The key to managing fracture is to achieve stable internal fixation,and currently,biologically and mechanically appropriate internal fixation devices are urgently needed.With excellent biocompatibility and corrosion r...The key to managing fracture is to achieve stable internal fixation,and currently,biologically and mechanically appropriate internal fixation devices are urgently needed.With excellent biocompatibility and corrosion resistance,titanium–niobium alloys have the potential to become a new generation of internal fixation materials for fractures.However,the role and mechanism of titanium–niobium alloys on promoting fracture healing are still undefined.Therefore,in this study,we systematically evaluated the bone-enabling properties of Ti45Nb via in vivo and in vitro experiments.In vitro,we found that Ti45Nb has an excellent ability to promote MC3T3-E1 cell adhesion and proliferation without obvious cytotoxicity.Alkaline phosphatase(ALP)activity and alizarin red staining and semiquantitative analysis showed that Ti45Nb enhanced the osteogenic differentiation of MC3T3-E1 cells compared to the Ti6Al4V control.In the polymerase chain reaction experiment,the expression of osteogenic genes in the Ti45Nb group,such as ALP,osteopontin(OPN),osteocalcin(OCN),type 1 collagen(Col-1)and runt-related transcription factor-2(Runx2),was significantly higher than that in the control group.Meanwhile,in the western blot experiment,the expression of osteogenic-related proteins in the Ti45Nb group was significantly increased,and the expression of PI3K–Akt-related proteins was also higher,which indicated that Ti45Nb might promote fracture healing by activating the PI3K–Akt signaling pathway.In vivo,we found that Ti45Nb implants accelerated fracture healing compared to Ti6Al4V,and the biosafety of Ti45Nb was confirmed by histological evaluation.Furthermore,immunohistochemical staining confirmed that Ti45Nb may promote osteogenesis by upregulating the PI3K/Akt signaling pathway.Our study demonstrated that Ti45Nb exerts an excellent ability to promote fracture healing as well as enhance osteoblast differentiation by activating the PI3K/Akt signaling pathway,and its good biosafety has been confirmed,which indicates its clinical translation potential.展开更多
This paper describes an experimental study about magnetic stimulation (MS) effects on the fracture healing of 120 fresh fractures and their blood biochemical parameters during their recovery. The mechanism of promotin...This paper describes an experimental study about magnetic stimulation (MS) effects on the fracture healing of 120 fresh fractures and their blood biochemical parameters during their recovery. The mechanism of promoting the recovering process by MS is discussed and analysed. The experiments show that MS can advance calcium deposit on fractured bones and metabolism of calcium and phosphorus, which promote the process of fracture healing.展开更多
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 rec...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展开更多
Bone fracture non-unions, the failure of a fracture to heal, occur in 10%-20% of fractures and are a costly and debilitating clinical problem. The Wnt/fl-catenin pathway is critical in bone development and fracture he...Bone fracture non-unions, the failure of a fracture to heal, occur in 10%-20% of fractures and are a costly and debilitating clinical problem. The Wnt/fl-catenin pathway is critical in bone development and fracture healing. Polymorphisms of linking low-density lipoprotein receptor-related protein 6 （LRP6）, a Wnt-binding receptor, have been associated with decreased bone mineral density and fragility fractures, although this remains controversial. Mice with a homozygous deletion of Lrp6 have severe skeletal abnormalities and are not viable, whereas mice with a heterozygous deletion have a combinatory effect with Lrp5 to decrease bone mineral density. As fracture healing closely models embryonic skeletal development, we investigated the process of fracture healing in mice heterozygous for Lrp6 （Lrp6~/-） and hypothesized that the heterozygous deletion of Lrp6 would impair fracture healing. Mid-diaphyseal femur fractures were induced in Lrp6~^- mice and wild-type controls （Lrp6~/~）. Fractures were analyzed using micro-computed tomography （~CT） scans, biomechanical testing, and histological analysis. Lrp6~/- mice had significantly decreased stiffness and strength at 28 days post fracture （PF） and significantly decreased BV/TV, total density, immature bone density, and mature area within the callus on day-14 and -21 PF; they had significantly increased empty callus area at days 14 and 21 PF. Our results demonstrate that the heterozygous deletion of Lrp6 impairs fracture healing, which suggests that Lrp6 has a role in fracture healing.展开更多
In vertebrates,bone is considered an osteoimmune system which encompasses functions of a locomotive organ,a mineral reservoir,a hormonal organ,a stem cell pool and a cradle for immune cells.This osteoimmune system is ...In vertebrates,bone is considered an osteoimmune system which encompasses functions of a locomotive organ,a mineral reservoir,a hormonal organ,a stem cell pool and a cradle for immune cells.This osteoimmune system is based on cooperatively acting bone and immune cells,cohabitating within the bone marrow.They are highly interdependent,a fact that is confounded by shared progenitors,mediators,and signaling pathways.Successful fracture healing requires the participation of all the precursors,immune and bone cells found in the osteoimmune system.Recent evidence demonstrated that changes of the immune cell composition and function may negatively influence bone healing.In this review,first the interplay between different immune cell types and osteoprogenitor cells will be elaborated more closely.The separate paragraphs focus on the specific cell types,starting with the cells of the innate immune response followed by cells of the adaptive immune response,and the complement system as mediator between them.Finally,a brief overview on the challenges of preclinical testing of immunebased therapeutic strategies to support fracture healing will be given.展开更多
BACKGROUND There is still no consensus on which concentration of mesenchymal stem cells(MSCs)to use for promoting fracture healing in a rat model of long bone fracture.AIM To assess the optimal concentration of MSCs f...BACKGROUND There is still no consensus on which concentration of mesenchymal stem cells(MSCs)to use for promoting fracture healing in a rat model of long bone fracture.AIM To assess the optimal concentration of MSCs for promoting fracture healing in a rat model.METHODS Wistar rats were divided into four groups according to MSC concentrations:Normal saline(C),2.5×10^(6)(L),5.0×10^(6)(M),and 10.0×10^(6)(H)groups.The MSCs were injected directly into the fracture site.The rats were sacrificed at 2 and 6 wk post-fracture.New bone formation[bone volume(BV)and percentage BV(PBV)]was evaluated using micro-computed tomography(CT).Histological analysis was performed to evaluate fracture healing score.The protein expression of factors related to MSC migration[stromal cell-derived factor 1(SDF-1),transforming growth factor-beta 1(TGF-β1)]and angiogenesis[vascular endothelial growth factor(VEGF)]was evaluated using western blot analysis.The expression of cytokines associated with osteogenesis[bone morphogenetic protein-2(BMP-2),TGF-β1 and VEGF]was evaluated using real-time polymerase chain reaction.RESULTS Micro-CT showed that BV and PBV was significantly increased in groups M and H compared to that in group C at 6 wk post-fracture(P=0.040,P=0.009;P=0.004,P=0.001,respectively).Significantly more cartilaginous tissue and immature bone were formed in groups M and H than in group C at 2 and 6 wk post-fracture(P=0.018,P=0.010;P=0.032,P=0.050,respectively).At 2 wk post fracture,SDF-1,TGF-β1 and VEGF expression were significantly higher in groups M and H than in group L(P=0.031,P=0.014;P<0.001,P<0.001;P=0.025,P<0.001,respectively).BMP-2 and VEGF expression were significantly higher in groups M and H than in group C at 6 wk postfracture(P=0.037,P=0.038;P=0.021,P=0.010).Compared to group L,TGF-β1 expression was significantly higher in groups H(P=0.016).There were no significant differences in expression levels of chemokines related to MSC migration,angiogenesis and cytokines associated with osteogenesis between M and H groups at 2 and 6 wk post-fracture.CONCLUSION The administration of at least 5.0×10^(6)MSCs was optimal to promote fracture healing in a rat model of long bone fractures.展开更多
