Regenerative medicine refers to the possibility of replacing aged/daniaged cells with genetically similar young and functional cells to restore or establish normal function.Kartogenin(KGN),a small heterocyclic,drug-li...Regenerative medicine refers to the possibility of replacing aged/daniaged cells with genetically similar young and functional cells to restore or establish normal function.Kartogenin(KGN),a small heterocyclic,drug-like compound was discovered in 2012,which is strongly associated with regenerative medicine.KGN has been applied in many regenerative fields,including cartilage regeneration and protection,tendon-bone healing,wound healing,and limb devclopmcnt.KGN could facilitate cartilage repair,promote fonnation of cartilage-like transition zone in tendon-bone junctions,stimulate collagen synthesis for wound healing,and regulate limb development in a coordinated manner.Considering the related mechanism,filamin A/CBFβ/RUNX1,Ihh,and TGFβ/Smad pathways have been reported to involve KGN.Therefore,KGN is proven a promising agent in regenerative medicine;however,studies conducted on the effect of KGN are limited to date and not convictive for Iong-term use.Further studies are recommended to explore the long-term effect and poteniial molecular mechanisms of KGN.Our investigations may motivate researchers to expand its applications in different forms and fields.展开更多
The integrated repair of bone and cartilage boasts advantages for osteochondral restoration such as a long-term repair effect and less deterioration compared to repairing cartilage alone.Constructing multifactorial,sp...The integrated repair of bone and cartilage boasts advantages for osteochondral restoration such as a long-term repair effect and less deterioration compared to repairing cartilage alone.Constructing multifactorial,spatially oriented scaffolds to stimulate osteochondral regeneration,has immense significance.Herein,targeted drugs,namely kartogenin@polydopamine(KGN@PDA)nanoparticles for cartilage repair and miRNA@calcium phosphate(miRNA@CaP)NPs for bone regeneration,were in situ deposited on a patterned supramolecular-assembled 2-ureido-4[lH]-pyrimidinone(UPy)modified gelation hydrogel film,facilitated by the dynamic and responsive coordination and complexation of metal ions and their ligands.This hydrogel film can be rolled into a cylindrical plug,mimicking the Haversian canal structure of natural bone.The resultant hydrogel demonstrates stable mechanical properties,a self-healing ability,a high capability for reactive oxygen species capture,and controlled release of KGN and miR-26a.In vitro,KGN@PDA and miRNA@CaP promote chondrogenic and osteogenic differentiation of mesenchymal stem cells via the JNK/RUNX1 and GSK-3β/β-catenin pathways,respectively.In vivo,the osteochondral plug exhibits optimal subchondral bone and cartilage regeneration,evidenced by a significant increase in glycosaminoglycan and collagen accumulation in specific zones,along with the successful integration of neocartilage with subchondral bone.This biomaterial delivery approach represents a significant toward improved osteochondral repair.展开更多
Abstract Meniscus injury is a common disease in clinic.If it was not treated in time,it leads to osteoarthritis which brings unbearable pain and heavy economic burden to the patients.At present,meniscectomy and menisc...Abstract Meniscus injury is a common disease in clinic.If it was not treated in time,it leads to osteoarthritis which brings unbearable pain and heavy economic burden to the patients.At present,meniscectomy and meniscus suture are widely used in the treatment for meniscus injury.Nevertheless,It is not ideal for poor self-healing ability of meniscus.The recruitment of endogenous stem cells is an attractive option for wounded meniscus healing.Fully reduced high-mobility group box 1 protein(HMGB1)can accelerate the regeneration of multiple tissues by endogenous stem cell activation,migration and differentiation.Kartogenin(KGN)has shown to induce the chondrogenesis of the stem cells.However,no study has explored such effects of HMGB1 and KGN in wounded meniscus healing.Therefore,in order to improve the regeneration of meniscus,we intend to use a novel bioactive microsphere which was developed by combining fully reduced high mobility group box 1(frHMGB1)and kartogenin(KGN)with alginate gel which slowly release high concentrations of HMGB1 and KGN to activate rat bone marrow stem cells(BMSCs)and promote cell proliferation.The results showed that this HMGB1–KGN microsphere released and kept high concentrations of HMGB1 and KGN in the wound area for more than 2 weeks.In vitro experimental results showed that the HMGB1–KGN microsphere can promote cell proliferation via recruiting rat bone marrow stem cells(BMSCs)and activating the BMSCs from G_(0) to G_(Alert) stage as evidenced by cell migration testing and 5-bromo-2′-deoxyuridine(BrdU)incorporation assay.In vivo results indicated that this HMGB-KGN microsphere can recruit GFP-labeled BMSCs from tail vein to wounded meniscus and induce these GFP-labeled BMSCs to differentiate into chondrocytes.Our results demonstrated that the HMGB1–KGN-containing bioactive microsphere induced cell migration in vitro and recruited the cells to wound area to promote wounded rat meniscus healing in vivo.展开更多
