Retraction: The role of Sox9 in collagen hydrogel-mediated chondrogenic differentiation of adult mesenchymal stem cells (MSCs).

Retraction of 'The role of Sox9 in collagen hydrogel-mediated chondrogenic differentiation of adult mesenchymal stem cells (MSCs)' by Xianfang Jiang et al., Biomater. Sci., 2018, 6, 1556-1568, https://doi.org/10.1039/C8BM00317C.

ROS-responsive PPGF nanofiber membrane as a drug delivery system for long-term drug release in attenuation of osteoarthritis.

Excessive reactive oxygen species (ROS) are one of the leading mechanisms in the initiation and development of osteoarthritis (OA). However, conventional injection of ROS-responsive drug delivery systems (DDSs) such as nanoparticles and hydrogels usually cannot provide effective treatment due to rapid clearance and degradation or low bioavailability. In this study, a ROS-responsive nanofiber membrane named PLA/PEGDA-EDT@rGO-Fucoxanthin (PPGF) is fabricated by electrospinning, wherein PEGDA-EDT served as the ROS-responsive motif, reduced graphene oxide (rGO) as the drug carrier and fucoxanthin (Fx) as the antioxidative and anti-inflammatory agent. The results demonstrated that the PPGF nanofiber membrane exhibited sustained and long-term Fx release behavior (at least 66 days) in response to hydrogen peroxide (H2O2) in vitro. With low cytotoxicity and smart ROS responsiveness, PPGF showed excellent anti-inflammatory and antioxidative effects on IL-1ß-induced chondrocytes by potent ROS scavenging potential and upregulation of antioxidative enzymes. It also demonstrated the attenuation of OA progression with the reduced Osteoarthritis Research Society International (OARSI) score by 93.17% in 8 weeks. The smart ROS-responsive, biodegradable and biocompatible nanofiber membranes possess great potential for OA therapy under arthroscopy.

[Corrigendum] Nano­hydroxyapatite/collagen film as a favorable substrate to maintain the phenotype and promote the growth of chondrocytes cultured in vitro.

Subsequently to the publication of the above article, and a corrigendum that has already been published with the intention of showing corrected versions of Figs. 3, 5 and 6 (DOI: 10.3892/ijmm.2020.4743; published online on September 30, 2020), the authors regret that the corrigendum failed to address the issue of one remaining pair of panels in Fig. 3A that contained overlapping data in the original paper (specifically, the 'nHC/6 days' and 'TGFß/4 days' data panels). The further corrected version of Fig. 3 is shown on the next page. The authors deeply regret that this error was not corrected in the previous corrigendum, but now consider that the errors made in the assembly of Fig. 3, and the other figures, have conclusively been attended to. These errors did not affect the major conclusions reported in the paper. All the authors agree to the publication of this Corrigendum, and thank the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this further corrigendum relating to the above paper. The authors regret this outstanding error went unnoticed during the compilation of the previous corrigendum, and apologize to the readership for any confusion that it may have caused. [the original article was published in International Journal of Molecular Medicine 41: 2150-2158, 2018; DOI: 10.3892/ijmm.2018.3431].

Dimethylamino group modified polydopamine nanoparticles with positive charges to scavenge cell-free DNA for rheumatoid arthritis therapy.

Excessive cell-free DNA (cfDNA) released by damaged or apoptotic cells can cause inflammation, impacting the progression of rheumatoid arthritis (RA). cfDNA scavengers, such as cationic nanoparticles (NPs), have been demonstrated as an efficient strategy for treating RA. However, most scavengers are limited by unfavorable biocompatibility and poor scavenging efficacy. Herein, by exploiting the favorable biocompatibility, biodegradability and bioadhesion of polydopamine (P), we modified P with dimethylamino groups to form altered charged DPs to bind negatively charged cfDNA for RA therapy. Results showed that DPs endowed with superior binding affinity of cfDNA and little cytotoxicity, which effectively inhibited lipopolysaccharide (LPS) stimulated inflammation in vitro, resulting in the relief of joint swelling, synovial hyperplasia and cartilage destruction in RA rats. Significantly, DPs with higher DS of bis dimethylamino group exhibited higher positive charge density and stronger cfDNA binding affinity, leading to excellent RA therapeutic effect among all of the treated groups, which was even close to normal rats. These finding provides a novel strategy for the treatment of cfDNA-associated diseases.

