Proximal Femur Bionic Nail (PFBN): A Panacea for Unstable Intertrochanteric Femur Fracture

With the aging population,intertrochanteric femur fracture in the elderly has become one of the most serious public health issues and a hot topic of research in trauma orthopedics.Due to the limitations of internal fixation techniques and the insufficient mechanical design of nails,the occurrence of complications delays patient recovery after surgical treatment.Design of a proximal femur bionic nail(PFBN)based on Zhang’s N triangle theory provides triangular supporting fixation,which dramatically decreases the occurrence of complications and has been widely used for clinical treatment of unstable intertrochanteric femur fracture worldwide.In this work,we developed an equivalent biomechanical model to analyze improvement in bone remodeling of unstable intertrochanteric femur fracture through PFBN use.The results show that compared with proximal femoral nail antirotation(PFNA)and InterTan,PFBN can dramatically decrease the maximum strain in the proximal femur.Based on Frost’s mechanostat theory,the local mechanical environment in the proximal femur can be regulated into the medium overload region by using a PFBN,which may render the proximal femur in a state of physiological overload,favoring post-operative recovery of intertrochanteric femur fracture in the elderly.This work shows that PFBN may constitute a panacea for unstable intertrochanteric femur fracture and provides insights into improving methods of internal fixation.

Characterizing the tumor microenvironment at the single-cell level reveals a novel immune evasion mechanism in osteosarcoma

The immune microenvironment extensively participates in tumorigenesis as well as progression in osteosarcoma(OS).However,the landscape and dynamics of immune cells in OS are poorly characterized.By analyzing single-cell RNA sequencing(sc RNA-seq)data,which characterize the transcription state at single-cell resolution,we produced an atlas of the immune microenvironment in OS.The results suggested that a cluster of regulatory dendritic cells(DCs)might shape the immunosuppressive microenvironment in OS by recruiting regulatory T cells.We also found that major histocompatibility complex class I(MHC-I)molecules were downregulated in cancer cells.The findings indicated a reduction in tumor immunogenicity in OS,which can be a potential mechanism of tumor immune escape.Of note,CD24 was identified as a novel“don’t eat me”signal that contributed to the immune evasion of OS cells.Altogether,our findings provide insights into the immune landscape of OS,suggesting that myeloid-targeted immunotherapy could be a promising approach to treat OS.

Single-cell RNA sequencing in orthopedic research

Although previous RNA sequencing methods have been widely used in orthopedic research and have provided ideas for therapeutic strategies,the specific mechanisms of some orthopedic disorders,including osteoarthritis,lumbar disc herniation,rheumatoid arthritis,fractures,tendon injuries,spinal cord injury,heterotopic ossification,and osteosarcoma,require further elucidation.The emergence of the single-cell RNA sequencing(sc RNA-seq)technique has introduced a new era of research on these topics,as this method provides information regarding cellular heterogeneity,new cell subtypes,functions of novel subclusters,potential molecular mechanisms,cell-fate transitions,and cell-cell interactions that are involved in the development of orthopedic diseases.Here,we summarize the cell subpopulations,genes,and underlying mechanisms involved in the development of orthopedic diseases identified by sc RNA-seq,improving our understanding of the pathology of these diseases and providing new insights into therapeutic approaches.

Electric stimulation and decimeter wave therapy improve the recovery of injured sciatic nerves

Drug treatment, electric stimulation and decimeter wave therapy have been shown to promote the repair and regeneration of the peripheral nerves at the injured site. This study prepared a Mackinnon’s model of rat sciatic nerve compression. Electric stimulation was given immediately after neurolysis, and decimeter wave radiation was performed at 1 and 12 weeks post-operation. Histological observation revealed that intraoperative electric stimulation and decimeter wave therapy could improve the local blood circulation of repaired sites, alleviate hypoxia of compressed nerves, and lessen adhesion of compressed nerves, thereby decreasing the formation of new entrapments and enhancing compressed nerve regeneration through an improved microenvironment for regeneration. Immunohistochemical staining results revealed that intraoperative electric stimulation and decimeter wave could promote the expression of S-100 protein. Motor nerve conduction velocity and amplitude, the number and diameter of myelinated nerve fibers, and sciatic functional index were significantly increased in the treated rats. These results verified that intraoperative electric stimulation and decimeter wave therapy contributed to the regeneration and the recovery of the functions in the compressed nerves.

