Pub Date : 2024-07-27DOI: 10.1016/j.jot.2024.07.005
Jinhui Wu , Jiangyi Wu , Zheng Liu , Yunquan Gong , Daibo Feng , Wei Xiang , Shunzheng Fang , Ran Chen , Yaran Wu , Shu Huang , Yizhao Zhou , Ningning Liu , Hao Xu , Siru Zhou , Baorong Liu , Zhenhong Ni
Joint diseases greatly impact the daily lives and occupational functioning of patients globally. However, conventional treatments for joint diseases have several limitations, such as unsatisfatory efficacy and side effects, necessitating the exploration of more efficacious therapeutic strategies. Mesenchymal stem cell (MSC)-derived EVs (MSC-EVs) have demonstrated high therapeutic efficacyin tissue repair and regeneration, with low immunogenicity and tumorigenicity. Recent studies have reported that EVs-based therapy has considerable therapeutic effects against joint diseases, including osteoarthritis, tendon and ligament injuries, femoral head osteonecrosis, and rheumatoid arthritis. Herein, we review the therapeutic potential of various types of MSC-EVs in the aforementioned joint diseases, summarise the mechanisms underlying specific biological effects of MSC-EVs, and discuss future prospects for basic research on MSC-EV-based therapeutic modalities and their clinical translation. In general, this review provides an in-depth understanding of the therapeutic effects of MSC-EVs in joint diseases, as well as the underlying mechanisms, which may be beneficial to the clinical translation of MSC-EV-based treatment.
The translational potential of this article: MSC-EV-based cell-free therapy can effectively promote regeneration and tissue repair. When used to treat joint diseases, MSC-EVs have demonstrated desirable therapeutic effects in preclinical research. This review may supplement further research on MSC-EV-based treatment of joint diseases and its clinical translation.
{"title":"Mesenchymal stem cell–derived extracellular vesicles in joint diseases: Therapeutic effects and underlying mechanisms","authors":"Jinhui Wu , Jiangyi Wu , Zheng Liu , Yunquan Gong , Daibo Feng , Wei Xiang , Shunzheng Fang , Ran Chen , Yaran Wu , Shu Huang , Yizhao Zhou , Ningning Liu , Hao Xu , Siru Zhou , Baorong Liu , Zhenhong Ni","doi":"10.1016/j.jot.2024.07.005","DOIUrl":"10.1016/j.jot.2024.07.005","url":null,"abstract":"<div><p>Joint diseases greatly impact the daily lives and occupational functioning of patients globally. However, conventional treatments for joint diseases have several limitations, such as unsatisfatory efficacy and side effects, necessitating the exploration of more efficacious therapeutic strategies. Mesenchymal stem cell (MSC)-derived EVs (MSC-EVs) have demonstrated high therapeutic efficacyin tissue repair and regeneration, with low immunogenicity and tumorigenicity. Recent studies have reported that EVs-based therapy has considerable therapeutic effects against joint diseases, including osteoarthritis, tendon and ligament injuries, femoral head osteonecrosis, and rheumatoid arthritis. Herein, we review the therapeutic potential of various types of MSC-EVs in the aforementioned joint diseases, summarise the mechanisms underlying specific biological effects of MSC-EVs, and discuss future prospects for basic research on MSC-EV-based therapeutic modalities and their clinical translation. In general, this review provides an in-depth understanding of the therapeutic effects of MSC-EVs in joint diseases, as well as the underlying mechanisms, which may be beneficial to the clinical translation of MSC-EV-based treatment.</p><p>The translational potential of this article: MSC-EV-based cell-free therapy can effectively promote regeneration and tissue repair. When used to treat joint diseases, MSC-EVs have demonstrated desirable therapeutic effects in preclinical research. This review may supplement further research on MSC-EV-based treatment of joint diseases and its clinical translation.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"48 ","pages":"Pages 53-69"},"PeriodicalIF":5.9,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000731/pdfft?md5=97c1428bd4a1be09b08809c15972de16&pid=1-s2.0-S2214031X24000731-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141886381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-26DOI: 10.1016/j.jot.2024.06.012
Yuze Ma , Na Liu , Xiaoyan Shao , Tianshu Shi , Jiaquan Lin , Bin Liu , Tao Shen , Baosheng Guo , Qing Jiang
Background
Osteocytes are the main stress-sensing cells in bone. The substances secreted by osteocytes under mechanical loading play a crucial role in maintaining body homeostasis. Osteocytes have recently been found to release exosomes into the circulation, but whether they are affected by mechanical loading or participate in the regulation of systemic homeostasis remains unclear.
Methods
We used a tail-suspension model to achieve mechanical unloading on osteocytes. Osteocyte-specific CD63 reporter mice were used for osteocyte exosome tracing. Exosome detection and inhibitor treatment were performed to confirm the effect of mechanical loading on exosome secretion by osteocytes. Co-culture, GW4869 and exosome treatment were used to investigate the biological functions of osteocyte-derived exosomes on brown adipose tissue (BAT) and primary brown adipocytes. Osteocyte-specific Dicer KO mice were used to screen for loading-sensitive miRNAs. Dual luciferase assay was performed to validate the selected target gene.
Results
Firstly, we found the thermogenic activity was increased in BAT of mice subjected to tail suspension, which is due to the effect of unloaded bone on circulating exosomes. Further, we showed that the secretion of exosomes from osteocytes is regulated by mechanical loading, and osteocyte-derived exosomes can reach BAT and affect thermogenic activity. More importantly, we confirmed the effect of osteocyte exosomes on BAT both in vivo and in vitro. Finally, we discovered that let-7e-5p contained in exosomes is under regulation of mechanical loading and regulates thermogenic activity of BAT by targeting Ppargc1a.
Conclusion
Exosomes derived from osteocytes are loading-sensitive, and play a vital role in regulation on BAT, suggesting that regulation of exosomes secretion can restore homeostasis.
The translational potential of this article
This study provides a biological rationale for using osteocyte exosomes as potential agents to modulate BAT and even whole-body homeostasis. It also provides a new pathological basis and a new treatment approach for mechanical unloading conditions such as spaceflight.