Cartilage-targeting poly(ethylene glycol) (PEG)-formononetin (FMN) nanodrug for the treatment of osteoarthritis.

Intra-articular (IA) injection is an efficient treatment for osteoarthritis, which will minimize systemic side effects. However, the joint experiences rapid clearance of therapeutics after intra-articular injection. Delivering system modified through active targeting strategies to facilitate localization within specific joint tissues such as cartilage is hopeful to increase the therapeutic effects. In this study, we designed a nanoscaled amphiphilic and cartilage-targeting polymer-drug delivery system by using formononetin (FMN)-poly(ethylene glycol) (PEG) (denoted as PCFMN), which was prepared by PEGylation of FMN followed by coupling with cartilage-targeting peptide (CollBP). Our results showed that PCFMN was approximately regular spherical with an average diameter about 218 nm. The in vitro test using IL-1ß stimulated chondrocytes indicated that PCFMN was biocompatible and upregulated anabolic genes while simultaneously downregulated catabolic genes of the articular cartilage. The therapeutic effects in vivo indicated that PCFMN could effectively attenuate the progression of OA as evidenced by immunohistochemical staining and histological analysis. In addition, PCFMN showed higher intention time in joints and better anti-inflammatory effects than FMN, indicating the efficacy of cartilage targeting nanodrug on OA. This study may provide a reference for clinical OA therapy.

[Corrigendum] Nano­hydroxyapatite/collagen film as a favorable substrate to maintain the phenotype and promote the growth of chondrocytes cultured in vitro.

During the preparation of the figures in the above article, the authors regret that errors occurred during the assembly of Figs. 3, 5 and 6. An incorrect image for the calcein­AM/PI staining data panel for nHC and transforming growth factor­ß (TGF­ß) group at 6 days was shown in Fig. 3A; similarly, in both Figs. 5A and 6, images were selected incorrectly for safranin O and collagen type â…¡ (COL II) staining for the hydroxyapatite/collagen (HC) group at 4 and 6 days, and also COL â…¡ staining for the TGF­ß group at 4 days in Fig. 6. Each of these errors were attributed to an accidental mix­up of the data during the image compilation process. Corrected versions of Figs. 3, 5 and 6 are shown on the next two pages. These errors did not affect the major conclusions reported in the paper. All the authors have agreed to this Corrigendum, and thank the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this. The authors regret these errors went unnoticed during the compilation of the three figures in question, and apologize to the readership for any confusion that it may have caused. [the original article was published in International Journal of Molecular Medicine 41: 2150-2158, 2018; DOI: 10.3892/ijmm.2018.3431].

Electrospun poly(3-hydroxybutyrate-co-4-hydroxybutyrate) /Octacalcium phosphate Nanofibrous membranes for effective guided bone regeneration.

Membranes used in guided bone regeneration (GBR) are required to exhibit high mechanical strength, biocompatibility, biodegradation, osteogenic and osteoinductive potential. In our study, poly(3-hydroxybutyrate-co-4-hydroxybutyrate)(P(3HB-co-4HB))/octacalcium phosphate (OCP) (P(3HB-co-4HB)/OCP) nanofibrous membranes were fabricated by electrospinning with two different P(3HB-co-4HB) to OCP ratios (P(3HB-co-4HB):OCP = 95:5 wt% and 90:10 wt%, termed P(3HB-co-4HB)/OCP(5)and P(3HB-co-4HB)/OCP (10), respectively) for GBR. The developed P(3HB-co-4HB)/OCP nanofibrous membranes were analysed for their osteogenic and osteoinductive properties using mesenchymal stem cells (MSCs) in vitro and in a calvarial bone defect rat model. The composite P(3HB-co-4HB)/OCP nanofibrous membranes showed decreased fibre size and enhanced tensile strength compared with those of P(3HB-co-4HB) nanofibrous membranes. In the in vitro studies, the P(3HB-co-4HB)/OCP membranes facilitated cell growth and osteoblastic differentiation of MSCs and were superior to P(3HB-co-4HB) membranes. After covered on the calvarial bone defects, P(3HB-co-4HB)/OCP membranes facilitated greater neobone formation than P(3HB-co-4HB) membranes did, as the result of histological evaluation and micro-CT analysis with higher bone volume/total volume (BV/TV) ratio and bone mineral density (BMD). P(3HB-co-4HB)/OCP(10) membranes with higher OCP content showed greater stiffness and osteoinductivity than P(3HB-co-4HB)/OCP (5)membranes, demonstrating the role of OCP in the composite membranes. These results indicated that electrospun P(3HB-co-4HB)/OCP nanofibrous membranes hold promise for the clinical application of GBR.

