Role of polyethylene particles in peri-prosthetic osteolysis:A review

There is convincing evidence that particles produced by the wear of joint prostheses are causal in the periprosthetic loss of bone,or osteolysis,which,if it progresses,leads to the phenomenon of aseptic loosening.It is important to fully understand the biology of this bone loss because it threatens prosthesis survival,and loosened implants can result in peri-prosthetic fracture,which is disastrous for the patient and presents a difficult surgical scenario.The focus of this review is the bioactivity of polyethylene(PE)particles,since there is evidence that these are major players in the development and progression of osteolysis around prostheses which use PE as the bearing surface.The review describes the biological consequences of interaction of PE particles with macrophages,osteoclasts and cells of the osteoblast lineage,including osteocytes.It explores the possible cellular mechanisms of action of PE and seeks to use the findings to date to propose potential nonsurgical treatments for osteolysis.In particular,a nonsurgical approach is likely to be applicable to implants containing newer,highly cross-linked PEs(HXLPEs),for which osteolysis seems to occur with much reduced PE wear compared with conventional PEs.The caveat here is that we know little as yet about the bioactivity of HXLPE particles and addressing this constitutes our next challenge.

A review of UHMWPE wear-induced osteolysis:the role for early detection of the immune response

In a world where increasing joint arthroplasties are being performed on increasingly younger patients, osteolysis as the leading cause of faiIure after total joint arthroplasty （TJA） has gained considerable attention. Ultra-high molecular weight polyethylene wear-induced osteolysis is the process by which prosthetic debris mechanicaIly released from the surface of prosthetic joints induces an immune response that favors bone catabolism, resulting in loosening of prostheses with eventual failure or fracture. The immune response initiated is innate in that it is nonspecific and self-propagating, with monocytic cells and osteoclasts being the main effectors. To date, detecting disease early enough to implement effective intervention without unwanted systemic side effects has been a major barrier. These barriers can be overcome using newer in vivo imaging techniques and modules linked with fluorescence and/or chemotherapies. We discuss the pathogenesis of osteolysis, and provide discussion of the challenges with imaging and therapeutics. We describe a positron emission tomography imaging cinnamoyl-Phe-（D）-Leu-Phe-（D）-Leu-Phe-Lys module, specific to maerophages, which holds promise in early detection of disease and localization of treatment. Further research and increased collaboration among therapeutic and three-dimensional imaging researchers are essential in realizing a solution to clinical osteolysis in TJA.

Osteolysis in total hip arthroplasty in relation to metal ion release: Comparison between monolithic prostheses and different modularities

BACKGROUND Among the various complications associated with total hip arthroplasty(THA)periprosthetic osteolysis and wear phenomena due to the release of metal particles,are two of the most common and have been reported to be correlated because of inflammatory responses directed towards released particles that generally activate macrophagic osteolytic effects.Therein,new masses known as pseudotumors can appear in soft tissues around a prosthetic implant.To date,there is paucity of reliable data from studies investigating for any association between the above mentioned adverse events.AIM To investigate for the existence of any association between serum and urine concentrations of metal-ions released in THA and periprosthetic osteolysis for modular neck and monolithic implants.METHODS Overall,76 patients were divided into three groups according to the type of hip prosthesis implants:Monoblock,modular with metal head and modular with ceramic head.With an average f-up of 4 years,we conducted a radiological evaluation in order to detect any area of osteolysis around the prosthesis of both the femur and the acetabulum.Moreover,serum and urinary tests were performed to assess the values of Chromium and Cobalt released.Statistical analysis was performed to determine any association between the ion release and osteolysis.RESULTS For the 3 study groups,the monolithic,modular ceramic-headed and modular metal-headed implants had different incidences of osteolysis events,which were higher for the modular implants.Furthermore,the most serious of these(grade 3)were detected almost exclusively for the modular implants with metal heads.A mapping of the affected areas was performed revealing that the highest incidences of osteolysis were evidenced in the pertrochanteric region at the femur level,and in the supero-external region at the acetabular level.Regarding the evaluation of the release of metals-ions from wear processes,serum and urinary chromium and cobalt values were found to be higher in cases of modularity,and even more so for those with metal head.Statistical linear correlation test results suggested positive correlations between increasing metal concentrations and incidences areas of osteolysis.However,no cases of pseudo-tumor were detected.CONCLUSION Future studies are needed to identify risk factors that increase peri-prosthetic metal ion levels and whether these factors might be implicated in the triggering of local events,including osteolysis and aseptic loosening.

