BACKGROUND Anterior cruciate ligament reconstruction(ACLR)is the dominant clinical modality for the treatment of anterior cruciate ligament injuries.The success of ACLR is largely dependent on tendon-bone healing,and ...BACKGROUND Anterior cruciate ligament reconstruction(ACLR)is the dominant clinical modality for the treatment of anterior cruciate ligament injuries.The success of ACLR is largely dependent on tendon-bone healing,and stem cell biotherapies are often used to facilitate this process.Histone lactylation modifications are involved in the regulation of various diseases.Lactate dehydrogenase A(LDHA)has been shown to play an important role in exosomes.AIM To explore the regulation of tendon-bone healing after ACLR by LDHA in exosomes derived from bone marrow mesenchymal stem cells(BMSC-Exos).METHODS BMSC-Exos and LDHA were characterized and analyzed by transmission electron microscopy,qNano,immunofluorescence and western blotting assay.The corresponding low expression cell lines were obtained using RNA interference transfection;LDHA expression in rat bone tissues after ACLR was analyzed by western blotting.The volume of newborn bone tissues was monitored by micro-computed tomography imaging.Tendon and fibrocartilage regeneration were further analyzed and calculated by histological analysis,including hematoxylin and eosin and Safranin O-Fast green staining,respectively;LDHA levels of chondrocyte stem cells(CSPCs)after co-incubation with BMSC-Exos were analyzed by western blotting.Extracellularly secreted lactic acid content was determined by lactate assay kit.Cell viability was assessed by cell counting kit 8 assay,and the proliferation and differentiation ability of cells was further examined by the expression of collagen II,SOX9 and aggrecan.Histone H3K18 lactylation modification was analyzed by western blotting.H3K18 La binding on bone morphogenetic protein 7(BMP7)promoter was analyzed by chromatin immunoprecipitation-quantitative polymerase chain reaction;BMP7 promoter activity was analyzed by dual luciferase reporter gene;BMP7 protein expression was analyzed using quantitative polymerase chain reaction and western blotting.Then,the proliferation of CSPCs promoted by BMSC-Exos LDHA was analyzed by protein expression levels of LDHA,BMP7,collagen II,SOX9,aggrecan,extracellular lactate content,and cell counting kit 8 assay.RESULTS The spherical nanosized BMSC-Exos could be uptaken by CSPCs.LDHA was highly expressed in BMSC-Exos,which could infiltrate into the bone tissue of ACLR rats and promoted the generation of new bone tissue,as well as significantly increased the regeneration of tendon and fibrocartilage.Co-incubation of CSPCs with high-expressing LDHA BMSC-Exos increased the secretion of lactate content from CSPCs,cell viability,and the expression of markers related to cell proliferation and differentiation,including collagen II,SOX9,and aggrecan;LDHA in BMSC-Exos upregulated BMP7 through histone H3K18 lactate modification;high LDHA expression reversed the knockdown of BMP7,further increasing the proliferation and differentiation of CSPCs,thereby inducing cartilage formation.CONCLUSION LDHA in BMSC-Exos promotes BMP7 expression via H3K18 lactylation modification,which further promotes tendon-bone healing after ACLR.展开更多
Tendon-bone healing remains a significant clinical challenge due to the high risk of re-rupture following injury.While mesenchymal stem cells(MSCs)show great potential in enhancing tendon-bone healing,their clinical a...Tendon-bone healing remains a significant clinical challenge due to the high risk of re-rupture following injury.While mesenchymal stem cells(MSCs)show great potential in enhancing tendon-bone healing,their clinical application is limited by issues such as low delivery efficiency,restricted differentiation potential,and potential immunogenicity.Recently,various strategies combining MSCs with other approaches,such as preconditioning,biomaterial integration,gene modification,and exosome application,have been developed,resulting in improved therapeutic outcomes.This review explored the current methods used to optimize MSC therapy for tendon-bone healing,examining the advantages,disadvantages,and underlying mechanisms of each approach,providing a foundation for future research and clinical applications.展开更多
AIM To quantitatively assess rotatory and anterior-posterior instability in vivo after anterior cruciate ligament(ACL) reconstruction using bone-patellar tendon-bone(BTB) autografts, and to clarify the influence of tu...AIM To quantitatively assess rotatory and anterior-posterior instability in vivo after anterior cruciate ligament(ACL) reconstruction using bone-patellar tendon-bone(BTB) autografts, and to clarify the influence of tunnel positions on the knee stability.METHODS Single-bundle ACL reconstruction with BTB autograft was performed on 50 patients with a mean age of 28 years using the trans-tibial(TT)(n = 20) and trans-portal(TP)(n = 30) techniques. Femoral and tibial tunnel positions were identified from the high-resolution 3 D-CT bone models two weeks after surgery. Anterolateral rotatory translation was examined using a Slocum anterolateral rotatory instability test in open magnetic resonance imaging(MRI) 1.0-1.5 years after surgery, by measuring anterior tibial translation at the medial and lateral compartments on its sagittal images. Anterior-posterior stability was evaluated with a Kneelax3 arthrometer.RESULTS A total of 40 patients(80%) were finally followed up. Femoral tunnel positions were shallower(P < 0.01) and higher(P < 0.001), and tibial tunnel positions were more posterior(P < 0.05) in the TT group compared with the TP group. Anterolateral rotatory translations in reconstructed knees were significantly correlated with the shallow femoral tunnel positions(R = 0.42, P < 0.01), and the rotatory translations were greater in the TT group(3.2 ± 1.6 mm) than in the TP group(2.0 ± 1.8 mm)(P < 0.05). Side-to-side differences of Kneelax3 arthrometer were 1.5 ± 1.3 mm in the TT, and 1.7 ± 1.6 mm in the TP group(N.S.). Lysholm scores, KOOS subscales and reinjury rate showed no difference between the two groups.CONCLUSION Anterolateral rotatory instability significantly correlated shallow femoral tunnel positions after ACL reconstruction using BTB autografts. Clinical outcomes, rotatory and anterior-posterior stability were overall satisfactory in both techniques, but the TT technique located femoral tunnels in shallower and higher positions, and tibial tunnels in more posterior positions than the TP technique, thus increased the anterolateral rotation. Anatomic ACL reconstruction with BTB autografts may restore knee function and stability.展开更多