Correction: Dopamine-melanin nanoparticles scavenge reactive oxygen and nitrogen species and activate autophagy for osteoarthritis therapy.

Correction for 'Dopamine-melanin nanoparticles scavenge reactive oxygen and nitrogen species and activate autophagy for osteoarthritis therapy' by Gang Zhong et al., Nanoscale, 2019, 11, 11605-11616.

Electrospun PLGA/PCL/OCP nanofiber membranes promote osteogenic differentiation of mesenchymal stem cells (MSCs).

Nanofibers as niche-biomimetic scaffolds hold promise in guided bone regeneration (GBR). Here we fabricated poly (lactic-co-glycolic acid) (PLGA)/poly(caprolactone) (PCL)-doped octacalcium phosphate (OCP) nanofiber membranes via electrospinning and investigated the osteogenic behavior of marrow mesenchymal stem cells (MSCs) on the membranes. By adjusting different ratio of OCP to PLGA/PCL, three hybrid stents including PLGA/PCL, PLGA/PCL/2 wt%OCP, PLGA/PCL/4wt%OCP were successfully prepared. The PLGA/PCL/OCP membranes showed a decrease in fiber diameter compared with PLGA/PCL, leading to enhanced mechanical strength. In-vitro studies showed that PLGA/PCL/OCP membranes better supported cell adhesion, spreading and proliferation than PLGA/PCL. The incorporation of OCP via electrospinning also endowed the membranes with osteoinductive capacity, as evidenced by activation of ALP activity, increased gene expression of bone specific markers (such as Runx2, ALP, Col 1a1, OPN, OCN, BMP2), and mineral nodules formation compared to PLGA/PCL. Comparatively, PLGA/PCL/4wt%OCP showed better mechanical and biological performance than PLGA/PCL/2 wt%OCP, demonstrating the role of OCP in nanofiber membranes. Thus, the electrospun PLGA/PCL/OCP nanofiber membranes can be potentially developed as a promising hybrid stent for GBR.

Correction: The role of Sox9 in collagen hydrogel-mediated chondrogenic differentiation of adult mesenchymal stem cells (MSCs).

Correction for 'The role of Sox9 in collagen hydrogel-mediated chondrogenic differentiation of adult mesenchymal stem cells (MSCs)' by Xianfang Jiang, et al., Biomater. Sci., 2018, 6, 1556-1568.

Dopamine-melanin nanoparticles scavenge reactive oxygen and nitrogen species and activate autophagy for osteoarthritis therapy.

Anti-oxidative agents hold great potential in osteoarthritis (OA) therapy. However, most radical scavengers have poor biocompatibility and potential cytotoxicity, which limit their applications. Herein we explore dopamine melanin (DM) nanoparticles as a novel scavenger of reactive oxygen species (ROS) and reactive nitrogen species (RNS). DM nanoparticles show low cytotoxicity and a strong ability to sequester a broad range of ROS and RNS, including superoxides, hydroxyl radicals, and peroxynitrite. This translates to excellent anti-inflammatory and chondro-protective effects by inhibiting intracellular ROS and RNS and promoting antioxidant enzyme activities. With an average diameter of 112.5 nm, DM nanoparticles can be intra-articularly (i.a.) injected into an affected joint and retained at the injection site. When tested in vivo in rodent OA models, DM nanoparticles showed diminished inflammatory cytokine release and reduced proteoglycan loss, which in turn slowed down cartilage degradation. Mechanistic studies suggest that DM nanoparticles also enhance autophagy that benefits OA control. In summary, our study suggests DM nanoparticles as a safe and promising therapeutic for OA.

