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Challenges and advances in materials and fabrication technologies of small-diameter vascular grafts. 小直径血管移植物材料和制造技术的挑战和进展。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-06-08 DOI: 10.1186/s40824-023-00399-2
Mei-Xian Li, Qian-Qi Wei, Hui-Lin Mo, Yu Ren, Wei Zhang, Huan-Jun Lu, Yoon Ki Joung

The arterial occlusive disease is one of the leading causes of cardiovascular diseases, often requiring revascularization. Lack of suitable small-diameter vascular grafts (SDVGs), infection, thrombosis, and intimal hyperplasia associated with synthetic vascular grafts lead to a low success rate of SDVGs (< 6 mm) transplantation in the clinical treatment of cardiovascular diseases. The development of fabrication technology along with vascular tissue engineering and regenerative medicine technology allows biological tissue-engineered vascular grafts to become living grafts, which can integrate, remodel, and repair the host vessels as well as respond to the surrounding mechanical and biochemical stimuli. Hence, they potentially alleviate the shortage of existing vascular grafts. This paper evaluates the current advanced fabrication technologies for SDVGs, including electrospinning, molding, 3D printing, decellularization, and so on. Various characteristics of synthetic polymers and surface modification methods are also introduced. In addition, it also provides interdisciplinary insights into the future of small-diameter prostheses and discusses vital factors and perspectives for developing such prostheses in clinical applications. We propose that the performance of SDVGs can be improved by integrating various technologies in the near future.

动脉闭塞性疾病是心血管疾病的主要原因之一,通常需要进行血运重建。缺乏合适的小直径血管移植物(SDVGs)、感染、血栓形成和与合成血管移植物相关的内膜增生导致SDVGs的成功率低(
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引用次数: 3
Progress of tissue adhesives based on proteins and synthetic polymers. 基于蛋白质和合成聚合物的组织粘接剂的研究进展。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-06-07 DOI: 10.1186/s40824-023-00397-4
Gi-Yeon Han, Soo-Kyung Hwang, Ki-Hyun Cho, Hyun-Joong Kim, Chong-Su Cho

In recent years, polymer-based tissue adhesives (TAs) have been developed as an alternative to sutures to close and seal incisions or wounds owing to their ease of use, rapid application time, low cost, and minimal tissue damage. Although significant research is being conducted to develop new TAs with improved performances using different strategies, the applications of TAs are limited by several factors, such as weak adhesion strength and poor mechanical properties. Therefore, the next-generation advanced TAs with biomimetic and multifunctional properties should be developed. Herein, we review the requirements, adhesive performances, characteristics, adhesive mechanisms, applications, commercial products, and advantages and disadvantages of proteins- and synthetic polymer-based TAs. Furthermore, future perspectives in the field of TA-based research have been discussed.

近年来,聚合物基组织粘接剂(TAs)因其易于使用、应用时间短、成本低和组织损伤小而成为缝合和密封切口或伤口的替代方法。尽管人们正在进行大量研究,以开发使用不同策略改善性能的新型TAs,但TAs的应用受到几个因素的限制,例如粘附强度弱和机械性能差。因此,应该开发具有仿生和多功能特性的下一代高级TAs。本文综述了蛋白质基和合成聚合物基TAs的要求、粘合性能、特性、粘合机理、应用、商业产品以及优缺点。最后,对未来的研究方向进行了展望。
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引用次数: 4
A hydrogel-based first-aid tissue adhesive with effective hemostasis and anti-bacteria for trauma emergency management. 一种用于创伤急救的有效止血和抗菌的水凝胶急救组织胶粘剂。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-06-02 DOI: 10.1186/s40824-023-00392-9
Dongjie Zhang, Li Mei, Yuanping Hao, Bingcheng Yi, Jilin Hu, Danyang Wang, Yaodong Zhao, Zhe Wang, Hailin Huang, Yongzhi Xu, Xuyang Deng, Cong Li, Xuewei Li, Qihui Zhou, Yun Lu

Background: Clinical tissue adhesives remain some critical drawbacks for managing emergency injuries, such as inadequate adhesive strength and insufficient anti-infection ability. Herein, a novel, self-healing, and antibacterial carboxymethyl chitosan/polyaldehyde dextran (CMCS/PD) hydrogel is designed as the first-aid tissue adhesive for effective trauma emergency management.

Methods: We examined the gel-forming time, porosity, self-healing, antibacterial properties, cytotoxicity, adhesive strength, and hemocompatibility. Liver hemorrhage, tail severance, and skin wound infection models of rats are constructed in vivo, respectively.

Results: Results demonstrate that the CMCS/PD hydrogel has the rapid gel-forming (~ 5 s), good self-healing, and effective antibacterial abilities, and could adhere to tissue firmly (adhesive strength of ~ 10 kPa and burst pressure of 327.5 mmHg) with excellent hemocompatibility and cytocompatibility. This suggests the great prospect of CMCS/PD hydrogel in acting as a first-aid tissue adhesive for trauma emergency management. The CMCS/PD hydrogel is observed to not only achieve rapid hemostasis for curing liver hemorrhage and tail severance in comparison to commercial hemostatic gel (Surgiflo ®) but also exhibit superior anti-infection for treating acute skin trauma compared with clinical disinfectant gel (Prontosan ®).