Incorporation of a tendon graft within the bone tunnel represents a challenging clinical problem. Successfulanterior cruciate ligament (ACL) reconstruction requires solid healing of the tendon graft in the bone tunnel...Incorporation of a tendon graft within the bone tunnel represents a challenging clinical problem. Successfulanterior cruciate ligament (ACL) reconstruction requires solid healing of the tendon graft in the bone tunnel. En-hancement of graft healing to bone is important to facilitate early aggressive rehabilitation and a rapid return topre-injury activity levels. No convenient, effective or inexpensive procedures exist to enhance tendon-bone (T-B)healing after surgery. Low-intensity pulsed ultrasound (LIPUS) improves local blood perfusion and angiogenesis,stimulates cartilage maturation, enhances differentiation and proliferation of osteoblasts, and motivates osteogenic differentiation of mesenchymal stem cells (MSCs), and therefore, appears to be a potential non-invasive tool for T-Bhealing in early stage of rehabilitation of ACL reconstruction. It is conceivable that LIPUS could be used to stimulateT-B tunnel healing in the home, with the aim of accelerating rehabilitation and an earlier return to normal activities inthe near future. The purpose of this review is to demonstrate how LIPUS stimulates T-B healing at the cellular andmolecular levels, describe studies in animal models, and provide a future direction for research.展开更多
The presence of excessive reactive oxygen species(ROS)after injuries to the enthesis could lead to cellular oxidative damage,high inflammatory response,chronic inflammation,and limited fibrochondral inductivity,making...The presence of excessive reactive oxygen species(ROS)after injuries to the enthesis could lead to cellular oxidative damage,high inflammatory response,chronic inflammation,and limited fibrochondral inductivity,making tissue repair and functional recovery difficult.Here,a multifunctional silk fibroin nanofiber modified with polydopamine and kartogenin was designed and fabricated to not only effectively reduce inflammation by scavenging ROS in the early stage of the enthesis healing but also enhance fibrocartilage formation with fibrochondrogenic induction in the later stages.The in vitro results confirmed the antioxidant capability and the fibrochondral inductivity of the functionalized nanofibers.In vivo studies showed that the multifunctional nanofiber can significantly improve the integration of tendon-bone and accelerate the regeneration of interface tissue,resulting in an excellent biomechanical property.Thus,the incorporation of antioxidant and bio-active molecules into extracellular matrix-like biomaterials in interface tissue engineering provides an integrative approach that facilitates damaged tissue regeneration and functional recovery,thereby improving the clinical outcome of the engineered tissue.展开更多
The tendon-bone interface effectively transfers mechanical stress for movement,yet its regeneration presents significant clinical challenges due to its hierarchical structure and composition.Biomimetic strategies that...The tendon-bone interface effectively transfers mechanical stress for movement,yet its regeneration presents significant clinical challenges due to its hierarchical structure and composition.Biomimetic strategies that replicate the distinctive characteristics have demonstrated potential for enhancing the healing process.However,there remains a challenge in developing a composite that replicates the nanostructure of the tendon-bone interface and embeds living cells.Here,we engineered a nanoscale biomimetic bilayer hydrogel embedded with tendon stem cells for tendon-bone interface healing.Specifically,the biomimetic hydrogel incorporates intra-and extrafibrillar mineralized collagen fibrils as well as non-mineralized collagen fibrils resembling the tendon-bone interface at the nanoscale.Furthermore,biomimetic mineralization with the presence of cells re-alizes living tendon-bone-like tissue constructs.In the in vivo patella-patellar tendon-interface injury model,the tendon stem cell-laden biomimetic hydrogel promoted tendon-bone interface regeneration,demonstrated by increased fibrocartilage formation,improved motor function,and enhanced biomechanical outcomes.This study highlights the potential of the stem cell-laden biomimetic hydrogel as an effective strategy for tendon-bone interface regeneration,offering a novel approach to engineering complex tissue interfaces.展开更多
Tendon-bone interface injuries pose a significant challenge in tissue regeneration,necessitating innovative approaches.Hydrogels with integrated supportive features and controlled release of therapeutic agents have em...Tendon-bone interface injuries pose a significant challenge in tissue regeneration,necessitating innovative approaches.Hydrogels with integrated supportive features and controlled release of therapeutic agents have emerged as promising candidates for the treatment of such injuries.In this study,we aimed to develop a temperature-sensitive composite hydrogel capable of providing sustained release of magnesium ions(Mg^(2+)).We synthesized magnesium-Procyanidin coordinated metal polyphenol nanoparticles(Mg-PC)through a self-assembly process and integrated them into a two-component hydrogel.The hydrogel was composed of dopamine-modified hyaluronic acid(Dop-HA)and F127.To ensure controlled release and mitigate the“burst release”effect of Mg^(2+),we covalently crosslinked the Mg-PC nanoparticles through coordination bonds with the catechol moiety within the hydrogel.This crosslinking strategy extended the release window of Mg^(2+)concentrations for up to 56 days.The resulting hydrogel(Mg-PC@Dop-HA/F127)exhibited favorable properties,including injectability,thermosensitivity and shape adaptability,making it suitable for injection and adaptation to irregularly shaped supraspinatus implantation sites.Furthermore,the hydrogel sustained the release of Mg^(2+)and Procyanidins,which attracted mesenchymal stem and progenitor cells,alleviated inflammation,and promoted macrophage polarization towards the M2 phenotype.Additionally,it enhanced collagen synthesis and mineralization,facilitating the repair of the tendon-bone interface.By incorporating multilevel metal phenolic networks(MPN)to control ion release,these hybridized hydrogels can be customized for various biomedical applications.展开更多