A first order system model is proposed for simulating the influence of stress stimulation on fracture strength during fracture healing. To validate the model, the diaphyses of bilateral tibiae in 70 New Zealand rabbit...A first order system model is proposed for simulating the influence of stress stimulation on fracture strength during fracture healing. To validate the model, the diaphyses of bilateral tibiae in 70 New Zealand rabbits were osteotomized and fixed with rigid plates and stress-relaxation plates, respectively. Stress shielding rate and ultimate bending strength of the healing bone were measured at 2 to 48 weeks postoperatively. Ratios of stress stimulation and fracture strength of the healing bone to those of intact bone were taken as the system input and output. The assumed first order system model can approximate the experimental data on fracture strength from the input of stress stimulation over time, both for the rigid plate group and the stress-relaxation plate group, with different system parameters of time constant and gain. The fitting curve indicates that the effect of mechanical stimulus occurs mainly in late stages of healing. First order system can model the stress adaptation process of fracture healing. This approach presents a simple bio-mathematical model of the relationship between stress stimulation and fracture strength, and has the potential to optimize planning of functional exercises and conduct parametric studies.展开更多
Summary: In order to investigate the effect of a new institute-designed absorbable hydroxyapatite microparticles/poly-DL-lactide (HA/PDLLA) fracture fixation devices on experimental fracture healing, 25 rabbits with a...Summary: In order to investigate the effect of a new institute-designed absorbable hydroxyapatite microparticles/poly-DL-lactide (HA/PDLLA) fracture fixation devices on experimental fracture healing, 25 rabbits with a transverse transcondylar osteotomy of the distal femur were fixed in- tramedullary by a HA/PDLLA rod (4. 5 mm in diameter, 30-40 mm in length). The follow-up time lasted 1, 2, 4, 6 and 12 week(s). Roentgenographic, histological and ultrastructural analyses were conducted. The results showed that all osteotomies united within 6 weeks without delay. No accumulation of inflammatory cells was seen. Ultrastructural studies showed that polymorphonuclear neutrophils and macrophages were observed mainly at the 1st week, but only few were noted at the 2nd week. The inflammatory and debridement stages were not prolonged. Large amount of active fibroblasts and some chondroblasts were observed at the 2nd week, suggesting a fibrous callus stage. The main cellularity at 4th week was osteoblasts and osteocytes. Part of osteocytes had already entered the static stage at the 6th week. Our experiment showed that the HA/PDLLA had good biocompatibility, sufficient mechanical strength and caused no delay to the fracture healing.展开更多
AIM： To examine whether vitamin D is of potential relevance in the healing process of fractures. METHODS： The present narrative review examined the bulk of the evidence based literature on the topic of vitamin D and...AIM： To examine whether vitamin D is of potential relevance in the healing process of fractures. METHODS： The present narrative review examined the bulk of the evidence based literature on the topic of vitamin D and bone healing in key electronic data bases from 1980 onwards using the terms vitamin D and bone healing, callus, fracture healing. All data were examined carefully and categorized according to type of study. A summary of the diverse terms and approaches employed in the research, as well as the rationale for hypothesizing vitamin D has a role in fracture healing was detailed.RESULTS： The results show very few human studies have been conducted to examine if vitamin D is effective at promoting post fracture healing, and the different ani-mal models that have been studied provide no consensus on this topic. The terms used in the related literature, as well as the methods used to arrive at conclusions on this clinical issue are highly diverse, there is no standardization of either of these important terms and methodolo-gies, hence no conclusive statements or clinical guide-lines can be forthcoming. There is a strong rational for continuing to examine if vitamin D supplements should be administered post-fracture, and ample evidence vitamin D is an essential hormone for functioning in general, as well as bone health and muscle as this relates to bone density.CONCLUSION： Whether those with low vitamin D levels can beneft from supplements if their nutritional practices do not cover recommended daily amounts, remains in question.展开更多
Objective:To study the effects of Shang Ke Jie Gu tablet on fracture healing in rabbits.Methods:40 New Zealand rabbits,half male and half female,were randomly divided into two groups:normal saline group(N group)and Sh...Objective:To study the effects of Shang Ke Jie Gu tablet on fracture healing in rabbits.Methods:40 New Zealand rabbits,half male and half female,were randomly divided into two groups:normal saline group(N group)and Shang Ke Jie Gu tablet group(S group).Each group consisted of 20 rabbits.Left radial fracture models in upper and middle sections were made in rabbits and then intra-gastric administration was given.Five rabbits in each group were killed on the 10 th,20^(th),30^(th) and 40^(th) day after surgery,left radius was taken to get an X-ray.The degree of healing was assessed by the evaluation criteria of Shanghai Orthopaedics Institute.Results:The degree of fracture healing in S group was higher in the comparison with that in N group.Conclusions:Shang Ke Jie Gu tablet might affect endochondral ossification during fracture healing of rabbits,and promote porosis and fracture healing.展开更多
