aim of this study was to investigate whether existing mechano-biological rules of bone regeneration can also explain scaffold-supported bone defect healing. In addition, we examined the distinct roles of bone grafting and scaffold structure on the regeneration process. To that end, scaffold-surface guided migration and tissue deposition as well as bone graft stimulatory effects were included in an in silico model and predictions were compared to in vivo data. We found graft osteoconductive properties and scaffold-surface guided extracellular matrix deposition to be essential features driving bone defect filling in a 3D-printed honeycomb titanium structure. This knowledge paves the way for the design of more effective 3D scaffold structures and their pre-clinical optimization, prior to their application in scaffold-based bone defect regeneration.

Thrombomodulin (TM) is a transmembrane glycoprotein that contains five functional domains. Soluble TM (sTM), comprising extracellular domains TMD1 (lectin‐like), TMD2 (epidermal growth factor [EGF]‐like repeat containing), and TMD3 (serine‐threonine rich), can be shed from cells by the intramembrane protease rhomboid‐like‐2 (RHBDL2). TM is expressed by osteoblasts, yet its role there has not been determined. Herein we aimed to investigate the properties of TM and its domains in osteoblast function and bone repair following injury in diabetes. In response to a scratch injury of cultured osteoblast‐like MG63 cells, expression of TM and RHBDL2 was enhanced, with increased release of sTM. Conditioned media from the injured cells promoted osteoblast migration, an effect that was lacking with conditioned media from MG63 cells in which TM was silenced by shRNA. Exogenous recombinant TMD1 had no effect on osteoblast activities or on bone repair in vivo. However, TM domains 2 and 3 (TMD2/3), induced MG63 cell migration, proliferation and mineralization in vitro, and when locally administered in mice, improved in vivo healing of injured calvarium. This beneficial effect of TMD2/3, mediated via fibroblast growth factor receptor (FGFR)/ERK signaling pathways, was also observed in vitro under high glucose conditions where endogenous TM expression was reduced, and in vivo in diabetic mice following tibia fracture or calvarium injury, where the osteoblastic response and healing were otherwise dampened. Taken together, osteoblast TM participates in bone healing, and recombinant TMD2/3 holds promise as a novel therapy for diabetic bone defect healing. © 2020 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Introduction: Menopause can lead to osteoporosis, which is characterized by destruction of bone microstructure, poor mechanical properties, and prone to fracture. LIPUS can effectively promote bone formation and fracture healing. MSTN is a transforming growth factor-β family member that acts as a negative regulator of skeletal muscle growth. A MSTN deficiency also has a positive effect on bone formation. However, whether LIPUS could inhibit bone loss and promote healing of bone injury of menopause through the inhibition of the MSTN signaling pathway has not been previously investigated. We herein investigated the effects of LIPUS on bone architecture, mechanical properties, the healing of bone defects, and its potential molecular mechanisms in ovariectomized rats.Materials and Methods: The rats were randomly divided into three groups: sham ovariectomized group (Sham), ovariectomized model group (OVX), ovariectomized model with LIPUS therapy group (OVX + LIPUS). The OVX + LIPUS rats were treated with LIPUS (1.5 MHz, 30 mW/cm2) on the femur for 20 min/day that lasted for 19 days.Results: LIPUS effectively improved the bone microstructure, increased mechanical properties and promoted the healing of bone defects in ovariectomized rats. Moreover, LIPUS effectively decreased the MSTN content in serum and quadriceps muscle in ovariectomized rats, and inhibited the expression of MSTN downstream signaling molecules and activated the Wnt signaling pathway in the femur.Conclusions: The present study shows that LIPUS improved osteoporosis and promoted bone defect healing in the ovariectomized rats may through the inhibition of the MSTN signal pathway. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) undergo osteogenic differentiation during bone defect healing. However, the role of JAK2/STAT3 in the osteogenic differentiation of MSCs and bone defect healing is still not fully understood. In this study, we aimed to analyze the effect of AG490, a JAK2-specific inhibitor, on MSCs proliferation and osteogenic differentiation as well as in bone defect healing. We used AG490 to inhibit the JAK2/STAT3 signaling in a mice bone marrow stromal cells (BMSCs) culture. AG490 inhibited BMSCs proliferation and osteogenic differentiation markers, i.e. Col1α, Alp and Ocn expression in mRNA and protein levels. Inhibition of JAK2 reduced ALP activity and matrix mineralization in BMSCs culture. Inhibition of JAK2 reduced phosphorylation of STAT3, AKT, P38, and JNK phosphorylation. Immunohistochemistry showed high numbers of pJAK2, pSTAT3 and ALP positive cells and AG490 reduced this effect in vivo. Histology and μ-computed tomography (CT) data showed that AG490 treatment inhibits bone regeneration and bone defect healing. Our results clearly showed the inhibitory effect of AG490 on proliferation and osteogenic differentiation of BMSCs, bone regeneration and bone defect healing. Moreover, AG490 inhibited phosphorylation of STAT3, P38, JNK and AKT. This suggests the possible role of JAK2/STAT3 signaling in hypoxia-induced osteogenic differentiation of MSCs and bone defect healing. [ABSTRACT FROM AUTHOR]