背景：骨细胞是骨骼中主要的应力感应细胞。在机械负荷作用下，骨细胞分泌的物质对维持机体平衡起着至关重要的作用。最近发现骨细胞可释放外泌体进入血液循环，但它们是否受机械负荷影响或参与调节全身稳态仍不清楚：方法：我们使用尾悬吊模型来实现对骨细胞的机械卸载。方法：我们利用尾悬吊模型实现了对骨细胞的机械卸载，并使用骨细胞特异性 CD63 报告小鼠进行骨细胞外泌体追踪。外泌体检测和抑制剂处理证实了机械负荷对骨细胞分泌外泌体的影响。通过共培养、GW4869和外泌体处理来研究骨细胞衍生的外泌体对棕色脂肪组织（BAT）和原生棕色脂肪细胞的生物学功能。用骨细胞特异性 Dicer KO 小鼠来筛选负载敏感的 miRNA。结果表明：首先，我们发现了miRNA的致热作用：结果：首先，我们发现尾巴悬吊小鼠 BAT 的生热活性增加，这是由于未加载的骨对循环外泌体的影响。此外，我们还发现骨细胞分泌的外泌体受机械负荷的调控，而骨细胞衍生的外泌体可到达 BAT 并影响生热活性。更重要的是，我们在体内和体外都证实了骨细胞外泌体对 BAT 的影响。最后，我们发现外泌体中含有的let-7e-5p受机械负荷的调节，并通过靶向Ppargc1a调节BAT的生热活性：本文的转化潜力：这项研究为利用成骨细胞外泌体作为潜在药物来调节BAT甚至全身稳态提供了生物学依据。它还为太空飞行等机械卸载条件提供了新的病理基础和新的治疗方法。
{"title":"Mechanical loading on osteocytes regulates thermogenesis homeostasis of brown adipose tissue by influencing osteocyte-derived exosomes","authors":"Yuze Ma , Na Liu , Xiaoyan Shao , Tianshu Shi , Jiaquan Lin , Bin Liu , Tao Shen , Baosheng Guo , Qing Jiang","doi":"10.1016/j.jot.2024.06.012","DOIUrl":"10.1016/j.jot.2024.06.012","url":null,"abstract":"<div><h3>Background</h3><p>Osteocytes are the main stress-sensing cells in bone. The substances secreted by osteocytes under mechanical loading play a crucial role in maintaining body homeostasis. Osteocytes have recently been found to release exosomes into the circulation, but whether they are affected by mechanical loading or participate in the regulation of systemic homeostasis remains unclear.</p></div><div><h3>Methods</h3><p>We used a tail-suspension model to achieve mechanical unloading on osteocytes. Osteocyte-specific CD63 reporter mice were used for osteocyte exosome tracing. Exosome detection and inhibitor treatment were performed to confirm the effect of mechanical loading on exosome secretion by osteocytes. Co-culture, GW4869 and exosome treatment were used to investigate the biological functions of osteocyte-derived exosomes on brown adipose tissue (BAT) and primary brown adipocytes. Osteocyte-specific Dicer KO mice were used to screen for loading-sensitive miRNAs. Dual luciferase assay was performed to validate the selected target gene.</p></div><div><h3>Results</h3><p>Firstly, we found the thermogenic activity was increased in BAT of mice subjected to tail suspension, which is due to the effect of unloaded bone on circulating exosomes. Further, we showed that the secretion of exosomes from osteocytes is regulated by mechanical loading, and osteocyte-derived exosomes can reach BAT and affect thermogenic activity. More importantly, we confirmed the effect of osteocyte exosomes on BAT both in vivo and in vitro. Finally, we discovered that let-7e-5p contained in exosomes is under regulation of mechanical loading and regulates thermogenic activity of BAT by targeting <em>Ppargc1a</em>.</p></div><div><h3>Conclusion</h3><p>Exosomes derived from osteocytes are loading-sensitive, and play a vital role in regulation on BAT, suggesting that regulation of exosomes secretion can restore homeostasis.</p></div><div><h3>The translational potential of this article</h3><p>This study provides a biological rationale for using osteocyte exosomes as potential agents to modulate BAT and even whole-body homeostasis. It also provides a new pathological basis and a new treatment approach for mechanical unloading conditions such as spaceflight.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"48 ","pages":"Pages 39-52"},"PeriodicalIF":5.9,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-25DOI: 10.1016/j.jot.2024.07.004
Gyula Ferenc Szőcs , Szilárd Váncsa , Gergely Agócs , Péter Hegyi , Dóra Matis , Gergely Pánics , Zoltán Bejek , György Márk Hangody
Aims
Currently, it is advised to perform meniscal repair instead of meniscectomy in certain cases of primary anterior cruciate ligament reconstruction (ACLR). However, the level of evidence is low. Therefore, this study aimed to compare the effectiveness of meniscectomy and meniscus repair in addition to ACLR.
Methods
The systematic search was conducted in three online databases (EMBASE, MEDLINE, and Cochrane) from inception until October 2021 for the literature on primary ACLR and concomitant meniscal surgery. Eligible studies compared the following outcomes between meniscal repair and meniscectomy groups: the Knee injury and Osteoarthritis Outcome Score (KOOS), Lysholm score, International Knee Documentation Committee (IKDC) score, and KT-arthrometer examinations. Lastly, we calculated pooled mean differences (MDs) with 95 % confidence intervals (CIs) from the change between pre- and post-intervention values.
Results
Of 10,565 studies, 22 met the inclusion criteria, with a follow-up between 6 and 43 months. We found no difference when comparing the KOOS subscale changes—only in the KOOS pain subscale (MD = −1.6; CI: −2.48, −0.72). However, these results were not clinically significant. We analyzed the lateral and media meniscal injuries separately and concluded the same results regarding KOOS changes. We found no significant differences in the Lysholm score change (MD = −2.61; CI: −5.51, 0.29), changes in IKDC score (MD = 1.08; CI: −4.05, 6.21) or the change for the KT-arthrometer side-to-side difference (MD = −0.50; CI: −1.06, 0.06).
Conclusion
Based on our result, we did not find a clinically significant difference between meniscus repair and meniscectomy during primary ACLR regarding patient-reported outcomes in a short-term follow-up.
Translational potential
Our research supports the prompt integration of findings into clinical practice for treating meniscus injuries during ACL reconstruction. We recommend considering both meniscus repair and meniscectomy, as the available data indicate their effectiveness. Further studies are necessary to assess the long-term impacts, particularly on osteoarthritis, and to identify patient subgroups that may benefit most from each technique.