Hypoxia endothelial cells-derived exosomes facilitate diabetic wound healing through improving endothelial cell function and promoting M2 macrophages polarization

It is imperative to develop and implement newer,more effective strategies to address refractory diabetic wounds.As of now,there is currently no optimal solution for these wounds.Hypoxic human umbilical vein endothelial cells(HUVECs)-derived exosomes have been postulated to promote diabetic wound healing,however,its effect and molecular mechanism need further study.In this study,we aimed to investigate whether hypoxic exosomes enhance wound healing in diabetics.Based on our high-throughput sequencing,differentially expressed lncRNAs(including 64 upregulated lncRNAs and 94 downregulated lncRNAs)were found in hypoxic exosomes compared to normoxic exosomes.Interestingly,lncHAR1B was one of the prominently upregulated lncRNAs in hypoxic exosomes,showing a notable correlation with diabetic wound healing.More specifically,hypoxic exosomes were transmitted to surrounding cells,which resulted in a significant increase in lncHAR1B level,thereby relieving the dysfunction of endothelial cells and promoting the switch from M1 to M2 macrophages under high glucose conditions.Mechanistically,lncHAR1B directly interacted with the transcription factor basic helix-loop-helix family member e23(BHLHE23),which subsequently led to its binding to the KLF transcription factor 4(KLF4)and promoted KLF4 expression.In our in vivo experiments,the use of hypoxic exosomes-loaded HGM-QCS hydrogels(Gel-H-Exos)resulted in rapid wound healing compared to that of normoxic exosomes-loaded HGM-QCS hydrogels(Gel-N-Exos)and diabetic groups.Consequently,our study provides potentially novel therapeutic approaches aimed at accelerating wound healing and developing a practical exosomes delivery platform.

Micro femoral head prosthesis in applications to collapsed femoral head necrosis in the weight-bearing dome(ARCO III):A case series with short-term follow-up

Osteonecrosis of the femoral head(ONFH)is mainly caused by a decrease in the vascular supply to the subchondral bone of the femoral head,leading to the death of bone cells,degeneration and necrosis of the subchondral bone,and eventually collapse of the femoral head.^([1])Early and accurate diagnosis is the key to successful hip-preserving therapy,and the size/location of necrosis is the main determinant for ONFH treatment.Previous studies have shown that many hip-preserving therapies achieved satisfactory results in ONFH patients with Association Research Circulation Osseous(ARCO)I–II.When ONFH progresses to ARCO IV with clinical manifestations of osteoarthrosis,total hip arthroplasty(THA)may be the only option.

A fully-fluorinated all-fused-ring acceptor for highly sensitive near-infrared organic photodetectors

Organic semiconductors play a pivotal role in the development of various organic opto-electronic devices, encompassing organic light-emitting diodes (OLEDs), organic field-effect transistors(OFETs), organic solar cells (OSCs), organic photodetectors (OPDs),etc.[1]. Material scientists continually refine the chemical structures of organic semiconductors to optimize their opto-electronic properties and thin film morphology, thereby enhancing device performance [2]. Among the diverse array of functional groups available for modification, fluorine stands out due to its minimal atomic radius and maximal electronegativity.

Clinical guidelines for indications,techniques,and complications of autogenous bone grafting

Autogenous bone grafts have long been considered the“gold standard”and most effective material in bone regeneration procedures.[1]Autogenous bone grafts are used to repair bone defects caused by nonunion,infection,tumor resection,and spinal and joint fusion.[2]It has been reported that more than 200,000 autologous bone grafts are performed in the United States each year.[3]Although there are no specific statistics on the annual number of bone grafts performed in China,autologous bone grafting is the most common surgical technique in orthopedics.The iliac crest remains the most common donor site,along with the fibula,ribs,tibial metaphysis,proximal humerus,distal radius,and greater trochanter.[4,5]Various bone-graft options provide different amounts and qualities of cortical,cancellous,and corticocancellous bone.[6,7]Autogenous bone graft is osteogenic,histocompatible,provides structural support.

Total hip arthroplasty after core decompression:Time-to-event analysis and risk factors

To the Editor:Core decompression(CD),the predominant hip-preserving procedure for pre-collapse osteonecrosis of the femoral head(ONFH),is renowned for its improved short-term outcomes and relatively low postoperative complication rates;however,the reported medium-tolong-term survival rates in the literature vary and are a subject of controversy.Consequently,we conducted a large,prospective cohort study to assess the frequency and timing of conversion from CD to total hip arthroplasty(THA)and the factors associated with it.

