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Purpose: Infected nonunion of the tibia with a large segmental bone defect is a complex and challenging condition for the patient and surgeon. This scoping review was conducted to identify existing evidence and knowledge gaps regarding this clinical scenario. Secondly, the objective of this study was to search for a valid recommendation on the optimal treatment. Methods: A comprehensive search was conducted in the bibliographic databases: PubMed, Embase.com, and Web of Science Core Collection. Studies reporting on bone transport techniques, the Masquelet technique, and vascularized fibular grafts in bone defects greater than 5 cm were included. Bone healing results and functional results were compared according to duration of nonunion, infection recurrence, bone consolidation, complication rate, external fixation time, and time until full weight-bearing. Results: Of the 2753 articles retrieved, 37 studies could be included on bone transport techniques (n = 23), the Masquelet technique (n = 7), and vascularized fibular grafts (n = 7). Respective bone union percentages were 94.3%, 89.5%, and 96.5%. The percentages of infection recurrence respectively were 1.6%, 14.4% and 7.0%, followed by respectively 1.58, 0.78, and 0.73 complications per patient. Conclusion: Bone transport was found to be the most widely studied technique in the literature. Depending on the surgeon's expertise, vascularized fibular grafts may be held as a favourable alternative. This review indicates that further high-quality research on large bone defects (≥ 5 cm) in patients with infected tibial nonunions is necessary to gain more insight into the potentially beneficial results of vascularized fibular grafts and the Masquelet technique. [ABSTRACT FROM AUTHOR]

Simple Summary: Bone tissue engineering is one of the most promising approaches for the restoration of large bone defects. Nevertheless, to date, several disadvantages limit its use due to an inability to completely fulfill all the clinical needs. In this context, in recent years, the application of nanotechnology to improve the mechanical, chemical–physical, and biological properties of biomaterials for bone tissue engineering has received great interest from researchers. Nanomaterials, including nanoparticles, are the key elements of such nanotechnologies due to their high penetrating ability and surface area, mechanical strength enhancement, improved cell adhesion, differentiation, and growth, enhanced antibacterial properties, and biocompatibility. In this review, we report on the latest in vitro and in vivo studies on the combination of nanotechnology and bone tissue engineering as promising approach for the regeneration of large bone defects. Large bone defects are the leading contributor to disability worldwide, affecting approximately 1.71 billion people. Conventional bone graft treatments show several disadvantages that negatively impact their therapeutic outcomes and limit their clinical practice. Therefore, much effort has been made to devise new and more effective approaches. In this context, bone tissue engineering (BTE), involving the use of biomaterials which are able to mimic the natural architecture of bone, has emerged as a key strategy for the regeneration of large defects. However, although different types of biomaterials for bone regeneration have been developed and investigated, to date, none of them has been able to completely fulfill the requirements of an ideal implantable material. In this context, in recent years, the field of nanotechnology and the application of nanomaterials to regenerative medicine have gained significant attention from researchers. Nanotechnology has revolutionized the BTE field due to the possibility of generating nanoengineered particles that are able to overcome the current limitations in regenerative strategies, including reduced cell proliferation and differentiation, the inadequate mechanical strength of biomaterials, and poor production of extrinsic factors which are necessary for efficient osteogenesis. In this review, we report on the latest in vitro and in vivo studies on the impact of nanotechnology in the field of BTE, focusing on the effects of nanoparticles on the properties of cells and the use of biomaterials for bone regeneration. [ABSTRACT FROM AUTHOR]

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Haoyu Zhao,1,* Yachao Jia,1,* Feng Wang,1 Yimin Chai,1 Chunfu Zhang,2 Jia Xu,1 Qinglin Kang1 1Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Department of Orthopedic Surgery, Shanghai, People’s Republic of China; 2Shanghai Jiao Tong University, School of Biomedical Engineering, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jia Xu; Qinglin Kang, Email xujia0117@126.com; orthokang@163.comIntroduction: Large bone abnormalities are commonly treated using distraction osteogenesis (DO), but it is not suitable for a long-term application; therefore, there is an urgent need for adjuvant therapy that can accelerate bone repair.Methods: We have synthesized mesoporous silica-coated magnetic nanoparticles doped with cobalt ions (Co-MMSNs) and assessed their capacity to quicken bone regrowth in a mouse model of DO. Furthermore, local injection of the Co-MMSNs significantly accelerated bone healing in DO, as demonstrated by X-ray imaging, micro-CT, mechanical tests, histological evaluation, and immunochemical analysis.Results: In vitro, the Co-MMSNs exhibited good biocompatibility and induced angiogenic gene expression and osteogenic development in bone mesenchymal stem cells. And the Co-MMSNs can promote bone regeneration in a rat DO model.Discussion: This study demonstrated the significant potential of Co-MMSNs to shorten the DO treatment duration and effectively reduce the incidence of complications.Keywords: mesoporous silica-coated magnetic nanoparticles, mesenchymal stem cells, large bone defects, distraction osteogenesis, bone regeneration

The challenge of reconstructing large mandibular bone defects with double-barrel fibula flap (DBFF) is limited by the availability of autogenous bone, which remains a significant issue in maxillofacial surgery. This study aims to compare the novel scaffold-driven double-barrel approach with the DBFF method, and investigate the biomechanical behavior of 3D-printed porous titanium scaffolds with varying design parameters. The mandibular reconstruction model underwent FEA in two surgery phases, under two experimental loads and two design parameters. The experimental scaffold design was categorized into 9 groups based on the porous diameters (DP = 4 mm, 5 mm, 6 mm) and strut diameters (DS = 0.4 mm,0.5 mm,0.6 mm). The results illustrated that the stress in fibula, cortical and trabecular bones for all groups were within the ranges of normal physiological levels. The porous scaffolds effectively transmit mechanical stimulation, resulting in bone graft materials achieving up to 99.9% strain, with low stiffness to avoid stress shielding. The study revealed that the design parameters of Group B and Group F were more conducive to meeting biomechanical demands and promoting bone regeneration. This study presents scientifically proven and effective clinical solution for restoring both function and aesthetics of mandibular defects, while also providing valuable insights for future design criteria in bone regeneration scaffolds.