{"title":"Does concomitant meniscus repair and meniscectomy show different efficacy in anterior cruciate ligament reconstruction? A systematic review and meta-analysis","authors":"Gyula Ferenc Szőcs , Szilárd Váncsa , Gergely Agócs , Péter Hegyi , Dóra Matis , Gergely Pánics , Zoltán Bejek , György Márk Hangody","doi":"10.1016/j.jot.2024.07.004","DOIUrl":"10.1016/j.jot.2024.07.004","url":null,"abstract":"<div><h3>Aims</h3><p>Currently, it is advised to perform meniscal repair instead of meniscectomy in certain cases of primary anterior cruciate ligament reconstruction (ACLR). However, the level of evidence is low. Therefore, this study aimed to compare the effectiveness of meniscectomy and meniscus repair in addition to ACLR.</p></div><div><h3>Methods</h3><p>The systematic search was conducted in three online databases (EMBASE, MEDLINE, and Cochrane) from inception until October 2021 for the literature on primary ACLR and concomitant meniscal surgery. Eligible studies compared the following outcomes between meniscal repair and meniscectomy groups: the Knee injury and Osteoarthritis Outcome Score (KOOS), Lysholm score, International Knee Documentation Committee (IKDC) score, and KT-arthrometer examinations. Lastly, we calculated pooled mean differences (MDs) with 95 % confidence intervals (CIs) from the change between pre- and post-intervention values.</p></div><div><h3>Results</h3><p>Of 10,565 studies, 22 met the inclusion criteria, with a follow-up between 6 and 43 months. We found no difference when comparing the KOOS subscale changes—only in the KOOS pain subscale (MD = −1.6; CI: −2.48, −0.72). However, these results were not clinically significant. We analyzed the lateral and media meniscal injuries separately and concluded the same results regarding KOOS changes. We found no significant differences in the Lysholm score change (MD = −2.61; CI: −5.51, 0.29), changes in IKDC score (MD = 1.08; CI: −4.05, 6.21) or the change for the KT-arthrometer side-to-side difference (MD = −0.50; CI: −1.06, 0.06).</p></div><div><h3>Conclusion</h3><p>Based on our result, we did not find a clinically significant difference between meniscus repair and meniscectomy during primary ACLR regarding patient-reported outcomes in a short-term follow-up.</p></div><div><h3>Translational potential</h3><p>Our research supports the prompt integration of findings into clinical practice for treating meniscus injuries during ACL reconstruction. We recommend considering both meniscus repair and meniscectomy, as the available data indicate their effectiveness. Further studies are necessary to assess the long-term impacts, particularly on osteoarthritis, and to identify patient subgroups that may benefit most from each technique.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"48 ","pages":"Pages 1-10"},"PeriodicalIF":5.9,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X2400072X/pdfft?md5=03e714c69538490fbcec652ac8f984f3&pid=1-s2.0-S2214031X2400072X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141886384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-25DOI: 10.1016/j.jot.2024.07.001
Hang Zhou , Hongzhi Liu , Minmin Lin , Hantang Wang , Jingjing Zhou , Ming Li , Xue Yang , Guibing Fu , Chao Liu
Background
Hyperbaric oxygen (HBO) therapy is widely used to treat bone defects, but the correlation of high oxygen concentration and pressure to osteogenesis is unclear.
Methods
Bilateral monocortical tibial defect surgeries were performed on 12-week-old Prrx1-Cre; Rosa26-tdTomato and Prrx1-Cre; Piezo1fl/+ mice. Daily HBO treatment was applied on post-surgery day (PSD) 1–9; and daily mechanical loading on tibia was from PSD 5 to 8. The mice were euthanized on PSD 10, and bone defect repair in their tibias was evaluated using μCT, biomechanical testing, and immunofluorescence deep-tissue imaging. The degree of angiogenesis–osteogenesis coupling was determined through spatial correlation analysis. Bone marrow stromal cells from knockout mice were cultured in vitro, and their osteogenic capacities of the cells were assessed. The activation of genes in the Piezo1–YAP pathway was evaluated using RNA sequencing and quantitative real-time polymerase chain reaction.
Results
Lineage tracing showed HBO therapy considerably altered the number of Prrx1+ cells and their progeny in a healing bone defect. Using conditional knockdown mice, we found that HBO stimulation activates the Piezo1–YAP axis in Prrx1+ cells and promotes osteogenesis–angiogenesis coupling during bone repair. The beneficial effect of HBO was similar to that of anabolic mechanical stimulation, which also acts through the Piezo1–YAP axis. Subsequent transcriptome sequencing results revealed that similar mechanosensitive pathways are activated by HBO therapy in a bone defect.
Conclusion
HBO therapy promotes bone tissue regeneration through the mechanosensitive Piezo1–YAP pathway in a population of Prrx1+ osteogenic progenitors. Our results contribute to the understanding of the mechanism by which HBO therapy treats bone defects.
The Translational Potential of this Article
Hyperbaric oxygen therapy is widely used in clinical settings. Our results show that osteogenesis was induced by the activation of the Piezo1–YAP pathway in osteoprogenitors after HBO stimulation, and the underlying mechanism was elucidated. These results may help improve current HBO methods and lead to the formulation of alternative treatments that achieve the same functional outcomes.