To investigate the impact of different kinds of nerve injuries of early-stage fracture healing.Methods Three groups of rats were included in the experiment among which group 1 was inflicted with femoral fracture and T...To investigate the impact of different kinds of nerve injuries of early-stage fracture healing.Methods Three groups of rats were included in the experiment among which group 1 was inflicted with femoral fracture and T10 spinal cord transsection (SCI),group 2 was inflicted with femoral and peripheral nerve resection (PNR),and group 3 with simple femoral fracture as control group.Two weeks after operation the femoral bones were collected for X-ray checking and 2 more weeks later X-ray checking was performed again followed by pathomorphologic exams.Results X-ray result showed no massive calluses in the bones in the 2nd week postoperatively,while in the 4th week,callus appeared with larger size in group 3 than that of group 1 and with smaller size than that of group 2.It was the same with the result of pathomorphologic examining.Cortical bone bridges between fracture point and osteiod were also found in group 2 and there were less normal blood vessels and worse bone remodeling than that of group 3.There were relatively immature calluses with more fibroblast-like cells and disordered bone structure in group 2.Group 3 showed normal healing process and callus structure.Conclusion Early-stage bone fracture healing can be influenced significantly by different kinds of nerve injuries.6 refs,6 figs.展开更多
The bone fracture cases have been increasing yearly,accompanied by the increased number of patients experiencing non-union or delayed union after their bone fracture.Although clinical materials facilitate fracture hea...The bone fracture cases have been increasing yearly,accompanied by the increased number of patients experiencing non-union or delayed union after their bone fracture.Although clinical materials facilitate fracture healing(e.g.,metallic and composite materials),they cannot fulfill the requirements due to the slow degradation rate,limited osteogenic activity,inadequate osseointegration ability,and suboptimal mechanical properties.Since early 2000,nanomaterials successfully mimic the nanoscale features of bones and offer unique properties,receiving extensive attention.This paper reviews the achievements of nanomaterials in treating bone fracture(e.g.,the intrinsic properties of nanomaterials,nanomaterials for bone defect filling,and nanoscale drug delivery systems in treating fracture delayed union).Furthermore,we discuss the perspectives on the challenges and future directions of developing nanomaterials to accelerate fracture healing.展开更多
Regulatory T cells(Tregs)suppress immune responses and inflammation.Here,we described the distinct nonimmunological role of Tregs in fracture healing.The recruitment from the circulation pool,peripheral induction,and ...Regulatory T cells(Tregs)suppress immune responses and inflammation.Here,we described the distinct nonimmunological role of Tregs in fracture healing.The recruitment from the circulation pool,peripheral induction,and local expansion rapidly enriched Tregs in the injured bone.The Tregs in the injured bone displayed superiority in direct osteogenesis over Tregs from lymphoid organs.Punctual depletion of Tregs compromised the fracture healing process,which leads to increased bone nonunion.In addition,bone callus Tregs showed unique T-cell receptor repertoires.Amphiregulin was the most overexpressed protein in bone callus Tregs,and it can directly facilitate the proliferation and differentiation of osteogenic precursor cells by activation of phosphatidylinositol 3-kinase/protein kinase B signaling pathways.The results of loss-and gain-function studies further evidenced that amphiregulin can reverse the compromised healing caused by Treg dysfunction.Tregs also enriched in patient bone callus and amphiregulin can promote the osteogenesis of human pre-osteoblastic cells.Our findings indicate the distinct and nonredundant role of Tregs in fracture healing,which will provide a new therapeutic target and strategy in the clinical treatment of fractures.展开更多
As a common clinical disease, fracture is often accompanied by pain, swelling, bleeding as well as other symptoms and has a high disability rate, even threatening life, seriously endangering patients’ physical and ps...As a common clinical disease, fracture is often accompanied by pain, swelling, bleeding as well as other symptoms and has a high disability rate, even threatening life, seriously endangering patients’ physical and psychological health and quality of life. Medical practitioners take many strategies for the treatment of fracture healing, including Traditional Chinese Medicine(TCM). In the early stage of fracture healing,the local fracture is often in a state of hypoxia, accompanied by the expression of hypoxia inducible factor-1α(HIF-1α), which is beneficial to wound healing. Through literature mining, we thought that hypoxia, HIF-1α and downstream factors affected the mechanism of fracture healing, as well as dominated this process. Therefore, we reviewed the local characteristics and related signaling pathways involved in the fracture healing process and summarized the intervention of TCM on these mechanisms,in order to inspirit the new strategy for fracture healing, as well as elaborate on the possible principles of TCM in treating fractures based on the HIF molecular mechanism.展开更多
Background:The Taylor Spatial Frame(TSF)has gained popularity among orthopedic surgeons for treating open fractures.However,a key challenge is the timely and safe removal of the frame.This study assessed the efficacy ...Background:The Taylor Spatial Frame(TSF)has gained popularity among orthopedic surgeons for treating open fractures.However,a key challenge is the timely and safe removal of the frame.This study assessed the efficacy and safety of axial load-share ratio(ALSR)testing to evaluate callus healing strength after TSF treatment of open tibial fractures.Methods:A retrospective case-control study was conducted,analyzing 180 adult patients with open tibial fractures treated at Tianjin Hospital’s Orthopedic Limb Correction Unit between August 2019 and August 2022.All patients underwent TSF external fixation surgery,and were divided into two groups based on ALSR testing.Group I(92 patients)underwent ALSR testing,with frame removal if the test value fell below 5%.Traditional methods were used for fixator removal guidance in Group II(88 patients).Clinical outcomes,including fixation duration,complications after fixator removal,and Johner-Wruhs functional scores,were compared between the two groups.Results:The groups showed no statistically significant differences(P>0.05)in sex,age,injury side,body mass index,surgery timing,or fracture type.Group I had a significantly shorter fixation duration(25.85±5.57 weeks)compared to Group II(31.82±6.98 weeks)(P<0.05).Following fixator removal,Group I demonstrated superior Johner-Wruhs scores compared to Group II,indicating better outcomes(P<0.05).Complication rates did not differ significantly between the groups at the last follow-up(P>0.05).Conclusion:Regular postoperative ALSR testing could safely and effectively guide TSF removal following open tibial fracture treatment.This method significantly reduced fixation duration compared to traditional guidance methods while maintaining efficacy and safety.展开更多
Diabetes mellitus is a chronically inflamed disease that predisposes to delayed fracture healing.Macrophages play a key role in the process of fracture healing by undergoing polarization into either M1 or M2 subtypes,...Diabetes mellitus is a chronically inflamed disease that predisposes to delayed fracture healing.Macrophages play a key role in the process of fracture healing by undergoing polarization into either M1 or M2 subtypes,which respectively exhibit pro-inflammatory or anti-inflammatory functions.Therefore,modulation of macrophage polarization to the M2 subtype is beneficial for fracture healing.Exosomes perform an important role in improving the osteoimmune microenvironment due to their extremely low immunogenicity and high bioactivity.In this study,we extracted the M2-exosomes and used them to intervene the bone repair in diabetic fractures.The results showed that M2-exosomes significantly modulate the osteoimmune microenvironment by decreasing the proportion of M1 macrophages,thereby accelerating diabetic fracture healing.We further confirmed that M2-exosomes induced the conversion of M1 macrophages into M2 macrophages by stimulating the PI3K/AKT pathway.Our study offers a fresh perspective and a potential therapeutic approach for M2-exosomes to improve diabetic fracture healing.展开更多