Periodontitis has been advocated as a systematic chronic low-grade infection burden. However, the relationship between periodontitis and bone defect healing has not been elucidated. One hundred and eight male Wister rats were randomly assigned into three groups: control (healthy) group, periodontitis group, and periodontitis plus human tumor necrosis factor receptorII:IgG Fc fusion protein (rhTNFR:Fc) group. The experimental periodontitis model was established by ligaturing with orthodontic wire and silk suture plus local administration of 20 μl of lipopolysaccharide (LPS). Mandibular bone defects in size of 4 × 2 × 1 mm were created for all the rats and rhTNFR:Fc subcutaneously injected at neck at a dose of 2.5 mg/kg every 3 days for the periodontitis plus rhTNFR:Fc group. The gene and protein expressions of bone-related markers in the healing tissue were monitored and new bone formation was histologically evaluated. Tartrate-resistant acid phosphatase (TRAP) staining was performed to determine the number of osteoclasts. The results showed that the mRNA and protein expressions of osteogenesis-related markers were significantly lower while nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) gene expression was significantly higher in the periodontitis group. The periodontitis group showed decreased new bone formation and increased number of osteoclasts when compared to the control group. However, there was no significant difference between the periodontitis plus rhTNFR:Fc group and the control group. These results demonstrated that periodontitis may restrain the mandibular bone healing via disturbing osteogenic and osteoclastic balance in which tumor necrosis factor-α (TNF-α) could act as a leverage. [ABSTRACT FROM AUTHOR]

Background: The aim of the present study was to evaluate the effects of low-level laser therapy (LLLT) on the healing of bone defects in rats with streptozotocin (STZ)-induced DM.Methods: 28 male Sprague-Dawley rats were used in this study. 14 animals received a single dose of STZ intraperitoneally (65 mg/kg) to induce Type I DM, whereas others were injected only with sterile saline solution. Four weeks later, standard bone defects were created in the tibiae of rats. Surgical wounds in one group from each of the diabetic and non-diabetic animals were irradiated with diode laser for every other day for 4 weeks and they were described as DM + LLLT and CONT + LLLT groups, respectively. Remaining two groups received no laser treatment. New bone formation, osteoblast and blood vessel counts were calculated in histologic sections.Results: DM group had significantly smaller bone area and lower blood vessel count when compared to DM + LLLT, CONT and CONT + LLLT groups (p< 0.05 for each). CONT and CONT + LLLT groups had significantly larger bone area than DM + LLLT group (p< 0.05 for both).Conclusions: LLLT application promoted vascularization and new bone formation in animals with DM to a limited extent, since it was unable to support the healing process up to the level of non-diabetic animals. [ABSTRACT FROM PUBLISHER]

Purpose Zirconia is a good candidate material in the dental field. In this study, we evaluated biological responses against a zirconia drill using a bone cavity healing model. Materials and Methods Zirconia drills, stainless steel drills, and the drilled bone surface were observed by scanning electron microscopy (SEM), before and after cavity preparation. For the bone cavity healing model, the upper first and second molars of Wistar rats were extracted. After 4 weeks, cavities were prepared with zirconia drills on the left side. As a control, a stainless steel drill was used on the right side. At 3, 7, and 14 days after surgery, micro-CT images were taken. Samples were prepared for histological staining. Results SEM images revealed that zirconia drills maintained sharpness even after 30 drilling procedures. The bone surface was smoother with the zirconia drill. Micro-CT images showed faster and earlier bone healing in the zirconia drill cavity. On H-E staining, at 7 days, the zirconia drill defect had a smaller blank lacunae area. At 14 days, the zirconia drill defect was filled with newly formed bone. Conclusions The zirconia drill induces less damage during cavity preparation and is advantageous for bone healing. (197 words) [ABSTRACT FROM AUTHOR]

