Piezoelectric stimulation has garnered substantial interest as a promising strategy for tissue regeneration.However,studies investigating its impact on tendon-to-bone healing characterized by fibrocartilage remain sca...Piezoelectric stimulation has garnered substantial interest as a promising strategy for tissue regeneration.However,studies investigating its impact on tendon-to-bone healing characterized by fibrocartilage remain scarce.Moreover,there are considerable technical challenges in achieving minimally invasive application of piezoelectric stimulation on the irregular tendon-to-bone interface.Herein,we developed Janus asymmetric piezoelectric adhesives by assembling adhesive hydrogel(GAN)and non-adhesive hydrogel(GM)on each side of piezoelectric poly(L-lactic acid)nanofiber.Piezoelectric adhesives exhibited superior anti-inflammatory effects both in vitro and ex vivo.Notably,the transient receptor potential(TRP)ion channels,a class of versatile signaling molecules,are closely associated with the regulation of inflammation.This study demonstrated that piezoelectric stimulation promoted Ca2+influx through the activation of transient receptor potential vanilloid 1(TRPV1),further enhancing cAMP signaling pathway in macrophages by RNA sequencing.Additionally,in vivo proteomic analysis revealed Arachidonic acid metabolism and TNF-αsignaling pathway downregulation and VEGF signaling pathway upregulation in a rat rotator cuff repair model.Piezoelectric adhesives ultimately achieved inflammation alleviation,angiogenesis enhancement,and fibrocartilage regeneration promotion,improving the biomechanical strength of the enthesis.This study elucidated the mechanism by which piezoelectric stimulation regulated tendon-to-bone healing through multi-omics analysis.The piezoelectric adhesives hold promise as a convenient and effective strategy for enhancing tendon-to-bone healing in clinical practice.展开更多
Electrospun fibers,with proven ability to promote tissue regeneration,are widely being explored for rotator cuff repairing.However,without post treatment,the microstructure of the electrospun scaffold is vastly differ...Electrospun fibers,with proven ability to promote tissue regeneration,are widely being explored for rotator cuff repairing.However,without post treatment,the microstructure of the electrospun scaffold is vastly different from that of natural extracellular matrix(ECM).Moreover,during mechanical loading,the nanofibers slip that hampers the proliferation and differentiation of migrating stem cells.Here,electrospun nanofiber scaffolds,with crimped nanofibers and welded joints to biomimic the intricate natural microstructure of tendon-to-bone insertion,were prepared using poly(ester-urethane)urea and gelatin via electrospinning and double crosslinking by a multi-bonding network densification strategy.The crimped nanofiber scaffold(CNS)features bionic tensile stress and induces chondrogenic differentiation,laying credible basis for in vivo experimentation.After repairing a rabbit massive rotator cuff tear using a CNS for 3 months,the continuous translational tendon-to-bone interface was fully regenerated,and fatty infiltration was simultaneously inhibited.Instead of micro-CT,μCT was employed to visualize the integrity and intricateness of the three-dimensional microstructure of the CNS-induced-healed tendon-to-bone interface at an ultra-high resolution of less than 1μm.This study sheds light on the correlation between nanofiber post treatment and massive rotator cuff repair and provides a general strategy for crimped nanofiber preparation and tendon-to-bone interface imaging characterization.展开更多
Regarding the current materials used for suture anchors for rotator cuff repair,there are still limitations in terms of degradability,mechanical properties,and bioactivities in clinical applications.Magnesium alloys h...Regarding the current materials used for suture anchors for rotator cuff repair,there are still limitations in terms of degradability,mechanical properties,and bioactivities in clinical applications.Magnesium alloys have preliminarily been shown to promote tendon-bone healing with good prospects for application as anchor materials.However,the design of anchor structures for the degradation characteristics of magnesium alloy materials has not been considered,which is critical for the practical application of magnesium alloy anchors.The mechanism by which magnesium promotes tendon bone healing remains to