Graphene oxide/gallium nanoderivative as a multifunctional modulator of osteoblastogenesis and osteoclastogenesis for the synergistic therapy of implant-related bone infection

Currently,implant-associated bacterial infections account for most hospital-acquired infections in patients suffering from bone fractures or defects.Poor osseointegration and aggravated osteolysis remain great challenges for the success of implants in infectious scenarios.Consequently,developing an effective surface modification strategy for implants is urgently needed.Here,a novel nanoplatform(GO/Ga)consisting of graphene oxide(GO)and gallium nanoparticles(GaNPs)was reported,followed by investigations of its in vitro antibacterial activity and potential bacterium inactivation mechanisms,cytocompatibility and regulatory actions on osteoblastogenesis and osteoclastogenesis.In addition,the possible molecular mechanisms underlying the regulatory effects of GO/Ga nanocomposites on osteoblast differentiation and osteoclast formation were clarified.Moreover,an in vivo infectious microenvironment was established in a rat model of implant-related femoral osteomyelitis to determine the therapeutic efficacy and biosafety of GO/Ga nanocomposites.Our results indicate that GO/Ga nanocomposites with excellent antibacterial potency have evident osteogenic potential and inhibitory effects on osteoclast differentiation by modulating the BMP/Smad,MAPK and NF-κB signaling pathways.The in vivo experiments revealed that the administration of GO/Ga nanocomposites significantly inhibited bone infections,reduced osteolysis,promoted osseointegration located in implant-bone interfaces,and resulted in satisfactory biocompatibility.In summary,this synergistic therapeutic system could accelerate the bone healing process in implant-associated infections and can significantly guide the future surface modification of implants used in bacteria-infected environments.

3D additive manufactured composite scaffolds with antibiotic-loaded lamellar fillers for bone infection prevention and tissue regeneration

Bone infections following open bone fracture or implant surgery remain a challenge in the orthopedics field.In order to avoid high doses of systemic drug administration,optimized local antibiotic release from scaffolds is required.3D additive manufactured(AM)scaffolds made with biodegradable polymers are ideal to support bone healing in non-union scenarios and can be given antimicrobial properties by the incorporation of antibiotics.In this study,ciprofloxacin and gentamicin intercalated in the interlamellar spaces of magnesium aluminum layered double hydroxides(MgAl)andα-zirconium phosphates(ZrP),respectively,are dispersed within a thermoplastic polymer by melt compounding and subsequently processed via high temperature melt extrusion AM(~190◦C)into 3D scaffolds.The inorganic fillers enable a sustained antibiotics release through the polymer matrix,controlled by antibiotics counterions exchange or pH conditions.Importantly,both antibiotics retain their functionality after the manufacturing process at high temperatures,as verified by their activity against both Gram+and Gram-bacterial strains.Moreover,scaffolds loaded with filler-antibiotic do not impair human mesenchymal stromal cells osteogenic differentiation,allowing matrix mineralization and the expression of relevant osteogenic markers.Overall,these results suggest the possibility of fabricating dual functionality 3D scaffolds via high temperature melt extrusion for bone regeneration and infection prevention.

Bone infection site targeting nanoparticle-antibiotics delivery vehicle to enhance treatment efficacy of orthopedic implant related infection

Orthopedic implants account for 99%of orthopedic surgeries,however,orthopedic implant-related infection is one of the most serious complications owing to the potential for limb-threatening sequelae and mortality.Current antibiotic treatments still lack the capacity to target bone infection sites,thereby resulting in unsatisfactory therapeutic effects.Here,the bone infection site targeting efficacy of D6 and UBI29-41 peptides was investigated,and bone-and-bacteria dual-targeted nanoparticles(NPs)with D6 and UBI29-41 peptides were first fabricated to target bone infection site and control the release of vancomycin in bone infection site.The results of this study demonstrated that the bone-and-bacteria dual-targeted mesoporous silica NPs exhibit excellent bone and bacteria targeting efficacy,excellent biocompatibility and effective antibacterial properties in vitro.Furthermore,in a rat model of orthopedic implant-related infection with methicillin-resistant Staphylococcus aureus,the growth of bacteria was evidently inhibited without cytotoxicity,thus realizing the early treatment of implant-related infection.Hence,the bone-and-bacteria dual-targeted molecule-modified NPs may target bacteria-infected bone sites and act as ideal candidates for the therapy of orthopedic implant-related infections.

New perspectives on traumatic bone infections

In this paper,we review the results of previous studies and summarize the effects of various factors on the regulation of bone metabolism in traumatic bone infections.Infection-related bone destruction incorporates pathogens and iatrogenic factors in the process of bone resorption dominated by the skeletal and immune systems.The development of bone immunology has established a bridge of communication between the skeletal system and the immune system.Exploring the effects of pathogens,skeletal systems,immune systems,and antibacterials on bone repair in infectious conditions can help improve the treatment of these diseases.

The Use of Autologous Tibia Strut Graft to Enhance Bone Healing of an Infected Long-Bone Nonunion

We treated five patients with an infected non-union of the femur and tibia with autologous tibia strut grafts. All patients had bone defects ranging from three to nine centimeters. Three patients suffered for more than seven years from chronic osteitis. Our objective was to describe this grafting technique and its results. We focussed on healing time, postoperative complications and functional recovery. We retrospectively studied five patients with an infected non-union of the lower limb who had undergone previous surgeries to overcome the bone healing problem. In this group of patients, we had four femur non-union and one tibia non-union. All of them had a previous infection episode, in which medical and surgical therapy was needed. Of the participants, three were men, and two were females with a mean age of 43.3 years (28 - 55).