Bone-targeting engineered small extracellular vesicles carrying anti-miR-6359-CGGGAGC prevent valproic acid-induced bone loss

The clinical role and underlying mechanisms of valproic acid(VPA)on bone homeostasis remain controversial.Herein,we confirmed that VPA treatment was associated with decreased bone mass and bone mineral density(BMD)in both patients and mice.This effect was attributed to VPA-induced elevation in osteoclast formation and activity.Through RNA-sequencing,we observed a significant rise in precursor miR-6359 expression in VPA-treated osteoclast precursors in vitro,and further,a marked upregulation of mature miR-6359(miR-6359)in vivo was demonstrated using quantitative real-time PCR(qRT-PCR)and miR-6359 fluorescent in situ hybridization(miR-6359-FISH).Specifically,the miR-6359 was predominantly increased in osteoclast precursors and macrophages but not in neutrophils,T lymphocytes,monocytes and bone marrow-derived mesenchymal stem cells(BMSCs)following VPA stimulation,which influenced osteoclast differentiation and bone-resorptive activity.Additionally,VPA-induced miR-6359 enrichment in osteoclast precursors enhanced reactive oxygen species(ROS)production by silencing the SIRT3 protein expression,followed by activation of the MAPK signaling pathway,which enhanced osteoclast formation and activity,thereby accelerating bone loss.Currently,there are no medications that can effectively treat VPA-induced bone loss.Therefore,we constructed engineered small extracellular vesicles(E-sEVs)targeting osteoclast precursors in bone and naturally carrying anti-miR-6359 by introducing of EXOmotif(CGGGAGC)in the 3’-end of the anti-miR-6359 sequence.We confirmed that the E-sEVs exhibited decent bone/osteoclast precursor targeting and exerted protective therapeutic effects on VPA-induced bone loss,but not on ovariectomy(OVX)and glucocorticoid-induced osteoporotic models,deepening our understanding of the underlying mechanism and treatment strategies for VPA-induced bone loss.

Traumatic brain injury stimulates sympathetic tone-mediated bone marrow myelopoiesis to favor fracture healing

Traumatic brain injury(TBI)accelerates fracture healing,but the underlying mechanism remains largely unknown.Accumulating evidence indicates that the central nervous system(CNS)plays a pivotal role in regulating immune system and skeletal homeostasis.However,the impact of CNS injury on hematopoiesis commitment was overlooked.Here,we found that the dramatically elevated sympathetic tone accompanied with TBI-accelerated fracture healing;chemical sympathectomy blocks TBIinduced fracture healing.TBI-induced hypersensitivity of adrenergic signaling promotes the proliferation of bone marrow hematopoietic stem cells(HSCs)and swiftly skews HSCs toward anti-inflammation myeloid cells within 14 days,which favor fracture healing.Knockout ofβ3-orβ2-adrenergic receptor(AR)eliminate TBI-mediated anti-inflammation macrophage expansion and TBIaccelerated fracture healing.RNA sequencing of bone marrow cells revealed that Adrb2 and Adrb3 maintain proliferation and commitment of immune cells.Importantly,flow cytometry confirmed that deletion ofβ2-AR inhibits M2 polarization of macrophages at 7th day and 14th day;and TBI-induced HSCs proliferation was impaired inβ3-AR knockout mice.Moreover,β3-andβ2-AR agonists synergistically promote infiltration of M2 macrophages in callus and accelerate bone healing process.Thus,we conclude that TBI accelerates bone formation during early stage of fracture healing process by shaping the anti-inflammation environment in the bone marrow.These results implicate that the adrenergic signals could serve as potential targets for fracture management.

“Genetic scissors”CRISPR/Cas9 genome editing cutting-edge biocarrier technology for bone and cartilage repair

CRISPR/Cas9 is a revolutionary genome editing technology with the tremendous advantages such as precisely targeting/shearing ability,low cost and convenient operation,becoming an efficient and indispensable tool in biological research.As a disruptive technique,CRISPR/Cas9 genome editing has a great potential to realize a future breakthrough in the clinical bone and cartilage repairing as well.This review highlights the research status of CRISPR/Cas9 system in bone and cartilage repair,illustrates its mechanism for promoting osteogenesis and chondrogenesis,and explores the development tendency of CRISPR/Cas9 in bone and cartilage repair to overcome the current limitations.

In Situ-Activated Phospholipid-Mimic Artemisinin Prodrug via Injectable Hydrogel Nano/Microsphere for Rheumatoid Arthritis Therapy