{"title":"Hyperbaric oxygen promotes bone regeneration by activating the mechanosensitive Piezo1 pathway in osteogenic progenitors","authors":"Hang Zhou , Hongzhi Liu , Minmin Lin , Hantang Wang , Jingjing Zhou , Ming Li , Xue Yang , Guibing Fu , Chao Liu","doi":"10.1016/j.jot.2024.07.001","DOIUrl":"10.1016/j.jot.2024.07.001","url":null,"abstract":"<div><h3>Background</h3><p>Hyperbaric oxygen (HBO) therapy is widely used to treat bone defects, but the correlation of high oxygen concentration and pressure to osteogenesis is unclear.</p></div><div><h3>Methods</h3><p>Bilateral monocortical tibial defect surgeries were performed on 12-week-old Prrx1-Cre; Rosa26-tdTomato and Prrx1-Cre; Piezo1<sup>fl/+</sup> mice. Daily HBO treatment was applied on post-surgery day (PSD) 1–9; and daily mechanical loading on tibia was from PSD 5 to 8. The mice were euthanized on PSD 10, and bone defect repair in their tibias was evaluated using μCT, biomechanical testing, and immunofluorescence deep-tissue imaging. The degree of angiogenesis–osteogenesis coupling was determined through spatial correlation analysis. Bone marrow stromal cells from knockout mice were cultured in vitro, and their osteogenic capacities of the cells were assessed. The activation of genes in the Piezo1–YAP pathway was evaluated using RNA sequencing and quantitative real-time polymerase chain reaction.</p></div><div><h3>Results</h3><p>Lineage tracing showed HBO therapy considerably altered the number of Prrx1<sup>+</sup> cells and their progeny in a healing bone defect. Using conditional knockdown mice, we found that HBO stimulation activates the Piezo1–YAP axis in Prrx1<sup>+</sup> cells and promotes osteogenesis–angiogenesis coupling during bone repair. The beneficial effect of HBO was similar to that of anabolic mechanical stimulation, which also acts through the Piezo1–YAP axis. Subsequent transcriptome sequencing results revealed that similar mechanosensitive pathways are activated by HBO therapy in a bone defect.</p></div><div><h3>Conclusion</h3><p>HBO therapy promotes bone tissue regeneration through the mechanosensitive Piezo1–YAP pathway in a population of Prrx1<sup>+</sup> osteogenic progenitors. Our results contribute to the understanding of the mechanism by which HBO therapy treats bone defects.</p></div><div><h3>The Translational Potential of this Article</h3><p>Hyperbaric oxygen therapy is widely used in clinical settings. Our results show that osteogenesis was induced by the activation of the Piezo1–YAP pathway in osteoprogenitors after HBO stimulation, and the underlying mechanism was elucidated. These results may help improve current HBO methods and lead to the formulation of alternative treatments that achieve the same functional outcomes.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"48 ","pages":"Pages 11-24"},"PeriodicalIF":5.9,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X2400069X/pdfft?md5=a06cbbc39aea7a87fcba5821eaf62a59&pid=1-s2.0-S2214031X2400069X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141950382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-25DOI: 10.1016/j.jot.2024.07.006
Jie Tan , Zecai Chen , Zhen Xu , Yafang Huang , Lei Qin , Yufeng Long , Jiayi Wu , Wanrong Luo , Xuchao Liu , Weihong Yi , Huaiyu Wang , Dazhi Yang
Background
Diabetic bone healing remains a great challenge due to its pathological features including biochemical disturbance, excessive inflammation, and reduced blood vessel formation. In previous studies, small intestine submucosa (SIS) has been demonstrated for its immunomodulatory and angiogenic properties, which are necessary to diabetic bone healing. However, the noticeable drawbacks of SIS such as fast degradation rate, slow gelling time, and weak mechanical property seriously impede the 3D printing of SIS for bone repair.
Method
In this study, we developed a novel kind of 3D-printed scaffold composed of alginate, nano-hydroxyapatite, and SIS. The morphological characterization, biocompatibility, and in vitro biological effects of the scaffolds were evaluated, and an established diabetic rat model was used for testing the in vivo biological effect of the scaffold after implantation.
Results
The in vitro and in vivo results show that the addition of SIS can tune the immunomodulatory properties and angiogenic and osteogenic performances of 3D-printed scaffold, where the macrophages polarization of M2 phenotype, migration and tube formation of HUVECs, as well as osteogenic expression of ALP, are all improved, which bode well with the functional requirements for treating diabetic bone nonunion. Furthermore, the incorporation of alginate substantially improves the printability of composites with tunable degradation properties, thereby broadening the application prospect of SIS-based materials in the field of tissue engineering.
Conclusion
The fabricated 3D-printed Alg/HA/SIS scaffold provides desirable immunomodulatory effect, as well as good osteogenic and angiogenic performances in vitro and in vivo, which properties are well-suited with the requirement for treating diabetic bone defects.
Translational potential of this article
The incorporation of SIS and alginate acid not only provides good printability of the newly fabricated 3D-printed Alg/HA/SIS scaffold, but also improves its immunoregulatory and angiogenic properties, which suits well with the requirement for treating diabetic bone disease and opens up new horizons for the development of implants associating diabetic bone healings.
背景：由于糖尿病的病理特征包括生化紊乱、过度炎症和血管形成减少，其骨愈合仍然是一个巨大的挑战。在以往的研究中，小肠粘膜下层（SIS）已被证实具有免疫调节和血管生成特性，而这正是糖尿病骨愈合所必需的。然而，小肠粘膜降解速度快、胶凝时间慢、机械性能弱等明显缺点严重阻碍了小肠粘膜用于骨修复的三维打印技术：本研究开发了一种由海藻酸盐、纳米羟基磷灰石和 SIS 组成的新型 3D 打印支架。方法：我们开发了一种由海藻酸盐、纳米羟基磷灰石和 SIS 组成的新型三维打印支架，评估了支架的形态特征、生物相容性和体外生物效应，并利用已建立的糖尿病大鼠模型测试了支架植入后的体内生物效应：体外和体内实验结果表明，SIS的加入可以调节三维打印支架的免疫调节性能、血管生成和成骨性能，其中巨噬细胞的M2表型极化、HUVECs的迁移和管形成以及ALP的成骨表达均得到改善，这与治疗糖尿病骨不连的功能要求相吻合。此外，海藻酸盐的加入大大提高了具有可调降解特性的复合材料的可打印性，从而拓宽了基于 SIS 的材料在组织工程领域的应用前景：本文的转化潜力：SIS和海藻酸的加入不仅为新制作的Alg/HA/SIS三维打印支架提供了良好的可打印性，还改善了其免疫调节和血管生成性能，非常适合治疗糖尿病骨病的要求，为开发与糖尿病骨愈合相关的植入物开辟了新天地。