Conclusions: Overall, the CMCS/PD hydrogel offers a promising candidate for first-aid tissue adhesives to manage the trauma emergency. Because of the rapid gel-forming time, it could also be applied as a liquid first-aid bandage for mini-invasive surgical treatment.

背景:临床组织粘接剂在处理急诊损伤时仍然存在一些严重的缺陷,如粘接剂强度不足和抗感染能力不足。本文设计了一种新型的、自愈的、抗菌的羧甲基壳聚糖/聚醛葡聚糖(CMCS/PD)水凝胶作为有效的创伤应急处理的急救组织粘接剂。方法:考察其成胶时间、孔隙度、自愈性、抗菌性能、细胞毒性、黏附强度和血液相容性。分别建立大鼠肝出血模型、断尾模型和皮肤创面感染模型。结果:结果表明,CMCS/PD水凝胶具有快速成胶(~ 5 s)、良好的自愈性和有效的抗菌能力,并能牢固地粘附组织(粘附强度~ 10 kPa,破裂压力327.5 mmHg),具有良好的血液相容性和细胞相容性。这表明CMCS/PD水凝胶作为创伤急救组织粘接剂具有广阔的应用前景。与商业止血凝胶(Surgiflo®)相比,CMCS/PD水凝胶不仅可以快速止血治疗肝出血和尾裂,而且与临床消毒凝胶(Prontosan®)相比,在治疗急性皮肤创伤方面也具有优越的抗感染能力。结论:总的来说,CMCS/PD水凝胶是一种很有前途的创伤急救组织粘接剂。由于凝胶形成时间快,它也可以作为液体急救绷带用于微创手术治疗。
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引用次数: 1
Trends in mechanobiology guided tissue engineering and tools to study cell-substrate interactions: a brief review. 机械生物学指导组织工程和工具研究细胞-底物相互作用的趋势:简要回顾。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-06-01 DOI: 10.1186/s40824-023-00393-8
Arun Kumar Rajendran, Deepthi Sankar, Sivashanmugam Amirthalingam, Hwan D Kim, Jayakumar Rangasamy, Nathaniel S Hwang

Sensing the mechanical properties of the substrates or the matrix by the cells and the tissues, the subsequent downstream responses at the cellular, nuclear and epigenetic levels and the outcomes are beginning to get unraveled more recently. There have been various instances where researchers have established the underlying connection between the cellular mechanosignalling pathways and cellular physiology, cellular differentiation, and also tissue pathology. It has been now accepted that mechanosignalling, alone or in combination with classical pathways, could play a significant role in fate determination, development, and organization of cells and tissues. Furthermore, as mechanobiology is gaining traction, so do the various techniques to ponder and gain insights into the still unraveled pathways. This review would briefly discuss some of the interesting works wherein it has been shown that specific alteration of the mechanical properties of the substrates would lead to fate determination of stem cells into various differentiated cells such as osteoblasts, adipocytes, tenocytes, cardiomyocytes, and neurons, and how these properties are being utilized for the development of organoids. This review would also cover various techniques that have been developed and employed to explore the effects of mechanosignalling, including imaging of mechanosensing proteins, atomic force microscopy (AFM), quartz crystal microbalance with dissipation measurements (QCMD), traction force microscopy (TFM), microdevice arrays, Spatio-temporal image analysis, optical tweezer force measurements, mechanoscanning ion conductance microscopy (mSICM), acoustofluidic interferometric device (AID) and so forth. This review would provide insights to the researchers who work on exploiting various mechanical properties of substrates to control the cellular and tissue functions for tissue engineering and regenerative applications, and also will shed light on the advancements of various techniques that could be utilized to unravel the unknown in the field of cellular mechanobiology.

通过细胞和组织感知底物或基质的机械特性,随后在细胞、细胞核和表观遗传水平上的下游反应及其结果最近开始得到揭示。研究人员已经建立了细胞机械信号通路与细胞生理学、细胞分化以及组织病理学之间的潜在联系。机械信号传导,单独或与经典途径结合,在细胞和组织的命运决定、发育和组织中发挥重要作用。此外,随着机械生物学的发展,各种各样的技术也在不断发展,以思考和洞察尚未解开的途径。本综述将简要讨论一些有趣的研究成果,其中表明基质机械特性的特定改变将导致干细胞分化为各种分化细胞(如成骨细胞、脂肪细胞、腱细胞、心肌细胞和神经元)的命运决定,以及如何利用这些特性开发类器官。这篇综述还将涵盖各种已经开发和用于探索机械信号效应的技术,包括机械传感蛋白成像、原子力显微镜(AFM)、石英晶体微平衡耗散测量(QCMD)、牵引力显微镜(TFM)、微器件阵列、时空图像分析、光镊力测量、机械扫描离子电导显微镜(mSICM)、声流干涉测量装置(AID)等。这一综述将为研究人员在组织工程和再生应用中利用基质的各种机械特性来控制细胞和组织功能提供见解,也将揭示各种技术的进展,这些技术可以用来解开细胞力学生物学领域的未知。
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引用次数: 7
High-glutathione mesenchymal stem cells isolated using the FreSHtracer probe enhance cartilage regeneration in a rabbit chondral defect model. 在兔软骨缺损模型中,使用FreSHtracer探针分离的高谷胱甘肽间充质干细胞增强软骨再生。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-05-31 DOI: 10.1186/s40824-023-00398-3
Gun Hee Cho, Hyun Cheol Bae, Won Young Cho, Eui Man Jeong, Hee Jung Park, Ha Ru Yang, Sun Young Wang, You Jung Kim, Dong Myung Shin, Hyung Min Chung, In Gyu Kim, Hyuk-Soo Han