Healing of an anterior cruciate ligament(ACL)autologous graft in a bone tunnel occurs through the formation of fibrovascular scar tissue,which is structurally and compositionally inferior to normal fibrocartilaginous ...Healing of an anterior cruciate ligament(ACL)autologous graft in a bone tunnel occurs through the formation of fibrovascular scar tissue,which is structurally and compositionally inferior to normal fibrocartilaginous insertion and thus may increase the reconstruction failure and the rate of failure recurrence.In this study,an injectable hydroxyapatite/type I collagen(HAp/Col I)paste was developed to construct a suitable local microenvironment to accelerate the healing of bone-tendon interface.Physicochemical characterization demonstrated that the HAp/Col I paste was injectable,uniform and stable.The in vitro cell culture illustrated that the paste could promote MC3T3-E1 cells proliferation and osteogenic expression.The results of a canine ACL reconstruction study showed that the reconstructive ACL had similar texture and color as the native ACL.The average width of the tunnel,total bone volume,bone volume/tissue volume and trabecular number acquired from micro-CT analysis suggested that the healing of tendon-bone interface in experimental group was better than that in control group.The biomechanical test showed the maximal loads in experimental group achieved approximately half of native ACL’s maximal load at 24 weeks.According to histological examination,Sharpey fibers could be observed as early as 12 weeks postoperatively while a typical four-layer transitional structure of insertion site was regenerated at 48 weeks in the experimental group.The injectable HAp/Col I paste provided a biomimetic scaffold and microenvironment for early cell attachment and proliferation,further osteogenic expression and extracellular matrix deposition,and in vivo structural and functional regeneration of the tendon-bone interface.展开更多
Tendon-bone healing is essential for an effective rotator cuff tendon repair surgery,however,this remains a significant challenge due to the lack of biomaterials with high strength and bioactivity.Inspired by the high...Tendon-bone healing is essential for an effective rotator cuff tendon repair surgery,however,this remains a significant challenge due to the lack of biomaterials with high strength and bioactivity.Inspired by the high-performance exoskeleton of natural organisms,we set out to apply natural fish scale(FS)modified by calcium silicate nanoparticles(CS NPs)as a new biomaterial(CS-FS)to overcome the challenge.Benefit from its“Bouligand”microstructure,such FS-based scaffold maintained excellent tensile strength(125.05 MPa)and toughness(14.16 MJ/m^(3)),which are 1.93 and 2.72 times that of natural tendon respectively,allowing it to well meet the requirements for rotator cuff tendon repair.Additionally,CS-FS showed diverse bioactivities by stimulating the differentiation and phenotypic maintenance of multiple types of cells participated into the composition of tendon-bone junction,(e.g.bone marrow mesenchymal stem cells(BMSCs),chondrocyte,and tendon stem/progenitor cells(TSPCs)).In both rat and rabbit rotator cuff tear(RCT)models,CS-FS played a key role in the tendon-bone interface regeneration and biomechanical function,which may be achieved by activating BMP-2/Smad/Runx2 pathway in BMSCs.Therefore,natural fish scale-based biomaterials are the promising candidate for clinical tendon repair due to their outstanding strength and bioactivity.展开更多
The treatment of rotator cuff tear is one of the major challenges for orthopedic surgeons.The key to treatment is the reconstruction of the tendon-bone interface(TBI).Autologous platelet-rich plasma(PRP)is used as a t...The treatment of rotator cuff tear is one of the major challenges for orthopedic surgeons.The key to treatment is the reconstruction of the tendon-bone interface(TBI).Autologous platelet-rich plasma(PRP)is used as a therapeutic agent to accelerate the healing of tendons,as it contains a variety of growth factors and is easy to prepare.Graphene oxide(GO)is known to improve the physical properties of biomaterials and promote tissue repair.In this study,PRP gels containing various concentrations of GO were prepared to promote TBI healing and supraspinatus tendon reconstruction in a rabbit model.The incorporation of GO improved the ultrastructure and mechanical properties of the PRP gels.The gels containing 0.5 mg/ml GO(0.5 GO/PRP)continuously released transforming growth factor-b1(TGF-b1)and platelet-derived growth factor(PDGF)-AB,and the released TGF-b1 and PDGF-AB were still at high concentrations,1063.451 pg/ml and814.217 pg/ml,respectively,on the 14th day.In vitro assays showed that the 0.5 GO/PRP gels had good biocompatibility and promoted bone marrow mesenchymal stem cells proliferation and osteogenic and chondrogenic differentiation.After 12 weeks of implantation,the magnetic resonance imaging,microcomputed tomography and histological results indicated that the newly regenerated tendons in the 0.5 GO/PRP group had a similar structure to natural tendons.Moreover,the biomechanical results showed that the newly formed tendons in the 0.5 GO/PRP group had better biomechanical properties compared to those in the other groups,and had more stable TBI tissue.Therefore,the combination of PRP and GO has the potential to be a powerful advancement in the treatment of rotator cuff injuries.展开更多