Local application of bone morphogenetic protein 2 (BMP2) is known to promote large bone defect healing and BMP2-initiated bone regeneration could be enhanced by an additional mechanical stimulation. The C-terminal 24-a.a. peptide of mechano growth factor (MGF24E), a mechanical-sensitive molecule, has been demonstrated to promote bone healing. Here, we propose a hypothesis that MGF24E could also improve the osteogenic efficacy of BMP2 by regulating the signaling events in the BMP pathway. To confirm the hypothesis, the potentials of MGF24E, BMP2 and BMP2/MGF24E combination treatments on the phosphorylation of Smad 1/5/8, the downstream osteogenesis-related gene expression and osteoblasts mineralization, are investigated with or without the blocking of Smad 5 siRNA. Furthermore, 15-mm rabbit radial bone defects were healed with the cytokine treatments and then evaluated by radiographic examination, histological assessment and immunohistochemical analysis. MGF24E could enhance the BMP2-induced Smad signaling pathway by upregulating the p-Smad protein expression and the downstream osteogenic gene expression. An amount of 5 nM BMP2 in a sub-25 nM concentration of MGF24E medium achieved a higher expression for ALP mRNA and a greater calcium mineral content compared with BMP2 alone. Nevertheless, the inhibition of the MGF24E-regulated BMP pathway could block osteogenesis induced by the dual treatment. In vivo, MGF24E treatment upregulated the endogenous BMP2 expression and the addition of MGF24E into the BMP2 treatment remarkably enhanced the bone mineral density (BMD), the radiographic scores and the histological restoration of the regenerated tissue against BMP2 treatment, suggesting a new strategy for BMP2 in bone defect healing. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the effect of Electro-Acupuncture (EA) and Static Magnetic Field (SMF) therapy on healing of bone defect in rabbits. Materials and Methods A2 mm bone defect was created at radial midshaft of 18 New Zealand White rabbits. The animals were then randomly divided into 3 equal groups. The animals in the group Adid not receive any physiotherapy and served as control. Group B animals were treated with the EA using 50 Hz and 3-10 mADD current for 10 min. Group C animals were treated with SMF therapy on alternate days till day 15. Activity of serum calcium (Ca), potassium (P) and ALP; Plasma Cortisol and LPO were evaluated preoperatively and on days 7, 15, 30 and 60 of experiment. Results: Postoperatively, SMF therapy treated animals exhibited higher Ca, P and ALP level and low initial level of Cortisol and LPO as compared to EAand control group animal. Conclusion: SMF and EAhad positive effect on bone defect healing and early resolution of stress, induced due to creation of bone defect, however SMF had an edge over EA. [ABSTRACT FROM AUTHOR]

The treatment of large bone defects represents a major clinical challenge. 3D printed scaffolds appear as a promising strategy to support bone defect regeneration. The 3D design of such scaffolds impacts the healing path and thus defect regeneration potential. Among others, scaffold architecture has been shown to influence the healing outcome. Gyroid architecture, characterized by a zero mean surface curvature, has been discussed as a promising scaffold design for bone regeneration. However, whether gyroid scaffolds are favourable for bone regeneration in large bone defects over traditional strut-like architecture scaffolds remains unknown. Therefore, the aim of this study was to investigate whether gyroid scaffolds present advantages over more traditional strut-like scaffolds in terms of their bone regeneration potential. Validated bone defect regeneration principles were applied in an in silico modeling approach that allows to predict bone formation in defect regeneration. Towards this aim, the mechano-biological bone regeneration principles were adapted to allow simulating bone regeneration within both gyroid and strut-like scaffolds. We found that the large surface curvatures of the gyroid scaffold led to a slower tissue formation dynamic and conclusively reduced bone regeneration. The initial claim, that an overall reduced zero mean surface curvature would enhance bone formation, could not be confirmed. The here presented approach illustrates the potential of in silico tools to evaluate in pre-clinical studies scaffold designs and eventually lead to optimized architectures of 3D printed implants for bone regeneration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jaber, Poh, Duda and Checa.)

Abstract: Angiogenesis is pivotal for bone metabolism and bone defect healing. Yet the role of vascularization in osteoporosis and osteoporotic bone repair mechanisms is unclear. Here we investigated effects of osteoporotic phenotype on vascularization during bone defect healing in a rodent osteotomy model using volumetric computed tomography (VCT), dynamic contrast-enhanced VCT (DCE-VCT), dynamic contrast-enhanced MRI (DCE-MRI) and histology. In 16 rats, 8 with physiological bone status (SHAM) and 8 with osteoporotic bone status induced by ovariectomy (OVX) in combination with a vitamin D- and low calcium diet, wedge-shaped defects were created at the left distal femur and stabilized internally by T-shaped miniplate. MRI and VCT were performed in all animals 6 weeks after this procedure. By VCT, relative bone density in the defect was evaluated. Using DCE-VCT and DCE-MRI, parameters associated with regional blood volume were calculated in the bone defect, vicinity of the defect, surrounding muscles and bone marrow: Amplitude A and exchange rate constant Kep (DCE-MRI, respectively) as well as peak enhancement PE and area under the curve AUC (DCE-VCT, respectively). In animals of osteoporotic phenotype, bone density within the osseous defect was significantly reduced as compared to SHAM rats. Vascularization parameters determined by DCE-MRI and DCE-VCT in the defect were significantly elevated compared to the adjacent tissues for both SHAM and OVX groups. However, comparing SHAM and OVX rats, no statistically different values were found by DCE-MRI and DCE-VCT concerning any determined vascularization parameter within the bone defect. Furthermore, parameters of vascularization were increased for OVX as compared to SHAM rats within the bone marrow although significant difference was only found for A. In a rat osteotomy model we showed that at the reparative healing stage, osteoporotic phenotype did influence osteogenic but not angiogenic response within bone defect as imaged by DCE-MRI and DCE-VCT. This study provides insight into the relationship between angiogenesis and osteogenesis during osteoporosis-related compromised bone healing. [Copyright &y& Elsevier]

