^(99m)TC-Methylene diphosphonate uptake at injury site correlates with osteoblast differentiation and mineralization during bone healing in mice

99mTc-Methylene diphosphonate （99mTc-MDP） is widely used in clinical settings to detect bone abnormalities. However, the mechanism of 99mTc-MDP uptake in bone is not well elucidated. In this study, we utilized a mouse tibia injury model, single-photon emission computed tomography （gamma scintigraphy or SPECT）, ex vivo micro-computed tomography, and histology to monitor 99mTc-MDP uptake in injury sites during skeletal healing. In an ex vivo culture system, calvarial cells were differentiated into osteoblasts with osteogenic medium, pulsed with 99mTc-MDP at different time points, and quantitated for 99mTc-MDP uptake with a gamma counter. We demonstrated that 99mTc-MDP uptake in the injury sites corresponded to osteoblast generation in those sites throughout the healing process. The 99mTc-MDP uptake within the injury sites peaked on day 7 post-injury, while the injury sites were occupied by mature osteoblasts also starting from day 7. ~mTc-MDP uptake started to decrease 14 days post-surgery, when we observed the highest level of bony tissue in the injury sites. We also found that 99mTc-MDP uptake was associated with osteoblast maturation and mineralization in vitro. This study provides direct and biological evidence for 99mTc-MDP uptake in osteoblasts during bone healing in vivo and in vitro.

Selective serotonin re-uptake inhibitor sertraline inhibits bone healing in a calvarial defect model

Bone wound healing is a highly dynamic and precisely controlled process through which damaged bone undergoes repair and complete regeneration. External factors can alter this process, leading to delayed or failed bone wound healing. The findings of recent studies suggest that the use of selective serotonin reuptake inhibitors(SSRIs) can reduce bone mass, precipitate osteoporotic fractures and increase the rate of dental implant failure. With 10% of Americans prescribed antidepressants, the potential of SSRIs to impair bone healing may adversely affect millions of patients’ ability to heal after sustaining trauma. Here, we investigate the effect of the SSRI sertraline on bone healing through pre-treatment with(10 mg·kg-1sertraline in drinking water, n = 26) or without(control, n = 30) SSRI followed by the creation of a 5-mm calvarial defect. Animals were randomized into three surgical groups:(a) empty/sham,(b) implanted with a DermaMatrix scaffold soak-loaded with sterile PBS or(c) DermaMatrix soak-loaded with542.5 ng BMP2. SSRI exposure continued until sacrifice in the exposed groups at 4 weeks after surgery. Sertraline exposure resulted in decreased bone healing with significant decreases in trabecular thickness, trabecular number and osteoclast dysfunction while significantly increasing mature collagen fiber formation. These findings indicate that sertraline exposure can impair bone wound healing through disruption of bone repair and regeneration while promoting or defaulting to scar formation within the defect site.

Perceiving the connection between the bone healing process and biodegradation of biodegradable metal implants through precise bioadaptability principle

The implants made of metallic biomaterials help healing the bone fracture but also affect the bone repair process.As proposed in Matter 4(2021)2548–2650 by Wang et al.,a precisely adaptable biomaterial ought to recapitulate the targeted tissue with spatiotemporal precision and hierarchical accuracy,ranging from atoms and molecules(genes,proteins,etc.)to cells(including organelles)and to tissues and organs.In comparison to traditional bio-inert metallic bone implants such as Co-based alloys and Ti alloys,biodegradable metal(Mg and Zn alloys)bone implants had been developed and might arise many unexpected variables in the bone repair,due to their bioactive nature.In this paper,the bone repair without and with the presence of metallic implants is compared.Thereafter,the perspectives concerning the interactions between the bone tissues and biodegradable metal implants are put forward,and how to better mimic in vivo biodegradation by in vitro experiments is proposed for further research and development of biodegradable metals.