According to Chinese medicine,the atlantoaxial joint is a composite joint composed of tendons and bones,and the stability of the joint depends on the‘tendon-bone balance’involving tendons,ligaments,atlas and axis.Mu...According to Chinese medicine,the atlantoaxial joint is a composite joint composed of tendons and bones,and the stability of the joint depends on the‘tendon-bone balance’involving tendons,ligaments,atlas and axis.Multiple causes of‘tendon off-position,joint subluxation’will lead to joint‘tendon-bone imbalance’,which will evolve into atlantoaxial subluxation(AAS),endangering human health.Chinese therapeutic massage(tuina)is a very effective treatment for AAS in adults,but conventional manipulations are prone to ineffectiveness or accidents due to neglect of the causal relationship of the‘tendon-bone imbalance’and inappropriate manipulations.Compared with conventional manipulations,the rational choice of modified manipulations under the guidance of‘tendon-bone balance’theory is more effective and less risky,and more worthy of clinical promotion.From the‘tendon-bone balance’theory,we considered the shortcomings of conventional manipulations,and introduced several modified manipulations that have their own strengths in‘tendon smoothing’and‘bone setting’,in order to provide new ideas for treatment of AAS in adults.展开更多
Background:We previously confirmed that mechanical stimulation is an important factor in the repair of tendon-bone insertion(TBI)injuries and that mechanoreceptors such as transient receptor potential ion-channel subf...Background:We previously confirmed that mechanical stimulation is an important factor in the repair of tendon-bone insertion(TBI)injuries and that mechanoreceptors such as transient receptor potential ion-channel subfamily V member 4(TRPV4;also known as transient receptor potential vanilloid 4)are key to transforming mechanical stimulation into intracellular biochemical signals.This study aims to elucidate the mechanism of mechanical stimulation regulating TRPV4.Methods:Immunohistochemical staining and western blotting were used to evaluate cartilage repair at the TBI after injury.The RNA expression and protein expression of mechanoreceptors and key pathway molecules regulating cartilage proliferation were analyzed.TBI samples were collected for transcriptome sequencing to detect gene expression.Calcium-ion imaging and flow cytometry were used to evaluate the function of TPRV4 and cellular communication network factor 2(CCN2)after the administration of siRNA,recombinant adenovirus and agonists.Results:We found that treadmill training improved the quality of TBI healing and enhanced fibrochondrocyte proliferation.The transcriptome sequencing results suggested that the elevated expression of the mechanistically stimulated regulator CCN2 and the exogenous administration of recombinant human CCN2 significantly promoted TRPV4 protein expression and fibrochondrocyte proliferation.In vitro,under mechanical stimulation conditions,small interfering RNA(siRNA)-CCN2 not only inhibited the proliferation of primary fibrochondrocytes but also suppressed TRPV4 protein expression and activity.Subsequently,primary fibrochondrocytes were treated with the TRPV4 agonist GSK1016790A and the recombinant adenovirus TRPV4(Ad-TRPV4),and GSK1016790A partially reversed the inhibitory effect of siRNA-CCN2.The phosphoinositide 3-kinase/protein kinase B(PI3K/AKT)signaling pathway participated in the above process.Conclusions:Mechanical stimulation promoted fibrochondrocyte proliferation and TBI healing by activating TRPV4 channels and the PI3K/AKT signaling pathway,and CCN2 may be a key regulatory protein in maintaining TRPV4 activation.展开更多
Entheses are highly specialised organs connecting ligaments and tendons to bones,facilitating force transmission,and providing mechanical strengths to absorb forces encountered.Two types of entheses,fibrocartilaginous...Entheses are highly specialised organs connecting ligaments and tendons to bones,facilitating force transmission,and providing mechanical strengths to absorb forces encountered.Two types of entheses,fibrocartilaginous and fibrous,exist in interfaces.The gradual fibrocartilaginous type is in rotator cuff tendons and is more frequently injured due to the poor healing capacity that leads to loss of the original structural and biomechanical properties and is attributed to the high prevalence of retears.Fluctuating methodologies and outcomes of biological approaches are challenges to overcome for them to be routinely used in clinics.Therefore,stratifying the existing literature according to different categories(chronicity,extent of tear,and studied population)would effectively guide repair approaches.This literature review supports tissue engineering approaches to promote rotator cuff enthesis healing employing cells,growth factors,and scaffolds period.Outcomes suggest its promising role in animal studies as well as some clinical trials and that combination therapies are more beneficial than individualized ones.It then highlights the importance of tailoring interventions according to the tear extent,chronicity,and the population being treated.Contributing factors such as loading,deficiencies,and lifestyle habits should also be taken into consideration.Optimum results can be achieved if biological,mechanical,and environmental factors are approached.It is challenging to determine whether variations are due to the interventions themselves,the animal models,loading regimen,materials,or tear mechanisms.Future research should focus on tailoring interventions for different categories to formulate protocols,which would best guide regenerative medicine decision making.展开更多
Tendon-related diseases(TRDs)are increasingly common in the current aging society and impose a significant burden on patients.Despite therapeutic advances,the pathophysiology of TRDs remains poorly understood,hinderin...Tendon-related diseases(TRDs)are increasingly common in the current aging society and impose a significant burden on patients.Despite therapeutic advances,the pathophysiology of TRDs remains poorly understood,hindering effective clinical management.The macrophages are highly plastic immune cells involved in the maintenance of in vivo homeostasis and the injury-healing process.Their dual role in TRDs has been widely investigated,either promoting tenogenic and chondrogenic differentiation or amplifying inflammatory response,underscoring their therapeutic potential for TRDs treatment.Therefore,the review aims to summarize the roles of macrophages in the healing of TRDs,characterized by limited regenerative capacity,and examine strategies for the modulation of macrophage phenotypes to accelerate the regeneration process.Finally,we review applications involving macrophage modulation within the context of tissue engineering of TRDs,providing novel insights for the design of biomaterials-based targeted delivery systems.展开更多