Background: Mesenchymal stem cells (MSCs) are a promising cell source for cartilage regeneration. However, the function of MSC can vary according to cell culture conditions, donor age, and heterogeneity of the MSC population, resulting in unregulated MSC quality control. To overcome these limitations, we previously developed a fluorescent real-time thiol tracer (FreSHtracer) that monitors cellular levels of glutathione (GSH), which are known to be closely associated with stem cell function. In this study, we investigated whether using FreSHtracer could selectively separate high-functioning MSCs based on GSH levels and evaluated the chondrogenic potential of MSCs with high GSH levels to repair cartilage defects in vivo.

Methods: Flow cytometry was conducted on FreSHtracer-loaded MSCs to select cells according to their GSH levels. To determine the function of FreSHtracer-isolated MSCs, mRNA expression, migration, and CFU assays were conducted. The MSCs underwent chondrogenic differentiation, followed by analysis of chondrogenic-related gene expression. For in vivo assessment, MSCs with different cellular GSH levels or cell culture densities were injected in a rabbit chondral defect model, followed by histological analysis of cartilage-regenerated defect sites.

Results: FreSHtracer successfully isolated MSCs according to GSH levels. MSCs with high cellular GSH levels showed enhanced MSC function, including stem cell marker mRNA expression, migration, CFU, and oxidant resistance. Regardless of the stem cell tissue source, FreSHtracer selectively isolated MSCs with high GSH levels and high functionality. The in vitro chondrogenic potential was the highest in pellets generated by MSCs with high GSH levels, with increased ECM formation and chondrogenic marker expression. Furthermore, the MSCs' function was dependent on cell culture conditions, with relatively higher cell culture densities resulting in higher GSH levels. In vivo, improved cartilage repair was achieved by articular injection of MSCs with high levels of cellular GSH and MSCs cultured under high-density conditions, as confirmed by Collagen type 2 IHC, Safranin-O staining and O'Driscoll scores showing that more hyaline cartilage was formed on the defects.

Conclusion: FreSHtracer selectively isolates highly functional MSCs that have enhanced in vitro chondrogenesis and in vivo hyaline cartilage regeneration, which can ultimately overcome the current limitations of MSC therapy.