Fullerol-hydrogel microfluidic spheres for in situ redox regulation of stem cell fate and refractory bone healing

The balance of redox homeostasis is key to stem cell maintenance and differentiation.However,this balance is disrupted by the overproduced reactive oxygen species(ROS)in pathological conditions,which seriously impair the therapeutic efficacy of stem cells.In the present study,highly dispersed fullerol nanocrystals with enhanced bioreactivity were incorporated into hydrogel microspheres using one-step innovative microfluidic technology to construct fullerol-hydrogel microfluidic spheres(FMSs)for in situ regulating the redox homeostasis of stem cells and promoting refractory bone healing.It was demonstrated that FMSs exhibited excellent antioxidant activity to quench both intracellular and extracellular ROS,sparing stem cells from oxidative stress damage.Furthermore,these could effectively promote the osteogenic differentiation of stem cells with the activation of FoxO1 signaling,indicating the intrinsically osteogenic property of FMSs.By injecting the stem cells-laden FMSs into rat calvarial defects,the formation of new bone was remarkably reinforced,which is a positive synergic effect from modulating the ROS microenvironment and enhancing the osteogenesis of stem cells.Collectively,the antioxidative FMSs,as injectable stem cell carriers,hold enormous promise for refractory bone healing,which can also be expanded to deliver a variety of other cells,targeting diseases that require in situ redox regulation.

Bone Injury and Fracture Healing Biology

Bones are organs of the skeletal system, providing shape, mechanical support, and protection to the body and facilitating the movement. In addition, bones contribute to the mineral homeostasis of the body and have recently been found to participate in endocrine regulation of energy metabolism. The well-known limitations associated with clinical use of autografts and allografts continue to drive efforts to develop bone graft substitutes, using the principles of biomaterials and tissue engineering. Under some stressful and continuous compressive conditions, the ability of the bone tissue to tolerate strength decreases. Whenever these forces overcome the toleration of the bone tissue, bone fracture occurs. years

Effect of non-steroidal anti-inflammatory drugs on fracture healing in children:A systematic review

BACKGROUND Non-steroidal anti-inflammatory drugs(NSAIDs)are among the most commonly prescribed medications in the United States.Although they are safe and effective means of analgesia for children with broken bones,there is considerable variation in their clinical use due to persistent concerns about their potentially adverse effect on fracture healing.AIM To assess whether NSAID exposure is a risk factor for fracture nonunion in children.METHODS We systematically reviewed the literature reporting the effect of NSAIDs on bone healing.We included all clinical studies that reported on adverse bone healing complications in children with respect to NSAID exposure.The outcomes of interest were delayed union or nonunion.Study quality was assessed using the Newcastle-Ottawa scale for non-randomized studies.A final table was constructed summarizing the available evidence.RESULTS A total of 120 articles were identified and screened,of which 6 articles were included for final review.Nonunion in children is extremely rare;among the studies included,there were 2011 nonunions among 238822 fractures(0.84%).None of the included studies documented an increased risk of nonunion or delayed bone healing in those children who are treated with NSAIDs in the immediate post-injury or peri-operative time period.Additionally,children are likely to take these medications for only a few days after injury or surgery,further decreasing their risk of adverse side-effects.CONCLUSION This systematic review suggests that NSAIDS can be safely prescribed to pediatric orthopaedic patients absent other contraindications without concern for increased risk of fracture non-union or delayed bone healing.Additional prospective studies are needed focusing on higher risk fractures and elective orthopaedic procedures such as osteotomies and spinal fusion.

Dynamic degradation patterns of porous polycaprolactone/β-tricalcium phosphate composites orchestrate macrophage responses and immunoregulatory bone regeneration

Biodegradable polycaprolactone/β-tricalcium phosphate(PT)composites are desirable candidates for bone tissue engineering applications.A higherβ-tricalcium phosphate(TCP)ceramic content improves the mechanical,hydrophilic and osteogenic properties of PT scaffolds in vitro.Using a dynamic degradation reactor,we estab-lished a steady in vitro degradation model to investigate the changes in the physio-chemical and biological properties of PT scaffolds during degradation.PT46 and PT37 scaffolds underwent degradation more rapidly than PT scaffolds with lower TCP contents.In vivo studies revealed the rapid degradation of PT(PT46 and PT37)scaffolds disturbed macrophage responses and lead to bone healing failure.Macrophage co-culture assays and a subcutaneous implantation model indicated that the scaffold degradation process dynamically affected macro-phage responses,especially polarization.RNA-Seq analysis indicated phagocytosis of the degradation products of PT37 scaffolds induces oxidative stress and inflammatory M1 polarization in macrophages.Overall,this study reveals that the dynamic patterns of biodegradation of degradable bone scaffolds highly orchestrate immune responses and thus determine the success of bone regeneration.Therefore,through evaluation of the biological effects of biomaterials during the entire process of degradation on immune responses and bone regeneration are necessary in order to develop more promising biomaterials for bone regeneration.