OBJECTIVE: To explore the concept and norm of fracture healing with osteopathy in traditional Mongolian medicine (TMM). METHODS: Based on the correspondence between man and the universe (including psychosomatic integr...OBJECTIVE: To explore the concept and norm of fracture healing with osteopathy in traditional Mongolian medicine (TMM). METHODS: Based on the correspondence between man and the universe (including psychosomatic integration) in fracture healing with osteopathy in TMM, we used modern physio-psychological and biomechanical principles and methods to probe the integrated, dynamic and functional characteristics of fracture healing. RESULTS: Based on the integration of limbs and the body, unification of the body and function and harmony of man and nature (including psychoso-matic integration), fracture healing with osteopathy in TMM comprises the concept of natural functional healing of fractures, and follows the norm of considering physiological healing and psychological function as well as limb healing and motor function. CONCLUSION: Fracture healing with osteopathy in TMM is characterized by a lack of trauma without future complications. This therapy makes the concept of fracture healing develop in the direction of humanity, behaviorism and integration.展开更多
Objective:: To observe the effect of recombinant human growth hormone (r-hGH) on osteoporotic fracture healing in rats, and to provide an effective therapy for osteoporotic fracture. Methods: Thirty-six female 8-month...Objective:: To observe the effect of recombinant human growth hormone (r-hGH) on osteoporotic fracture healing in rats, and to provide an effective therapy for osteoporotic fracture. Methods: Thirty-six female 8-month-old SD rats were randomized into two groups: therapy group and control group. After the experimental model of osteoporotic fracture was established, the therapy group was treated with r-hGH of 2.7 mg/kg body weigh/day (1 mg=3 IU) for 10 days continuously by daily subcutaneous injection; whereas the control group was treated with equivalent saline. Plasma insulin-like growth factor I concentration was detected and bone mineral density (BMD) as well as biomechanical strength of callus were measured at 2, 4, 8 weeks. Results: Plasma insulin-like growth factor I concentration in the therapy group was higher than that in the control group (P< 0.005 ) at 2nd week and began to decline at 4th week. At 8th week, there was no significant difference between the two groups. At 4th week, callus area and BMD in therapy group were higher than those in the control group, but at 8th week, they were lower and BMD had a significant difference between the two groups (P< 0.001 ). Biomechanical testing of callus showed that torsional strength of the therapy group was higher than that of the control group at 4th or 8th week, meanwhile maximum torsional angle had a significant difference between the two groups (P< 0.005 ).Conclusions: The results show that exogenous r-hGH can stimulate osteoporotic fracture healing in rats.展开更多
Objective:To study the effect of vascular endothelial growth factor(VEGF)and anti-VEGF on the expression of fracture healing-related factors and observe pathological changes at fractured sites. Methods:Fracture models...Objective:To study the effect of vascular endothelial growth factor(VEGF)and anti-VEGF on the expression of fracture healing-related factors and observe pathological changes at fractured sites. Methods:Fracture models were established in 105 New Zealand white rabbits and they were randomly divided into control group,VEGF group and anti-VEGF group. The relevant factors expression at fractured sites was assayed and pathological changes were observed in decalcified samples at 8,24,72 hours and 1,3,5,8 weeks after fracture. Results:After application of VGEF,the expression of BMP appeared earlier and expression time lasted longer. On the contrary,anti-VEGF completely inhibited the expression of BMP.The fractured sites were filled with fibrous callus,cartilaginous callus and bony callus at the 3rd week and woven bone was constructed at the 5th week. Fracture healing was accomplished at the 8th week in VEGF group.In anti-VEGF polyclonal antibody group, cellular necrosis increased at early period.Continuous focal necrosis was seen in the fractured sites from the 1st week to 5th week.Vascularization reduced obviously at the 3rd week. Conclusions:Fracture healing is a result of mutual regulation and coordination among many factors.VEGF may be an important factor in fracture healing.展开更多
A moderate inflammatory response at the early stages of fracture healing is necessary for callus formation.Over-active and continuous inflammation,however,impairs fracture healing and leads to excessive tissue damage....A moderate inflammatory response at the early stages of fracture healing is necessary for callus formation.Over-active and continuous inflammation,however,impairs fracture healing and leads to excessive tissue damage.Adequate fracture healing could be promoted through suppression of local over-active immune cells in the fracture site.In the present study,we achieved an enriched concentration of PD-L1 from exosomes(Exos)of a genetically engineered Human Umbilical Vein Endothelial Cell(HUVECs),and demonstrated that exosomes overexpressing PD-L1 specifically bind to PD-1 on the T cell surface,suppressing the activation of T cells.Furthermore,exosomal PD-L1 induced Mesenchymal Stem Cells(MSCs)towards osteogenic differentiation when pre-cultured with T cells.Moreover,embedding of Exos into an injectable hydrogel allowed Exos delivery to the surrounding microenvironment in a time-released manner.Additionally,exosomal PD-L1,embedded in a hydrogel,markedly promoted callus formation and fracture healing in a murine model at the early over-active inflammation phase.Importantly,our results suggested that activation of T cells in the peripheral lymphatic tissues was inhibited after local administration of PD-L1-enriched Exos to the fracture sites,while T cells in distant immune organs such as the spleen were not affected.In summary,this study provides the first example of using PD-L1-enriched Exos for bone fracture repair,and highlights the potential of Hydrogel@Exos systems for bone fracture therapy through immune inhibitory effects.展开更多
基金This work was supported by the National Natural Science Foundation of China(Nos.81972058,81902194 and 82202680)the Science and Technology Commission of Shanghai Municipality(No.22YF1422900)+3 种基金the Shanghai Municipal Key Clinical Specialty,China(No.shslczdzk06701)the National Facility for Translational Medicine(Shanghai),China(No.TMSZ-2020-207)the Shanghai Engineering Research Center of Orthopedic Innovative Instruments and Personalized Medicine Instruments and Personalized Medicine(No.19DZ2250200)the Key R&D Program of Ningxia,China(Nos.2020BCH01001 and 2021BEG02037).