Introduction: Large bone defects (LBD) caused by trauma, infection, and tumor resection remain a significant clinical challenge. Although therapeutic agents such as bone morphogenetic protein-2 (BMP-2), have shown substantial potency in various clinical scenarios, their uncontrollable release kinetics has raised considerable concern from the clinical viewpoint. Mineral-coated microparticle (MCM) has shown its excellent biologics loading and delivery potential due to its superior protein-binding capacity and controllable degradation behaviors; thus, it is conceivable that MCM can be combined with hydrogel systems to enable optimized BMP-2 delivery for LBD healing.Methods: Herein, BMP-2 was immobilized on MCMs via electrostatic interaction between its side chains with the coating surface. Subsequently, MCM@BMP-2 is anchored into a hydrogel by the crosslinking of chitosan (CS) and polyethylene glycol (PEG).Results and Discussion: This microparticle–hydrogel system exhibits good biocompatibility, excellent vascularization, and the sustained release of BMP-2 in the bone defect. Furthermore, it is observed that this microsphere–hydrogel system accelerates bone formation by promoting the expression of osteogenesis-related proteins such as RUNX2, osteopontin, and osteocalcin in bone marrow mesenchymal stem cells (BMSCs). Thus, this newly developed multifunctional microparticle–hydrogel system with vascularization, osteogenesis, and sustained release of growth factor demonstrates an effective therapeutic strategy toward LBD.

Large bone defects are the leading contributor to disability worldwide, affecting approximately 1.71 billion people. Conventional bone graft treatments show several disadvantages that negatively impact their therapeutic outcomes and limit their clinical practice. Therefore, much effort has been made to devise new and more effective approaches. In this context, bone tissue engineering (BTE), involving the use of biomaterials which are able to mimic the natural architecture of bone, has emerged as a key strategy for the regeneration of large defects. However, although different types of biomaterials for bone regeneration have been developed and investigated, to date, none of them has been able to completely fulfill the requirements of an ideal implantable material. In this context, in recent years, the field of nanotechnology and the application of nanomaterials to regenerative medicine have gained significant attention from researchers. Nanotechnology has revolutionized the BTE field due to the possibility of generating nanoengineered particles that are able to overcome the current limitations in regenerative strategies, including reduced cell proliferation and differentiation, the inadequate mechanical strength of biomaterials, and poor production of extrinsic factors which are necessary for efficient osteogenesis. In this review, we report on the latest in vitro and in vivo studies on the impact of nanotechnology in the field of BTE, focusing on the effects of nanoparticles on the properties of cells and the use of biomaterials for bone regeneration.

Bone can be affected by different neoplastic conditions. Limb salvage surgery has become the preferred treatment strategy for most malignant tumors of the extremities. Advanced 3D printing technology has transformed the conventional view of oncological surgery. These types of implants are produced by electron beam melting (EBM) technology by sintering titanium powder in a scaffold shape designed following a project designed from HRCT and MRI. The aim of our study was to evaluate the outcomes and the mid-term follow-up of a population treated with 3D-printed custom-made prosthesis implantation in major oncological bone resection or after failure of primary implants. The primary outcome was the general patient satisfaction one year after surgery. The secondary outcomes were: mortality rate, treatment related complication rate, functional and clinical outcomes (KPS, ADL and IADL). Eight patients were included, five females and two males, with a mean age of 50.3 (±23.72) years at the surgery. The enrolled patients reported a mean satisfaction rate after surgery of 7.38 (±2) where 10 was the maximum value. There were no changes between pre- and postoperative mean KPS (81.43 +/−10.69). Mean preoperative ADL and IADL score was in both cases 4.86 (±1.07), while postoperative was 5 (±0.82), with a delta of 0.13 (p > 0.05). Custom-made prosthesis permits reconstructing bone defects caused by large tumor resection, especially in anatomically complex areas, restoring articular function.