be clarified.Here,we proposed a novel split hollowed magnesium alloy suture anchors for the repair of rabbit rotator cuff injury.We found that novel split hollowed magnesium alloy anchors structure effectively solved the problem of failure due to degradation of traditional eyelet structure,providing reliable suture fixation.The open architecture facilitates the metabolic resorption of the degradation products of and promotes the ingrowth of bone tissue.Histological staining showed that magnesium anchors have better ability to promote regeneration at the fibrocartilage interface compared to PLLA anchors.The higher expression of fibrocartilage markers(Aggrecan,COL2A1,and Sox9)at the tendon-bone interface in magnesium anchors,which promotes chondrocyte differentiation at the tendon-bone interface and matrix formation,which is more conducive to achieving regeneration and maturation of fibrocartilage enthesis.Hence,this study provides a basis for further research on the clinical application of degradable magnesium alloy suture anchors.展开更多
The rate of retear after surgical repair remains high.Mesenchymal stem cells(MSCs)have been extensively employed in regenerative medicine for several decades.However,safety and ethical concerns constrain their clinica...The rate of retear after surgical repair remains high.Mesenchymal stem cells(MSCs)have been extensively employed in regenerative medicine for several decades.However,safety and ethical concerns constrain their clinical application.Tendon Stem/Progenitor Cells(TSPCs)-derived exosomes have emerged as promising cellfree therapeutic agents.Therefore,urgent studies are needed to investigate whether TSPC-Exos could enhance tendon-bone healing and elucidate the underlying mechanisms.In this study,TSPC-Exos were found to promote the proliferation,migration,and expression of fibrogenesis markers in BMSCs.Furthermore,TSPC-Exos demonstrated an ability to suppress the polarization of M1 macrophages while promoting M2 macrophage polarization.In a rat model of rotator cuff repair,TSPC-Exos modulated inflammation and improved the histological structure of the tendon-bone interface,the biomechanical properties of the repaired tendon,and the function of the joint.Mechanistically,TSPC-Exos exhibited high expression of miR-21a-5p,which regulated the expression of PDCD4.The PDCD4/AKT/mTOR axis was implicated in the therapeutic effects of TSPC-Exos on proliferation,migration,and fibrogenesis in BMSCs.This study introduces a novel approach utilizing TSPC-Exos therapy as a promising strategy for cell-free therapies,potentially benefiting patients with rotator cuff tear in the future.展开更多
Degradable rotator cuff patches,followed over five years,have been observed to exhibit high re-tear rates exceeding 50%,which is attributed to the inability of degradable polymers alone to restore the post-rotator cuf...Degradable rotator cuff patches,followed over five years,have been observed to exhibit high re-tear rates exceeding 50%,which is attributed to the inability of degradable polymers alone to restore the post-rotator cuff tear(RCT)inflammatory niche.Herein,poly(ester-ferulic acid-urethane)urea(PEFUU)was developed,featuring prolonged anti-inflammatory functionality,achieved by the integration of ferulic acid(FA)into the polyurethane repeating units.PEFUU stably releases FA in vitro,reversing the inflammatory niche produced by M1 macrophages and restoring the directed differentiation of stem cells.Utilizing PEFUU,hierarchical composite nanofiber patch(HCNP)was fabricated,simulating the natural microstructure of the tendon-to-bone interface with an aligned-random alignment.The incorporation of enzymatic hydrolysate derived from decellularized Wharton jelly tissue into the random layer could further enhance cartilage regeneration at the tendon-to-bone interface.Via rat RCT repairing model,HCNP possessing prolonged anti-inflammatory properties uniquely facilitated physiological healing at the tendon-to-bone interface’s microstructure.The alignment of fibers was restored,and histologically,the characteristic tripartite distribution of collagen I-collagen II-collagen I was achieved.This study offers a universal approach to the functionalization of degradable polymers and provides a foundational reference for their future applications in promoting the in vivo regeneration of musculoskeletal tissues.展开更多
基金the National Natural Science Foundation of China(Grant No.82372491,82172509,82102634,32371402).