Correction: Therapy for cartilage defects: functional ectopic cartilage constructed by cartilage-simulating collagen, chondroitin sulfate and hyaluronic acid (CCH) hybrid hydrogel with allogeneic chondrocytes.

Correction for 'Therapy for cartilage defects: functional ectopic cartilage constructed by cartilage-simulating collagen, chondroitin sulfate and hyaluronic acid (CCH) hybrid hydrogel with allogeneic chondrocytes' by Xianfang Jiang et al., Biomater. Sci., 2018, 6, 1616-1626.

Therapy for cartilage defects: functional ectopic cartilage constructed by cartilage-simulating collagen, chondroitin sulfate and hyaluronic acid (CCH) hybrid hydrogel with allogeneic chondrocytes.

OBJECTIVE: To regenerate functional cartilage-mimicking ectopic cartilage as a source for the restoration of cartilage defects, we used a previously synthesized three-phase collagen, chondroitin sulfate and hyaluronic acid (CCH) hydrogel for the encapsulation of allogeneic chondrocytes with a diffusion chamber system that was buried subcutaneously in the host for 4 weeks and then implanted into a cartilage defect. METHODS: The CCH hydrogel was prepared and seeded with allogeneic chondrocytes from new-born rabbits, prior to being enveloped in a diffusion chamber that prevents cell ingrowth and vascular invasion of the host, as described previously. A collagen hydrogel (C) was used as the control. The diffusion chamber was embedded subcutaneously in an adult rabbit. 4 weeks later, the regenerated tissue was harvested from the diffusion chamber and then further used for cartilage repair in the same host. To evaluate the regenerated tissue, cell viability assay using calcein-acetoxymethyl (calcein-AM)/propidium iodide (PI) staining, biochemical analysis by examination of total DNA and GAG content, gene expression detection using RT-PCR for Col 1a1, Col 2a1, Acan, and Sox9, biomechanical detection and histological evaluation were implemented. RESULTS: Analysis of the cell activity and biochemical evaluation in vitro showed that cell proliferation, GAG secretion and gene/protein expression of cartilage specific markers were much higher in the CCH group than those in the C group. The CCH constructed ectopic cartilage tissue in vivo showed the typical characteristics of hyaline cartilage with higher expression of cartilage matrix markers compared with the C groups, as evidenced by morphological and histological findings as well as RT-PCR analysis. Furthermore, ectopic cartilage from CCH successfully facilitated the cartilage restoration, with higher morphological and histological scores and greater mechanical strength than that from C. CONCLUSION: The three-phase CCH hydrogel, which is closer to natural cartilage matrix and is stiffer than collagen, may replace collagen as the "gold standard" for cartilage tissue engineering. This study may provide a new insight for cartilage repair using ectopic cartilage reconstructed from functional materials and allogeneic cells.

The role of Sox9 in collagen hydrogel-mediated chondrogenic differentiation of adult mesenchymal stem cells (MSCs).