Small extracellular vesicles derived from hypoxic preconditioned dental pulp stem cells ameliorate inflammatory osteolysis by modulating macrophage polarization and osteoclastogenesis

Extensive macrophage inflammatory responses and osteoclast formation are predominant during inflammatory or infective osteolysis.Mesenchymal stem cell(MSC)-derived small extracellular vesicles(MSC-sEV)have been shown to exert therapeutic effects on bone defects.However,cultured MSCs are typically exposed to normoxia(21%O2)in vitro,which differs largely from the oxygen concentration in vivo under hypoxic conditions.It is largely unknown whether sEV derived from dental pulp stem cells(DPSCs)cultured under hypoxic conditions(Hypo-sEV)exert better therapeutic effects on lipopolysaccharide(LPS)-induced inflammatory osteolysis than those cultured under normoxic conditions(Nor-sEV)by simultaneously inhibiting the macrophage inflammatory response and osteoclastogenesis.In this study,we show that hypoxia significantly induces the release of sEV from DPSCs.Moreover,Hypo-sEV exhibit significantly improved efficacy in promoting M2 macrophage polarization and suppressing osteoclast formation to alleviate LPS-induced inflammatory calvarial bone loss compared with Nor-sEV.Mechanistically,hypoxia preconditioning markedly alters the miRNA profiles of DPSC-sEV.MiR-210-3p is enriched in Hypo-sEV,and can simultaneously induce M2 macrophage generation and inhibit osteoclastogenesis by targeting NF-κB1 p105,which attenuates osteolysis.Our study suggests a promising potential for hypoxia-induced DPSC-sEV to treat inflammatory or infective osteolysis and identifies a novel role of miR-210-3p in concurrently hindering osteoclastogenesis and macrophage inflammatory response by inhibiting NF-kB1 expression.

Macrophage-derived exosomes modulate wear particle-induced osteolysis via miR-3470b targeting TAB3/NF-κB signaling

Aseptic prosthesis loosening(APL)is one of the most prevalent complications associated with arthroplasty.The main cause is the periprosthetic osteolysis induced by wear particles.However,the specific mechanisms of crosstalk between immune cells and osteoclasts/osteoblasts during osteolysis are unclear.In this study,we report the role and mechanism of macrophage-derived exosomes in wear particle-induced osteolysis.The results of exosomes up-taken experiments revealed that osteoblast and mature osteoclasts capture macrophage-derived exosomes(M-Exo).Next-generation sequencing and RT-qPCR on M-Exo revealed that exosomal microRNA miR-3470b was downregulated in wear particle-induced osteolysis.The results of analysis on Luciferase reporter assays/fluorescence in situ hybridization(FISH)/immunofluorescence(IF)/immunohistochemistry(IHC)and co-culture experiments demonstrated that wear particles induced osteoclast differentiation by increasing the expression of NFatc1 via M-Exo miR-3470b targeting TAB3/NF-κB signaling.We also illustrate that engineered exosomes enriching miR-3470b facilitated to suppressed the osteolysis;the microenvironment enriching with miR-3470b could suppress wear particle-induced osteolysis via inhibition of TAB3/NF-κB in vivo.In summary,our findings indicate that macrophage-derived exosomes transfer to osteoclasts to induce osteolysis in wear particle-induced APL.Engineering exosomes enriching with miR-3470b might be a novel strategy for the targeting treatment of bone resorption-related diseases.

Post-traumatic osteolysis of the distal clavicle,pubis and ischium in 7 patients

Post-traumatic osteolysis (PTOL) is a very rare disease occurring after acute trauma or repetitive micro-trauma, which is characterized by persistent pain in the injured site. In this study, we reported 7 patients, in whom osteolysis developed in the distal clavicle, pubis and ischium.