文摘The key to managing fracture is to achieve stable internal fixation,and currently,biologically and mechanically appropriate internal fixation devices are urgently needed.With excellent biocompatibility and corrosion resistance,titanium–niobium alloys have the potential to become a new generation of internal fixation materials for fractures.However,the role and mechanism of titanium–niobium alloys on promoting fracture healing are still undefined.Therefore,in this study,we systematically evaluated the bone-enabling properties of Ti45Nb via in vivo and in vitro experiments.In vitro,we found that Ti45Nb has an excellent ability to promote MC3T3-E1 cell adhesion and proliferation without obvious cytotoxicity.Alkaline phosphatase(ALP)activity and alizarin red staining and semiquantitative analysis showed that Ti45Nb enhanced the osteogenic differentiation of MC3T3-E1 cells compared to the Ti6Al4V control.In the polymerase chain reaction experiment,the expression of osteogenic genes in the Ti45Nb group,such as ALP,osteopontin(OPN),osteocalcin(OCN),type 1 collagen(Col-1)and runt-related transcription factor-2(Runx2),was significantly higher than that in the control group.Meanwhile,in the western blot experiment,the expression of osteogenic-related proteins in the Ti45Nb group was significantly increased,and the expression of PI3K–Akt-related proteins was also higher,which indicated that Ti45Nb might promote fracture healing by activating the PI3K–Akt signaling pathway.In vivo,we found that Ti45Nb implants accelerated fracture healing compared to Ti6Al4V,and the biosafety of Ti45Nb was confirmed by histological evaluation.Furthermore,immunohistochemical staining confirmed that Ti45Nb may promote osteogenesis by upregulating the PI3K/Akt signaling pathway.Our study demonstrated that Ti45Nb exerts an excellent ability to promote fracture healing as well as enhance osteoblast differentiation by activating the PI3K/Akt signaling pathway,and its good biosafety has been confirmed,which indicates its clinical translation potential.
文摘This paper describes an experimental study about magnetic stimulation (MS) effects on the fracture healing of 120 fresh fractures and their blood biochemical parameters during their recovery. The mechanism of promoting the recovering process by MS is discussed and analysed. The experiments show that MS can advance calcium deposit on fractured bones and metabolism of calcium and phosphorus, which promote the process of fracture healing.
文摘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
基金Grand Rapids Area Pre-College Engineering Programsupported by NIH grant AR053293
文摘Bone fracture non-unions, the failure of a fracture to heal, occur in 10%-20% of fractures and are a costly and debilitating clinical problem. The Wnt/fl-catenin pathway is critical in bone development and fracture healing. Polymorphisms of linking low-density lipoprotein receptor-related protein 6 （LRP6）, a Wnt-binding receptor, have been associated with decreased bone mineral density and fragility fractures, although this remains controversial. Mice with a homozygous deletion of Lrp6 have severe skeletal abnormalities and are not viable, whereas mice with a heterozygous deletion have a combinatory effect with Lrp5 to decrease bone mineral density. As fracture healing closely models embryonic skeletal development, we investigated the process of fracture healing in mice heterozygous for Lrp6 （Lrp6~/-） and hypothesized that the heterozygous deletion of Lrp6 would impair fracture healing. Mid-diaphyseal femur fractures were induced in Lrp6~^- mice and wild-type controls （Lrp6~/~）. Fractures were analyzed using micro-computed tomography （~CT） scans, biomechanical testing, and histological analysis. Lrp6~/- mice had significantly decreased stiffness and strength at 28 days post fracture （PF） and significantly decreased BV/TV, total density, immature bone density, and mature area within the callus on day-14 and -21 PF; they had significantly increased empty callus area at days 14 and 21 PF. Our results demonstrate that the heterozygous deletion of Lrp6 impairs fracture healing, which suggests that Lrp6 has a role in fracture healing.
基金Supported by German Research Foundation(DFG)focusing on“Interplay between mononuclear and osteogenic cells during fracture healing in type 2 diabetics”,No.EH 471/2(to Ehnert S)German Research Foundation within the context of the Collaborative Research Center(CRC)1149“Danger Response,Disturbance Factors and Regenerative Potential after Acute Trauma”,No.251293561,C01(to Ignatius A and Fischer V)+1 种基金DFG in context of the CRC 1149,No.251293561,A01 and No.251293561 Z02(to Huber-Lang M)and DFG in the context of the CRC 1149,No.251293561,C07(to Kalbitz M).
文摘In vertebrates,bone is considered an osteoimmune system which encompasses functions of a locomotive organ,a mineral reservoir,a hormonal organ,a stem cell pool and a cradle for immune cells.This osteoimmune system is based on cooperatively acting bone and immune cells,cohabitating within the bone marrow.They are highly interdependent,a fact that is confounded by shared progenitors,mediators,and signaling pathways.Successful fracture healing requires the participation of all the precursors,immune and bone cells found in the osteoimmune system.Recent evidence demonstrated that changes of the immune cell composition and function may negatively influence bone healing.In this review,first the interplay between different immune cell types and osteoprogenitor cells will be elaborated more closely.The separate paragraphs focus on the specific cell types,starting with the cells of the innate immune response followed by cells of the adaptive immune response,and the complement system as mediator between them.Finally,a brief overview on the challenges of preclinical testing of immunebased therapeutic strategies to support fracture healing will be given.