Sclerostin is a glycoprotein secreted by osteocytes and inhibits osteoblastogenesis via inhibition of Wnt signaling. We hypothesized that sclerostin antibody (Scl-AbIII) would accelerate the healing of a murine femoral non-critical size bone defect model. A unilateral and unicortical 0.8 mm-sized drill hole was made in the proximal femoral shaft of adult female nude mice. One group of mice received subcutaneous injections of Scl-AbIII and a second group received vehicle only. Reporter MC3T3 osteoprogenitor cells were injected via the tail vein 3 days after surgery to monitor systemic trafficking of exogenous osteoprogenitors. Bioluminescence imaging (BLI), microcomputed tomography (microCT), micropositron emission tomography (microPET) and histological analysis were used to compare the bone healing responses to Scl-AbIII treatment. Bone mineral density (BMD) significantly increased at the defect site after week 1, and was significantly higher in the treatment compared with the control group at all time points. This finding was also confirmed on histological analysis by increased deposition of new woven bone. MicroPET scanning showed a trend for greater activity in the control group at day 21 compared with the Scl-AbIII group, indicating early bone maturation following treatment with Scl-AbIII. Whereas the BLI signals derived from the injected osteoprogenitor cells showed no differences between vehicle and Scl-AbIII treated groups, systemic migration of MC3T3 cells to the bone defect was clearly identified in both groups using immunohistochemistry. Systemic administration of Scl-AbIII resulted in earlier healing and maturation of a non-critical size bone defect. These findings underscore the potential use of Scl-AbIII for treatment of complicated fractures, non-unions, and other clinical scenarios. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:155-163, 2012 [ABSTRACT FROM AUTHOR]

Introduction Cystic lesions of the jaws and the impacted teeth are two of the most common cases that require surgical intervention in oral and maxillofacial surgery; however, surgeons also frequently use a traditional technique that involves the removal of the buccal bone plate. This study was conducted to compare the clinical and radiologic outcomes of the bone lid technique and the traditional technique. Methods This randomized controlled trial included 20 patients who were randomly divided into two groups (n = 10 each): the T group, in which the lesions were accessed using the traditional technique with classical rotating instruments, and the BL group, in which the lesions were accessed with the bone lid technique performed using a piezoelectric device, with repositioning of the buccal bone plate. Operative time, pain, edema, inferior alveolar nerve injury, and bone defect healing were measured during clinical and radiological follow-ups at 24 h, 72 h, one week, one month, and six months after the surgery. Results Normal soft tissue and bone healing were observed in all cases except one case in the BL group. The T group had a shorter mean operative time than the BL group. In terms of pain, edema, and inferior alveolar nerve injury, the groups did not differ statistically significantly. The percentage of bone defect healing was significantly greater in the BL group than in the T group after six months of follow-up. Conclusion The bone lid technique performed using a piezoelectric device was effective and safe for managing lesions in the posterior mandibular region and was not associated with increased postoperative complications. The disadvantages of this technique include a longer operative time and the need for fixation tools in some cases. In contrast, this technique outperforms the traditional technique in terms of reducing bone loss and improving the healing of bone defects., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Abu hawa et al.)