Congenital insensitivity to pain with anhidrosis and progressing acro-osteolysis:a case report with 7-year follow-up

Congenital insensitivity to pain is a rare disorder, first described by Dearborn in 1932. Since the discovery of congenital insensitivity to pain with anhidrosis or hereditary sensory neuropathy type Ⅳ in 1983, fewer than 60 cases have been reported. Congenital insensitivity to pain with anhidrosis and progressing acro-osteolysis is a very rare disorder characterized by absence of painful perception after birth. Severe problems may arise if pain sensation is absent, causing injury to oral structures as teeth, lips and the tongue by self mutilation. The patient is at a risk of late presentation with systemic illnesses associated with pain, such as fracture and joint dislocation. Importantly, the patient may suffer from acro-osteolysis with growth, for instance, osteolysis of the distal extremities.

Niobium carbide(MXene)reduces UHMWPE particle-induced osteolysis

Joint replacement surgery is one of the orthopedic surgeries with high successful rates;however,wear debris generated from prostheses can ultimately lead to periprosthetic osteolysis and failure of the implant.The implant-derived particulate debris such as ultrahigh molecular weight polyethylene(UHMWPE)can initiate the local immune response and recruit monocytic cells to phagocytose particles for generating reactive oxygen species(ROS).ROS induces osteoclastogenesis and macrophages to secrete cytokines which ultimately promote the development of osteolysis.In this work,we develop the few-layered Nb_(2)C(FNC)as an antioxidant which possesses the feature of decreasing the production of cytokines and inhibiting osteoclastogenesis by its ROS adsorption.Moreover,local injection of FNC attenuates the UHMWPE-induced osteolysis in a mouse calvarial model.In sum,our results suggest that FNC can be used for treating osteolytic bone disease caused by excessive osteoclastogenesis.

Biological response to prosthetic debris

Joint arthroplasty had revolutionized the outcome of orthopaedic surgery. Extensive and collaborative work of many innovator surgeons had led to the development of durable bearing surfaces, yet no single material is considered absolutely perfect. Generation of wear debris from any part of the prosthesis is unavoidable. Implant loosening secondary to osteolysis is the most common mode of failure of arthroplasty. Osteolysis is the resultant of complex contribution of the generated wear debris and the mechanical instability of the prosthetic components. Roughly speaking, all orthopedic biomaterials may induce a universal biologic hostresponse to generated wear débris with little specific characteristics for each material; but some debris has been shown to be more cytotoxic than others. Prosthetic wear debris induces an extensive biological cascade of adverse cellular responses, where macrophages are the main cellular type involved in this hostile inflammatory process. Macrophages cause osteolysis indirectly by releasing numerous chemotactic inflammatory mediators, and directly by resorbing bone with their membrane microstructures. The bio-reactivity of wear particles depends on two major elements: particle characteristics(size, concentration and composition) and host characteristics. While any particle type may enhance hostile cellular reaction, cytological examination demonstrated that more than 70% of the debris burden is constituted of polyethylene particles. Comprehensive understanding of the intricate process of osteolysis is of utmost importance for future development of therapeutic modalities that may delay or prevent the disease progression.

Osteocyte Remodeling of the Perilacunar and Pericanalicular Matrix

With additional functions of osteocytes being identified, the concept that osteocytes are just ＂static lacunar-dwelling cells＂ is no longer accepted. We reviewed most of the relevant literature on osteocyte＇s function in the direct remodeling of the perilucunar matrix, discussing the advantages and disadvantages. Special attention was paid to how the negative researchers argue about the ＂osteocytic osteolysis＂ principle, and how the positive side addressed the arguments. We also discussed the newly found data of osteocytic remodeling function from our group. With more biotechnology in hand, there is increased excitement in the prospect of now being able to answer the two important questions： do osteocytes have the capability to remove mineral from the perilacunar matrix and if so what are the molecular and cellular mechanisms？ do osteocytes have the capability to deposit new mineral on the perilacunar matrix and if so what are the cellular and molecular mechanisms？