Application of a new anatomic hook-rod-pedicle screw system in young patients with lumbar spondylolysis:A pilot study

BACKGROUND The pedicle screw-laminar hook system has strong fixation and is conducive to bone graft fusion for lumbar spondylolysis.However,the current pedicle screwlaminar hook fixation system is not specifically designed for lumbar spondylolysis.AIM To investigate the clinical effects of a new anatomical hook-rod-pedicle screw system in the treatment of lumbar spondylolysis in young adults.METHODS We designed a new anatomic hook-rod-pedicle screw system for young patients with lumbar spondylolysis.The isthmus and the corresponding pedicle screw entry point were exposed through the intermuscular approach.Autogenous iliac bone graft was obtained to bridge the isthmus defect,and then the anatomic hook-rod-pedicle screw system was used to fix the isthmus in 15 young patients.RESULTS At 24 mo follow-up,the visual analogue scale score of low back pain decreased from 6.73±0.88 to 0.73±0.59,and the Oswestry disability index score decreased from 58.20±8.99 to 7.87±4.97.Computed tomography showed bilateral isthmic bone healing in 14 cases and unilateral isthmic bone healing in 1 case.Magnetic resonance imaging showed that the lumbar disc signal of diseased segment and adjacent segments had no change compared with that before surgery.The pain visual analogue scale score of the donor site was 0.20±0.41 at the last follow-up.According to the Modified Macnab score,the excellent and good rate was 100%.CONCLUSION The application of this new anatomical hook-rod-pedicle screw system to treat young patients with lumbar spondylolysis has the advantages of less trauma,a simple operation and satisfactory clinical effects.

Waders(Scolopacidae)surviving despite malaligned leg fractures in the wild:kinematics of bipedal locomotion

Background: Bone fracture frequencies and survival rates are essential parameters in skeleton evolution, but information on the functional consequences of naturally healed fractures is scarce. No leg bone fracture healing in the wild has been reported so far from long-legged Charadriiformes(waders), which depend on bipedal locomotion for feeding.Methods: We documented a healed but malaligned tarsometatarsus fracture in a wild Willet(Tringa [Catoptrophorus]semipalmata), and a malaligned tibiotarsus fracture in a Curlew(Numenius arquata) skeleton from a museum collection. Functional consequences of the malalignments were evaluated by kinematic analyses of videos(Willet) and in silico 3D modeling(Curlew).Results: The Willet's left tarsometatarsus exhibited an angular malalignment of 70°, resulting in a limping gait that was less pronounced at high than at low walking speed. The bird seemed unable to club the toes of the left foot together, apparently a secondary effect of the deformity. The Curlew's tibiotarsus showed an angular and an axial malalignment, causing the foot to rotate outwards when the intertarsal joint was flexed. Despite the severe effects of their injuries, the birds had survived at least long enough for the fractures to heal completely.Conclusions: Somewhat unexpectedly, leg fractures are not necessarily fatal in long-legged waders, even if deformities occur in the healing process. Bipedal locomotion on vegetated grounds must have been impeded due to the bone malalignments in both analyzed cases. The birds probably alleviated the impact of their handicaps by shifting a larger proportion of their activities to vegetation-free habitats.