Abstract: Earlier studies have shown that the influence of fixation stability on bone healing diminishes with advanced age. The goal of this study was to unravel the relationship between mechanical stimulus and age on callus competence at a tissue level. Using 3D in vitro micro-computed tomography derived metrics, 2D in vivo radiography, and histology, we investigated the influences of age and varying fixation stability on callus size, geometry, microstructure, composition, remodeling, and vascularity. Compared were four groups with a 1.5-mm osteotomy gap in the femora of Sprague–Dawley rats: Young rigid (YR), Young semirigid (YSR), Old rigid (OR), Old semirigid (OSR). Hypothesis was that calcified callus microstructure and composition is impaired due to the influence of advanced age, and these individuals would show a reduced response to fixation stabilities. Semirigid fixations resulted in a larger ΔCSA (Callus cross-sectional area) compared to rigid groups. In vitro µCT analysis at 6weeks postmortem showed callus bridging scores in younger animals to be superior than their older counterparts (p <0.01). Younger animals showed (i) larger callus strut thickness (p <0.001), (ii) lower perforation in struts (p <0.01), and (iii) higher mineralization of callus struts (p <0.001). Callus mineralization was reduced in young animals with semirigid fracture fixation but remained unaffected in the aged group. While stability had an influence, age showed none on callus size and geometry of callus. With no differences observed in relative osteoid areas in the callus ROI, old as well as semirigid fixated animals showed a higher osteoclast count (p <0.05). Blood vessel density was reduced in animals with semirigid fixation (p <0.05). In conclusion, in vivo monitoring indicated delayed callus maturation in aged individuals. Callus bridging and callus competence (microstructure and mineralization) were impaired in individuals with an advanced age. This matched with increased bone resorption due to higher osteoclast numbers. Varying fixator configurations in older individuals did not alter the dominant effect of advanced age on callus tissue mineralization, unlike in their younger counterparts. Age-associated influences appeared independent from stability. This study illustrates the dominating role of osteoclastic activity in age-related impaired healing, while demonstrating the optimization of fixation parameters such as stiffness appeared to be less effective in influencing healing in aged individuals. [Copyright &y& Elsevier]

Abstract: Mechanical conditions have a significant influence on the biological processes of bone healing. Small animal models that allow controlling the mechanical environment of fracture and bone defect healing are needed. The aim of this study was to develop a new animal model that allows to reliably control the mechanical environment in fracture and bone defect healing in rats using different implant materials. An external fixator was designed and mounted in vitro to rat femurs using four Kirschner-wires (titanium (T) or steel (S)) of 1.2mm diameter. The specimens were distracted to a gap of 1.5mm. Axial and torsional stiffness of the device was tested increasing the offset (distance between bone and fixator crossbar) from 5 to 15mm. In vivo performance (well-being, infection, breaking of wires and bone healing) was evaluated in four groups of 24 Sprague-Dawley rats varying in offset (7.5 and 15mm) and implant material (S/T) over 6 weeks. Torsional and axial stiffness were higher in steel compared to titanium setups. A decrease in all configurations was observed by increasing the offset. The offset 7.5mm showed a significantly higher torsional (S: p<0.01, T: p<0.001) and axial in vitro stiffness (S: p<0.001, T: p<0.001) compared to 15mm offset of the fixator. Although in vitro designed to be different in mechanical stiffness, no difference was found between the groups regarding complication rate. The overall-complication rate was 5.2%. In conclusion, we were able to establish a small animal model for bone defect healing which allows modeling the mechanical conditions at the defect site in a defined manner. [Copyright &y& Elsevier]

Abstract: Non-unions and delayed healing are still prevalent complications in fracture and bone defect healing. Both mechanical stability and age are known to influence this process. However, it remains unclear which factor dominates and how they interact. Within this study, we sought a link between both factors. In 36 female Sprague–Dawley rats, the left femur was osteotomized, distracted to an osteotomy gap of 1.5 mm and externally fixated. Variation of age (12 vs. 52 weeks — biologically challenging) and fixator stiffness (mechanically challenging) resulted in 4 groups (each 9 animals): YS: young semi-rigid, OS: old semi-rigid, YR: young rigid and OR: old rigid. Qualitative and quantitative radiographical analyses were performed at weeks 2, 4 and 6 after surgery. Six weeks post-op, rats were sacrificed and femora were harvested for biomechanical testing (torsional stiffness (TS) and maximum torque at failure (MTF)). Six weeks after surgery, TS showed a significant interaction between age and fixation stiffness (p <0.0001). TS in YR was significantly higher than that in the other groups (YS: p <0.001; OR: p <0.001; OS: p <0.001). Additionally, YS showed a significantly higher TS compared to the OS (p =0.006) and OR (p =0.046). Testing of MTF showed a significant interaction of both variables (p =0.0002) and led to significant differences between OR and YS (p <0.001), OS (p =0.046) and YR (p <0.001). The YR showed a higher MTF compared to YS (p =0.012) and OS (p =0.001), whereas OR''s MTF was inferior compared to OS. At 2-week follow-up, YR (p =0.006), and at 6-week follow-up, YS and YR (p =0.032) showed significantly higher radiographic scores. At 2-week follow-up, YS''s callus was larger than that of the old groups (OS: p =0.025; OR: p =0.003). In YR a significantly smaller callus was observed compared to YS at time points 4 and 6 weeks (p =0.002 for both) and compared to OS at 6-week follow-up (p =0.03). The effect of age seems to invert the effect of mechanical properties of the callus, which was not correlated to callus size. Optimization of mechanics alone seems to be not sufficient. The underlying mechanisms and causes of the age-related influences and their clinical counterparts need to be further investigated. [Copyright &y& Elsevier]