{"title":"A 3D-printed scaffold composed of Alg/HA/SIS for the treatment of diabetic bone defects","authors":"Jie Tan , Zecai Chen , Zhen Xu , Yafang Huang , Lei Qin , Yufeng Long , Jiayi Wu , Wanrong Luo , Xuchao Liu , Weihong Yi , Huaiyu Wang , Dazhi Yang","doi":"10.1016/j.jot.2024.07.006","DOIUrl":"10.1016/j.jot.2024.07.006","url":null,"abstract":"<div><h3>Background</h3><p>Diabetic bone healing remains a great challenge due to its pathological features including biochemical disturbance, excessive inflammation, and reduced blood vessel formation. In previous studies, small intestine submucosa (SIS) has been demonstrated for its immunomodulatory and angiogenic properties, which are necessary to diabetic bone healing. However, the noticeable drawbacks of SIS such as fast degradation rate, slow gelling time, and weak mechanical property seriously impede the 3D printing of SIS for bone repair.</p></div><div><h3>Method</h3><p>In this study, we developed a novel kind of 3D-printed scaffold composed of alginate, nano-hydroxyapatite, and SIS. The morphological characterization, biocompatibility, and <em>in vitro</em> biological effects of the scaffolds were evaluated, and an established diabetic rat model was used for testing the <em>in vivo</em> biological effect of the scaffold after implantation.</p></div><div><h3>Results</h3><p>The <em>in vitro</em> and <em>in vivo</em> results show that the addition of SIS can tune the immunomodulatory properties and angiogenic and osteogenic performances of 3D-printed scaffold, where the macrophages polarization of M2 phenotype, migration and tube formation of HUVECs, as well as osteogenic expression of ALP, are all improved, which bode well with the functional requirements for treating diabetic bone nonunion. Furthermore, the incorporation of alginate substantially improves the printability of composites with tunable degradation properties, thereby broadening the application prospect of SIS-based materials in the field of tissue engineering.</p></div><div><h3>Conclusion</h3><p>The fabricated 3D-printed Alg/HA/SIS scaffold provides desirable immunomodulatory effect, as well as good osteogenic and angiogenic performances <em>in vitro</em> and <em>in vivo</em>, which properties are well-suited with the requirement for treating diabetic bone defects.</p></div><div><h3>Translational potential of this article</h3><p>The incorporation of SIS and alginate acid not only provides good printability of the newly fabricated 3D-printed Alg/HA/SIS scaffold, but also improves its immunoregulatory and angiogenic properties, which suits well with the requirement for treating diabetic bone disease and opens up new horizons for the development of implants associating diabetic bone healings.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"48 ","pages":"Pages 25-38"},"PeriodicalIF":5.9,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1016/j.jot.2024.06.010
Zhiyuan Wei , Jian Zhou , Jie Shen , Dong Sun , Tianbao Gao , Qin Liu , Hongri Wu , Xiaohua Wang , Shulin Wang , Shiyu Xiao , Chao Han , Di Yang , Hui Dong , Yuzhang Wu , Yi Zhang , Shuai Xu , Xian Wang , Jie Luo , Qijie Dai , Jun Zhu , Zhao Xie
<div><h3>Background</h3><p>Osteomyelitis (OM) is an inflammatory condition of bone characterized by cortical bone devascularization and necrosis. Dysregulation of bone remodelling is triggered by OM. Bone remodelling is precisely coordinated by bone resorption and formation via a reversal phase. However, the cellular and molecular mechanisms underlying bone remodelling failure after osteomyelitis remain elusive.</p></div><div><h3>Methods</h3><p>To elucidate the cellular and molecular mechanism underlying bone healing after osteomyelitis, we employed single-cell RNA sequencing (scRNA-seq) to depict the atlas of human cortical bone in normal, infected and reconstructed states. Dimensionality reduction by t-stochastic neighbourhood embedding (t-SNE) and graph-based clustering were applied to analyse the detailed clusters of osteoclast lineages. After trajectory analysis of osteoclast lineages over pseudotime, real-time PCR and immunofluorescence (IF) staining were applied to identify marker gene expression of various osteoclast lineages in the osteoclast induction model and human bone sections, respectively. The potential function and communication of osteoclasts were analysed via gene set enrichment analysis (GSEA) and CellChat. The chemotactic ability of mesenchymal stem cells (MSCs) and osteoclast lineage cells in various differentiation states was determined by transwell assays and coculture assays. The effects of various osteoclast lineages on the osteogenic differentiation potential of MSCs were also determined by using this coculture system. A normal mouse tibia fracture model and an osteomyelitis-related tibia fracture model were generated via injection of luciferase-labelled <em>Staphylococcus aureus</em> to verify the relationships between a novel osteoclast lineage and MSCs. Then, the infection was detected by a bioluminescence imaging system. Finally, immunofluorescence staining was used to detect the expression of markers of MSCs and novel osteoclast lineages in different remodelling phases in normal and infected bone remodelling models.</p></div><div><h3>Results</h3><p>In this study, we constructed a cell atlas encompassing normal, infected, and reconstructed cortical bone. Then, we identified a novel subset at the earlier stage of the osteoclast lineage that exhibited increased expression of IDO1, CCL3, and CCL4. These IDO1<sup>high</sup>CCL3<sup>high</sup>CCL4<sup>high</sup> cells, termed osteostaticytes (OSCs), were further regarded as the reservoir of osteoclasts in the reversal phase. Notably, OSCs exhibited the highest chemotactic activity, surpassing other lineage subsets. We also discovered that cells at the earlier stage of the osteoclast lineage play a significant role in recruiting mesenchymal stem cells (MSCs). Finally, the data revealed that OSCs might be positively related to the occurrence of bone MSCs and the contribution of bone remodelling.</p></div><div><h3>Conclusion</h3><p>Collectively, our findings revealed a nove
{"title":"Osteostaticytes: A novel osteoclast subset couples bone resorption and bone formation","authors":"Zhiyuan Wei , Jian Zhou , Jie Shen , Dong Sun , Tianbao Gao , Qin Liu , Hongri Wu , Xiaohua Wang , Shulin Wang , Shiyu Xiao , Chao Han , Di Yang , Hui Dong , Yuzhang Wu , Yi Zhang , Shuai Xu , Xian Wang , Jie Luo , Qijie Dai , Jun Zhu , Zhao Xie","doi":"10.1016/j.jot.2024.06.010","DOIUrl":"https://doi.org/10.1016/j.jot.2024.06.010","url":null,"abstract":"<div><h3>Background</h3><p>Osteomyelitis (OM) is an inflammatory condition of bone characterized by cortical bone devascularization and necrosis. Dysregulation of bone remodelling is triggered by OM. Bone remodelling is precisely coordinated by bone resorption and formation via a reversal phase. However, the cellular and molecular mechanisms underlying bone remodelling failure after osteomyelitis remain elusive.