Innovations in osteomyelitis research:A review of animal models

Infection of bone tissue,or osteomyelitis,has become a growing concern in modern healthcare due in no small part to a rise in antibiotic resistance among bacteria,notably Staphylococcus aureus.The current standard of care involves aggressive,prolonged antibiotic therapy combined with surgical debridement of infected tissues.While this treatment may be sufficient for resolving a portion of cases,recurrences of the infection and associated risks including toxicity with long-term antibiotic usage have been reported.Therefore,there exists a need to produce safer,more efficacious options of treatment for osteomyelitis.In order to test treatment regimens,animal models that closely mimic the clinical condition and allow for accurate evaluation of therapeutics are necessary.Establishing a model that replicates features of osteomyelitis in humans continues to be a challenge to scientists,as there are many variables involved,including choosing an appropriate species and method to establish infection.This review addresses the refinement of animal models of osteomyelitis to reflect the clinical disease and test prospective therapeutics.The aim of this review is to explore studies regarding the use of animals for osteomyelitis therapeutics research and encourage further development of such animal models for the translation of results from the animal experiment to human medicine.

Fabrication, bacteriostasis and osteointegration properties researches of the additively-manufactured porous tantalum scaffolds loading vancomycin

Infected bone defects(IBDs)remains a challenging problem for orthopedists.Clinically,routine management for IBDs has two stages:debridement and systematic antibiotics administration to control infection,and secondary grafting to repair bone defects.Whereas the efficacy is not satisfactory,because the overuse of antibiotics may lead to systemic toxicity,and the emergence of drug-resistant bacteria,as well as the secondary surgery would cause additional trauma and economic burden to the patients.Therefore,it is imperative to develop a novel scaffold for one-stage repair of IBDs.In this study,vancomycin(Van)was encapsulated into poly(lactic co-glycolic acid)(PLGA)microspheres through the double emulsion method,which were then loaded into the additively-manufactured porous tantalum(AM-Ta)through gelatin methacryloyl(GelMA)hydrogel to produce the composite Ta/GelMA hydrogel(Gel)/PLGA/vancomycin(Van)scaffolds for repairing IBDs.Physiochemical characterization of the newly-developed scaffold indicated that the releasing duration of Van was over 2 weeks.Biological experiments indicated good biocompatibility of the composite scaffold,as well as bacteriostasis and osteointegration properties,which showed great potential for clinical application.The construction of this novel scaffold would provide new sight into the development of orthopaedic implants,shedding a novel light on the treatment of IBDs.

Current opinions on the mechanism,classification,imaging diagnosis and treatment of post-traumatic osteomyelitis

Post-traumatic osteomyelitis(PTO)is a worldwide problem in the field of orthopaedic trauma.So far,there is no ideal treatment or consensus-based gold standard for its management.This paper reviews the representative literature focusing on PTO,mainly from the following four aspects:(1)the pathophysiological mechanism of PTO and the interaction mechanism between bacteria and the body,including fracture stress,different components of internal fixation devices,immune response,occurrence and development mechanisms of inflammation in PTO,as well as the occurrence and development mechanisms of PTO in skeletal system;(2)clinical classification,mainly the etiological classification,histological classification,anatomical classification and the newly proposed new classifications(a brief analysis of their scope and limitations);(3)imaging diagnosis,including non-invasive examination and invasive examination(this paper discusses their advantages and disadvantages respectively,and briefly compares the sensitivity and effectiveness of the current examinations);and(4)strategies,including antibiotic administration,surgical choices and other treatment programs.Based on the above-mentioned four aspects,we try to put forward some noteworthy sections,in order to make the existing opinions more specific.

RESEARCH ARTICLE Open Access Investigating clinical characteristics and prognostic factors in patients with chronic osteomyelitis of humerus

Background:Chronic osteomyelitis in the humerus,which has complex neuroanatomy and a good soft tissue envelope,represents a unique clinical challenge.However,there are relatively few related studies in the literature.This article retrospectively reviewed a large case series with the aims of sharing our management experiences and further determining factors associated with the outcomes.Methods:Twenty-eight consecutive adult patients with a mean age of 36 years were identified by reviewing the osteomyelitis database of our clinic centre.The database was used to prospectively identify all osteomyelitis cases between 2013 and 2017,and all data then was retrospectively analysed.Results:The mean follow-up period was 35 months(range 24–60).The aetiology was trauma in 43%(12)of the patients and haematogenous in 57%(16)of the patients,and Staphylococcus aureus was a solitary agent in 50%(14)of the patients.Host-type(Cierny’s classification)was IA in 8,IIIB in 11 and IVB in 9 patients.All patients required debridement followed by the placement of a temporary antibiotic-impregnated cement spacer(rod).Seventeen patients received a cement-coated plate for internal fixation after debridement,and 13 patients needed bone grafts when the spacer was staged removed.All patients attained an infection-free bone healing state at the final follow-up.The final average DASH(disabilities of the arm,shoulder and hand)score was 18.14±5.39,while 6 patients(two developed traumatic olecranarthritis,four developed radial nerve injuries)showed the lowest levels of limb function(p=0.000)and were unemployed.Three patients(type I;significant difference between type I versus type III and type IV patients,p<0.05)experienced recurrence after debridement and underwent a second revision,which was not related to the bone graft(p=0.226)or plate fixation(p=0.050).Conclusions:Humeral chronic osteomyelitis can be treated with general surgery and anti-infective therapy;medullary(type I)infection presents a challenge,and the antibiotic-coated cement plate provides favourable fixation without increasing recurrence of infections.Clinicians should be aware of potential iatrogenic nerve injuries when treating these patients with complicated cases,and an experienced surgeon may improve the outcome.