Objective: For mandibular injury, how to utilize 3D implants with novel structures to promote the reconstruction of large mandibular bone defect is the major focus of clinical and basic research. This study proposed a novel 3D titanium lattice-like implant for mandibular injuries based on simulation model, which is designed and optimized by a biomechanical/mechanobiological approach, and the working framework for optimal design and preparation processes of the implant has been validated to tailored to specific patient biomechanical, physiological and clinical requirements.Methods: This objective has been achieved by matching and assembling different morphologies of a lattice-like implant mimicking cancellous and cortical bone morphologies and properties, namely, an internal spongy trabecular-like structure that can be filled with bone graft materials and an external grid-like structure that can ensure the mechanical bearing capacity. Finite element analysis has been applied to evaluate the stress/strain distribution of the implant and bone graft materials under physiological loading conditions to determine whether and where the implant needs to be optimized. A topological optimization approach was employed to improve biomechanical and mechanobiological properties by adjusting the overall/local structural design of the implant.Results: The computational results demonstrated that, on average, values of the maximum von-Mises stress in the implant model nodes could be decreased by 43.14% and that the percentage of optimal physiological strains in the bone graft materials can be increased from 35.79 to 93.36% since early regeneration stages. Metal additive manufacturing technology was adopted to prepare the 3D lattice-like implant to verify its feasibility for fabrication. Following the working framework proposed in this study, the well-designed customized implants have both excellent biomechanical and mechanobiological properties, avoiding mechanical failure and providing sufficient biomechanical stimuli to promote new bone regeneration.Conclusion: This study is expected to provide a scientific and feasible clinical strategy for repairing large injuries of mandibular bone defects by offering new insights into design criteria for regenerative implants.

Bone can be affected by different neoplastic conditions. Limb salvage surgery has become the preferred treatment strategy for most malignant tumors of the extremities. Advanced 3D printing technology has transformed the conventional view of oncological surgery. These types of implants are produced by electron beam melting (EBM) technology by sintering titanium powder in a scaffold shape designed following a project designed from HRCT and MRI. The aim of our study was to evaluate the outcomes and the mid-term follow-up of a population treated with 3D-printed custom-made prosthesis implantation in major oncological bone resection or after failure of primary implants. The primary outcome was the general patient satisfaction one year after surgery. The secondary outcomes were: mortality rate, treatment related complication rate, functional and clinical outcomes (KPS, ADL and IADL). Eight patients were included, five females and two males, with a mean age of 50.3 (±23.72) years at the surgery. The enrolled patients reported a mean satisfaction rate after surgery of 7.38 (±2) where 10 was the maximum value. There were no changes between pre- and postoperative mean KPS (81.43 +/−10.69). Mean preoperative ADL and IADL score was in both cases 4.86 (±1.07), while postoperative was 5 (±0.82), with a delta of 0.13 (p > 0.05). Custom-made prosthesis permits reconstructing bone defects caused by large tumor resection, especially in anatomically complex areas, restoring articular function. [ABSTRACT FROM AUTHOR]

Drynariae Rhizoma (DR) has been demonstrated to be effective in promoting fracture healing in clinical use. In the study, we tried to predicate potential signaling pathways and active ingredients of DR via network pharmacology, uncover its regulation mechanism to improve large bone defects by in vivo and in vitro experiment. We total discovered 18 potential active ingredients such as flavonoids and 81 corresponding targets, in which mitogen-activated protein kinase (MAPK) signaling pathway has the highest correlation with bone defects in pathway and functional enrichment analysis. Therefore, we hypothesized that flavonoids in DR improve large bone defects by activating MAPK signaling pathway. Animal experiments were carried out and all rats randomly divided into TFDR low, medium, and high dosage group, model group and control group. 12 weeks after treatment, according to X-ray and Micro-CT, TFDR medium dosage group significantly promote new bone mineralization compared with other groups. The results of HE and Masson staining and in vitro ALP level of BMSC also demonstrated the formation of bone matrix and mineralization in the TFDR groups. Also, angiographic imaging suggested that flavonoids in DR promoting angiogenesis in the defect area. Consistently, TFDR significantly enhanced the expression of BMP-2, RUNX-2, VEGF, HIF-1 in large bone defect rats based on ELISA and Real-Time PCR. Overall, we not only discover the active ingredients of DR in this study, but also explained how flavonoids in DR regulating MAPK signaling pathway to improve large bone defects.

Drynariae Rhizoma (DR) has been demonstrated to be effective in promoting fracture healing in clinical use. In the study, we tried to predicate potential signaling pathways and active ingredients of DR via network pharmacology, uncover its regulation mechanism to improve large bone defects by in vivo and in vitro experiment. We total discovered 18 potential active ingredients such as flavonoids and 81 corresponding targets, in which mitogen-activated protein kinase (MAPK) signaling pathway has the highest correlation with bone defects in pathway and functional enrichment analysis. Therefore, we hypothesized that flavonoids in DR improve large bone defects by activating MAPK signaling pathway. Animal experiments were carried out and all rats randomly divided into TFDR low, medium, and high dosage group, model group and control group. 12 weeks after treatment, according to X-ray and Micro-CT, TFDR medium dosage group significantly promote new bone mineralization compared with other groups. The results of HE and Masson staining and in vitro ALP level of BMSC also demonstrated the formation of bone matrix and mineralization in the TFDR groups. Also, angiographic imaging suggested that flavonoids in DR promoting angiogenesis in the defect area. Consistently, TFDR significantly enhanced the expression of BMP-2, RUNX-2, VEGF, HIF-1 in large bone defect rats based on ELISA and Real-Time PCR. Overall, we not only discover the active ingredients of DR in this study, but also explained how flavonoids in DR regulating MAPK signaling pathway to improve large bone defects. [ABSTRACT FROM AUTHOR]