Advancing application of mesenchymal stem cell-based bone tissue regeneration

Reconstruction of bone defects,especially the critical-sized defects,with mechanical integrity to the skeleton is important for a patient's rehabilitation,however,it still remains challenge.Utilizing biomaterials of human origin bone tissue for therapeutic purposes has provided a facilitated approach that closely mimics the critical aspects of natural bone tissue with regard to its properties.However,not only efficacious and safe but also costeffective and convenient are important for regenerative biomaterials to achieve clinical translation and commercial success.Advances in our understanding of regenerative biomaterials and their roles in new bone formation potentially opened a new frontier in the fast-growing field of regenerative medicine.Taking inspiration from the role and multicomponent construction of native extracellular matrix(ECM)for cell accommodation,the ECM-mimicking biomaterials and the naturally decellularized ECM scaffolds were used to create new tissues for bone restoration.On the other hand,with the going deep in understanding of mesenchymal stem cells(MSCs),they have shown great promise to jumpstart and facilitate bone healing even in diseased microenvironments with pharmacology-based endogenous MSCs rescue/mobilization,systemic/local infusion of MSCs for cytotherapy,biomaterials-based approaches,cell-sheets/-aggregates technology and usage of subcellular vesicles of MSCs to achieve scaffolds-free or cell-free delivery system,all of them have been shown can improve MSCsmediated regeneration in preclinical studies and several clinical trials.Here,following an overview discussed autogenous/allogenic and ECM-based bone biomaterials for reconstructive surgery and applications of MSCsmediated bone healing and tissue engineering to further offer principles and effective strategies to optimize MSCs-based bone regeneration.

Biodegradable magnesium barrier membrane used for guided bone regeneration in dental surgery

Barrier membranes are commonly used as part of the dental surgical technique guided bone regeneration(GBR)and are often made of resorbable collagen or non-resorbable materials such as PTFE.While collagen membranes do not provide sufficient mechanical protection of the covered bone defect,titanium reinforced membranes and non-resorbable membranes need to be removed in a second surgery.Thus,biodegradable GBR membranes made of pure magnesium might be an alternative.In this study a biodegradable pure magnesium(99.95%)membrane has been proven to have all of the necessary requirements for an optimal regenerative outcome from both a mechanical and biological perspective.After implantation,the magnesium membrane separates the regenerating bone from the overlying,faster proliferating soft tissue.During the initial healing period,the membrane maintained a barrier function and space provision,whilst retaining the positioning of the bone graft material within the defect space.As the magnesium metal corroded,it formed a salty corrosion layer and local gas cavities,both of which extended the functional lifespan of the membrane barrier capabilities.During the resorption of the magnesium metal and magnesium salts,it was observed that the membrane became surrounded and then replaced by new bone.After the membrane had completely resorbed,only healthy tissue remained.The in vivo performance study demonstrated that the magnesium membrane has a comparable healing response and tissue regeneration to that of a resorbable collagen membrane.Overall,the magnesium membrane demonstrated all of the ideal qualities for a barrier membrane used in GBR treatment.

Biodegradable magnesium fixation screw for barrier membranes used in guided bone regeneration

An ideal fixation system for guided bone(GBR)regeneration in oral surgery must fulfil several criteria that includes the provision of adequate mechanical fixation,complete resorption when no longer needed,complete replacement by bone,as well as be biocompatible and have a good clinical manageability.For the first time,a biodegradable magnesium fixation screw made of the magnesium alloy WZM211 with a MgF2 coating has been designed and tested to fulfill these criteria.Adequate mechanical fixation was shown for the magnesium fixation screw in several benchtop tests that directly compared the magnesium fixation screw with an equivalent polymeric resorbable device.Results demonstrated slightly superior mechanical properties of the magnesium device in comparison to the polymeric device even after 4 weeks of degradation.Biocompatibility of the magnesium fixation screw was demonstrated in several in vitro and in vivo tests.Degradation of the magnesium screw was investigated in in vitro and in vivo tests,where it was found that the screw is resorbed slowly and completely after 52 weeks,providing adequate fixation in the early critical healing phase.Overall,the magnesium fixation screw demonstrates all of the key properties required for an ideal fixation screw of membranes used in guided bone regeneration(GBR)surgeries.

Rotary self-locking intramedullary nail for long tubular bone fractures

Background Intramedullary nails had been widely used in the treatment of long-bone fractures because of less interference of fractures and center bearing biomechanical advantage. However, it had been also found many shortcomings such as broken nails, delayed healing and was modified in order to achieve better efficacy and reduce complications. The aim of the present study is to compare the efficacy of rotary self-locking intramedullary nails （RSIN） with that of interlocking intramedullary nails （IIN） in the treatment of long-bone fractures.