</p></div><div><h3>Methods</h3><p>To elucidate the cellular and molecular mechanism underlying bone healing after osteomyelitis, we employed single-cell RNA sequencing (scRNA-seq) to depict the atlas of human cortical bone in normal, infected and reconstructed states. Dimensionality reduction by t-stochastic neighbourhood embedding (t-SNE) and graph-based clustering were applied to analyse the detailed clusters of osteoclast lineages. After trajectory analysis of osteoclast lineages over pseudotime, real-time PCR and immunofluorescence (IF) staining were applied to identify marker gene expression of various osteoclast lineages in the osteoclast induction model and human bone sections, respectively. The potential function and communication of osteoclasts were analysed via gene set enrichment analysis (GSEA) and CellChat. The chemotactic ability of mesenchymal stem cells (MSCs) and osteoclast lineage cells in various differentiation states was determined by transwell assays and coculture assays. The effects of various osteoclast lineages on the osteogenic differentiation potential of MSCs were also determined by using this coculture system. A normal mouse tibia fracture model and an osteomyelitis-related tibia fracture model were generated via injection of luciferase-labelled <em>Staphylococcus aureus</em> to verify the relationships between a novel osteoclast lineage and MSCs. Then, the infection was detected by a bioluminescence imaging system. Finally, immunofluorescence staining was used to detect the expression of markers of MSCs and novel osteoclast lineages in different remodelling phases in normal and infected bone remodelling models.</p></div><div><h3>Results</h3><p>In this study, we constructed a cell atlas encompassing normal, infected, and reconstructed cortical bone. Then, we identified a novel subset at the earlier stage of the osteoclast lineage that exhibited increased expression of IDO1, CCL3, and CCL4. These IDO1<sup>high</sup>CCL3<sup>high</sup>CCL4<sup>high</sup> cells, termed osteostaticytes (OSCs), were further regarded as the reservoir of osteoclasts in the reversal phase. Notably, OSCs exhibited the highest chemotactic activity, surpassing other lineage subsets. We also discovered that cells at the earlier stage of the osteoclast lineage play a significant role in recruiting mesenchymal stem cells (MSCs). Finally, the data revealed that OSCs might be positively related to the occurrence of bone MSCs and the contribution of bone remodelling.</p></div><div><h3>Conclusion</h3><p>Collectively, our findings revealed a nove","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"47 ","pages":"Pages 144-160"},"PeriodicalIF":5.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000639/pdfft?md5=bdb204ccae657e06dcbcdb9506fa69ff&pid=1-s2.0-S2214031X24000639-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141479177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<div><h3>Background</h3><p>Zinc finger-containing transcription factor Osterix/Specificity protein-7 (Sp7) is an essential transcription factor for osteoblast differentiation. However, its functions in differentiated osteoblasts remain unclear and the effects of osteoblast-specific <em>Sp7</em> deletion on osteocytes have not been sufficiently studied.</p></div><div><h3>Methods</h3><p><em>Sp7</em><sup>floxneo/floxneo</sup> mice, in which <em>Sp7</em> expression was 30 % of that in wild-type mice because of disturbed splicing by neo gene insertion, and osteoblast-specific knockout (<em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup>) mice using 2.3-kb <em>Col1a1</em> enhanced green fluorescent protein (EGFP)-Cre were examined by micro-computed tomography (micro-CT), bone histomorphometry, serum markers, and histological analyses. The expression of osteoblast and osteocyte marker genes was examined by real-time reverse transcription (RT)-PCR analysis. Osteoblastogenesis, osteoclastogenesis, and regulation of the expression of collagen type I alpha 1 chain (<em>Col1a1</em>) were examined in primary osteoblasts.</p></div><div><h3>Results</h3><p>Femoral trabecular bone volume was higher in female <em>Sp7</em><sup>floxneo/floxneo</sup> and <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice than in the respective controls, but not in males. Bromodeoxyuridine (BrdU)-positive osteoblastic cells were increased in male <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice, and osteoblast number and the bone formation rate were increased in tibial trabecular bone in female <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice, although osteoblast maturation was inhibited in female <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice as shown by the increased expression of an immature osteoblast marker gene, secreted phosphoprotein 1 (<em>Spp1</em>), and reduced expression of a mature osteoblast marker gene, bone gamma-carboxyglutamate protein/bone gamma-carboxyglutamate protein 2 (<em>Bglap/Bglap2</em>). Furthermore, alkaline phosphatase activity was increased but mineralization was reduced in the culture of primary osteoblasts from <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice. Therefore, the accumulated immature osteoblasts in <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice was likely compensated for the inhibition of osteoblast maturation at different levels in males and females. Vertebral trabecular bone volume was lower in both male and female <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice than in the controls and the osteoblast parameters and bone formation rate in females were lower in <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice than in <em>Sp7</em><sup>fl/fl</sup> mice, suggesting differential regulatory mechanisms in long bones and vertebrae. The femoral cortical bone was thin and porous in <em>Sp7</em><sup>floxneo/floxneo</sup> and <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice of both sexes, the number of can