Sox9 is a transcription factor that regulates chondrogenesis, but its role in the chondrogenic differentiation of mesenchymal stem cells (MSCs) triggered by materials is poorly understood. In this study, we investigated the effect of Sox9 interference on collagen-induced chondrogenesis and further collagen-based therapies for cartilage defects. In this paper, MSCs were infected with a vector carrying the Sox9 promoter and related markers were detected. A lentivirus-mediated vector targeting the silencing of the Sox9 gene was used in bone marrow-derived MSCs prior to being encapsulated in a collagen hydrogel. The collagen hydrogel as a sole inducer was also compared with transforming growth factor-ß1 (TGF-ß1). Before being implanted into the articular cartilage defect in rats, the cell-hydrogel pellets were cultured in vitro for 14 days. The effect of Sox9 transfection on cell proliferation was evaluated by measuring the total DNA content. Safranin-O staining and a biochemistry assay were performed to assess the synthesis and secretion of glycosaminoglycan (GAG) of MSCs. The real-time fluorescent quantitative polymerase chain reaction (RT-PCR) was performed to detect the gene expression levels of Col1a1, Col2a1, Acan and Sox9. The protein expression of collagen type II and collagen type I was analyzed by immunohistochemical analysis. Collagen alone significantly increased the luciferase activity of the Sox9 promoter, which was in parallel with the upregulation of cartilage specific markers. In vitro, the chondrogenic differentiation ability of MSCs was greatly inhibited after Sox9 interference, both in the collagen and TGF-ß1-induced groups. In vivo, a further study showed that cartilage regeneration was arrested by using transfected MSCs with an injectable collagen gel or induced by TGF-ß1. The results indicated that collagen may mediate Sox9 expression by providing a biomimetic microenvironment favoring cell condensation prior to chondrogenesis. The role of Sox9 regulation by materials is similar to that by growth factors, suggesting that well-designed scaffolds may replace growth factors in chondrogenesis. Thus, interventions targeting Sox9 may help improve articular cartilage repair.

Nano-hydroxyapatite/collagen film as a favorable substrate to maintain the phenotype and promote the growth of chondrocytes cultured in vitro.

Autologous chondrocyte implantation (ACI) has emerged as a novel approach to cartilage repair through the use of harvested chondrocytes. However, the expansion of the chondrocytes from the donor tissue in vitro is restricted by the limited cell numbers and the dedifferentiation of the chondrocytes. The present study investigated the effect of collagen-based films, including collagen, hydroxyapatite (HA)/collagen (HC) and in situ synthesis of nano­HC (nHC), on monolayer cultures of chondrocytes. As a substrate for the chondrocytes monolayer culture in vitro, nHC was able to restrain the dedifferentiation of chondrocytes and facilitate cell expansion, which was detected by methyl thiazolyl tetrazolium assay, scanning electron microscopy, calcein­acetoxymethyl/propidium iodide staining, hematoxylin and eosin staining, Safranin O staining, immunohistochemical staining and reverse transcription­quantitative polymerase chain reaction. Furthermore, the nHC films significantly facilitated cell growth and enhanced the expression of cartilage­specific extracellular matrix (ECM) components, including aggrecan and type II collagen. In addition, nHC films markedly downregulated the expression of collagen type I, an indicator of dedifferentiation. The results indicated that nHC, a collagen­based substrate optimized by nanoparticles, was able to better support cell growth and preserve cell phenotype compared with collagen alone or HC. The nHC film, which favors cell growth and prevents the dedifferentiation of chondrocytes, may therefore serve as a useful cartilage­like ECM for chondrocytes. In conclusion, nHC film is a promising substrate for the culture of chondrocytes in cell-based therapy.

Dynamic Analysis of New Bone Obtained by Nonvascular Transport Distraction Osteogenesis in Canines.

PURPOSE: The aim of the present study was to construct a nonvascular transport disc to repair the canine mandibular defects model and to perform a dynamic analysis of the new bone obtained by nonvascular transport distraction osteogenesis (NTDO) in canines. MATERIALS AND METHODS: Thirty adult dogs were randomly divided into 3 groups, with 10 dogs in each group. Canine mandibular defect models of NTDO were constructed. All the dogs were marked by tetracycline hydrochloride at a different distraction stage. The dogs were euthanized at 2, 4, and 12 weeks after distraction, and the quality ratio of calcium and phosphate for the new bone was measured using electron dispersive spectroscopy. RESULTS: The canine mandibular defects were successfully repaired. Using tetracycline hydrochloride, we successfully observed the quality and speed of new bone formation. The quality ratio of calcium and phosphate was similar between the new bone formation and the original bone. The time spent using a nonvascular transport disc to repair mandibular defects was consistent with using a vascularized transport disc, and the quality of the new bone and the original bone was exactly the same. CONCLUSION: When the bone mass is insufficient or the conditions are not suitable for a vascularized transport disc, the nonvascular transport disc can be used as an alternative.

Evaluation of novel in situ synthesized nano-hydroxyapatite/collagen/alginate hydrogels for osteochondral tissue engineering.