Osteochondral defects (OCD) are common but difficult to heal due to the low intrinsic repair capacity of cartilage and its complex hierarchical structure. In osteoarthritis (OA), OCD become more challenging to repair ...Osteochondral defects (OCD) are common but difficult to heal due to the low intrinsic repair capacity of cartilage and its complex hierarchical structure. In osteoarthritis (OA), OCD become more challenging to repair as both cartilage and subchondral bone regeneration are further impaired due to the arthritic environment. Numerous biomaterials have been developed and tested in osteochondral defects while ignoring the inflammatory environment. To target this challenging underlying pathophysiology, we designed and fabricated a biphasic porous and degradable scaffold incorporating anti-inflammatory and anabolic molecules by low-temperature rapid prototyping technology, and its effects on promoting osteochondral regeneration were evaluated using our well-established OA-OCD rabbit model. The biphasic porous scaffolds consisted of poly lactic-co-glycolic acid (PLGA) with kartogenin (KGN) for cartilage repair and PLGA and β-calcium phosphate (PLGA/β-TCP) with cinnamaldehyde (CIN) for subchondral bone repair. KGN is a molecule for promoting chondrogenesis and CIN is a phytomolecule for enhancing osteogenesis and alleviating inflammation. The biphasic scaffolds PLGA/KGN-PLGA/β-TCP/CIN (PK/PTC) with bio-mimic structure provided stable mechanical properties and exhibited excellent biocompatibility to support cell adhesion, proliferation, migration, and distribution. Furthermore, KGN and CIN within biphasic scaffolds could be released in a controlled and sustained mode, and the biphasic scaffold degraded slowly in vitro . Evaluating the repair of 16-weeks post-implantation into critically sized OA-OCD rabbit models revealed that the biphasic scaffold could promote subchondral bone and cartilage regeneration, as well as reverse subchondral osteosclerosis caused by inflammation in vivo . These findings support the utilization of the PK/PTC scaffold for osteochondral regeneration and provide a promising potential strategy for clinical application for the treatment of patients with OA-OCD.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
基金the National Key R&D Program of China(No.2016YFC1100300,No.2017YFC0840100 and No.2017YFC0840106)the National Natural Science Foundation of China(No.81572108 and No.81772339)+5 种基金the Key Clinical Medicine Center of Shanghai(No.2017ZZ01006)the Sanming Project of Mcdicine in Shenzhen(No.SZSM20161207)the Shanghai Rising Star Project(No.18QB1400500)the Introduction Project of Clinical Medicine Expert Team for Suzhou(No.SZYJTD2017I4)CAS Key Laboratory of Nano-Bio Interface(No.17NBI01)State Key Laboratory of Molecular Engineering of Polymers(No.K2018-17).
文摘Regenerative medicine refers to the possibility of replacing aged/daniaged cells with genetically similar young and functional cells to restore or establish normal function.Kartogenin(KGN),a small heterocyclic,drug-like compound was discovered in 2012,which is strongly associated with regenerative medicine.KGN has been applied in many regenerative fields,including cartilage regeneration and protection,tendon-bone healing,wound healing,and limb devclopmcnt.KGN could facilitate cartilage repair,promote fonnation of cartilage-like transition zone in tendon-bone junctions,stimulate collagen synthesis for wound healing,and regulate limb development in a coordinated manner.Considering the related mechanism,filamin A/CBFβ/RUNX1,Ihh,and TGFβ/Smad pathways have been reported to involve KGN.Therefore,KGN is proven a promising agent in regenerative medicine;however,studies conducted on the effect of KGN are limited to date and not convictive for Iong-term use.Further studies are recommended to explore the long-term effect and poteniial molecular mechanisms of KGN.Our investigations may motivate researchers to expand its applications in different forms and fields.
基金the Natural Science Foundation of China(Grant Nos.82072413,82101649)National Key Research and Development Program of China(Grant Nos.2021YFE0105400).
文摘The integrated repair of bone and cartilage boasts advantages for osteochondral restoration such as a long-term repair effect and less deterioration compared to repairing cartilage alone.Constructing multifactorial,spatially oriented scaffolds to stimulate osteochondral regeneration,has immense significance.Herein,targeted drugs,namely kartogenin@polydopamine(KGN@PDA)nanoparticles for cartilage repair and miRNA@calcium phosphate(miRNA@CaP)NPs for bone regeneration,were in situ deposited on a patterned supramolecular-assembled 2-ureido-4[lH]-pyrimidinone(UPy)modified gelation hydrogel film,facilitated by the dynamic and responsive coordination and complexation of metal ions and their ligands.This hydrogel film can be rolled into a cylindrical plug,mimicking the Haversian canal structure of natural bone.The resultant hydrogel demonstrates stable mechanical properties,a self-healing ability,a high capability for reactive oxygen species capture,and controlled release of KGN and miR-26a.In vitro,KGN@PDA and miRNA@CaP promote chondrogenic and osteogenic differentiation of mesenchymal stem cells via the JNK/RUNX1 and GSK-3β/β-catenin pathways,respectively.In vivo,the osteochondral plug exhibits optimal subchondral bone and cartilage regeneration,evidenced by a significant increase in glycosaminoglycan and collagen accumulation in specific zones,along with the successful integration of neocartilage with subchondral bone.This biomaterial delivery approach represents a significant toward improved osteochondral repair.