{"title":"Roles of Sp7 in osteoblasts for the proliferation, differentiation, and osteocyte process formation","authors":"Qing Jiang , Kenichi Nagano , Takeshi Moriishi , Hisato Komori , Chiharu Sakane , Yuki Matsuo , Zhiguo Zhang , Riko Nishimura , Kosei Ito , Xin Qin , Toshihisa Komori","doi":"10.1016/j.jot.2024.06.005","DOIUrl":"https://doi.org/10.1016/j.jot.2024.06.005","url":null,"abstract":"<div><h3>Background</h3><p>Zinc finger-containing transcription factor Osterix/Specificity protein-7 (Sp7) is an essential transcription factor for osteoblast differentiation. However, its functions in differentiated osteoblasts remain unclear and the effects of osteoblast-specific <em>Sp7</em> deletion on osteocytes have not been sufficiently studied.</p></div><div><h3>Methods</h3><p><em>Sp7</em><sup>floxneo/floxneo</sup> mice, in which <em>Sp7</em> expression was 30 % of that in wild-type mice because of disturbed splicing by neo gene insertion, and osteoblast-specific knockout (<em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup>) mice using 2.3-kb <em>Col1a1</em> enhanced green fluorescent protein (EGFP)-Cre were examined by micro-computed tomography (micro-CT), bone histomorphometry, serum markers, and histological analyses. The expression of osteoblast and osteocyte marker genes was examined by real-time reverse transcription (RT)-PCR analysis. Osteoblastogenesis, osteoclastogenesis, and regulation of the expression of collagen type I alpha 1 chain (<em>Col1a1</em>) were examined in primary osteoblasts.</p></div><div><h3>Results</h3><p>Femoral trabecular bone volume was higher in female <em>Sp7</em><sup>floxneo/floxneo</sup> and <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice than in the respective controls, but not in males. Bromodeoxyuridine (BrdU)-positive osteoblastic cells were increased in male <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice, and osteoblast number and the bone formation rate were increased in tibial trabecular bone in female <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice, although osteoblast maturation was inhibited in female <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice as shown by the increased expression of an immature osteoblast marker gene, secreted phosphoprotein 1 (<em>Spp1</em>), and reduced expression of a mature osteoblast marker gene, bone gamma-carboxyglutamate protein/bone gamma-carboxyglutamate protein 2 (<em>Bglap/Bglap2</em>). Furthermore, alkaline phosphatase activity was increased but mineralization was reduced in the culture of primary osteoblasts from <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice. Therefore, the accumulated immature osteoblasts in <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice was likely compensated for the inhibition of osteoblast maturation at different levels in males and females. Vertebral trabecular bone volume was lower in both male and female <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice than in the controls and the osteoblast parameters and bone formation rate in females were lower in <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice than in <em>Sp7</em><sup>fl/fl</sup> mice, suggesting differential regulatory mechanisms in long bones and vertebrae. The femoral cortical bone was thin and porous in <em>Sp7</em><sup>floxneo/floxneo</sup> and <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice of both sexes, the number of can","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"47 ","pages":"Pages 161-175"},"PeriodicalIF":5.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000536/pdfft?md5=fcf3b3db8cc860edc417dcaa8f83f032&pid=1-s2.0-S2214031X24000536-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141479178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1016/j.jot.2024.06.013
Hetong Li , Beini Mao , Jintao Zhong, Xiuwang Li, Hongxun Sang
Background
Diabetic bone defects present significant challenges for individuals with diabetes. While metformin has been explored for bone regeneration via local delivery, its application in treating diabetic bone defects remains under-explored. In this study, we aim to leverage 3D printing technology to fabricate a GelMA-Nanoclay hydrogel scaffold loaded with metformin specifically for this purpose. The objective is to assess whether the in situ release of metformin can effectively enhance osteogenesis, angiogenesis, and immunomodulation in the context of diabetic bone defects.
Materials and methods
Utilizing 3D printing technology, we constructed a GelMA-Nanoclay-Metformin hydrogel scaffold with optimal physical properties and biocompatibility. The osteogenic, angiogenic, and immunomodulatory characteristics of the hydrogel scaffold were thoroughly investigated through both in vitro and in vivo experiments.
Results
GelMA10%-Nanoclay8%-Metformin5mg/mL was selected as the bioink for 3D printing due to its favorable swelling rate, degradation rate, mechanical strength, and drug release rate. Through in vitro investigations, the hydrogel scaffold extract, enriched with metformin, demonstrated a substantial enhancement in the proliferation and migration of BMSCs within a high-glucose microenvironment. It effectively enhances osteogenesis, angiogenesis, and immunomodulation. In vivo experimental outcomes further underscored the efficacy of the metformin-loaded GelMA-Nanoclay hydrogel scaffold in promoting superior bone regeneration within diabetic bone defects.
Conclusions
In conclusion, while previous studies have explored local delivery of metformin for bone regeneration, our research is pioneering in its application to diabetic bone defects using a 3D printed GelMA-Nanoclay hydrogel scaffold. This localized delivery approach demonstrates significant potential for enhancing bone regeneration in diabetic patients, offering a novel approach for treating diabetic bone defects.
The translational potential of this article
Our study demonstrates, for the first time, the successful loading of the systemic antidiabetic drug metformin onto a hydrogel scaffold for localized delivery. This approach exhibits significant efficacy in mending diabetic bone defects, presenting a promising new avenue for the treatment of such conditions.
{"title":"Localized delivery of metformin via 3D printed GelMA-Nanoclay hydrogel scaffold for enhanced treatment of diabetic bone defects","authors":"Hetong Li , Beini Mao , Jintao Zhong, Xiuwang Li, Hongxun Sang","doi":"10.1016/j.jot.2024.06.013","DOIUrl":"https://doi.org/10.1016/j.jot.2024.06.013","url":null,"abstract":"<div><h3>Background</h3><p>Diabetic bone defects present significant challenges for individuals with diabetes. While metformin has been explored for bone regeneration via local delivery, its application in treating diabetic bone defects remains under-explored. In this study, we aim to leverage 3D printing technology to fabricate a GelMA-Nanoclay hydrogel scaffold loaded with metformin specifically for this purpose. The objective is to assess whether the in situ release of metformin can effectively enhance osteogenesis, angiogenesis, and immunomodulation in the context of diabetic bone defects.</p></div><div><h3>Materials and methods</h3><p>Utilizing 3D printing technology, we constructed a GelMA-Nanoclay-Metformin hydrogel scaffold with optimal physical properties and biocompatibility. The osteogenic, angiogenic, and immunomodulatory characteristics of the hydrogel scaffold were thoroughly investigated through both in vitro and in vivo experiments.