The healing of bone fractures is a well-orchestrated physiological process involving multiple cell types and signaling molecules interacting at the fracture site to replace and repair bone tissue without scar formation. However, when the lesion is too large, normal healing is compromised. These so-called non-union bone fractures, mostly arising due to trauma, tumor resection or disease, represent a major therapeutic challenge for orthopedic and reconstructive surgeons. In this review, we firstly present the current commonly employed surgical strategies comprising auto-, allo-, and xenograft transplantations, as well as synthetic biomaterials. Further to this, we discuss the multiple factors influencing the effectiveness of the reconstructive therapy. One essential parameter is adequate vascularization that ensures the vitality of the bone grafts thereby supporting the regeneration process, however deficient vascularization presents a frequently encountered problem in current management strategies. To address this challenge, vascularized bone grafts, including free or pedicled fibula flaps, or in situ approaches using the Masquelet induced membrane, or the patient’s body as a bioreactor, comprise feasible alternatives. Finally, we highlight future directions and novel strategies such as 3D printing and bioprinting which could overcome some of the current challenges in the field of bone defect reconstruction, with the benefit of fabricating personalized and vascularized scaffolds.

Purpose: The aim of this study was to evaluate the clinical and functional outcomes of patients with large post-traumatic tibial bone defects managed by double-level bone transport using the Ilizarov technique and compare it with one-level bone transport technique.Methods: A retrospective cohort study was conducted on 26 patients with open tibial fracture from January 2010 to January 2017. All cases were Gustilo III. Depending on the site of osteotomy, the patients were divided into single-level (n = 13) and double-level groups (n = 13). The bone transport time, consolidation time of the distraction gap, docking site healing time, external fixation time, external fixation index, soft tissue defect area, soft tissue growth index, operating time, and surgical bleeding volume were recorded and compared between the two groups. Bone and functional results were evaluated according to the Association for the Study and Application of the Method of Ilizarov (ASAMI) criteria.Results: The mean duration of follow-up was 28.5 ± 5.8 months (range 13-38 months) since the Orthofix fixator was removed, all patients achieved complete union in the docking site and consolidation in the regenerate bone; moreover, the wound was closed The mean bone defect length after debridement was 7.2 cm (range 5.8-9.0 cm) in single-level group vs. 10.7 cm (range 7.5-15.0 cm) in the double-level group (P < 0.05). The mean docking site healing time was 10.85 ± 1.52 months in the single-level group vs. 8.93 ± 2.29 months in the double-level group (P < 0.05); external frame time was 18.06 months (range 15-20 months) in single-level group vs. 12.71 months (range 9.5-16.0 months) in the double-level group (P < 0.05); external fixation index was 2.52 months/cm (range 2.15-2.94 months/cm) versus 1.22 months/cm (range 0.96-1.67 months/cm) in double-level group (P < 0.01); and soft tissue growth index was 0.29 months/cm2 (range 0.21-0.45 months/cm2) in the single-level group versus 0.62 months/cm2 (range 0.47-0.86 months/cm2) in the double-level group (P < 0.01). According to the ASAMI classification, the clinical and functional results in the double-level group were better than in the single-level group.Conclusion: The Ilizarov technique of double-level bone transport with Orthofix external fixator can be used successfully to repair and reconstruct the tibial bone loss and accompanying soft tissue defect. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The treatment of large bone defects (LBDs) represents a major challenge in clinical orthopedics. Patients with LBDs caused by trauma, infections, or tissue resections due to cancer, often undergo multiple surgeries with long recovery times leading to deteriorated life quality and increased healthcare costs. The project HyBioComBone aims to develop novel biomimetic macroporous composites with multifunctional properties for bone repair, regeneration, and cancer treatment. EXPERIMENTAL: The composites will be designed by combining the interpenetrating network (IPN) hydrogels, inorganic nanostructured bioglasses (BAG), and multi-ion doped calcium phosphates (CaP). Optimized composites will be further developed in three directions: a) as carriers for the extracellular vesicles (EVs) derived from adipose-derived stem cells (ADSCs); b) for loading and controlled delivery of commercial and newly synthesized antiproliferative drugs, and c) for loading and controlled delivery of antibiotics. RESULTS AND DISCUSSION: Biocompatible, bioresorbable, macroporous IPN hydrogels based on synthetic and natural polymers will be obtained. The network parameters of hydrogels will be tuned to obtain a broad range of materials with different biodegradability, mechanical and viscoelastic properties. Scaffolds, microgels, and 3D-printed hydrogels will be developed. Multi-ion doped bioactive inorganic particles (mesoporous BAG nanoparticles, rod-like HAp nanoparticles with morphology similar to the biological apatite, and highly bioactive calcinated CaP spherical microparticles) will be combined with the polymer matrix to improve bioactivity, provide therapeutic ions release and tune mechanical properties. The composites of desired properties will be loaded with commercially available antibiotics, to fight infection, and chemotherapy drug, for treatment of different types of cancer, but also with newly synthesized anticancer drugs. The encapsulation of ADSC-derived EVs in the composites with controlled biodegradation would enable the gradual release of EVs to the surrounding tissue and provide improved osteointegration and bone tissue regeneration. CONCLUSIONS: New macroporous bioactive composites with adequate mechanical properties, biocompatibility, and tuned biodegradability for hard tissue restoration, coupled with either drugs for the prevention of osteosarcoma recurrence and/or osteomyelitis, or with adipose-derived EVs for the regeneration of large bone defects, will be developed through the project HyBioComBone. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Large bone defects in the field of orthopedic surgery remains challenging, primarily due to restricted regenerative capacity of bone tissue. The biomimetic bone implants could improve the osteoregeneration process, but the optimal composition for biomimetics remains unknown. Considering the great potential of extracellular vesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) in regenerative medicine, our aim was to investigate the osteoinductive potential of EVs derived from MSCs from the dental pulp of human exfoliated deciduous teeth (SHEDs) either undifferentiated or those undergone differentiation into osteoblasts (osteoSHED-EVs), for potential use in biomimetic bone implants. EXPERIMENTAL: SHEDs were isolated from the dental pulp of 5 different donors of deciduous teeth and subjected to characterization by Flow cytometry (FCM). EVs-SHED and EVs-osteoSHED were isolated by sequential ultracentrifugation, and analysed by Western blot, NTA, and electron microscopy. Uptake of PKH67-labelled EVs by SHED was analysed by confocal microscopy and FCM. The effects of EVs on osteogenic differentiation of SHED cells were analysed by monitoring RUNX2 and BMP2 expression by RT-PCR. RESULTS AND DISCUSSION: SHEDs displayed typical MSC morphology and phenotype, as well as potential to differentiate into osteoblasts as confirmed by FCM, alkaline phosphatase activity, Alizarin red S staining, and gene expression analysis. Both types of EVs were internalized by SHED, as shown by the confocal microscopy and FCM after 4h and 24h incubation, and no significant differences were observed between the two EVs types. Importantly, the osteogenic differentiation of SHEDs cultivated in basal medium was significantly improved in the presence of osteoSHED-EVs, as shown by the upregulation of early osteogenic genes RUNX2 and BMP2. CONCLUSIONS: These findings significantly improved our understanding on the potential of EVs derived from SHEDs in osteoinduction, laying the groundwork for developing targeted methods that utilize EVs from SHED as biomimetics for effective repair of bone defects. [ABSTRACT FROM AUTHOR]