背景:间充质干细胞(MSCs)是一种很有前途的软骨再生细胞来源。然而,MSC的功能可能因细胞培养条件、供体年龄和MSC群体的异质性而异,导致MSC质量控制不受监管。为了克服这些限制,我们之前开发了一种荧光实时硫醇示踪剂(FreSHtracer),用于监测谷胱甘肽(GSH)的细胞水平,已知谷胱甘肽与干细胞功能密切相关。在本研究中,我们研究了使用FreSHtracer是否可以根据GSH水平选择性分离高功能MSCs,并评估了具有高GSH水平的MSCs在体内修复软骨缺损的软骨形成潜力。方法:用流式细胞仪对负载FreSH示踪剂的MSCs进行流式细胞术,根据其GSH水平选择细胞。为了确定FreSHtracer分离的MSCs的功能,进行了mRNA表达、迁移和CFU测定。MSCs进行软骨分化,然后分析软骨相关基因的表达。为了进行体内评估,将具有不同细胞GSH水平或细胞培养密度的MSCs注射到兔软骨缺损模型中,然后对软骨再生缺损部位进行组织学分析。结果:FreSHtracer根据GSH水平成功分离出MSCs。具有高细胞GSH水平的MSC显示出增强的MSC功能,包括干细胞标记物mRNA表达、迁移、CFU和抗氧化性。无论干细胞组织来源如何,FreSHtracer都选择性地分离出具有高GSH水平和高功能的MSC。在具有高GSH水平的MSCs产生的颗粒中,体外软骨形成潜力最高,ECM形成和软骨形成标记物表达增加。此外,MSC的功能取决于细胞培养条件,相对较高的细胞培养密度导致较高的GSH水平。在体内,通过关节注射具有高水平细胞GSH的MSCs和在高密度条件下培养的MSCs来改善软骨修复,如2型胶原IHC、番红-O染色和奥德里斯科评分所证实的,显示在缺陷上形成了更多的透明软骨。结论:FreSHtracer选择性分离出具有增强体外软骨生成和体内透明软骨再生的高功能MSC,最终可以克服MSC治疗的局限性。
{"title":"High-glutathione mesenchymal stem cells isolated using the FreSHtracer probe enhance cartilage regeneration in a rabbit chondral defect model.","authors":"Gun Hee Cho, Hyun Cheol Bae, Won Young Cho, Eui Man Jeong, Hee Jung Park, Ha Ru Yang, Sun Young Wang, You Jung Kim, Dong Myung Shin, Hyung Min Chung, In Gyu Kim, Hyuk-Soo Han","doi":"10.1186/s40824-023-00398-3","DOIUrl":"10.1186/s40824-023-00398-3","url":null,"abstract":"<p><strong>Background: </strong>Mesenchymal stem cells (MSCs) are a promising cell source for cartilage regeneration. However, the function of MSC can vary according to cell culture conditions, donor age, and heterogeneity of the MSC population, resulting in unregulated MSC quality control. To overcome these limitations, we previously developed a fluorescent real-time thiol tracer (FreSHtracer) that monitors cellular levels of glutathione (GSH), which are known to be closely associated with stem cell function. In this study, we investigated whether using FreSHtracer could selectively separate high-functioning MSCs based on GSH levels and evaluated the chondrogenic potential of MSCs with high GSH levels to repair cartilage defects in vivo.</p><p><strong>Methods: </strong>Flow cytometry was conducted on FreSHtracer-loaded MSCs to select cells according to their GSH levels. To determine the function of FreSHtracer-isolated MSCs, mRNA expression, migration, and CFU assays were conducted. The MSCs underwent chondrogenic differentiation, followed by analysis of chondrogenic-related gene expression. For in vivo assessment, MSCs with different cellular GSH levels or cell culture densities were injected in a rabbit chondral defect model, followed by histological analysis of cartilage-regenerated defect sites.</p><p><strong>Results: </strong>FreSHtracer successfully isolated MSCs according to GSH levels. MSCs with high cellular GSH levels showed enhanced MSC function, including stem cell marker mRNA expression, migration, CFU, and oxidant resistance. Regardless of the stem cell tissue source, FreSHtracer selectively isolated MSCs with high GSH levels and high functionality. The in vitro chondrogenic potential was the highest in pellets generated by MSCs with high GSH levels, with increased ECM formation and chondrogenic marker expression. Furthermore, the MSCs' function was dependent on cell culture conditions, with relatively higher cell culture densities resulting in higher GSH levels. In vivo, improved cartilage repair was achieved by articular injection of MSCs with high levels of cellular GSH and MSCs cultured under high-density conditions, as confirmed by Collagen type 2 IHC, Safranin-O staining and O'Driscoll scores showing that more hyaline cartilage was formed on the defects.</p><p><strong>Conclusion: </strong>FreSHtracer selectively isolates highly functional MSCs that have enhanced in vitro chondrogenesis and in vivo hyaline cartilage regeneration, which can ultimately overcome the current limitations of MSC therapy.</p>","PeriodicalId":9079,"journal":{"name":"Biomaterials Research","volume":null,"pages":null},"PeriodicalIF":11.3,"publicationDate":"2023-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10233867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9568759","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}
引用次数: 0
Liposomes targeting the cancer cell-exposed receptor, claudin-4, for pancreatic cancer chemotherapy. 靶向癌细胞暴露受体claudin-4的脂质体用于胰腺癌化疗。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-05-26 DOI: 10.1186/s40824-023-00394-7
Chaeeun Bang, Min Gyu Park, In Kyung Cho, Da-Eun Lee, Gye Lim Kim, Eun Hyang Jang, Man Kyu Shim, Hong Yeol Yoon, Sangmin Lee, Jong-Ho Kim

Background: Claudin-4 (CLDN4), a tight junction protein, is overexpressed in several types of cancer, and is considered a biomarker for cancer-targeted treatment. CLDN4 is not exposed in normal cells, but becomes accessible in cancer cells, in which tight junctions are weakened. Notably, surface-exposed CLDN4 has recently been found to act as a receptor for Clostridium perfringens enterotoxin (CPE) and fragment of CPE (CPE17) that binds to the second domain of CLDN4.

Methods: Here, we sought to develop a CPE17-containing liposome that targets pancreatic cancers through binding to exposed CLDN4.

Results: Doxorubicin (Dox)-loaded, CPE17-conjugated liposomes (D@C-LPs) preferentially targeted CLDN4-expressing cell lines, as evidenced by greater uptake and cytotoxicity compared with CLDN4-negative cell lines, whereas uptake and cytotoxicity of Dox-loaded liposomes lacking CPE17 (D@LPs) was similar for both CLDN4-positive and negative cell lines. Notably, D@C-LPs showed greater accumulation in targeted pancreatic tumor tissues compared with normal pancreas tissue; in contrast, Dox-loaded liposomes lacking CPE17 (D@LPs) showed little accumulation in pancreatic tumor tissues. Consistent with this, D@C-LPs showed greater anticancer efficacy compared with other liposome formulations and significantly extended survival.

Conclusions: We expect our findings will aid in the prevention and treatment of pancreatic cancer and provide a framework for identifying cancer-specific strategies that target exposed receptors.