基金the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI),funded by the Ministry of Health&Welfare,Republic of Korea,No.HI20C1405。
文摘BACKGROUND There is still no consensus on which concentration of mesenchymal stem cells(MSCs)to use for promoting fracture healing in a rat model of long bone fracture.AIM To assess the optimal concentration of MSCs for promoting fracture healing in a rat model.METHODS Wistar rats were divided into four groups according to MSC concentrations:Normal saline(C),2.5×10^(6)(L),5.0×10^(6)(M),and 10.0×10^(6)(H)groups.The MSCs were injected directly into the fracture site.The rats were sacrificed at 2 and 6 wk post-fracture.New bone formation[bone volume(BV)and percentage BV(PBV)]was evaluated using micro-computed tomography(CT).Histological analysis was performed to evaluate fracture healing score.The protein expression of factors related to MSC migration[stromal cell-derived factor 1(SDF-1),transforming growth factor-beta 1(TGF-β1)]and angiogenesis[vascular endothelial growth factor(VEGF)]was evaluated using western blot analysis.The expression of cytokines associated with osteogenesis[bone morphogenetic protein-2(BMP-2),TGF-β1 and VEGF]was evaluated using real-time polymerase chain reaction.RESULTS Micro-CT showed that BV and PBV was significantly increased in groups M and H compared to that in group C at 6 wk post-fracture(P=0.040,P=0.009;P=0.004,P=0.001,respectively).Significantly more cartilaginous tissue and immature bone were formed in groups M and H than in group C at 2 and 6 wk post-fracture(P=0.018,P=0.010;P=0.032,P=0.050,respectively).At 2 wk post fracture,SDF-1,TGF-β1 and VEGF expression were significantly higher in groups M and H than in group L(P=0.031,P=0.014;P<0.001,P<0.001;P=0.025,P<0.001,respectively).BMP-2 and VEGF expression were significantly higher in groups M and H than in group C at 6 wk postfracture(P=0.037,P=0.038;P=0.021,P=0.010).Compared to group L,TGF-β1 expression was significantly higher in groups H(P=0.016).There were no significant differences in expression levels of chemokines related to MSC migration,angiogenesis and cytokines associated with osteogenesis between M and H groups at 2 and 6 wk post-fracture.CONCLUSION The administration of at least 5.0×10^(6)MSCs was optimal to promote fracture healing in a rat model of long bone fractures.
基金Project (No. 39470698) supported by the National Natural Science Foundation of China
文摘A first order system model is proposed for simulating the influence of stress stimulation on fracture strength during fracture healing. To validate the model, the diaphyses of bilateral tibiae in 70 New Zealand rabbits were osteotomized and fixed with rigid plates and stress-relaxation plates, respectively. Stress shielding rate and ultimate bending strength of the healing bone were measured at 2 to 48 weeks postoperatively. Ratios of stress stimulation and fracture strength of the healing bone to those of intact bone were taken as the system input and output. The assumed first order system model can approximate the experimental data on fracture strength from the input of stress stimulation over time, both for the rigid plate group and the stress-relaxation plate group, with different system parameters of time constant and gain. The fitting curve indicates that the effect of mechanical stimulus occurs mainly in late stages of healing. First order system can model the stress adaptation process of fracture healing. This approach presents a simple bio-mathematical model of the relationship between stress stimulation and fracture strength, and has the potential to optimize planning of functional exercises and conduct parametric studies.
基金This project was supported by the National Natural Science Foundation of China !(No. 969202011 ) by Hubei Province Natural S
文摘Summary: In order to investigate the effect of a new institute-designed absorbable hydroxyapatite microparticles/poly-DL-lactide (HA/PDLLA) fracture fixation devices on experimental fracture healing, 25 rabbits with a transverse transcondylar osteotomy of the distal femur were fixed in- tramedullary by a HA/PDLLA rod (4. 5 mm in diameter, 30-40 mm in length). The follow-up time lasted 1, 2, 4, 6 and 12 week(s). Roentgenographic, histological and ultrastructural analyses were conducted. The results showed that all osteotomies united within 6 weeks without delay. No accumulation of inflammatory cells was seen. Ultrastructural studies showed that polymorphonuclear neutrophils and macrophages were observed mainly at the 1st week, but only few were noted at the 2nd week. The inflammatory and debridement stages were not prolonged. Large amount of active fibroblasts and some chondroblasts were observed at the 2nd week, suggesting a fibrous callus stage. The main cellularity at 4th week was osteoblasts and osteocytes. Part of osteocytes had already entered the static stage at the 6th week. Our experiment showed that the HA/PDLLA had good biocompatibility, sufficient mechanical strength and caused no delay to the fracture healing.
文摘AIM： To examine whether vitamin D is of potential relevance in the healing process of fractures. METHODS： The present narrative review examined the bulk of the evidence based literature on the topic of vitamin D and bone healing in key electronic data bases from 1980 onwards using the terms vitamin D and bone healing, callus, fracture healing. All data were examined carefully and categorized according to type of study. A summary of the diverse terms and approaches employed in the research, as well as the rationale for hypothesizing vitamin D has a role in fracture healing was detailed.RESULTS： The results show very few human studies have been conducted to examine if vitamin D is effective at promoting post fracture healing, and the different ani-mal models that have been studied provide no consensus on this topic. The terms used in the related literature, as well as the methods used to arrive at conclusions on this clinical issue are highly diverse, there is no standardization of either of these important terms and methodolo-gies, hence no conclusive statements or clinical guide-lines can be forthcoming. There is a strong rational for continuing to examine if vitamin D supplements should be administered post-fracture, and ample evidence vitamin D is an essential hormone for functioning in general, as well as bone health and muscle as this relates to bone density.CONCLUSION： Whether those with low vitamin D levels can beneft from supplements if their nutritional practices do not cover recommended daily amounts, remains in question.
文摘Objective:To study the effects of Shang Ke Jie Gu tablet on fracture healing in rabbits.Methods:40 New Zealand rabbits,half male and half female,were randomly divided into two groups:normal saline group(N group)and Shang Ke Jie Gu tablet group(S group).Each group consisted of 20 rabbits.Left radial fracture models in upper and middle sections were made in rabbits and then intra-gastric administration was given.Five rabbits in each group were killed on the 10 th,20^(th),30^(th) and 40^(th) day after surgery,left radius was taken to get an X-ray.The degree of healing was assessed by the evaluation criteria of Shanghai Orthopaedics Institute.Results:The degree of fracture healing in S group was higher in the comparison with that in N group.Conclusions:Shang Ke Jie Gu tablet might affect endochondral ossification during fracture healing of rabbits,and promote porosis and fracture healing.