Introduction: The induced membrane technique for the treatment of large bone defects consists of a 2-stage procedure. In the first stage, a polymethylmethacrylate (PMMA) cement spacer is inserted into the bony defect of a rat's femur and over a period of 2-4 weeks a membrane forms that encapsulates the defect/spacer. In a second operation the membrane is opened, the PMMA spacer is removed and the resulting cavity is filled with autologous bone. Since little effort has been made to replace the need for autologous bone this study was performed to elucidate the influence of different stem cells and the membrane itself on bone healing in a critical size femur defect model in rats. Especially the question should be addressed whether the use of stem cells seeded on a β-TCP scaffold is equivalent to syngeneic bone as defect filling in combination with the induced membrane technique.Materials and Methods: A total of 96 male Sprague-Dawley (SD) rats received a 10 mm critical size defect of the femur, which was stabilized by a plate osteosynthesis and filled with PMMA cement. In a second step the spacer was extracted and the defects were filled with syngeneic bone, β-TCP with MSC + EPC or BM-MNC. In order to elucidate the influence of the induced membrane on bone defect healing the induced membrane was removed in half of the operated femurs. The defect area was analysed 8 weeks later for bone formation (osteocalcin staining), bone mineral density (BMD) and bone strength (3-point bending test).Results: New bone formation, bone mineral density and bone stiffness increased significantly, if the membrane was kept. The transplantation of biologically active material (syngeneic bone, stem cells on b-TCP) into the bone defect mostly led to a further increase of bone healing. Syngeneic bone had the greatest impact on bone healing however defects treated with stem cells were oftentimes comparable.Conclusion: For the first time we demonstrated the effect of the induced membrane itself and different stem cells on critical size defect healing. This could be a promising approach to reduce the need for autologous bone transplantation with its' limited availability and donor site morbidity. [ABSTRACT FROM AUTHOR]

[Display omitted] • The scaffold-driven DBFF for mandibular reconstruction, by using scaffold filled with bone graft combined with fibula flaps. • The biomechanical behavior of 3D-printed porous titanium scaffolds with different design parameters was investigated by FEA. • Biomechanical differences of fibula, articular disc, cortical and trabecular bone were investigated and compared. • The scaffold transmit mechanical stimulus to promote bone regeneration in bone grafts, achieving mandibular reconstruction. The challenge of reconstructing large mandibular bone defects with double-barrel fibula flap (DBFF) is limited by the availability of autogenous bone, which remains a significant issue in maxillofacial surgery. This study aims to compare the novel scaffold-driven double-barrel approach with the DBFF method, and investigate the biomechanical behavior of 3D-printed porous titanium scaffolds with varying design parameters. The mandibular reconstruction model underwent FEA in two surgery phases, under two experimental loads and two design parameters. The experimental scaffold design was categorized into 9 groups based on the porous diameters (D P = 4 mm, 5 mm, 6 mm) and strut diameters (D S = 0.4 mm,0.5 mm,0.6 mm). The results illustrated that the stress in fibula, cortical and trabecular bones for all groups were within the ranges of normal physiological levels. The porous scaffolds effectively transmit mechanical stimulation, resulting in bone graft materials achieving up to 99.9% strain, with low stiffness to avoid stress shielding. The study revealed that the design parameters of Group B and Group F were more conducive to meeting biomechanical demands and promoting bone regeneration. This study presents scientifically proven and effective clinical solution for restoring both function and aesthetics of mandibular defects, while also providing valuable insights for future design criteria in bone regeneration scaffolds. [ABSTRACT FROM AUTHOR]

Large bone defects in the jaws can occur as a result of previous trauma, tumor or bone destruction caused by infection. Significant loss of bone volume also may be caused by premature loss of teeth, application of inadequate extraction technique, periodontitis or trauma caused by incorrect prosthetic reconstruction. Very few of these defects are treated using materials for bone augmentation or regeneration in order to preserve the total volume of bone. Depending on the size of a defect, spontaneous bone regeneration of untreated defects is limited by proliferation of surrounding soft tissue. Bone replacement by connective tissue leads to loss of stability, reduces function and disturbs anatomical form of the jaws. The aim of the study was to present a case from clinical praxis which demonstrates bone regeneration provided by bone substitute or its combination with bone grafts.