Primary bone anaplastic lymphoma kinase positive anaplastic largecell lymphoma: A case report and review of the literature

BACKGROUND Primary bone lymphoma(PBL)is an uncommon extranodal disease that represents approximately 1%-3%of lymphomas.Anaplastic lymphoma kinase(ALK)positive anaplastic large-cell lymphoma(ALCL)is an extremely rare type of PBL.The aim of this report is describe the symptoms,diagnosis,and treatment of primary bone ALK-positive ALCL.CASE SUMMARY A 66-year-old man presented to our hospital with neck and shoulder pain and intermittent fever that lasted for 1 mo.After extensive evaluation,positron emission tomography-computed tomography(CT)examination showed multiple osteolytic bone lesions without other sites lesions.CT-guided biopsy of the T10 vertebral body was performed,and the pathology results showed that neoplastic cells were positive for ALK-1,CD30,and CD3.A diagnosis of primary bone ALK positive ALCL was ultimately made.The patient was in partial response after four cycle soft cyclophosphamide,doxorubicin,vincristine,and prednisone chemotherapy,and we planned to repeat the biopsy and radiological examination after completion of the fifth cycle of therapy.CONCLUSION Primary bone ALK positive ALCL is a rare disease and physicians should keep in mind that ALCL can present with isolated osseous involvement without nodal involvement,and lymphoma should be considered in the differential diagnosis of primary bone lesions.

Propionate and butyrate attenuate macrophage pyroptosis and osteoclastogenesis induced by CoCrMo alloy particles

Background:Wear particles-induced osteolysis is a major long-term complication after total joint arthroplasty.Up to now,there is no effective treatment for wear particles-induced osteolysis except for the revision surgery,which is a heavy psychological and economic burden to patients.A metabolite of gut microbiota,short chain fatty acids(SCFAs),has been reported to be beneficial for many chronic inflammatory diseases.This study aimed to investigate the therapeutic effect of SCFAs on osteolysis.Methods:A model of inflammatory osteolysis was established by applying CoCrMo alloy particles to mouse calvarium.After two weeks of intervention,the anti-inflammatory effects of SCFAs on wear particle-induced osteolysis were evaluated by micro-CT analysis and immunohistochemistry staining.In vitro study,lipopolysaccharide(LPS)primed bone marrow-derived macrophages(BMDMs)and Tohoku hospital pediatrics-1(THP-1)macrophages were stimulated with CoCrMo particles to activate inflammasome in the presence of acetate(C2),propionate(C3),and butyrate(C4).Western blotting,enzyme-linked immunosorbent assay,and immunofluorescence were used to detect the activation of NLRP3 inflammasome.The effects of SCFAs on osteoclasts were evaluate by qRT-PCR,Western blotting,immunofluorescence,and tartrate-resistant acid phosphatase(TRAP)staining.Additionally,histone deacetylase(HDAC)inhibitors,agonists of GPR41,GPR43,and GPR109A were applied to confirm the underlying mechanism of SCFAs on the inflammasome activation of macrophages and osteoclastogenesis.Results:C3 and C4 but not C2 could alleviate wear particles-induced osteolysis with fewer bone erosion pits(P<0.001),higher level of bone volume to tissue volume(BV/TV,P<0.001),bone mineral density(BMD,P<0.001),and a lower total porosity(P<0.001).C3 and C4 prevented CoCrMo alloy particles-induced ASC speck formation and nucleationinduced oligomerization,suppressing the cleavage of caspase-1(P<0.05)and IL-1β(P<0.05)stimulated by CoCrMo alloy particles.C3 and C4 also inhibited the generation of gasdermin D-N-terminal fragment(GSDMD-NT)to regulate pyroptosis.Besides,C3 and C4 have a negative impact on osteoclast differentiation(P<0.05)and its function(P<0.05),affecting the podosome arrangement and morphologically normal podosome belts formation.Conclusions:Our work showed that C3 and C4 are qualified candidates for the treatment of wear particle-induced osteolysis.