文摘To investigate the impact of different kinds of nerve injuries of early-stage fracture healing.Methods Three groups of rats were included in the experiment among which group 1 was inflicted with femoral fracture and T10 spinal cord transsection (SCI),group 2 was inflicted with femoral and peripheral nerve resection (PNR),and group 3 with simple femoral fracture as control group.Two weeks after operation the femoral bones were collected for X-ray checking and 2 more weeks later X-ray checking was performed again followed by pathomorphologic exams.Results X-ray result showed no massive calluses in the bones in the 2nd week postoperatively,while in the 4th week,callus appeared with larger size in group 3 than that of group 1 and with smaller size than that of group 2.It was the same with the result of pathomorphologic examining.Cortical bone bridges between fracture point and osteiod were also found in group 2 and there were less normal blood vessels and worse bone remodeling than that of group 3.There were relatively immature calluses with more fibroblast-like cells and disordered bone structure in group 2.Group 3 showed normal healing process and callus structure.Conclusion Early-stage bone fracture healing can be influenced significantly by different kinds of nerve injuries.6 refs,6 figs.
基金the financial support from the Postdoctoral Fund of Hebei Medical University,Key Supported Projects of the Joint Fund of the National Natural Science Foundation of China(Grant No.U22A20357)National Key R&D Program of China(Grant No.2020YFC1107601)+1 种基金Chunyu Project Outstanding Youth Fund of Hebei Medical University(No.CYYQ2023004)the China Postdoctoral Science Foundation(No.2023M730914 and 2023TQ0103).
文摘The bone fracture cases have been increasing yearly,accompanied by the increased number of patients experiencing non-union or delayed union after their bone fracture.Although clinical materials facilitate fracture healing(e.g.,metallic and composite materials),they cannot fulfill the requirements due to the slow degradation rate,limited osteogenic activity,inadequate osseointegration ability,and suboptimal mechanical properties.Since early 2000,nanomaterials successfully mimic the nanoscale features of bones and offer unique properties,receiving extensive attention.This paper reviews the achievements of nanomaterials in treating bone fracture(e.g.,the intrinsic properties of nanomaterials,nanomaterials for bone defect filling,and nanoscale drug delivery systems in treating fracture delayed union).Furthermore,we discuss the perspectives on the challenges and future directions of developing nanomaterials to accelerate fracture healing.
基金supported by the National Natural Science Foundation of China(Nos.82274026 and 81901884).
文摘Regulatory T cells(Tregs)suppress immune responses and inflammation.Here,we described the distinct nonimmunological role of Tregs in fracture healing.The recruitment from the circulation pool,peripheral induction,and local expansion rapidly enriched Tregs in the injured bone.The Tregs in the injured bone displayed superiority in direct osteogenesis over Tregs from lymphoid organs.Punctual depletion of Tregs compromised the fracture healing process,which leads to increased bone nonunion.In addition,bone callus Tregs showed unique T-cell receptor repertoires.Amphiregulin was the most overexpressed protein in bone callus Tregs,and it can directly facilitate the proliferation and differentiation of osteogenic precursor cells by activation of phosphatidylinositol 3-kinase/protein kinase B signaling pathways.The results of loss-and gain-function studies further evidenced that amphiregulin can reverse the compromised healing caused by Treg dysfunction.Tregs also enriched in patient bone callus and amphiregulin can promote the osteogenesis of human pre-osteoblastic cells.Our findings indicate the distinct and nonredundant role of Tregs in fracture healing,which will provide a new therapeutic target and strategy in the clinical treatment of fractures.
基金This work is financially supported by National Natural Science Foundation of China(No.82060877,82104527)the Science and Technology Planning Project of Tibet Autonomous Region(No.XZ202101ZD 0022G)Fundamental Research Funds for the Central Universities(No.lzujbky-2022-ct03).
文摘As a common clinical disease, fracture is often accompanied by pain, swelling, bleeding as well as other symptoms and has a high disability rate, even threatening life, seriously endangering patients’ physical and psychological health and quality of life. Medical practitioners take many strategies for the treatment of fracture healing, including Traditional Chinese Medicine(TCM). In the early stage of fracture healing,the local fracture is often in a state of hypoxia, accompanied by the expression of hypoxia inducible factor-1α(HIF-1α), which is beneficial to wound healing. Through literature mining, we thought that hypoxia, HIF-1α and downstream factors affected the mechanism of fracture healing, as well as dominated this process. Therefore, we reviewed the local characteristics and related signaling pathways involved in the fracture healing process and summarized the intervention of TCM on these mechanisms,in order to inspirit the new strategy for fracture healing, as well as elaborate on the possible principles of TCM in treating fractures based on the HIF molecular mechanism.
基金funding support from Natural Science Foundation Key Project of Tianjin(20JCZDJC00600)Tianjin Health Research Project(TJWJ2023QN050)+2 种基金Applied Basic Research Foundation of Tianjin(22JCQNJC00230,22JCQNJC00360)Beijing-Tianjin-Hebei Basic Research Cooperation Project(J230007/23JCZXJC00050)Tianjin Municipal Health Commission Key Discipline Specialization(TJWJ2024XK015).
文摘Background:The Taylor Spatial Frame(TSF)has gained popularity among orthopedic surgeons for treating open fractures.However,a key challenge is the timely and safe removal of the frame.This study assessed the efficacy and safety of axial load-share ratio(ALSR)testing to evaluate callus healing strength after TSF treatment of open tibial fractures.Methods:A retrospective case-control study was conducted,analyzing 180 adult patients with open tibial fractures treated at Tianjin Hospital’s Orthopedic Limb Correction Unit between August 2019 and August 2022.All patients underwent TSF external fixation surgery,and were divided into two groups based on ALSR testing.Group I(92 patients)underwent ALSR testing,with frame removal if the test value fell below 5%.Traditional methods were used for fixator removal guidance in Group II(88 patients).Clinical outcomes,including fixation duration,complications after fixator removal,and Johner-Wruhs functional scores,were compared between the two groups.Results:The groups showed no statistically significant differences(P>0.05)in sex,age,injury side,body mass index,surgery timing,or fracture type.Group I had a significantly shorter fixation duration(25.85±5.57 weeks)compared to Group II(31.82±6.98 weeks)(P<0.05).Following fixator removal,Group I demonstrated superior Johner-Wruhs scores compared to Group II,indicating better outcomes(P<0.05).Complication rates did not differ significantly between the groups at the last follow-up(P>0.05).Conclusion:Regular postoperative ALSR testing could safely and effectively guide TSF removal following open tibial fracture treatment.This method significantly reduced fixation duration compared to traditional guidance methods while maintaining efficacy and safety.