文摘BACKGROUND Anterior cruciate ligament reconstruction(ACLR)is the dominant clinical modality for the treatment of anterior cruciate ligament injuries.The success of ACLR is largely dependent on tendon-bone healing,and stem cell biotherapies are often used to facilitate this process.Histone lactylation modifications are involved in the regulation of various diseases.Lactate dehydrogenase A(LDHA)has been shown to play an important role in exosomes.AIM To explore the regulation of tendon-bone healing after ACLR by LDHA in exosomes derived from bone marrow mesenchymal stem cells(BMSC-Exos).METHODS BMSC-Exos and LDHA were characterized and analyzed by transmission electron microscopy,qNano,immunofluorescence and western blotting assay.The corresponding low expression cell lines were obtained using RNA interference transfection;LDHA expression in rat bone tissues after ACLR was analyzed by western blotting.The volume of newborn bone tissues was monitored by micro-computed tomography imaging.Tendon and fibrocartilage regeneration were further analyzed and calculated by histological analysis,including hematoxylin and eosin and Safranin O-Fast green staining,respectively;LDHA levels of chondrocyte stem cells(CSPCs)after co-incubation with BMSC-Exos were analyzed by western blotting.Extracellularly secreted lactic acid content was determined by lactate assay kit.Cell viability was assessed by cell counting kit 8 assay,and the proliferation and differentiation ability of cells was further examined by the expression of collagen II,SOX9 and aggrecan.Histone H3K18 lactylation modification was analyzed by western blotting.H3K18 La binding on bone morphogenetic protein 7(BMP7)promoter was analyzed by chromatin immunoprecipitation-quantitative polymerase chain reaction;BMP7 promoter activity was analyzed by dual luciferase reporter gene;BMP7 protein expression was analyzed using quantitative polymerase chain reaction and western blotting.Then,the proliferation of CSPCs promoted by BMSC-Exos LDHA was analyzed by protein expression levels of LDHA,BMP7,collagen II,SOX9,aggrecan,extracellular lactate content,and cell counting kit 8 assay.RESULTS The spherical nanosized BMSC-Exos could be uptaken by CSPCs.LDHA was highly expressed in BMSC-Exos,which could infiltrate into the bone tissue of ACLR rats and promoted the generation of new bone tissue,as well as significantly increased the regeneration of tendon and fibrocartilage.Co-incubation of CSPCs with high-expressing LDHA BMSC-Exos increased the secretion of lactate content from CSPCs,cell viability,and the expression of markers related to cell proliferation and differentiation,including collagen II,SOX9,and aggrecan;LDHA in BMSC-Exos upregulated BMP7 through histone H3K18 lactate modification;high LDHA expression reversed the knockdown of BMP7,further increasing the proliferation and differentiation of CSPCs,thereby inducing cartilage formation.CONCLUSION LDHA in BMSC-Exos promotes BMP7 expression via H3K18 lactylation modification,which further promotes tendon-bone healing after ACLR.
基金Jinhua Public Welfare Technology Application Research Project,No.2025-4-229Zhejiang Province Medical and Health Science and Technology Plan,No.2022KY1343.
文摘Tendon-bone healing remains a significant clinical challenge due to the high risk of re-rupture following injury.While mesenchymal stem cells(MSCs)show great potential in enhancing tendon-bone healing,their clinical application is limited by issues such as low delivery efficiency,restricted differentiation potential,and potential immunogenicity.Recently,various strategies combining MSCs with other approaches,such as preconditioning,biomaterial integration,gene modification,and exosome application,have been developed,resulting in improved therapeutic outcomes.This review explored the current methods used to optimize MSC therapy for tendon-bone healing,examining the advantages,disadvantages,and underlying mechanisms of each approach,providing a foundation for future research and clinical applications.
基金Supported by JSPS Fellowships for Research Abroad,No.H27-787International Research Fund for Subsidy of Kyushu University School of Medicine Alumni
文摘AIM To quantitatively assess rotatory and anterior-posterior instability in vivo after anterior cruciate ligament(ACL) reconstruction using bone-patellar tendon-bone(BTB) autografts, and to clarify the influence of tunnel positions on the knee stability.METHODS Single-bundle ACL reconstruction with BTB autograft was performed on 50 patients with a mean age of 28 years using the trans-tibial(TT)(n = 20) and trans-portal(TP)(n = 30) techniques. Femoral and tibial tunnel positions were identified from the high-resolution 3 D-CT bone models two weeks after surgery. Anterolateral rotatory translation was examined using a Slocum anterolateral rotatory instability test in open magnetic resonance imaging(MRI) 1.0-1.5 years after surgery, by measuring anterior tibial translation at the medial and lateral compartments on its sagittal images. Anterior-posterior stability was evaluated with a Kneelax3 arthrometer.RESULTS A total of 40 patients(80%) were finally followed up. Femoral tunnel positions were shallower(P < 0.01) and higher(P < 0.001), and tibial tunnel positions were more posterior(P < 0.05) in the TT group compared with the TP group. Anterolateral rotatory translations in reconstructed knees were significantly correlated with the shallow femoral tunnel positions(R = 0.42, P < 0.01), and the rotatory translations were greater in the TT group(3.2 ± 1.6 mm) than in the TP group(2.0 ± 1.8 mm)(P < 0.05). Side-to-side differences of Kneelax3 arthrometer were 1.5 ± 1.3 mm in the TT, and 1.7 ± 1.6 mm in the TP group(N.S.). Lysholm scores, KOOS subscales and reinjury rate showed no difference between the two groups.CONCLUSION Anterolateral rotatory instability significantly correlated shallow femoral tunnel positions after ACL reconstruction using BTB autografts. Clinical outcomes, rotatory and anterior-posterior stability were overall satisfactory in both techniques, but the TT technique located femoral tunnels in shallower and higher positions, and tibial tunnels in more posterior positions than the TP technique, thus increased the anterolateral rotation. Anatomic ACL reconstruction with BTB autografts may restore knee function and stability.