文摘Piezoelectric stimulation has garnered substantial interest as a promising strategy for tissue regeneration.However,studies investigating its impact on tendon-to-bone healing characterized by fibrocartilage remain scarce.Moreover,there are considerable technical challenges in achieving minimally invasive application of piezoelectric stimulation on the irregular tendon-to-bone interface.Herein,we developed Janus asymmetric piezoelectric adhesives by assembling adhesive hydrogel(GAN)and non-adhesive hydrogel(GM)on each side of piezoelectric poly(L-lactic acid)nanofiber.Piezoelectric adhesives exhibited superior anti-inflammatory effects both in vitro and ex vivo.Notably,the transient receptor potential(TRP)ion channels,a class of versatile signaling molecules,are closely associated with the regulation of inflammation.This study demonstrated that piezoelectric stimulation promoted Ca2+influx through the activation of transient receptor potential vanilloid 1(TRPV1),further enhancing cAMP signaling pathway in macrophages by RNA sequencing.Additionally,in vivo proteomic analysis revealed Arachidonic acid metabolism and TNF-αsignaling pathway downregulation and VEGF signaling pathway upregulation in a rat rotator cuff repair model.Piezoelectric adhesives ultimately achieved inflammation alleviation,angiogenesis enhancement,and fibrocartilage regeneration promotion,improving the biomechanical strength of the enthesis.This study elucidated the mechanism by which piezoelectric stimulation regulated tendon-to-bone healing through multi-omics analysis.The piezoelectric adhesives hold promise as a convenient and effective strategy for enhancing tendon-to-bone healing in clinical practice.
基金supported by Instrumental Analysis Center of Shanghai Jiao Tong University.This work was supported by the National Natural Science Foundation of China[Grant No.81902186,81671920,31972923,81871753,81772341]National Key Research and Development Program of China[Grant No.2018YFC1106200,2018YFC1106201,2018YFC1106202]Technology Support Project of Science and Technology Commission of Shanghai Municipality of China[Grant No.19441901700,19441901701,19441901702,18441902800].
文摘Electrospun fibers,with proven ability to promote tissue regeneration,are widely being explored for rotator cuff repairing.However,without post treatment,the microstructure of the electrospun scaffold is vastly different from that of natural extracellular matrix(ECM).Moreover,during mechanical loading,the nanofibers slip that hampers the proliferation and differentiation of migrating stem cells.Here,electrospun nanofiber scaffolds,with crimped nanofibers and welded joints to biomimic the intricate natural microstructure of tendon-to-bone insertion,were prepared using poly(ester-urethane)urea and gelatin via electrospinning and double crosslinking by a multi-bonding network densification strategy.The crimped nanofiber scaffold(CNS)features bionic tensile stress and induces chondrogenic differentiation,laying credible basis for in vivo experimentation.After repairing a rabbit massive rotator cuff tear using a CNS for 3 months,the continuous translational tendon-to-bone interface was fully regenerated,and fatty infiltration was simultaneously inhibited.Instead of micro-CT,μCT was employed to visualize the integrity and intricateness of the three-dimensional microstructure of the CNS-induced-healed tendon-to-bone interface at an ultra-high resolution of less than 1μm.This study sheds light on the correlation between nanofiber post treatment and massive rotator cuff repair and provides a general strategy for crimped nanofiber preparation and tendon-to-bone interface imaging characterization.