基金This work was supported by Nanjing Municipal Science and Technology Bureau International Joint Research and Development(No.201911041)Science and Technology Development Foundation of Nanjing Medical University(No.NMUB2018327)Social Development project of Jiangsu Province(No.BE2020623).
文摘Abstract Meniscus injury is a common disease in clinic.If it was not treated in time,it leads to osteoarthritis which brings unbearable pain and heavy economic burden to the patients.At present,meniscectomy and meniscus suture are widely used in the treatment for meniscus injury.Nevertheless,It is not ideal for poor self-healing ability of meniscus.The recruitment of endogenous stem cells is an attractive option for wounded meniscus healing.Fully reduced high-mobility group box 1 protein(HMGB1)can accelerate the regeneration of multiple tissues by endogenous stem cell activation,migration and differentiation.Kartogenin(KGN)has shown to induce the chondrogenesis of the stem cells.However,no study has explored such effects of HMGB1 and KGN in wounded meniscus healing.Therefore,in order to improve the regeneration of meniscus,we intend to use a novel bioactive microsphere which was developed by combining fully reduced high mobility group box 1(frHMGB1)and kartogenin(KGN)with alginate gel which slowly release high concentrations of HMGB1 and KGN to activate rat bone marrow stem cells(BMSCs)and promote cell proliferation.The results showed that this HMGB1–KGN microsphere released and kept high concentrations of HMGB1 and KGN in the wound area for more than 2 weeks.In vitro experimental results showed that the HMGB1–KGN microsphere can promote cell proliferation via recruiting rat bone marrow stem cells(BMSCs)and activating the BMSCs from G_(0) to G_(Alert) stage as evidenced by cell migration testing and 5-bromo-2′-deoxyuridine(BrdU)incorporation assay.In vivo results indicated that this HMGB-KGN microsphere can recruit GFP-labeled BMSCs from tail vein to wounded meniscus and induce these GFP-labeled BMSCs to differentiate into chondrocytes.Our results demonstrated that the HMGB1–KGN-containing bioactive microsphere induced cell migration in vitro and recruited the cells to wound area to promote wounded rat meniscus healing in vivo.
基金supported by the collaborative project from the National Key R&D Program of China and Innovation and Tech-nology Fund Mainland-Hong Kong Joint Funding Scheme(Nos.2021YFE0202300 and MHP/011/20)the Sino-Swiss collaborative project from the Ministry of Science and Technology and the Swiss National Science Foundation under the SSSTC program(Grant Nos.2015DFG32200 and 156362)+2 种基金Shenzhen Collaborative Innovation Plan-International Cooperation Project(Grant No.GJHZ20190821160803823)Development and Reform Commission of Shenzhen Municipality(2019)(No.561)Shenzhen Double Chain Project for Innovation and Development Industry supported by Bureau of Industry and Information Technology of Shenzhen(No.201908141541).
文摘Osteochondral defects (OCD) are common but difficult to heal due to the low intrinsic repair capacity of cartilage and its complex hierarchical structure. In osteoarthritis (OA), OCD become more challenging to repair as both cartilage and subchondral bone regeneration are further impaired due to the arthritic environment. Numerous biomaterials have been developed and tested in osteochondral defects while ignoring the inflammatory environment. To target this challenging underlying pathophysiology, we designed and fabricated a biphasic porous and degradable scaffold incorporating anti-inflammatory and anabolic molecules by low-temperature rapid prototyping technology, and its effects on promoting osteochondral regeneration were evaluated using our well-established OA-OCD rabbit model. The biphasic porous scaffolds consisted of poly lactic-co-glycolic acid (PLGA) with kartogenin (KGN) for cartilage repair and PLGA and β-calcium phosphate (PLGA/β-TCP) with cinnamaldehyde (CIN) for subchondral bone repair. KGN is a molecule for promoting chondrogenesis and CIN is a phytomolecule for enhancing osteogenesis and alleviating inflammation. The biphasic scaffolds PLGA/KGN-PLGA/β-TCP/CIN (PK/PTC) with bio-mimic structure provided stable mechanical properties and exhibited excellent biocompatibility to support cell adhesion, proliferation, migration, and distribution. Furthermore, KGN and CIN within biphasic scaffolds could be released in a controlled and sustained mode, and the biphasic scaffold degraded slowly in vitro . Evaluating the repair of 16-weeks post-implantation into critically sized OA-OCD rabbit models revealed that the biphasic scaffold could promote subchondral bone and cartilage regeneration, as well as reverse subchondral osteosclerosis caused by inflammation in vivo . These findings support the utilization of the PK/PTC scaffold for osteochondral regeneration and provide a promising potential strategy for clinical application for the treatment of patients with OA-OCD.
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.