背景:Claudin-4 (CLDN4)是一种紧密连接蛋白,在几种类型的癌症中过表达,被认为是癌症靶向治疗的生物标志物。CLDN4在正常细胞中不暴露,但在紧密连接被削弱的癌细胞中可以接触到。值得注意的是,最近发现表面暴露的CLDN4作为产气荚膜梭菌肠毒素(CPE)和CPE片段(CPE17)的受体与CLDN4的第二结构域结合。方法:在这里,我们试图开发一种含有cpe17的脂质体,通过与暴露的CLDN4结合来靶向胰腺癌。结果:多柔比星(Dox)负载,CPE17偶联脂质体(D@C-LPs)优先靶向表达cldn4的细胞系,与cldn4阴性细胞系相比,有更大的摄取和细胞毒性,而在cldn4阳性和阴性细胞系中,缺乏CPE17的多柔比星负载脂质体(D@LPs)的摄取和细胞毒性相似。值得注意的是,与正常胰腺组织相比,D@C-LPs在靶向胰腺肿瘤组织中的蓄积更大;相比之下,缺乏CPE17的载dox脂质体(D@LPs)在胰腺肿瘤组织中几乎没有积累。与此一致,D@C-LPs与其他脂质体制剂相比显示出更大的抗癌功效,并显着延长了生存期。结论:我们期望我们的发现将有助于胰腺癌的预防和治疗,并为确定针对暴露受体的癌症特异性策略提供框架。
{"title":"Liposomes targeting the cancer cell-exposed receptor, claudin-4, for pancreatic cancer chemotherapy.","authors":"Chaeeun Bang,&nbsp;Min Gyu Park,&nbsp;In Kyung Cho,&nbsp;Da-Eun Lee,&nbsp;Gye Lim Kim,&nbsp;Eun Hyang Jang,&nbsp;Man Kyu Shim,&nbsp;Hong Yeol Yoon,&nbsp;Sangmin Lee,&nbsp;Jong-Ho Kim","doi":"10.1186/s40824-023-00394-7","DOIUrl":"https://doi.org/10.1186/s40824-023-00394-7","url":null,"abstract":"<p><strong>Background: </strong>Claudin-4 (CLDN4), a tight junction protein, is overexpressed in several types of cancer, and is considered a biomarker for cancer-targeted treatment. CLDN4 is not exposed in normal cells, but becomes accessible in cancer cells, in which tight junctions are weakened. Notably, surface-exposed CLDN4 has recently been found to act as a receptor for Clostridium perfringens enterotoxin (CPE) and fragment of CPE (CPE17) that binds to the second domain of CLDN4.</p><p><strong>Methods: </strong>Here, we sought to develop a CPE17-containing liposome that targets pancreatic cancers through binding to exposed CLDN4.</p><p><strong>Results: </strong>Doxorubicin (Dox)-loaded, CPE17-conjugated liposomes (D@C-LPs) preferentially targeted CLDN4-expressing cell lines, as evidenced by greater uptake and cytotoxicity compared with CLDN4-negative cell lines, whereas uptake and cytotoxicity of Dox-loaded liposomes lacking CPE17 (D@LPs) was similar for both CLDN4-positive and negative cell lines. Notably, D@C-LPs showed greater accumulation in targeted pancreatic tumor tissues compared with normal pancreas tissue; in contrast, Dox-loaded liposomes lacking CPE17 (D@LPs) showed little accumulation in pancreatic tumor tissues. Consistent with this, D@C-LPs showed greater anticancer efficacy compared with other liposome formulations and significantly extended survival.</p><p><strong>Conclusions: </strong>We expect our findings will aid in the prevention and treatment of pancreatic cancer and provide a framework for identifying cancer-specific strategies that target exposed receptors.</p>","PeriodicalId":9079,"journal":{"name":"Biomaterials Research","volume":null,"pages":null},"PeriodicalIF":11.3,"publicationDate":"2023-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10214683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9538921","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}
引用次数: 0
Inhibition of DAMP actions in the tumoral microenvironment using lactoferrin-glycyrrhizin conjugate for glioblastoma therapy. 乳铁蛋白-甘草酸偶联物用于胶质母细胞瘤治疗抑制肿瘤微环境中DAMP的作用。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-05-20 DOI: 10.1186/s40824-023-00391-w
Hyung Shik Kim, Seok Chan Park, Hae Jin Kim, Dong Yun Lee

Background: High-mobility group box-1 (HMGB1) released from the tumor microenvironment plays a pivotal role in the tumor progression. HMGB1 serves as a damaged-associated molecular pattern (DAMP) that induces tumor angiogenesis and its development. Glycyrrhizin (GL) is an effective intracellular antagonist of tumor released HMGB1, but its pharmacokinetics (PK) and delivery to tumor site is deficient. To address this shortcoming, we developed lactoferrin-glycyrrhizin (Lf-GL) conjugate.

Methods: Biomolecular interaction between Lf-GL and HMGB1 was evaluated by surface plasmon resonance (SPR) binding affinity assay. Inhibition of tumor angiogenesis and development by Lf-GL attenuating HMGB1 action in the tumor microenvironment was comprehensively evaluated through in vitro, ex vivo, and in vivo. Pharmacokinetic study and anti-tumor effects of Lf-GL were investigated in orthotopic glioblastoma mice model.

Results: Lf-GL interacts with lactoferrin receptor (LfR) expressed on BBB and GBM, therefore, efficiently inhibits HMGB1 in both the cytoplasmic and extracellular regions of tumors. Regarding the tumor microenvironment, Lf-GL inhibits angiogenesis and tumor growth by blocking HMGB1 released from necrotic tumors and preventing recruitment of vascular endothelial cells. In addition, Lf-GL improved the PK properties of GL approximately tenfold in the GBM mouse model and reduced tumor growth by 32%. Concurrently, various biomarkers for tumor were radically diminished.

Conclusion: Collectively, our study demonstrates a close association between HMGB1 and tumor progression, suggesting Lf-GL as a potential strategy for coping with DAMP-related tumor microenvironment. HMGB1 is a tumor-promoting DAMP in the tumor microenvironment. The high binding capability of Lf-GL to HMGB1 inhibits tumor progression cascade such as tumor angiogenesis, development, and metastasis. Lf-GL targets GBM through interaction with LfR and allows to arrest HMGB1 released from the tumor microenvironment. Therefore, Lf-GL can be a GBM treatment by modulating HMGB1 activity.