Posterior Positioning of a Clavicle Hook Plate Is a Risk Factor for Acromial Fractures after Acromioclavicular Joint Dislocation

Purpose: Acromioclavicular (AC) joint dislocation is commonly treated using a clavicle hook plate (HP). However, previous reports have indicated that acromial fractures may occur after HP fixation. The purpose of this study was to identify risk factors for acromial fractures. Methods: A retrospective study was conducted on 39 patients with AC joint dislocation who were treated using clavicle HP fixation in our hospital between 2006 and 2017. Related parameters, including Rockwood classification, hook angle, the degree of reduction, the coverage of the hook under the acromion, and the anteroposterior position of the hook under the acromion, were evaluated to identify risk factors for acromial fractures. Results: The mean age of the participants was 51.7 (range 19 - 81) years;34 were men and 5 were women. Injury occurred on the right side in 18 patients and on the left side in 21. Injuries were categorized as follows: 24 were Rockwood type III, one was type IV, and 14 were type V. Four of the 39 patients (10%) experienced acromial fractures. Statistical analyses indicated that the degree of reduction at the final follow-up was moderately correlated with the Constant score. Posterior positioning of the hook was the only identified risk factor for acromial fractures. Hook angle and the degree of reduction at the time of surgery were not significantly associated with acromial fractures. Conclusions: Postoperative shoulder function was associated with the degree of reduction at the final follow-up, suggesting that anatomical reduction is recommended for AC joint dislocation. Posterior positioning of the hook is a risk factor for acromial fractures;however, clavicle HP fixation provides a positive outcome for AC joint dislocation. Therefore, careful positioning of the hook is required for preventing acromial fractures.

Anesthetic Management for a Patient of Gorham’s Syndrome: The Vanishing Bone Disease

Gorham-Stout (GS) syndrome or the vanishing bone disease is a very rare chronic disease characterized by the destruction of the osseous matrix and proliferation of vascular structures. Review of the general anesthesia showed only a few cases till date. We report general anesthesia for tooth extraction in a 21-year-old male patient with Gorham-Stout syndrome. In this case, the most concerning issue was limited mouth opening due to mandible osteolysis and difficult intubation was anticipated. To anticipate difficult airway management, it is very important to consider the preoperative airway assessment including the cervical spine screening. In this case, the McGrath video laryngoscope prevented the anticipated difficult intubation due to the limited mouth opening due to mandible osteolysis.

CD16⁺Monocyte Subsets in Patients with Total Joint Arthroplasty

Objective: There are two monocyte populations in human blood: CD14+CD16- classical monocytes and CD14+CD16+ inflammatory monocytes. CD14+CD16+ inflammatory monocytes, account for approximately 10% of the total monocytes, may be expanded in various types of inflammatory conditions. The purpose of this study was to investigate whether the expansion of the CD14+CD16+ monocyte population represents a risk factor of aseptic loosening (AL). Methods: Peripheral monocytes subsets were measured in revision patients with AL (n = 35) and in patients with stable implants (SI, n = 56). The gene profiles of TNFα, IL-1β, CD16, CD68 and TRAP5B from collected loosening periprosthetic tissues were analyzed. Results: There were no significant differences in the CD14+CD16+ monocyte populations between the SI and AL patients. The CD14+CD16+ monocytes were marginally higher in revision patients with osteolysis (n = 30), compared to patients without osteolysis (n = 5) though no statistically difference was found. There was an association between the CD14+CD16+ monocyte subpopulation and the tissue gene profiles, including IL-1β (p = 0.063), CD68 (p = 0.036), and TRAP5B (p = 0.073). Conclusion: It was demonstrated that the expansion of CD14+CD16+ monocytes reflects, to some extent, the inflammatory status of the loosening periprosthetic tissues. It is unclear if some of those SI patients (no pain and negative radiograph) who have a higher frequency of CD14+CD16+ monocytes may be at the early stage of AL. Further evaluation of CD14+CD16+ monocyte population, independently or combined with other factors, will be useful to design a risk profile for AL incidence and progression.