基金Project (No. 81171687/H0604) supported by the National Natural Science Foundation of China
文摘Incorporation of a tendon graft within the bone tunnel represents a challenging clinical problem. Successfulanterior cruciate ligament (ACL) reconstruction requires solid healing of the tendon graft in the bone tunnel. En-hancement of graft healing to bone is important to facilitate early aggressive rehabilitation and a rapid return topre-injury activity levels. No convenient, effective or inexpensive procedures exist to enhance tendon-bone (T-B)healing after surgery. Low-intensity pulsed ultrasound (LIPUS) improves local blood perfusion and angiogenesis,stimulates cartilage maturation, enhances differentiation and proliferation of osteoblasts, and motivates osteogenic differentiation of mesenchymal stem cells (MSCs), and therefore, appears to be a potential non-invasive tool for T-Bhealing in early stage of rehabilitation of ACL reconstruction. It is conceivable that LIPUS could be used to stimulateT-B tunnel healing in the home, with the aim of accelerating rehabilitation and an earlier return to normal activities inthe near future. The purpose of this review is to demonstrate how LIPUS stimulates T-B healing at the cellular andmolecular levels, describe studies in animal models, and provide a future direction for research.
基金supported financially by the National Natural Science Foundation of China[No.11532004,11832008]Innovation and Attracting Talents Program for College and University(“111”Project)[No.B06023]。
文摘The presence of excessive reactive oxygen species(ROS)after injuries to the enthesis could lead to cellular oxidative damage,high inflammatory response,chronic inflammation,and limited fibrochondral inductivity,making tissue repair and functional recovery difficult.Here,a multifunctional silk fibroin nanofiber modified with polydopamine and kartogenin was designed and fabricated to not only effectively reduce inflammation by scavenging ROS in the early stage of the enthesis healing but also enhance fibrocartilage formation with fibrochondrogenic induction in the later stages.The in vitro results confirmed the antioxidant capability and the fibrochondral inductivity of the functionalized nanofibers.In vivo studies showed that the multifunctional nanofiber can significantly improve the integration of tendon-bone and accelerate the regeneration of interface tissue,resulting in an excellent biomechanical property.Thus,the incorporation of antioxidant and bio-active molecules into extracellular matrix-like biomaterials in interface tissue engineering provides an integrative approach that facilitates damaged tissue regeneration and functional recovery,thereby improving the clinical outcome of the engineered tissue.
基金supported by the National key research and development program of China(2022YFA1106800)NSFC grants(82222044,T2121004,32271404)+2 种基金Key R&D Program of Zhejiang(2024SSYS0026)“Leading Goose”Science and Technology Project of Zhejiang Province(2023C03093)Zhejiang Provincial Natural Science Foundation of China(LZ22H060002).
文摘The tendon-bone interface effectively transfers mechanical stress for movement,yet its regeneration presents significant clinical challenges due to its hierarchical structure and composition.Biomimetic strategies that replicate the distinctive characteristics have demonstrated potential for enhancing the healing process.However,there remains a challenge in developing a composite that replicates the nanostructure of the tendon-bone interface and embeds living cells.Here,we engineered a nanoscale biomimetic bilayer hydrogel embedded with tendon stem cells for tendon-bone interface healing.Specifically,the biomimetic hydrogel incorporates intra-and extrafibrillar mineralized collagen fibrils as well as non-mineralized collagen fibrils resembling the tendon-bone interface at the nanoscale.Furthermore,biomimetic mineralization with the presence of cells re-alizes living tendon-bone-like tissue constructs.In the in vivo patella-patellar tendon-interface injury model,the tendon stem cell-laden biomimetic hydrogel promoted tendon-bone interface regeneration,demonstrated by increased fibrocartilage formation,improved motor function,and enhanced biomechanical outcomes.This study highlights the potential of the stem cell-laden biomimetic hydrogel as an effective strategy for tendon-bone interface regeneration,offering a novel approach to engineering complex tissue interfaces.
基金supported by the National Natural Science Foundation of China[grant numbers:82302639,81974327,81974328 and 82372358]National Students’Platform for Innovation and Entrepreneurship Training Program of China[grant number:No.202212121004]+1 种基金Natural Science Funds for Distinguished Young Scholar of Guangdong province[grant number:2022B1515020044]the Natural Science Foundation of Guangdong Province[grant number:2022A1515011101].
文摘Tendon-bone interface injuries pose a significant challenge in tissue regeneration,necessitating innovative approaches.Hydrogels with integrated supportive features and controlled release of therapeutic agents have emerged as promising candidates for the treatment of such injuries.In this study,we aimed to develop a temperature-sensitive composite hydrogel capable of providing sustained release of magnesium ions(Mg^(2+)).We synthesized magnesium-Procyanidin coordinated metal polyphenol nanoparticles(Mg-PC)through a self-assembly process and integrated them into a two-component hydrogel.The hydrogel was composed of dopamine-modified hyaluronic acid(Dop-HA)and F127.To ensure controlled release and mitigate the“burst release”effect of Mg^(2+),we covalently crosslinked the Mg-PC nanoparticles through coordination bonds with the catechol moiety within the hydrogel.This crosslinking strategy extended the release window of Mg^(2+)concentrations for up to 56 days.The resulting hydrogel(Mg-PC@Dop-HA/F127)exhibited favorable properties,including injectability,thermosensitivity and shape adaptability,making it suitable for injection and adaptation to irregularly shaped supraspinatus implantation sites.Furthermore,the hydrogel sustained the release of Mg^(2+)and Procyanidins,which attracted mesenchymal stem and progenitor cells,alleviated inflammation,and promoted macrophage polarization towards the M2 phenotype.Additionally,it enhanced collagen synthesis and mineralization,facilitating the repair of the tendon-bone interface.By incorporating multilevel metal phenolic networks(MPN)to control ion release,these hybridized hydrogels can be customized for various biomedical applications.