基金supported by Capital Health Development Research Special Project(2022-2-5051)DongGuan Innovative Research Team Program.Basic applied research program of Liaoning Province of China(No.2022020347-JH2/1013)。
文摘Regarding the current materials used for suture anchors for rotator cuff repair,there are still limitations in terms of degradability,mechanical properties,and bioactivities in clinical applications.Magnesium alloys have preliminarily been shown to promote tendon-bone healing with good prospects for application as anchor materials.However,the design of anchor structures for the degradation characteristics of magnesium alloy materials has not been considered,which is critical for the practical application of magnesium alloy anchors.The mechanism by which magnesium promotes tendon bone healing remains to be clarified.Here,we proposed a novel split hollowed magnesium alloy suture anchors for the repair of rabbit rotator cuff injury.We found that novel split hollowed magnesium alloy anchors structure effectively solved the problem of failure due to degradation of traditional eyelet structure,providing reliable suture fixation.The open architecture facilitates the metabolic resorption of the degradation products of and promotes the ingrowth of bone tissue.Histological staining showed that magnesium anchors have better ability to promote regeneration at the fibrocartilage interface compared to PLLA anchors.The higher expression of fibrocartilage markers(Aggrecan,COL2A1,and Sox9)at the tendon-bone interface in magnesium anchors,which promotes chondrocyte differentiation at the tendon-bone interface and matrix formation,which is more conducive to achieving regeneration and maturation of fibrocartilage enthesis.Hence,this study provides a basis for further research on the clinical application of degradable magnesium alloy suture anchors.
基金supported by the National Natural Science Foundation of China(Grant No.82172511,81972125 and 82172510)Shenzhen“San-Ming”Project of Medicine(No.SZSM202211019).
文摘The rate of retear after surgical repair remains high.Mesenchymal stem cells(MSCs)have been extensively employed in regenerative medicine for several decades.However,safety and ethical concerns constrain their clinical application.Tendon Stem/Progenitor Cells(TSPCs)-derived exosomes have emerged as promising cellfree therapeutic agents.Therefore,urgent studies are needed to investigate whether TSPC-Exos could enhance tendon-bone healing and elucidate the underlying mechanisms.In this study,TSPC-Exos were found to promote the proliferation,migration,and expression of fibrogenesis markers in BMSCs.Furthermore,TSPC-Exos demonstrated an ability to suppress the polarization of M1 macrophages while promoting M2 macrophage polarization.In a rat model of rotator cuff repair,TSPC-Exos modulated inflammation and improved the histological structure of the tendon-bone interface,the biomechanical properties of the repaired tendon,and the function of the joint.Mechanistically,TSPC-Exos exhibited high expression of miR-21a-5p,which regulated the expression of PDCD4.The PDCD4/AKT/mTOR axis was implicated in the therapeutic effects of TSPC-Exos on proliferation,migration,and fibrogenesis in BMSCs.This study introduces a novel approach utilizing TSPC-Exos therapy as a promising strategy for cell-free therapies,potentially benefiting patients with rotator cuff tear in the future.
基金The 74nd Postdoctoral Science Foundation of China 2024M362720(L.W.)Regenerative Sports Medicine and Translational Youth Science and Technology Innovation Workroom(J.Z.)Technology Support Project of Science and Technology Commission of Shanghai Municipality 21S31908500(J.Z.).
文摘Degradable rotator cuff patches,followed over five years,have been observed to exhibit high re-tear rates exceeding 50%,which is attributed to the inability of degradable polymers alone to restore the post-rotator cuff tear(RCT)inflammatory niche.Herein,poly(ester-ferulic acid-urethane)urea(PEFUU)was developed,featuring prolonged anti-inflammatory functionality,achieved by the integration of ferulic acid(FA)into the polyurethane repeating units.PEFUU stably releases FA in vitro,reversing the inflammatory niche produced by M1 macrophages and restoring the directed differentiation of stem cells.Utilizing PEFUU,hierarchical composite nanofiber patch(HCNP)was fabricated,simulating the natural microstructure of the tendon-to-bone interface with an aligned-random alignment.The incorporation of enzymatic hydrolysate derived from decellularized Wharton jelly tissue into the random layer could further enhance cartilage regeneration at the tendon-to-bone interface.Via rat RCT repairing model,HCNP possessing prolonged anti-inflammatory properties uniquely facilitated physiological healing at the tendon-to-bone interface’s microstructure.The alignment of fibers was restored,and histologically,the characteristic tripartite distribution of collagen I-collagen II-collagen I was achieved.This study offers a universal approach to the functionalization of degradable polymers and provides a foundational reference for their future applications in promoting the in vivo regeneration of musculoskeletal tissues.