Repurposing Denosumab to Stabilize Acetabular Protrusio: Obviating Surgery

Intrapelvic prosthetic migration prosthesis following hip arthroplasty can occur due to aseptic loosening, infection, injury and malposition of the cup with chronic instability. Revision surgery is the treatment option, but is often complex, is high risk owing to the co-morbidities of the patient, has higher complications and sometimes even patients refuse for the surgery. Osteoclast mediated bone resorption at the prosthetic bone interface is the main pathophysiology process involved in aseptic loosening associated intrapelvic migration. RANK/RANKL (Receptor Activated Nuclear factor κB Ligand) is the primary pathway responsible for the periprosthetic osteolysis, therefore, we have offered Denosumab which binds to RANKL and inhibits osteoclasts mediated bone resorption, to our two patients with intrapelvic prosthetic migration who have refused for the revision surgery. Here, we report the outcome of these two cases of Intrapelvic prosthetic migration following a hip arthroplasty that was treated using subcutaneous injection of 120 mg denosumab monthly for 3 months. Both the cases had good functional outcomes and radiographs showed good consolidation of bone around the prosthesis. These cases suggest denosumab can be repurposed to arrest further intrapelvic prosthetic migration due to its anti-resorptive and bone forming action and can avoid the need for a complex revision surgery.

Buechel-Pappas Total Ankle Replacement: Use of Highly Cross-Linked Polyethylene Meniscal Bearings over a 13 - 15 Year Interval

Background: The Buechel-Pappas (BP) meniscal bearing total ankle replace-ment was initially developed as a “shallow-sulcus” talar component device using cobalt-chromium-molybdenum alloy, in 1978, and later, modified to a “deep-sulcus” talar component device using titanium nitride (TiN) ceramic and porous coating in 1989. Wear related osteolytic cysts were noted in the tibia and talus surrounding these devices that compromised long term fixation and stability when using standard ultra-high molecular weight polyethylene (UHMWPe) as a bearing material. This study explores the use of highly cross-linked UHMWPe (HXLPe) to minimize osteolysis by replacing standard UHMWPe with this more wear-resistant material. Methods: There were 12 primary and 8 revision total ankle replacements followed for 13 to 15 years. HXLPe was used in all meniscal bearings, either as primary or revision implants. All stable metallic tibial and talar components were retained in revision cases. Osteolytic cysts greater than 10 mm in diameter were bone grafted with homologous morselized banked bone through cortical windows in the tibia or talus. No adjuvant screw fixation was used to stabilize any metallic implant. Results: No HXLPe bearings failed in this study, and no re-revisions were performed. No primary total ankle replacement failed in this study, and there were no substantial osteolytic cysts (>2 mm) observed in primary total ankle replacements on plain X-rays. All bone grafted osteolytic cysts in revision ankle replacements remained stable, even though partial resorption of the grafted material was identified in most of the ankles. No loosening of porous coated and TiN coated tibial and talar components were seen;the longest surviving metal components in the revision group was 24 years with the revised bearing at 15 years. Conclusions: HXLPe has greatly improved wear resistance in meniscal-bearing BP total ankle replacements in both primary and revision arthroplasties. Osteolytic cysts can be successfully bone grafted during bearing exchange revisions. Primary and revision, cementless BP metallic total ankle components have remained well-fixed to bone in the long term (greater than 20 years), without the use of adjuvant screw fixation.

Reduced expression of semaphorin 3A in osteoclasts causes lymphatic expansion in a Gorham-Stout disease(GSD)mouse model