Collagen hydrogel has been widely used for osteochondral repair, but its mechanical properties cannot meet the requirements of clinical application. Previous studies have shown that the addition of either polysaccharide or inorganic particles could reinforce the polymer matrix. However, their synergic effects on collagen-based hydrogel have seldom been studied, and the potential application of triple-phased composite gel in osteochondral regeneration has not been reported. In this study, nano-hydroxyapatite (nano-HA) reinforced collagen-alginate hydrogel (nHCA) was prepared by the in situ synthesis of nano-HA in collagen gel followed by the addition of alginate and Ca(2+). The properties of triple-phased nHCA hydrogel were studied and compared with pure collagen and biphasic gels, and the triple-phased composite of collagen-alginate-HA gels showed a superiority in not only mechanical but also biological features, as evidenced by the enhanced tensile and compressive modulus, higher cell viability, faster cell proliferation and upregulated hyaline cartilage markers. In addition, it was found that the synthesis process could also affect the properties of the triple-phased composite, compared to blend-mixing HCA. The in situ-synthesized nHCA hydrogel showed an enhanced tensile modulus, as well as enhanced biological features compared with HCA. Our study demonstrated that the nHCA composite hydrogel holds promise in osteochondral regeneration. The addition of alginate and nano-HA contribute to the increase in both mechanical and biological properties. This study may provide a valuable reference for the design of an appropriate composite scaffold for osteochondral tissue engineering.

[Application of joint reconstruction with autogenous coronoid process graft to treat temporomandibular joint ankylosis].

PURPOSE: To evaluate the clinical effect of joint reconstruction by using autogenous coronoid process graft to treat temporomandibular joint(TMJ) ankylosis. METHODS: Nine cases of TMJ ankylosis from September 2008 to September 2010 were surgically treated by joint reconstruction with autogenous coronoid process graft, using autogenous articular disc or prosthodontic membrane as interpositional material. Mouth opening, occlusion and cone beam CT(CBCT) were used for evaluation before and after surgery. RESULTS: Satisfactory mouth opening was achieved in all patients and no one got occlusal changes or reankylosis during follow-up. CBCT showed that coronoid process graft reached bone union with the ramus and turned to be round. CONCLUSIONS: It is effective to cure TMJ ankylosis through joint reconstruction with autogenous coronoid process graft.

[Experimental study on transplantation of bone morphogenetic protein-2 gene transfected bone mesenchymal stem cells compounded with Pluronic F-127 for promoting bone regeneration in rabbit mandibular distraction].

OBJECTIVE: To investigate the promotive effect of transplantation of bone morphogenetic protein-2 (BMP-2) gene transfected bone mesenchymal stem cells (BMSCs) compounded with injectable bone tissue engineering scaffold material Pluronic F-127 on bone regeneration in rabbit mandibular distraction osteogenesis(DO). METHODS: Forty-eight New Zealand's white rabbits were randomized into four groups with twelve in each. All the objects were prepared into DO surgical model. On the 2nd day of consolidation, group A, B, C and D were injected with the same amount of 200 microL of the compound of BMP-2 gene transfected BMSCs with Pluronic F-127, the solution with BMP-2 gene transfected BMSCs, the solution of BMSCs and physiological saline at distraction zone, respectively. Two halves of the objects of all groups were sacrificed at the end of 2nd and 6th week consolidation, respectively. And the specimens of right mandible were prepared for radiological, histomorphological and immunohistochemical examinations to evaluate bone regeneration. RESULTS: Both radiological and immunohistochemical images were analyzed and processed with professional software. At the end of 2nd and 6th week consolidation, the bone mineral density and the expression of BMP-2 protein in distraction area of group A were significantly higher than those of B, C, D group (P<0.01). Group B was significantly higher than that in group C and D (P<0.01). There was no significant difference between group C and D (P>0.05). And the regeneration quality of distraction zone in group A and B were better than those in group C and D, just as that of group A better than group B. Conclusion The transplantation of BMP-2 gene transfected BMSCs compound with Pluronic F-127 could effectively promote bone regeneration in rabbit mandibular DO.