</p></div><div><h3>Results</h3><p>GelMA10%-Nanoclay8%-Metformin5mg/mL was selected as the bioink for 3D printing due to its favorable swelling rate, degradation rate, mechanical strength, and drug release rate. Through in vitro investigations, the hydrogel scaffold extract, enriched with metformin, demonstrated a substantial enhancement in the proliferation and migration of BMSCs within a high-glucose microenvironment. It effectively enhances osteogenesis, angiogenesis, and immunomodulation. In vivo experimental outcomes further underscored the efficacy of the metformin-loaded GelMA-Nanoclay hydrogel scaffold in promoting superior bone regeneration within diabetic bone defects.</p></div><div><h3>Conclusions</h3><p>In conclusion, while previous studies have explored local delivery of metformin for bone regeneration, our research is pioneering in its application to diabetic bone defects using a 3D printed GelMA-Nanoclay hydrogel scaffold. This localized delivery approach demonstrates significant potential for enhancing bone regeneration in diabetic patients, offering a novel approach for treating diabetic bone defects.</p></div><div><h3>The translational potential of this article</h3><p>Our study demonstrates, for the first time, the successful loading of the systemic antidiabetic drug metformin onto a hydrogel scaffold for localized delivery. This approach exhibits significant efficacy in mending diabetic bone defects, presenting a promising new avenue for the treatment of such conditions.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"47 ","pages":"Pages 249-260"},"PeriodicalIF":5.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000664/pdfft?md5=49e870b4d7434a75f558a1352e15d3ca&pid=1-s2.0-S2214031X24000664-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141542541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1016/j.jot.2024.07.003
Ling Qin (Prof)
{"title":"Understanding pathophysiology and injury mechanisms is the foundation for invention/innovation and clinical translation in orthopaedics","authors":"Ling Qin (Prof)","doi":"10.1016/j.jot.2024.07.003","DOIUrl":"10.1016/j.jot.2024.07.003","url":null,"abstract":"","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"47 ","pages":"Pages A1-A2"},"PeriodicalIF":5.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000718/pdfft?md5=c0520133f484f6ac36c367d5f097c670&pid=1-s2.0-S2214031X24000718-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141692130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1016/j.jot.2024.06.015
Yanzhi Liu , Rui Lin , Haiping Fang , Lixian Li, Min Zhang, Lujiao Lu, Xiang Gao, Jintong Song, Jinsong Wei, Qixian Xiao, Fucheng Zhang, Kefeng Wu, Liao Cui
<div><h3>Background</h3><p>Osteoarthritis (OA) presents a formidable challenge, characterized by as-yet-unclear mechanical intricacies within cartilage and the dysregulation of bone homeostasis. Our preliminary data revealed the encouraging potential of a Sargassum polysaccharide (SP), in promoting chondrogenesis. The aim of our study is to comprehensively assess the therapeutic effects of SP on OA models and further elucidate its potential mechanism.</p></div><div><h3>Methods</h3><p>The protective effects of SP were initially evaluated in an inflammation-induced human chondrocyte (C28) cell model. CCK-8 assays, Alcian blue staining, RT-qPCR and Western blotting were used to verify the chondrogenesis of SP <em>in vitro</em>. To assess the efficacy of SP <em>in vivo</em>, surgically induced medial meniscus destabilization (DMM) OA rats underwent an 8-week SP treatment. The therapeutic effects of SP in OA rats were comprehensively evaluated using X-ray imaging, micro-computed tomography (μ-CT), histopathological analysis, as well as immunohistochemical and immunofluorescent staining. Following these assessments, we delved into the potential signaling pathways of SP in inflammatory chondrocytes utilizing RNA-seq analysis. Validation of these findings was conducted through RT-qPCR and western blotting techniques.</p></div><div><h3>Results</h3><p>SP significantly enhance the viability of C28 chondrocytes, and increased the secretion of acidic glycoproteins. Moreover, SP stimulated the expression of chondrogenic genes (<em>Aggrecan</em>, <em>Sox9</em>, <em>Col2a1</em>) and facilitated the synthesis of Collagen II protein in C28 inflammatory chondrocytes. <em>In vivo</em> experiments revealed that SP markedly ameliorated knee joint stenosis, alleviated bone and cartilage injuries, and reduced the histopathological scores in the OA rats. μ-CT analysis confirmed that SP lessened bone impairments in the medial femoral condyle and the subchondral bone of the tibial plateau, significantly improving the microarchitectural parameters of the subchondral bone. Histopathological analyses indicated that SP notably enhanced cartilage quality on the surface of the tibial plateau, leading to increased cartilage thickness and area. Immunohistochemistry staining and immunofluorescence staining corroborated these findings by showing a significant promotion of Collagen II expression in OA joints treated with SP. RNA-seq analysis suggest that SP's effects were mediated through the regulation of the ITGβ1-PI3K-AKT signaling axis, thereby stimulating chondrogenesis. Verification through RT-qPCR and Western blot analyses confirmed that SP significantly upregulated the expression of ITGβ1, p110δ, AKT1, ACAN, and Col2a1. Notably, knock-down of ITGβ1 using siRNA in C28 chondrocytes inhibited the expression of ITGβ1, p110δ, AKT1, and ACAN. However, these inhibitory effects were not completely reversed by supplemental SP intervention.</p></div><div><h3>Conclusions</h3><p>In summa
背景骨关节炎（OA）是一项艰巨的挑战，其特点是软骨内错综复杂的机械结构和骨平衡失调。我们的初步数据显示，马尾藻多糖（SP）在促进软骨生成方面具有令人鼓舞的潜力。我们研究的目的是全面评估马尾藻多糖对 OA 模型的治疗效果，并进一步阐明其潜在机制。方法首先在炎症诱导的人软骨细胞（C28）模型中评估马尾藻多糖的保护作用。方法首先在炎症诱导的人软骨细胞（C28）模型中评估了SP的保护作用，并使用CCK-8测定、阿尔西恩蓝染色、RT-qPCR和Western印迹法验证了SP在体外的软骨生成作用。为了评估SP在体内的疗效，对手术诱导的内侧半月板失稳（DMM）OA大鼠进行了为期8周的SP治疗。我们使用 X 射线成像、微型计算机断层扫描（μ-CT）、组织病理学分析以及免疫组织化学和免疫荧光染色对 SP 对 OA 大鼠的治疗效果进行了全面评估。在这些评估之后，我们利用 RNA-seq 分析深入研究了 SP 在炎性软骨细胞中的潜在信号通路。结果 SP 显著提高了 C28 软骨细胞的活力，并增加了酸性糖蛋白的分泌。此外，SP 还能刺激 C28 炎性软骨细胞中软骨生成基因（Aggrecan、Sox9、Col2a1）的表达，促进胶原蛋白 II 的合成。μ-CT分析证实，SP减轻了股骨内侧髁和胫骨平台软骨下骨的骨损伤，显著改善了软骨下骨的微结构参数。组织病理学分析表明，SP 显著提高了胫骨平台表面软骨的质量，增加了软骨的厚度和面积。免疫组化染色和免疫荧光染色也证实了这些发现，显示在使用 SP 治疗的 OA 关节中，胶原蛋白 II 的表达明显增加。RNA-seq分析表明，SP的作用是通过调节ITGβ1-PI3K-AKT信号轴介导的，从而刺激软骨生成。RT-qPCR 和 Western 印迹分析证实，SP 能显著上调 ITGβ1、p110δ、AKT1、ACAN 和 Col2a1 的表达。值得注意的是，在 C28 软骨细胞中使用 siRNA 敲除 ITGβ1，可抑制 ITGβ1、p110δ、AKT1 和 ACAN 的表达。总之，我们的研究结果表明，SP 能显著增强体外和体内的软骨生成，缓解骨和软骨中的 OA 进展。我们的研究首次揭示了 SP 在治疗 OA 中的优势作用和潜在机制。SP的临床前景为下一代多糖类药物治疗OA提供了令人信服的新证据。
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