Aim: To evaluate histologically the morphology and characteristics of bone chips harvested intraorally by Safescraper®, a specially designed cortical bone collector. Material and methods: Bone chips harvested near a bone defect or in other intraoral sites were grafted into a post-extractive socket or applied in procedures for maxillary sinus floor augmentation or guided bone regeneration. Core biopsies were performed at implant insertion. Undecalcified specimens embedded in PMMA were studied by histology, histochemistry and SEM. Results: Intraoral harvesting by Safescraper® provided a simple, clinically effective regenerative procedure with low morbidity for collecting cortical bone chips (0.9–1.7 mm in length, roughly 100 μm thick). Chips had an oblong or quadrangular shape and contained live osteocytes (mean viability: 45–72%). Bone chip grafting produced newly formed bone tissue suitable for implant insertion. Trabecular bone volume measured on biopsies decreased with time (from 45–55% to 23%). Grafted chips made up 50% or less of the calcified tissue in biopsies. Biopsies presented remodeling activities, new bone formation by apposition and live osteocytes (35% or higher). Discussion and conclusions: In conclusion, Safescraper® is capable of collecting adequate amounts of cortical bone chips from different intraoral sites. The procedure is effective for treating alveolar defects for endosseous implant insertion and provides good healing of small bone defects after grafting with bone chips. The study indicates that Safescraper® is a very useful device for in-office bone harvesting procedures in routine peri-implant bone regeneration. [ABSTRACT FROM AUTHOR]

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Insulin-dependent type 1 diabetes mellitus (IDDM) has been shown to alter the properties of bone and impair bone repair in both humans and animals. The objective of this study was the detailed histomorphometric evaluation of the influence of the diabetic metabolic state on bone formation and remodeling during bone defect healing depending on the defect size in spontaneously diabetic BB/O(ttawa)K(arlsburg) rats, a rat strain that represents a close homology to IDDM in man.Based on blood-glucose values at the time of surgery, postoperative blood-glucose course, and postoperative insulin requirements, 80 spontaneously diabetic BB/OK rats were divided into groups with well-compensated or poorly compensated metabolic state. Forty LEW.1A rats served as normoglycemic controls. Using a Kirschner wire, bone defects of different sizes were created proximal to the knee joint space in both femora. Ten animals from each group were killed on postoperative days 7, 14, 24, and 42, and specimens were processed undecalcified for quantitative bone histomorphometry.In terms of bone histomorphometry, our study did not show any differences in bone defect healing between the groups where the defect size was 0.4 mm. Larger bone defects (0.8 mm) only showed significant differences in the structural calculations after the 24th postoperative day exclusively in poorly compensated diabetic rats compared to well-compensated diabetic and control rats (P < 0.05 or P < 0.01). In bone defect sizes more than 1.2 mm, severe mineralization disorders occurred within the first 14 days exclusively in rats with poorly compensated diabetic metabolic state with a highly significant (P < 0.001) or significant (P < 0.01) decrease of all fluorochrome-based parameters of mineralization, apposition, formation, and timing of mineralization in comparison to spontaneously diabetic rats with well-compensated diabetic metabolic state and control rats.These results demonstrate that the bone repair of minor bone defects (0.4 mm) is independent of the diabetic metabolic state in spontaneously diabetic BB/OK rats. In larger bone defects (more than 0.8 mm), the bone defect healing in spontaneously diabetic BB/OK rats is impaired exclusively in poorly compensated diabetic metabolic states. This study suggests that strictly controlled insulin treatment resulting in a well-compensated diabetic metabolic state will ameliorate the impaired histomorphometric parameters of IDDM bone defect healing. [Copyright &y& Elsevier]