Gorham-Stout disease(GSD)is a sporadic chronic disease characterized by progressive bone dissolution,absorption,and disappearance along with lymphatic vessel infiltration in bone-marrow cavities.Although the osteolytic mechanism of GSD has been widely studied,the cause of lymphatic hyperplasia in GSD is rarely investigated.In this study,by comparing the RNA expression profile of osteoclasts(OCs)with that of OC precursors(OCPs)by RNA sequencing,we identified a new factor,semaphorin 3A(Sema3A),which is an osteoprotective factor involved in the lymphatic expansion of GSD.Compared to OCPs,OCs enhanced the growth,migration,and tube formation of lymphatic endothelial cells(LECs),in which the expression of Sema3A is low compared to that in OCPs.In the presence of recombinant Sema3A,the growth,migration,and tube formation of LECs were inhibited,further confirming the inhibitory effect of Sema3A on LECs in vitro.Using an LEC-induced GSD mouse model,the effect of Sema3A was examined by injecting lentivirus-expressing Sema3A into the tibiae in vivo.We found that the overexpression of Sema3A in tibiae suppressed the expansion of LECs and alleviated bone loss,whereas the injection of lentivirus expressing Sema3A short hairpin RNA(shRNA)into the tibiae caused GSD-like phenotypes.Histological staining further demonstrated that OCs decreased and osteocalcin increased after Sema3A lentiviral treatment,compared with the control.Based on the above results,we propose that reduced Sema3A in OCs is one of the mechanisms contributing to the pathogeneses of GSD and that expressing Sema3A represents a new approach for the treatment of GSD.

Macrophage polarization in response to wear particles in vitro

Total joint replacement is a highly successful surgical procedure for treatment of patients with disabling arthritis and joint dysfunction. However, over time, with high levels of activity and usage of the joint, implant wear particles are generated from the articulating surfaces. These wear particles can lead to activation of an inflammatory reaction, and subsequent bone resorption around the implant （periprosthetic osteolysis）. Cells of the monocyte/macrophage lineage orchestrate this chronic inflammatory response, which is dominated by a pro-inflammatory （M 1） macrophage phenotype rather than an anti-inflammatory pro-tissue healing （M2） macrophage phenotype. While it has been shown that interleukin-4 （IL-4） selectively polarizes macrophages towards an M2 anti-inflammatory phenotype which promotes bone healing, rather than inflammation, little is known about the time course in which this occurs or conditions in which repolarization through I L-4 is most effective. The goal of this work was to study the time course of murine macrophage polarization and cytokine release in response to challenge with combinations of polymethyl methacrylate （PMMA） particles, lipopolysaccharide （LPS） and IL-4 in vitro. Treatment of particle-challenged monocyte/macrophages with IL-4 led to an initial suppression of pro-inflammatory cytokines and inducible nitric oxide synthase （iNOS） production and subsequent polarization into an M2 anti-inflammatory phenotype. This result was optimized when IL-4 was delivered before PMMA particle challenge, to an M 1 phenotype rather than to uncommitted （MO） macrophages. The effects of this polarization were sustained over a 5-day time course. Polarization of M1 macrophages into an M2 phenotype may be a strategy to mitigate wear particle associated periprosthetic osteolysis.

Zinc alloy-based bone internal fixation screw with antibacterial and anti-osteolytic properties

There is no targeted effective treatment for patients undergoing internal fixation surgery/two-stage total joint revision surgery with a high risk of postoperative infection and osteolysis,while the rate of reoperation due to infection and osteolysis remains high.In this study,we report a pioneering application of implants made of biodegradable Zn-Ag alloy with active antibacterial and anti-osteolytic properties in three classical animal models,illustrating antibacterial,anti-osteolysis,and internal fixation for fractures.The antibacterial activity of the Zn-2Ag alloy was verified in a rat femur osteomyelitis prevention model,while the anti-osteolytic properties were evaluated using a mouse cranial osteolysis model.Moreover,the Zn-2Ag based screws showed similar performance in bone fracture fixation compared to the Ti-6Al-4V counterpart.The fracture healed completely after 3 months in the rabbit femoral condyle fracture model.Furthermore,the underlying antibacterial mechanism may include inhibition of biofilm formation,autolysis-related pathways,and antibiotic resistance pathways.Osseointegration mechanisms may include inhibition of osteoclast-associated protein expression,no effect on osteogenic protein expression,and no activation of related inflammatory protein expression.The empirical findings here reveal the great potential of Zn-Ag-based alloys for degradable biomaterials in internal fixation surgery/two-stage total joint revision surgery for patients with a high risk of postoperative infection and osteolysis.