背景:肿瘤微环境释放的高迁移率组框-1 (HMGB1)在肿瘤进展中起关键作用。HMGB1作为一种损伤相关分子模式(DAMP),诱导肿瘤血管生成及其发展。甘草酸(Glycyrrhizin, GL)是肿瘤释放的HMGB1的有效细胞内拮抗剂,但其药代动力学(PK)和向肿瘤部位的递送缺乏。为了解决这一缺点,我们开发了乳铁蛋白-甘草酸(Lf-GL)偶联物。方法:采用表面等离子体共振(SPR)结合亲和实验,评价Lf-GL与HMGB1之间的生物分子相互作用。通过体外、离体和体内综合评价Lf-GL减弱HMGB1在肿瘤微环境中的作用对肿瘤血管生成和发育的抑制作用。研究了Lf-GL在原位胶质母细胞瘤小鼠模型中的药动学研究和抗肿瘤作用。结果:Lf-GL与血脑屏障和GBM上表达的乳铁蛋白受体(LfR)相互作用,从而有效抑制肿瘤细胞质和细胞外区域的HMGB1。在肿瘤微环境方面,Lf-GL通过阻断坏死肿瘤释放的HMGB1,阻止血管内皮细胞的募集,抑制血管生成和肿瘤生长。此外,Lf-GL在GBM小鼠模型中使GL的PK特性提高了约10倍,并使肿瘤生长降低了32%。同时,肿瘤的各种生物标志物也从根本上减少。结论:总的来说,我们的研究表明HMGB1与肿瘤进展密切相关,提示Lf-GL可能是应对damp相关肿瘤微环境的潜在策略。HMGB1是肿瘤微环境中促肿瘤的DAMP。Lf-GL与HMGB1的高结合能力抑制肿瘤的级联进展,如肿瘤血管生成、发展和转移。Lf-GL通过与LfR的相互作用靶向GBM,并允许从肿瘤微环境中释放HMGB1。因此,Lf-GL可以通过调节HMGB1活性来治疗GBM。
{"title":"Inhibition of DAMP actions in the tumoral microenvironment using lactoferrin-glycyrrhizin conjugate for glioblastoma therapy.","authors":"Hyung Shik Kim,&nbsp;Seok Chan Park,&nbsp;Hae Jin Kim,&nbsp;Dong Yun Lee","doi":"10.1186/s40824-023-00391-w","DOIUrl":"https://doi.org/10.1186/s40824-023-00391-w","url":null,"abstract":"<p><strong>Background: </strong>High-mobility group box-1 (HMGB1) released from the tumor microenvironment plays a pivotal role in the tumor progression. HMGB1 serves as a damaged-associated molecular pattern (DAMP) that induces tumor angiogenesis and its development. Glycyrrhizin (GL) is an effective intracellular antagonist of tumor released HMGB1, but its pharmacokinetics (PK) and delivery to tumor site is deficient. To address this shortcoming, we developed lactoferrin-glycyrrhizin (Lf-GL) conjugate.</p><p><strong>Methods: </strong>Biomolecular interaction between Lf-GL and HMGB1 was evaluated by surface plasmon resonance (SPR) binding affinity assay. Inhibition of tumor angiogenesis and development by Lf-GL attenuating HMGB1 action in the tumor microenvironment was comprehensively evaluated through in vitro, ex vivo, and in vivo. Pharmacokinetic study and anti-tumor effects of Lf-GL were investigated in orthotopic glioblastoma mice model.</p><p><strong>Results: </strong>Lf-GL interacts with lactoferrin receptor (LfR) expressed on BBB and GBM, therefore, efficiently inhibits HMGB1 in both the cytoplasmic and extracellular regions of tumors. Regarding the tumor microenvironment, Lf-GL inhibits angiogenesis and tumor growth by blocking HMGB1 released from necrotic tumors and preventing recruitment of vascular endothelial cells. In addition, Lf-GL improved the PK properties of GL approximately tenfold in the GBM mouse model and reduced tumor growth by 32%. Concurrently, various biomarkers for tumor were radically diminished.</p><p><strong>Conclusion: </strong>Collectively, our study demonstrates a close association between HMGB1 and tumor progression, suggesting Lf-GL as a potential strategy for coping with DAMP-related tumor microenvironment. HMGB1 is a tumor-promoting DAMP in the tumor microenvironment. The high binding capability of Lf-GL to HMGB1 inhibits tumor progression cascade such as tumor angiogenesis, development, and metastasis. Lf-GL targets GBM through interaction with LfR and allows to arrest HMGB1 released from the tumor microenvironment. Therefore, Lf-GL can be a GBM treatment by modulating HMGB1 activity.</p>","PeriodicalId":9079,"journal":{"name":"Biomaterials Research","volume":null,"pages":null},"PeriodicalIF":11.3,"publicationDate":"2023-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10200060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9502251","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}
引用次数: 2
Regenerated silk fibroin based on small aperture scaffolds and marginal sealing hydrogel for osteochondral defect repair. 基于小孔径支架和边缘密封水凝胶的再生丝素修复骨软骨缺损。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-05-19 DOI: 10.1186/s40824-023-00370-1
Yinyue Luo, Menglin Xiao, Bushra Sufyan Almaqrami, Hong Kang, Zhengzhong Shao, Xin Chen, Ying Zhang

Background: Osteochondral defects pose an enormous challenge without satisfactory repair strategy to date. In particular, the lateral integration of neo-cartilage into the surrounding native cartilage is a difficult and inadequately addressed problem determining tissue repair's success.