Insulin-dependent type 1 diabetes mellitus (IDDM) has been shown to alter the properties of bone and to impair fracture-healing in both humans and animals. The objective of this study was to examine changes in the histomorphometric and mechanical parameters of bone and remodeling during bone-defect healing, depending on the diabetic metabolic state in spontaneously diabetic BB/O(ttawa)K(arlsburg) rats, a rat strain that represents a close homology to IDDM in humans. A standardized bone-defect model was chosen and based on blood-glucose values at the time of surgery (mg%), postoperative blood-glucose course (mg%), and postoperative insulin requirements (IU/kg). A total of 120 spontaneously diabetic BB/OK rats were divided into groups with a well-compensated (n = 60; 169 ± 102 mg%; 230 ± 126 mg%; and 2.2 ± 1.1 IU/kg) or poorly compensated (n = 60; 380 ± 159 mg%; 359 ± 89 mg%; and 5.4 ± 1.1 IU/kg) metabolic state. Sixty LEW.1A rats served as the normoglycemic controls (93 ± 19 mg%). Fifteen animals from each group were killed on postoperative days 7, 14, 24, and 42, and specimens were processed undecalcified for quantitative bone histomorphometry and for biomechanical testing. Our study showed in terms of bone histomorphometry, within the first 14 days, that severe mineralization disorders occurred exclusively in the rats with a poorly compensated diabetic metabolic state with a highly significant (P < 0.001) or significant (P < 0.01) decrease of all fluorochrome-based parameters of mineralization, apposition, formation and timing of mineralization, as well as significantly decreased values of biomechanical properties (P < 0.05) in comparison to the spontaneously diabetic rats with a well-compensated metabolic state and to the control rats. Bone-defect healing in spontaneously diabetic BB/OK rats is retarded exclusively in a poorly compensated diabetic metabolic state. This study suggests that strictly controlled insulin treatment resulting in a well-compensated diabetic metabolic state will ameliorate the impaired early and late parameters of IDDM bone-defect healing. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases are important in the physiological and pathological degradation of extracellular matrix including that of bone and cartilage. The process of bone defect healing is associated with formation of cartilage callus and cancelous bone. With maturation and aging, the response of skeletal tissues to injury is limited. The ability of growth factors to enhance bone defect healing in aged rats was studied. Partial bone defects were induced in femurs of aged rats. A single dose of IGF-1, TGF-β+IGF-1 or saline was inserted in the defect and bones were examined after 2 and 4 weeks. Morphology revealed that after 2 weeks of treatment with TGF-β the defects were filled with mesenchyme-like tissue and delicate bone trabeculae. Positive staining for metalloproteinase-2 (MMP-2) was shown at the sites of new bone formation. In defects treated with IGF-1 or TGF-β+IGF-1 nodules of cartilage and fine bone trabeculae along with positive staining for both MMP-2 and MMP-3 were demonstrated in the healing defects. After 4 weeks radiology revealed mineralization in defects treated with TGF-β and less pronounced mineralization after treatment with IGF-1, or with TGF-β+IGF-1, whereas only partial healing of the defects was observed in control specimens. MMP-2 and MMP-3 were detected at sites of new bone formation after treatment with TGF-β, IGF-1, and TGF-β+IGF-1. It is concluded that TGF-β and IGF-1 induced bone defect healing in aged rats. TGF-β induced bone formation while IGF-1 induced cartilage and than bone formation via endochondral ossification. The localization of MMP-2 and MMP-3 in the healing defects reflected the synthesis of bone or cartilage matrices in the defect, reflecting the involvement of MMPs in the process of bone formation and endochondral ossification. The ability to induce bone defect healing in aging is of great clinical importance and understanding the involvement of MMPs in this process can contribute to future treatment with growth factors to enhance bone defect healing in 20-month-old female rats. [Copyright &y& Elsevier]

Background: Periosteum plays a significant role in bone formation and regeneration by storing progenitor cells, and also acts as a source of local growth factors and a scaffold for recruiting cells and other growth factors. Recently, tissue-engineered periosteum has been studied extensively and shown to be important for osteogenesis and chondrogenesis. Using biomimetic methods for artificial periosteum synthesis, membranous tissues with similar function and structure to native periosteum are produced that significantly improve the efficacy of bone grafting and scaffold engineering, and can serve as direct replacements for native periosteum. Many problems involving bone defects can be solved by preparation of idealized periosteum from materials with different properties using various techniques., Methods: This review summarizes the significance of periosteum for osteogenesis and chondrogenesis from the aspects of periosteum tissue structure, osteogenesis performance, clinical application, and development of periosteum tissue engineering. The advantages and disadvantages of different tissue engineering methods are also summarized., Results: The fast-developing field of periosteum tissue engineering is aimed toward synthesis of bionic periosteum that can ensure or accelerate the repair of bone defects. Artificial periosteum materials can be similar to natural periosteum in both structure and function, and have good therapeutic potential. Induction of periosteum tissue regeneration and bone regeneration by biomimetic periosteum is the ideal process for bone repair., Conclusions: Periosteum is essential for bone formation and regeneration, and it is indispensable in bone repair. Achieving personalized structure and composition in the construction of tissue engineering periosteum is in accordance with the design concept of both universality and emphasis on individual differences and ensures the combination of commonness and individuality, which are expected to meet the clinical needs of bone repair more effectively., The Translational Potential of This Article: To better understand the role of periosteum in bone repair, clarify the present research situation of periosteum and tissue engineering periosteum, and determine the development and optimization direction of tissue engineering periosteum in the future. It is hoped that periosteum tissue engineering will play a greater role in meeting the clinical needs of bone repair in the future, and makes it possible to achieve optimization of bone tissue therapy., Competing Interests: The authors have no conflict of interest relevant to this review., (© 2022 The Authors.)