In order to achieve consistent and predictable fracture healing, a broad spectrum of growth factors are required to interact with one another in a highly organized response. Critically important, the mechanical environment around the fracture site will significantly influence the way bone heals, or if it heals at all. The role of the various biological factors, the timing, and spatial relationship of their introduction, and how the mechanical environment orchestrates this activity, are all crucial aspects to consider. This review will synthesize decades of work and the acquired knowledge that has been used to develop new treatments and technologies for the regeneration and healing of bone. Moreover, it will discuss the current state of the art in experimental and clinical studies concerning the application of these mechano-biological principles to enhance bone healing, by controlling the mechanical environment under which bone regeneration takes place. This includes everything from the basic principles of fracture healing, to the influence of mechanical forces on bone regeneration, and how this knowledge has influenced current clinical practice. Finally, it will examine the efforts now being made for the integration of this research together with the findings of complementary studies in biology, tissue engineering, and regenerative medicine. By bringing together these diverse disciplines in a cohesive manner, the potential exists to enhance fracture healing and ultimately improve clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: This meta-analysis aimed to determine the bone union rate of bone defects treated with the different autologous bone graft techniques. Methods: The PubMed and the Cochrane Library databases were searched using the terms: 'fracture' AND ('bone loss' OR 'defect' OR 'defects') AND 'bone graft', restricted to English language, to human species, and to a publication period from January 1999 to November 2014. Data were extracted by one of the reviewers and then checked by the second. A quality of evidence score and a methodology score were used. Heterogeneity was assessed. A random effects model approach was used to combine estimates. Results: Out of 376 selected studies only 34 met the inclusion criteria. The summary pooled union rate was 91 % (95 % CI: 87-95 %) while union rate after additional procedures raised to 98 % (95 % CI 96-99 %). No association between union rate and bone defect size was found. (Univariable regression model: vascularized: P = 0.677; non-vascularized: 0.202. Multivariable regression model: vascularized: P = 0.381; non-vascularized: P = 0.226). Vascularized graft was associated with a lower risk of infection after surgery when compared to non-vascularized graft (95 % CI 0.03 to 0.23, p < 0.001). Conclusion: The results of this meta-analysis demonstrate the effectiveness of autologous graft for bone defects. Furthermore, from the available clinical evidence bone defect size does not seem to have an impact on bone union when treated with autologous bone graft techniques. [ABSTRACT FROM AUTHOR]

Background: Although the contribution of fibroblast growth factor (FGF)-2 and mesenchymal stromal cells (MSCs) to bone formation is well known, few studies have investigated the combination of an autologous bone graft with FGF-2 or MSCs for large bone defects. Methods: We studied an atrophic non-union model with a large bone defect, created by resecting a 10-mm section from the center of each femoral shaft of 12-week-old Sprague-Dawley rats. The periosteum of the proximal and distal ends of the femur was cauterized circumferentially, and excised portions were used in the contralateral femur as autologous bone grafts. The rats were randomized to three groups and given no further treatment (group A), administered FGF-2 at 20 µg/20 µL (group B), or 1.0 x 106 MSCs (group C). Radiographs were taken every 2 weeks up to 12 weeks, with CT performed at 12 weeks. Harvested femurs were stained with toluidine blue and evaluated using radiographic and histology scores. Results: Radiographic and histological evaluation showed that bone union had been achieved at 12 weeks in group C, while group B showed callus formation and bridging callus but non-union, and in group A, callus formation alone was evident. Both radiographic and histological scores were significantly higher at 2,4, 6, 8, 10, and 12 weeks in groups B and C than group A and also significantly higher in group C than group B at 12 weeks. Conclusions: These data suggest that autologous bone grafts in combination with MSCs benefit difficult cases which cannot be treated with autologous bone grafts alone. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The development of new megaprosthesis for the treatment of large bone defects provides important options to orthopaedic oncologic surgeons for the replacement of skeletal segments, such as the long bones of the upper and lower limbs and the relative joints. We implanted megaprosthesis using either a one-step or two-step technique depending on the patient's condition. The aim of this study was to evaluate retrospectively both clinical and radiological outcomes in patients who underwent lower limb megaprosthesis implant. Materials and methods: A total of 32 patients were treated with mono- and bi-articular megaprosthesis subdivided as follows: proximal femur, distal femur, proximal tibia and total femur. The mean follow-up of patients was about 18 months (range 3 months to 5 years). Clinical and serial radiographic evaluations were conducted using standard methods (X-ray at 45 days, 3, 6, 12, 18 and 24 months) and blood parameters of inflammation were monitored for at least 2 months. Results: Although the mean length of follow-up was only 18 months, the first patients to enter the study were monitored for 5 years and showed encouraging clinical results, with good articulation of the segments, no somato-sensory or motor deficit and acceptable functional recovery. During surgery and, more importantly, in pre-operative planning, much attention should be given to the evaluation of the extensor apparatus, preserving it and, when necessary, reinforcing it with tendon substitutes. Discussion: Megaprosthesis in extreme cases of severe bone loss and prosthetic failure is a potential solution for the orthopaedic surgeon. In oncological surgery, the opportunity to restore functionality to the patient (although not ad integrum) is important for both the patient and the surgeon. The high mortality associated with cancer precludes long-term patient follow-up; therefore, there is a lack of certainty about the survival of this type of prosthesis and any medium- to long-term complications that may occur. Nevertheless, patients should be considered as an oncologic patient, not because of the disease, but because of the limited therapeutic options available. Conclusions: Megaprosthesis provides a valuable opportunity to restore functionality to patients with highly disabling diseases. [Copyright &y& Elsevier]