In situ-activated therapy is a decent option for localized diseases with improved efficacies and reduced side effects,which is heavily dependent on the local conversion or activation of bioinert components.In this work,we applied a phospholipid-mimic artemisinin prodrug(ARP)for preparing an injectable nano/microsphere to first realize an in situ-activated therapy of the typical systemically administrated artemisinin-based medicines for a localized rheumatoid arthritis(RA)lesion.ARP is simultaneously an alternative of phospholipids and an enzyme-independent activable prodrug,which can formulate“drug-in-drug”co-delivery liposomes with cargo of partner drugs(e.g.,methotrexate).To further stabilize ARP/methotrexate“drug-in-drug”liposomes(MTX/ARPL)for a long-term intra-articular retention,a liposome-embedded hydrogel nano/microsphere(MTX/ARPL@MS)was prepared.After the local injection,the MTX/ARPL could be slowly released because of imine hydrolysis and targeted to RA synovial macrophages and fibroblasts simultaneously.ARP assembly is relatively stable before cellular internalization but disassembled ARP after lysosomal escape and converted into dihydroartemisinin rapidly to realize the effective in situ activation.Taken together,phospholipid-mimic ARP was applied for the firstly localized in situ-activated RA therapy of artemisinin-based drugs,which also provided a brand-new phospholipid-mimic strategy for other systemically administrated prodrugs to realize a remodeling therapeutic schedule for localized diseases.

An n-Type All-Fused-Ring Molecule with Narrow Bandgap

All-fused-ringπ-conjugated molecules have received considerable attention because of their unique electronic structures,low conformation disorder,and excellent optoelectronic properties.Most all-fused-ring molecules are p-type organic semiconductors and possess medium bandgaps.In this work,we design and synthesize an all-fused-ring molecule(FM1)with an n-type property and narrow bandgap,which is a 10-fused-ring system composed of one electrondeficient benzotriazole core,two electron-rich thienopyrrole bridging units,and two electron-deficient malononitrile-functionalized end-cappers.FM1 exhibits low-lying highest occupied molecular orbit/lowest unoccupied molecular orbit energy levels of−5.77 eV/−3.89 eV,high electron mobility of 6.0×10^(−4)cm^(2)V^(−1)s^(−1),an optical bandgap of 1.50 eV,and a maximum absorption wavelength of 769nm.Because of the all-fused-ring skeleton,FM1 shows superior photostability and chemical stability.We use FM1 as an electron acceptor and successfully construct organic solar cell(OSC)devices with a decent power conversion efficiency(PCE)of 10.8%.Most importantly,the intrinsic stability of FM1 leads to its excellent OSC device stability.After irradiation with simulated solar light for 16 h,while control of the OSC device of the state-of-the-art small molecule electron acceptor shows a 46%decrease of PCE,the FM1’s unencapsulated OSC device exhibits only a 9%decrease of PCE.

National incidence of joint dislocation in China:a retrospective survey of 512,187 individuals

Background:Joint dislocations significantly impact public health.However,a comprehensive study on the incidence,distribution,and risk factors for joint dislocations in China is lacking.We conducted the China National Joint Dislocation Study,which is a part of the China National Fracture Study conducted to obtain the national incidence and risk factors for traumatic fractures,and to investigate the incidence and risk factors for joint dislocations.Methods:For this national retrospective epidemiological study,512,187 participants were recruited using stratified random sampling and probability-proportional-to-size method from January 19 to May 16,2015.Participants who sustained joint dislocations of the trunk,arms,or legs(skull,sternum,and ribs being excluded)in 2014 were personally interviewed to obtain data on age,educational background,ethnic origin,occupation,geographic region,and urbanization degree.The joint-dislocation incidence was calculated based on age,sex,body site,and demographic factors.The risk factors for different groups were examined using multiple logistic regression.Results:One hundred and nineteen participants sustained 121 joint dislocations in 2014.The population-weighted incidence rate of joint dislocations of the trunk,arms,or legs was 0.22(95%confidence interval[CI]:0.16,0.27)per 1000 population in 2014(men,0.27[0.20,0.34];women,0.16[0.10,0.23]).For all ages,previous dislocation history(male:OR 42.33,95%confidence interval[CI]:12.03-148.90;female:OR 54.43,95%CI:17.37-170.50)and alcohol consumption(male:OR 3.50,95%CI:1.49-8.22;female:OR 2.65,95%CI:1.08-6.50)were risk factors for joint dislocation.Sleeping less than 7 h/day was a risk factor for men.Compared with children,women aged≥15 years(female 15-64 years:OR 0.16,95%CI:0.04-0.61;female≥65 years:OR 0.06,95%CI:0.01-0.41)were less likely to sustain joint dislocations.Women with more than three children were at higher dislocation risk than women without children(OR 6.92,95%CI:1.18-40.78).Conclusions:The up-to-date data on joint dislocation incidence,distribution,and risk factors can be used as a reference for national healthcare,prevention,and management in China.Specific strategies for decreasing alcohol consumption and encouraging adequate sleeping hours should be developed to prevent or reduce dislocation incidents.Trial Registration:Chinese Clinical Trial Registry,ChiCTR-EPR-15005878.