Background: Bone grafts are in high demand due to the increase in the cases of bone defects mainly caused by trauma, old age, and disease-related bone damages. Tissue-engineered calcium phosphate (CaP) biomaterials match the major inorganic contents of bone, thereby could be the potential bone graft substitute. However, CaP-bone grafts lack the osteoinductivity that is vital for effective bone regeneration. In this study, we aimed to test the bone defect healing potential of biomimetically fabricated low dose BMP2-doped CaP (BMP2.BioCaP) grafts in a large animal model. Methods: Low dose BMP2 was doped internally (BMP2-int.BioCaP) or on the surface of CaP (BMP2-sur.BioCaP) grafts during the fabrication process. Our previous study showed the robust bone regenerative potential of BMP2-int.BioCaP and BMP2-sur.BioCaP grafts in the rat ectopic model. In this study, we investigated the bone defect healing potential of BMP2.BioCaP grafts in sheep humerus/femoral defects, as well as compared with that of autologous bone graft and clinically used deproteinized bovine bone (DBB) xenograft. Results: Different ways of BMP2 doping did not affect the surface morphology and degradation properties of the graft materials. Micro-CT and histology results showed robustly higher bone defect-healing potential of the BMP2.BioCaP grafts compared to clinically used DBB grafts. The bone defect healing potential of BMP2.BioCaP grafts was as effective as that of the autologous bone graft. Although, BMP2-int.BioCaP doped half the amount of BMP2 compared to BMP2-sur.BioCaP, its' bone defect healing potential was even robust. The BMP2.BioCaP grafts showed less immunogenicity compared to BioCaP or DBB grafts. The volume density of blood vessel-like and bone marrow-like structures in both BMP2.BioCaP graft groups were in a similar extent to the autologous group. Meticulous observation of higher magnification histological images showed active bone regeneration and remodeling during bone defect healing in BMP2.BioCaP graft groups. Conclusion: The robust bone regenerative potential of BMP2.BioCaP grafts in the ectopic model and in-situ bone defects in small and large animals warrant the pre-clinical studies on large animal critical-sized segmental bone defects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Fang, Wu, Li, Pathak and Liu.)

This study investigated the role of muscle damage in bone defect healing using skull and tibial double-defect and tibial fracture models in dystrophin -/- /Utrophin -/- double-knockout (dKO-Hom) mice. The skull and tibia bone defect and fracture healing was monitored using micro-CT, histology, immuohistochemistry and quantitative PCR. We found the skull defect healing is not impaired while the tibial defect healing was delayed at day 7 in the dKO-Hom group compared to wild-type (WT) group as revealed by micro-CT. Mechanistically, the number of osteoclasts and osteoblasts significantly decreased in the defect area in dKO-Hom group compared to WT group on day 21. DKO-Hom mice showed higher mortality after fracture (6/12) and significantly impaired fracture healing compared to the other groups as revealed by the micro-CT parameters of the calluses. Histology showed higher osteoclast number in the calluses of dKO-Hom mice than other groups. Furthermore, dKO-Hom mice showed down-regulation of 15-Pgdh, Il-4, Bmp7, and Bmp9 at 10 days after tibia fracture and BMP6 and 7 in the muscle. In conclusion, the long bone defect and fracture healing are impaired in dKO-Hom mice which demonstrated significantly muscle sarcopenia and related with disturbance of osteoclastogenesis and osteoblastogenesis. The impaired tibial fracture healing was associated with down-regulation of several genes in the muscle., Competing Interests: None., (AJTR Copyright © 2020.)

Unlabelled: AIM.: The aim of this study is to evaluate the capability of Hyaloss™ matrix (Fab - Fidia Advanced Biopolymers - Pd - Italy), a biomaterial based on hyaluronic acid, used as organic scaffold in bone repair in post-extractive defects., Materials and Methods: 20 post-extractive sockets were selected, with similar size defects in the same patient and in the same hemiarch. Hyaluronic acid with high molecular weight (Hyaloss™ matrix, Fab - Pd - Italy) was mixed with autologous bone obtained using Safescraper(®) curve (Meta - Re - Italy) to repair post-extractive sites. Safescraper(®) is a cutting edge system that allows to the collection of autologous bone without using traditional, incision-based collection techniques, which could cause discomfort to the patient., Results: Clinical and hystological evaluations were performed, four months after grafting, in the maxilla and in the mandible. From a clinical point of view Hyaloss™ matrix mixed with autologous bone and patient's blood becomes a substance similar to gel, which is easy to insert in to the defect. From a hystological point of view, in the treated site there is the presence of an erosive activity, with accelerated angiogenetic and bone remodelling activities., Conclusions: The preliminary results show an acceleration of the bone deposit process and of its remodelling due to the presence of Hyaloss™ matrix, which, from a clinical point of view, improves the handling and application of the bone matrix inside the defects and, from a hystologic point of view makes it possible to obtain bone regeneration in less time when it is used with autologous bone.