Background: Common cell based strategies for the treatment of osseous defects require the isolation and expansion of autologous cells. Since this makes such approaches time-consuming and expensive, we developed anovel expedited technology creating gene activated muscle grafts. We have previously shown that large segmental bone defects in rats can be regenerated by implantation of muscle tissue fragments activated by BMP-2 genetransfer. Results: In the present study, we compared the bone healing capacities of such gene activated muscle grafts withbone isografts, mimicking autologous bone grafting, the clinical gold standard for treatment of bone defects inpatients. Two of 14 male, syngeneic Fischer 344 rats used for this experiment served as donors for muscle and bone. Muscle tissue was harvested from both hind limbs and incubated with an adenoviral vector carrying the cDNA encoding BMP-2. Bone was harvested from the iliac crest and long bone epiphyses. Bone defects (5 mm)were created in the right femora of 12 rats and were filled with either BMP-2 activated muscle tissue or bone grafts.After eight weeks, femora were evaluated by radiographs, micro-computed tomography (μCT), and biomechanicaltesting. In the group receiving BMP-2 activated muscle grafts as well as in the bone-grafting group, 100% of thebone defects were healed, as documented by radiographs and μCT-imaging. Bone volume was similar in bothgroups and biomechanical stability of the two groups was statistically indistinguishable. Conclusions: This study demonstrates that treatment of large bone defects by implantation of BMP-2 gene activated muscle tissue leads to similar bone volume and stability as bone isografts, mimicking autologous bone grafting. [ABSTRACT FROM AUTHOR]

ABSTRACT Bone marrow-derived stromal cells (BMSCs) contain mesenchymal stem cells that are capable of forming various mesenchymal tissues. We hypothesized that BMSCs and β-tricalcium phosphate (β-TCP) composites would promote the remodeling of large-sized autologous devitalized bone grafts; therefore, the aim of this study was to evaluate the effects of the composites on the remodeling of autologous devitalized bone grafts. Autologous BMSCs cultured in culture medium containing dexamethasone (10−7 M) were loaded into porous β-TCP granules under low-pressure. Theses BMSC/TCP composites were put into the bone marrow cavity of autologous heat-treated bone (femoral diaphysis, 65-mm long, 100°C, 30 min) and put back to the harvest site. In the contralateral side, β-TCP without BMSC were used in the same manner as the opposite side as the control. Treatment with the BMSC/TCP composites resulted in a significant increase in thickness, bone mineral density, and matured bone volume of the cortical bone at the center of the graft compared to the control. Histological analysis showed matured regenerated bone in the BMSC loaded group. These results indicate that BMSC/TCP composites facilitated bone regeneration and maturation at the graft site of large-sized devitalized bone. This method could potentially be applied for clinical use in the reconstruction of large bone defects such as those associated with bone tumors. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:1308-1316, 2013 [ABSTRACT FROM AUTHOR]

Large segmental bone defects remain a clinical challenge. Titanium lattice-structured implants in combination with laser sintering technology promises to be an alternative to bone grafting in the treatment of critical sized bone defects. Laser sintering allows the rapid manufacturing of patient specific 3D-structured scaffolds with highly interconnected macroporous networks and tunable mechanical properties. Unknown remains to what degree the mechanical properties of these implants could be tuned, without leading to mechanical failure but still providing adequate mechanical stimuli for tissue ingrowth. The aim of this study was to evaluate various implant designs for their mechanical potential towards (a) optimized safety against stress failure and (b) optimal intrastructural straining for bone ingrowth. Finite element analyses of several lattice-structured configurations were performed. Results illustrated a strong influence of the configuration on the load carrying capacity of the constructs. The likelihood of mechanical failure was predicted to be highly dependent on structure configuration with little influence of implant porosity. Increasing porosity did not result in an increase in the implant intrastructural straining in all configurations; however, the lattice configuration was the determinant factor for implant load transfer capacity. This study provides a framework for the design of effective implants with open pore structures to ensure mechanical stability as well as promote mechanical stimulation and encourage in vivo osseointegration. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2012. [ABSTRACT FROM AUTHOR]

Reconstruction of large skeletal defects secondary to osteomyelitis or open fracture is a challenging problem. The purpose of this study was to evaluate the results of using free vascularized fibular graft (FVFG) combined with locking plate in the treatment of large skeletal defects from open fracture and infection. Ten patients with a mean age of 34 years (ranged 13–57 years) and a mean length of 8.7 cm (range 6–17 cm) skeletal defect were treated with FVFG and locking plate. The mean follow-up time was 26 months. Grafting union occurred in all patients, with a mean healing time of 4.5 months. No recurrence of osteomyelitis and stress fractures was observed. The mean time to full weight-bearing was 10 months, and all patients were pain-free and able to walk without supportive devices. FVFG combined with locking plate is a viable option for the management of large skeletal defects from open fracture and infection. [ABSTRACT FROM AUTHOR]