Methods: Regenerated silk fibroin (RSF) based on small aperture scaffolds was prepared with n-butanol innovatively. Then, the rabbit knee chondrocytes and bone mesenchymal stem cells (BMSCs) were cultured on RSF scaffolds, and after induction of chondrogenic differentiation, cell-scaffold complexes strengthened by a 14 wt% RSF solution were prepared for in vivo experiments.

Results: A porous scaffold and an RSF sealant exhibiting biocompatibility and excellent adhesive properties are developed and confirmed to promote chondrocyte migration and differentiation. Thus, osteochondral repair and superior horizontal integration are achieved in vivo with this composite.

Conclusions: Overall, the new approach of marginal sealing around the RSF scaffolds exhibits preeminent repair results, confirming the ability of this novel graft to facilitate simultaneous regeneration of cartilage-subchondral bone.

背景:骨软骨缺损是一个巨大的挑战,至今没有令人满意的修复策略。特别是,新软骨与周围原生软骨的横向整合是决定组织修复成功的一个困难和不充分解决的问题。方法:采用正丁醇创新制备基于小孔径支架的再生丝素(RSF)。然后,在RSF支架上培养兔膝关节软骨细胞和骨间充质干细胞(BMSCs),诱导成软骨分化后,制备经14wt % RSF溶液强化的细胞-支架复合物进行体内实验。结果:制备并证实了具有生物相容性和良好粘附性能的多孔支架和RSF密封剂可促进软骨细胞迁移和分化。因此,这种复合材料在体内可实现骨软骨修复和良好的水平整合。结论:总的来说,RSF支架周围边缘封闭的新方法显示出卓越的修复效果,证实了这种新型移植物促进软骨-软骨下骨同时再生的能力。
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引用次数: 2
Subaqueous 3D stem cell spheroid levitation culture using anti-gravity bioreactor based on sound wave superposition. 基于声波叠加的反重力生物反应器水下三维干细胞球形悬浮培养。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-05-19 DOI: 10.1186/s40824-023-00383-w
Jung Hwan Park, Ju-Ro Lee, Sungkwon Park, Yu-Jin Kim, Jeong-Kee Yoon, Hyun Su Park, Jiyu Hyun, Yoon Ki Joung, Tae Il Lee, Suk Ho Bhang

Background: Recently, various studies have revealed that 3D cell spheroids have several advantages over 2D cells in stem cell culture. However, conventional 3D spheroid culture methods have some disadvantages and limitations such as time required for spheroid formation and complexity of the experimental process. Here, we used acoustic levitation as cell culture platform to overcome the limitation of conventional 3D culture methods.

Methods: In our anti-gravity bioreactor, continuous standing sonic waves created pressure field for 3D culture of human mesenchymal stem cells (hMSCs). hMSCs were trapped and aggerated in pressure field and consequently formed spheroids. The structure, viability, gene and protein expression of spheroids formed in the anti-gravity bioreactor were analyzed by electron microscope, immunostaining, polymerase chain reaction, and western blot. We injected hMSC spheroids fabricated by anti-gravity bioreactor into the mouse hindlimb ischemia model. Limb salvage was quantified to evaluate therapeutic efficacy of hMSC spheroids.

Results: The acoustic levitation in anti-gravity bioreactor made spheroids faster and more compact compared to the conventional hanging drop method, which resulted in the upregulation of angiogenic paracrine factors of hMSCs, such as vascular endothelial growth factor and angiopoietin 2. Injected hMSCs spheroids cultured in the anti-gravity bioreactor exhibited improved therapeutic efficacy, including the degree of limb salvage, capillary formation, and attenuation of fibrosis and inflammation, for mouse hindlimb ischemia model compared to spheroids formed by the conventional hanging drop method.

Conclusion: Our stem cell culture system using acoustic levitation will be proposed as a new platform for the future 3D cell culture system.