基金supported by the National Key Research and Development Program of China(2018YFC1106200,2018YFC1106203)the National Natural Science Foundation of China(32071330)+1 种基金the Sichuan Science and Technology Innovation Team(2019JDTD0008)the Key Science and Technology Program of Guangxi Province(AA17204085-2).
文摘Healing of an anterior cruciate ligament(ACL)autologous graft in a bone tunnel occurs through the formation of fibrovascular scar tissue,which is structurally and compositionally inferior to normal fibrocartilaginous insertion and thus may increase the reconstruction failure and the rate of failure recurrence.In this study,an injectable hydroxyapatite/type I collagen(HAp/Col I)paste was developed to construct a suitable local microenvironment to accelerate the healing of bone-tendon interface.Physicochemical characterization demonstrated that the HAp/Col I paste was injectable,uniform and stable.The in vitro cell culture illustrated that the paste could promote MC3T3-E1 cells proliferation and osteogenic expression.The results of a canine ACL reconstruction study showed that the reconstructive ACL had similar texture and color as the native ACL.The average width of the tunnel,total bone volume,bone volume/tissue volume and trabecular number acquired from micro-CT analysis suggested that the healing of tendon-bone interface in experimental group was better than that in control group.The biomechanical test showed the maximal loads in experimental group achieved approximately half of native ACL’s maximal load at 24 weeks.According to histological examination,Sharpey fibers could be observed as early as 12 weeks postoperatively while a typical four-layer transitional structure of insertion site was regenerated at 48 weeks in the experimental group.The injectable HAp/Col I paste provided a biomimetic scaffold and microenvironment for early cell attachment and proliferation,further osteogenic expression and extracellular matrix deposition,and in vivo structural and functional regeneration of the tendon-bone interface.
基金supported by the National Basic Research Program of China(grant No.2021YFA0715700)the Natural Science Foundation of China(32130062)+1 种基金Innovation Cross Team of Chinese Academy of Sciences(JCTD-2018-13)Science and Technology Commission of Shanghai Municipality(20442420300,21DZ1205600).
文摘Tendon-bone healing is essential for an effective rotator cuff tendon repair surgery,however,this remains a significant challenge due to the lack of biomaterials with high strength and bioactivity.Inspired by the high-performance exoskeleton of natural organisms,we set out to apply natural fish scale(FS)modified by calcium silicate nanoparticles(CS NPs)as a new biomaterial(CS-FS)to overcome the challenge.Benefit from its“Bouligand”microstructure,such FS-based scaffold maintained excellent tensile strength(125.05 MPa)and toughness(14.16 MJ/m^(3)),which are 1.93 and 2.72 times that of natural tendon respectively,allowing it to well meet the requirements for rotator cuff tendon repair.Additionally,CS-FS showed diverse bioactivities by stimulating the differentiation and phenotypic maintenance of multiple types of cells participated into the composition of tendon-bone junction,(e.g.bone marrow mesenchymal stem cells(BMSCs),chondrocyte,and tendon stem/progenitor cells(TSPCs)).In both rat and rabbit rotator cuff tear(RCT)models,CS-FS played a key role in the tendon-bone interface regeneration and biomechanical function,which may be achieved by activating BMP-2/Smad/Runx2 pathway in BMSCs.Therefore,natural fish scale-based biomaterials are the promising candidate for clinical tendon repair due to their outstanding strength and bioactivity.
基金supported by the Luzhou Municipal People’s Government-SouthwestMedical University Science and Technology Cooperation Achievements Transformation Project(2019LZXNYDJ20C01).
文摘The treatment of rotator cuff tear is one of the major challenges for orthopedic surgeons.The key to treatment is the reconstruction of the tendon-bone interface(TBI).Autologous platelet-rich plasma(PRP)is used as a therapeutic agent to accelerate the healing of tendons,as it contains a variety of growth factors and is easy to prepare.Graphene oxide(GO)is known to improve the physical properties of biomaterials and promote tissue repair.In this study,PRP gels containing various concentrations of GO were prepared to promote TBI healing and supraspinatus tendon reconstruction in a rabbit model.The incorporation of GO improved the ultrastructure and mechanical properties of the PRP gels.The gels containing 0.5 mg/ml GO(0.5 GO/PRP)continuously released transforming growth factor-b1(TGF-b1)and platelet-derived growth factor(PDGF)-AB,and the released TGF-b1 and PDGF-AB were still at high concentrations,1063.451 pg/ml and814.217 pg/ml,respectively,on the 14th day.In vitro assays showed that the 0.5 GO/PRP gels had good biocompatibility and promoted bone marrow mesenchymal stem cells proliferation and osteogenic and chondrogenic differentiation.After 12 weeks of implantation,the magnetic resonance imaging,microcomputed tomography and histological results indicated that the newly regenerated tendons in the 0.5 GO/PRP group had a similar structure to natural tendons.Moreover,the biomechanical results showed that the newly formed tendons in the 0.5 GO/PRP group had better biomechanical properties compared to those in the other groups,and had more stable TBI tissue.Therefore,the combination of PRP and GO has the potential to be a powerful advancement in the treatment of rotator cuff injuries.