It was hypothesized that strontium (Sr)-doped β-tricalcium phosphate (TCP)-based scaffolds have a positive effect on the regeneration of large bone defects (LBD). Readouts in our mice models were nuclear factor-kappa beta (NF-κB) activity and vascular endothelial growth factor receptor-2 (VEGFR-2) promoter activity during the healing process. A 2-mm critical-size femoral fracture was performed in transgenic NF-κB- and VEGFR-2-luciferase reporter mice. The fracture was filled with a 3D-printed β-TCP scaffold with or without Sr. A bioluminescence in-vivo imaging system was used to sequentially investigate NF-κB and VEGFR-2 expression for two months. After sacrifice, soft and osseous tissue formation in the fracture sites was histologically examined. NF-κB activity increased in the β-TCP + Sr group in the latter stage (day 40–60). VEGFR-2 activity increased in the + Sr group from days 0–15 but decreased and showed significantly less activity than the β-TCP and non-scaffold groups from days 40–60. The new bone formation and soft tissue formation in the + Sr group were significantly higher than in the β-TCP group, whereas the percentage of osseous tissue formation in the β-TCP group was significantly higher than in the β-TCP + Sr group. We analyzed longitudinal VEGFR-2 promoter activity and NF-κB activity profiles, as respective agents of angiogenesis and inflammation, during LBD healing. The extended inflammation phase and eventually more rapid resorption of scaffold caused by the addition of strontium accelerates temporary bridging of the fracture gaps. This finding has the potential to inform an improved treatment strategy for patients who suffer from osteoporosis. [ABSTRACT FROM AUTHOR]

Recently, a novel 3D titanium-mesh scaffold with bone grafting material has been proposed to reconstruct the large defect of mandible. However, how to design and optimize the 3D scaffolds of mandible is still unclear. Therefore, the aim of this study was to investigate the optimization of 3D scaffolds for mandibular defect. Both the biomechanical behavior and mechanobiological property of scaffolds were considered in this study. Four configurations (regular hexahedron, cuboctahedron, regular dodecahedron, and diamond) and three strut diameters (0.2 mm, 0.5 mm and 0.8 mm) were divided into 12 groups. By employing Finite Element Analysis and bone "Mechnostat" theory, the optimal unit cell was selected from 12 scaffolds. Then, the original implant for mandible defects was designed with the optimal unit cell, and the final implant was optimized to promote osteogenesis and avoid mechanical failure under bi-lateral chewing bite (200N) and maximum force (worse-case) bite (800 N). The results illustrated a strong correlation between the configurations and the load transmission capacity, while mechanical failure highly depended on strut size and architecture. Regular dodecahedron with a strut diameter of 0.8 mm provided a good load transfer to bone tissue while resisting the mechanical failure. Ultimately, the optimized implant was constructed with regular dodecahedron unit cell, and the strut diameters of scaffold gradually varied according to the biomechanical analysis. The computational results indicated that the optimized implant can provide an excellent mechanical environment for bone regeneration, thus achieving a long-term stability and occlusal reconstruction with dental implant. This study is expected to provide a scientific basis for the design and optimization of 3D mesh scaffolds to reconstruct a mandibular functionally and aesthetically. • Bone "Mechnostat" theory was incorporated into FEA to optimize the structure of 3D Ti-mesh for large mandibular defect. • 12 different types of scaffolds with various configurations and strut diameters were investigated. • A integrated maxillofacial simulation model was built to evaluate the mechanobiological properties of 3D Ti-mesh implants. • Optimized prosthesis can provide an excellent biomechanical environment for mandibular reconstruction. [ABSTRACT FROM AUTHOR]

Distraction osteogenesis (DO) represents an effective but undesirably lengthy treatment for large bone defects. Both magnetic nanoparticles and silicon have been shown to induce osteogenic differentiation of mesenchymal stem cells (MSCs), the key participant in bone regeneration. We herein synthesized mesoporous silica coated magnetic (Fe 3 O 4) nanoparticles (M-MSNs) and evaluated its potential for acceleration of bone regeneration in a rat DO model. The M-MSNs exhibited good biocompatibility and remarkable capability in promoting the osteogenic differentiation of MSCs via the canonical Wnt/β-catenin pathway in vitro. More importantly, local injection of M-MSNs dramatically accelerated bone regeneration in a rat DO model according to the results of X-ray imaging, micro-CT, mechanical testing, histological examination, and immunochemical analysis. This study demonstrates the notable potential of M-MSNs in promoting bone regeneration during DO by enhancing the osteogenic differentiation of MSCs, paving the way for clinical translation of M-MSNs in DO to repair large bone defects. Translational potential of mesoporous silica coated iron oxide nanoparticles (M-MSNs) in regenerating long bone defects during distraction osteogenesis. Local injection of M-MSNs to the distraction gap promotes new bone formation and consolidation through enhancing the osteogenic differentiation of mesenchymal stem cells via the Wnt/β-catenin signaling pathway. Unlabelled Image [ABSTRACT FROM AUTHOR]