In vitro and in vivo study on fine-grained Mg-Zn-RE-Zr alloy as a biodegradeable orthopedic implant produced by friction stir processing

Magnesium alloys containing biocompatible components show tremendous promise for applications as temporary biomedical devices. However, to ensure their safe use as biodegradeable implants, it is essential to control their corrosion rates. In concentrated Mg alloys, a microgalvanic coupling between the α-Mg matrix and secondary precipitates exists which results in increased corrosion rate. To address this challenge, we engineered the microstructure of a biodegradable Mg-Zn-RE-Zr alloy by friction stir processing (FSP), improving its corrosion resistance and mechanical properties simultaneously. The FS processed alloy with refined grains and broken and uniformly distributed secondary precipitates showed a relatively uniform corrosion morphology accompanied with the formation of a stable passive layer on the alloy surface. In vivo corrosion evaluation of the processed alloy in a small animal model showed that the material was well-tolerated with no signs of inflammation or harmful by-products. Remarkably, the processed alloy supported bone until it healed till eight weeks with a low in vivo corrosion rate of 0.7 mm/year. Moreover, we analyzed blood and histology of the critical organs such as liver and kidney, which showed normal functionality and consistent ion and enzyme levels, throughout the 12- week study period. These results demonstrate that the processed Mg-Zn-RE-Zr alloy offers promising potential for osseointegration in bone tissue healing while also exhibiting controlled biodegradability due to its engineered microstructure. The results from the present study will have profound benefit for bone fracture management, particularly in pediatric and elderly patients.

Application of osteoinductive calcium phosphate ceramics in children’s endoscopic neurosurgery:report of five cases

This work aimed at investigating the possibility and effectiveness of osteoinductive calcium phosphate(CaP)ceramics to close the drilled skull holes and prevent the postoperative cerebrospinal fluid(CSF)leaking in children’s endoscopic neurosurgery.Five children patients(four boys and one girl,3-to 8-years old)underwent the surgery,in which the endoscopic third ventriculostomy(ETV)was operated in four cases of hydrocephalus,and biopsy and ETV were both performed in one case of pineal tumor.The drilled skull holes were filled with the commercial osteoinductive CaP ceramics.The patients were followed up by CT scan at 1,7 days,3 and 6 months postoperatively.All the five cases were successful,and the holes were closed well after filled with the ceramics.The follow-up survey showed that no CSF leaking or rejection reaction was found.The CT scan indicated that the drilled holes began healing at 7 days postoperatively,and a relatively complete healing happened at 6 months postoperatively.The excellent ability of the CaP ceramics to induce bone regeneration was also confirmed by repairing the skull defects in a monkey model.The results of μ-CT and histological analysis showed that a bony structure with irregular array occurred at the defect area,and the newly formed bone volume density reached 65.7%.In conclusion,the osteoinductive CaP ceramics could be an ideal material to treat the drilled skull holes in children’s endoscopic neurosurgery and prevent CSF leaking afterwards.However,further investigation with more cases and longer follow-up was required to evaluate the clinical effect.

Bioactive polymeric materials and electrical stimulation strategies for musculoskeletal tissue repair and regeneration

Electrical stimulation(ES)is predominantly used as a physical therapy modality to promote tissue healing and functional recovery.Research efforts in both laboratory and clinical settings have shown the beneficial effects of this technique for the repair and regeneration of damaged tissues,which include muscle,bone,skin,nerve,tendons,and ligaments.The collective findings of these studies suggest ES enhances cell proliferation,extracellular matrix(ECM)production,secretion of several cytokines,and vasculature development leading to better tissue regeneration in multiple tissues.However,there is still a gap in the clinical relevance for ES to better repair tissue interfaces,as ES applied clinically is ineffective on deeper tissue.The use of a conducting material can transmit the stimulation applied from skin electrodes to the desired tissue and lead to an increased function on the repair of that tissue.Ionically conductive(IC)polymeric scaffolds in conjunction with ES may provide solutions to utilize this approach effectively.Injectable IC formulations and their scaffolds may provide solutions for applying ES into difficult to reach tissue types to enable tissue repair and regeneration.A better understanding of ES-mediated cell differentiation and associated molecular mechanisms including the immune response will allow standardization of procedures applicable for the next generation of regenerative medicine.ES,along with the use of IC scaffolds is more than sufficient for use as a treatment option for single tissue healing and may fulfill a role in interfacing multiple tissue types during the repair process.