基金supported by the Integrated Project of Major Research Plan of National Natural Science Foundation of China(92249303)Key Project of the National Natural Science Foundation of China(82230071)National Natural Science Foundation of China(32101084,82202344).
文摘Diabetes mellitus is a chronically inflamed disease that predisposes to delayed fracture healing.Macrophages play a key role in the process of fracture healing by undergoing polarization into either M1 or M2 subtypes,which respectively exhibit pro-inflammatory or anti-inflammatory functions.Therefore,modulation of macrophage polarization to the M2 subtype is beneficial for fracture healing.Exosomes perform an important role in improving the osteoimmune microenvironment due to their extremely low immunogenicity and high bioactivity.In this study,we extracted the M2-exosomes and used them to intervene the bone repair in diabetic fractures.The results showed that M2-exosomes significantly modulate the osteoimmune microenvironment by decreasing the proportion of M1 macrophages,thereby accelerating diabetic fracture healing.We further confirmed that M2-exosomes induced the conversion of M1 macrophages into M2 macrophages by stimulating the PI3K/AKT pathway.Our study offers a fresh perspective and a potential therapeutic approach for M2-exosomes to improve diabetic fracture healing.
基金Supported by the Project of the 2009 State Natural Science Fund (No. 30960518)a Project of the 2012 State Natural Science Fund (No. 81260513)a Major Project of the Scitech Plan of the Inner Mongolian Autonomous Region(2010-2012)
文摘OBJECTIVE: To explore the concept and norm of fracture healing with osteopathy in traditional Mongolian medicine (TMM). METHODS: Based on the correspondence between man and the universe (including psychosomatic integration) in fracture healing with osteopathy in TMM, we used modern physio-psychological and biomechanical principles and methods to probe the integrated, dynamic and functional characteristics of fracture healing. RESULTS: Based on the integration of limbs and the body, unification of the body and function and harmony of man and nature (including psychoso-matic integration), fracture healing with osteopathy in TMM comprises the concept of natural functional healing of fractures, and follows the norm of considering physiological healing and psychological function as well as limb healing and motor function. CONCLUSION: Fracture healing with osteopathy in TMM is characterized by a lack of trauma without future complications. This therapy makes the concept of fracture healing develop in the direction of humanity, behaviorism and integration.
文摘Objective:: To observe the effect of recombinant human growth hormone (r-hGH) on osteoporotic fracture healing in rats, and to provide an effective therapy for osteoporotic fracture. Methods: Thirty-six female 8-month-old SD rats were randomized into two groups: therapy group and control group. After the experimental model of osteoporotic fracture was established, the therapy group was treated with r-hGH of 2.7 mg/kg body weigh/day (1 mg=3 IU) for 10 days continuously by daily subcutaneous injection; whereas the control group was treated with equivalent saline. Plasma insulin-like growth factor I concentration was detected and bone mineral density (BMD) as well as biomechanical strength of callus were measured at 2, 4, 8 weeks. Results: Plasma insulin-like growth factor I concentration in the therapy group was higher than that in the control group (P< 0.005 ) at 2nd week and began to decline at 4th week. At 8th week, there was no significant difference between the two groups. At 4th week, callus area and BMD in therapy group were higher than those in the control group, but at 8th week, they were lower and BMD had a significant difference between the two groups (P< 0.001 ). Biomechanical testing of callus showed that torsional strength of the therapy group was higher than that of the control group at 4th or 8th week, meanwhile maximum torsional angle had a significant difference between the two groups (P< 0.005 ).Conclusions: The results show that exogenous r-hGH can stimulate osteoporotic fracture healing in rats.
基金Special Funds for Major State Basic Research Projects of China(G1999054204).
文摘Objective:To study the effect of vascular endothelial growth factor(VEGF)and anti-VEGF on the expression of fracture healing-related factors and observe pathological changes at fractured sites. Methods:Fracture models were established in 105 New Zealand white rabbits and they were randomly divided into control group,VEGF group and anti-VEGF group. The relevant factors expression at fractured sites was assayed and pathological changes were observed in decalcified samples at 8,24,72 hours and 1,3,5,8 weeks after fracture. Results:After application of VGEF,the expression of BMP appeared earlier and expression time lasted longer. On the contrary,anti-VEGF completely inhibited the expression of BMP.The fractured sites were filled with fibrous callus,cartilaginous callus and bony callus at the 3rd week and woven bone was constructed at the 5th week. Fracture healing was accomplished at the 8th week in VEGF group.In anti-VEGF polyclonal antibody group, cellular necrosis increased at early period.Continuous focal necrosis was seen in the fractured sites from the 1st week to 5th week.Vascularization reduced obviously at the 3rd week. Conclusions:Fracture healing is a result of mutual regulation and coordination among many factors.VEGF may be an important factor in fracture healing.
基金This work was supported by the National Science Foundation of China(No.82002313,No.82072444,31900963)Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration(No.2020kqhm008)+2 种基金the Health Commission of Hubei Province(No.WJ2019Z009)the Wuhan Union Hospital"Pharmaceutical Technology nursing"special fund(No.2019xhyn021)the China Postdoctoral Science Foundation(No.2021TQ0118).
文摘A moderate inflammatory response at the early stages of fracture healing is necessary for callus formation.Over-active and continuous inflammation,however,impairs fracture healing and leads to excessive tissue damage.Adequate fracture healing could be promoted through suppression of local over-active immune cells in the fracture site.In the present study,we achieved an enriched concentration of PD-L1 from exosomes(Exos)of a genetically engineered Human Umbilical Vein Endothelial Cell(HUVECs),and demonstrated that exosomes overexpressing PD-L1 specifically bind to PD-1 on the T cell surface,suppressing the activation of T cells.Furthermore,exosomal PD-L1 induced Mesenchymal Stem Cells(MSCs)towards osteogenic differentiation when pre-cultured with T cells.Moreover,embedding of Exos into an injectable hydrogel allowed Exos delivery to the surrounding microenvironment in a time-released manner.Additionally,exosomal PD-L1,embedded in a hydrogel,markedly promoted callus formation and fracture healing in a murine model at the early over-active inflammation phase.Importantly,our results suggested that activation of T cells in the peripheral lymphatic tissues was inhibited after local administration of PD-L1-enriched Exos to the fracture sites,while T cells in distant immune organs such as the spleen were not affected.In summary,this study provides the first example of using PD-L1-enriched Exos for bone fracture repair,and highlights the potential of Hydrogel@Exos systems for bone fracture therapy through immune inhibitory effects.