文摘According to Chinese medicine,the atlantoaxial joint is a composite joint composed of tendons and bones,and the stability of the joint depends on the‘tendon-bone balance’involving tendons,ligaments,atlas and axis.Multiple causes of‘tendon off-position,joint subluxation’will lead to joint‘tendon-bone imbalance’,which will evolve into atlantoaxial subluxation(AAS),endangering human health.Chinese therapeutic massage(tuina)is a very effective treatment for AAS in adults,but conventional manipulations are prone to ineffectiveness or accidents due to neglect of the causal relationship of the‘tendon-bone imbalance’and inappropriate manipulations.Compared with conventional manipulations,the rational choice of modified manipulations under the guidance of‘tendon-bone balance’theory is more effective and less risky,and more worthy of clinical promotion.From the‘tendon-bone balance’theory,we considered the shortcomings of conventional manipulations,and introduced several modified manipulations that have their own strengths in‘tendon smoothing’and‘bone setting’,in order to provide new ideas for treatment of AAS in adults.
基金supported by the National Natural Science Foundation of China(NSFC,Nos.82130071 and 82072516).
文摘Background:We previously confirmed that mechanical stimulation is an important factor in the repair of tendon-bone insertion(TBI)injuries and that mechanoreceptors such as transient receptor potential ion-channel subfamily V member 4(TRPV4;also known as transient receptor potential vanilloid 4)are key to transforming mechanical stimulation into intracellular biochemical signals.This study aims to elucidate the mechanism of mechanical stimulation regulating TRPV4.Methods:Immunohistochemical staining and western blotting were used to evaluate cartilage repair at the TBI after injury.The RNA expression and protein expression of mechanoreceptors and key pathway molecules regulating cartilage proliferation were analyzed.TBI samples were collected for transcriptome sequencing to detect gene expression.Calcium-ion imaging and flow cytometry were used to evaluate the function of TPRV4 and cellular communication network factor 2(CCN2)after the administration of siRNA,recombinant adenovirus and agonists.Results:We found that treadmill training improved the quality of TBI healing and enhanced fibrochondrocyte proliferation.The transcriptome sequencing results suggested that the elevated expression of the mechanistically stimulated regulator CCN2 and the exogenous administration of recombinant human CCN2 significantly promoted TRPV4 protein expression and fibrochondrocyte proliferation.In vitro,under mechanical stimulation conditions,small interfering RNA(siRNA)-CCN2 not only inhibited the proliferation of primary fibrochondrocytes but also suppressed TRPV4 protein expression and activity.Subsequently,primary fibrochondrocytes were treated with the TRPV4 agonist GSK1016790A and the recombinant adenovirus TRPV4(Ad-TRPV4),and GSK1016790A partially reversed the inhibitory effect of siRNA-CCN2.The phosphoinositide 3-kinase/protein kinase B(PI3K/AKT)signaling pathway participated in the above process.Conclusions:Mechanical stimulation promoted fibrochondrocyte proliferation and TBI healing by activating TRPV4 channels and the PI3K/AKT signaling pathway,and CCN2 may be a key regulatory protein in maintaining TRPV4 activation.
文摘Entheses are highly specialised organs connecting ligaments and tendons to bones,facilitating force transmission,and providing mechanical strengths to absorb forces encountered.Two types of entheses,fibrocartilaginous and fibrous,exist in interfaces.The gradual fibrocartilaginous type is in rotator cuff tendons and is more frequently injured due to the poor healing capacity that leads to loss of the original structural and biomechanical properties and is attributed to the high prevalence of retears.Fluctuating methodologies and outcomes of biological approaches are challenges to overcome for them to be routinely used in clinics.Therefore,stratifying the existing literature according to different categories(chronicity,extent of tear,and studied population)would effectively guide repair approaches.This literature review supports tissue engineering approaches to promote rotator cuff enthesis healing employing cells,growth factors,and scaffolds period.Outcomes suggest its promising role in animal studies as well as some clinical trials and that combination therapies are more beneficial than individualized ones.It then highlights the importance of tailoring interventions according to the tear extent,chronicity,and the population being treated.Contributing factors such as loading,deficiencies,and lifestyle habits should also be taken into consideration.Optimum results can be achieved if biological,mechanical,and environmental factors are approached.It is challenging to determine whether variations are due to the interventions themselves,the animal models,loading regimen,materials,or tear mechanisms.Future research should focus on tailoring interventions for different categories to formulate protocols,which would best guide regenerative medicine decision making.
基金supported by the Guangxi Natural Science Foundation(AD21220065 to JX)the National Natural Science Foundation of China(82102632 and 82160412 to JX)the Guangdong Basic and Applied Basic Research Foundation(2023A1515220072 to ZHD)。
文摘Tendon-related diseases(TRDs)are increasingly common in the current aging society and impose a significant burden on patients.Despite therapeutic advances,the pathophysiology of TRDs remains poorly understood,hindering effective clinical management.The macrophages are highly plastic immune cells involved in the maintenance of in vivo homeostasis and the injury-healing process.Their dual role in TRDs has been widely investigated,either promoting tenogenic and chondrogenic differentiation or amplifying inflammatory response,underscoring their therapeutic potential for TRDs treatment.Therefore,the review aims to summarize the roles of macrophages in the healing of TRDs,characterized by limited regenerative capacity,and examine strategies for the modulation of macrophage phenotypes to accelerate the regeneration process.Finally,we review applications involving macrophage modulation within the context of tissue engineering of TRDs,providing novel insights for the design of biomaterials-based targeted delivery systems.