背景:近年来,各种研究表明,在干细胞培养中,3D细胞球体比2D细胞具有许多优势。然而,传统的三维球体培养方法存在球体形成时间长、实验过程复杂等缺点和局限性。在这里,我们利用声悬浮作为细胞培养平台,克服了传统3D培养方法的局限性。方法:在反重力生物反应器中,连续驻声波形成压力场,用于人间充质干细胞(hMSCs)的三维培养。hMSCs在压力场中被捕获和聚集,形成球状体。采用电镜、免疫染色、聚合酶链反应、western blot等方法对反重力生物反应器中球体的结构、活力、基因和蛋白表达进行分析。将反重力生物反应器制备的造血干细胞球体注射到小鼠后肢缺血模型中。对残肢进行量化,评价hMSC球体的治疗效果。结果:反重力生物反应器中的声悬浮使球状体比常规悬滴法更快、更致密,导致造血干细胞血管内皮生长因子、血管生成素2等血管生成旁分泌因子上调。反重力生物反应器培养的hMSCs球体注射后对小鼠后肢缺血模型的治疗效果,包括保肢程度、毛细血管形成、纤维化和炎症的衰减,均优于常规吊滴法形成的球体。结论:我们的干细胞声悬浮培养系统将为未来的三维细胞培养系统提供一个新的平台。
{"title":"Subaqueous 3D stem cell spheroid levitation culture using anti-gravity bioreactor based on sound wave superposition.","authors":"Jung Hwan Park,&nbsp;Ju-Ro Lee,&nbsp;Sungkwon Park,&nbsp;Yu-Jin Kim,&nbsp;Jeong-Kee Yoon,&nbsp;Hyun Su Park,&nbsp;Jiyu Hyun,&nbsp;Yoon Ki Joung,&nbsp;Tae Il Lee,&nbsp;Suk Ho Bhang","doi":"10.1186/s40824-023-00383-w","DOIUrl":"https://doi.org/10.1186/s40824-023-00383-w","url":null,"abstract":"<p><strong>Background: </strong>Recently, various studies have revealed that 3D cell spheroids have several advantages over 2D cells in stem cell culture. However, conventional 3D spheroid culture methods have some disadvantages and limitations such as time required for spheroid formation and complexity of the experimental process. Here, we used acoustic levitation as cell culture platform to overcome the limitation of conventional 3D culture methods.</p><p><strong>Methods: </strong>In our anti-gravity bioreactor, continuous standing sonic waves created pressure field for 3D culture of human mesenchymal stem cells (hMSCs). hMSCs were trapped and aggerated in pressure field and consequently formed spheroids. The structure, viability, gene and protein expression of spheroids formed in the anti-gravity bioreactor were analyzed by electron microscope, immunostaining, polymerase chain reaction, and western blot. We injected hMSC spheroids fabricated by anti-gravity bioreactor into the mouse hindlimb ischemia model. Limb salvage was quantified to evaluate therapeutic efficacy of hMSC spheroids.</p><p><strong>Results: </strong>The acoustic levitation in anti-gravity bioreactor made spheroids faster and more compact compared to the conventional hanging drop method, which resulted in the upregulation of angiogenic paracrine factors of hMSCs, such as vascular endothelial growth factor and angiopoietin 2. Injected hMSCs spheroids cultured in the anti-gravity bioreactor exhibited improved therapeutic efficacy, including the degree of limb salvage, capillary formation, and attenuation of fibrosis and inflammation, for mouse hindlimb ischemia model compared to spheroids formed by the conventional hanging drop method.</p><p><strong>Conclusion: </strong>Our stem cell culture system using acoustic levitation will be proposed as a new platform for the future 3D cell culture system.</p>","PeriodicalId":9079,"journal":{"name":"Biomaterials Research","volume":null,"pages":null},"PeriodicalIF":11.3,"publicationDate":"2023-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10197840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9500333","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}
引用次数: 1
Effervescent cannabidiol solid dispersion-doped dissolving microneedles for boosted melanoma therapy via the "TRPV1-NFATc1-ATF3" pathway and tumor microenvironment engineering. 泡腾大麻二酚固体分散体掺杂溶解微针通过“TRPV1-NFATc1-ATF3”途径和肿瘤微环境工程促进黑色素瘤治疗。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-05-18 DOI: 10.1186/s40824-023-00390-x
Jiachen Shi, Qiuling Ma, Wenting Su, Congyan Liu, Huangqin Zhang, Yuping Liu, Xiaoqi Li, Xi Jiang, Chang Ge, Fei Kong, Yan Chen, Ding Qu

Background: Conventional dissolving microneedles (DMNs) face significant challenges in anti-melanoma therapy due to the lack of active thrust to achieve efficient transdermal drug delivery and intra-tumoral penetration.

Methods: In this study, the effervescent cannabidiol solid dispersion-doped dissolving microneedles (Ef/CBD-SD@DMNs) composed of the combined effervescent components (CaCO3 & NaHCO3) and CBD-based solid dispersion (CBD-SD) were facilely fabricated by the "one-step micro-molding" method for boosted transdermal and tumoral delivery of cannabidiol (CBD).

Results: Upon pressing into the skin, Ef/CBD-SD@DMNs rapidly produce CO2 bubbles through proton elimination, significantly enhancing the skin permeation and tumoral penetration of CBD. Once reaching the tumors, Ef/CBD-SD@DMNs can activate transient receptor potential vanilloid 1 (TRPV1) to increase Ca2+ influx and inhibit the downstream NFATc1-ATF3 signal to induce cell apoptosis. Additionally, Ef/CBD-SD@DMNs raise intra-tumoral pH environment to trigger the engineering of the tumor microenvironment (TME), including the M1 polarization of tumor-associated macrophages (TAMs) and increase of T cells infiltration. The introduction of Ca2+ can not only amplify the effervescent effect but also provide sufficient Ca2+ with CBD to potentiate the anti-melanoma efficacy. Such a "one stone, two birds" strategy combines the advantages of effervescent effects on transdermal delivery and TME regulation, creating favorable therapeutic conditions for CBD to obtain stronger inhibition of melanoma growth in vitro and in vivo.

Conclusions: This study holds promising potential in the transdermal delivery of CBD for melanoma therapy and offers a facile tool for transdermal therapies of skin tumors.

背景:传统的溶解微针(DMNs)在抗黑色素瘤治疗中面临重大挑战,因为缺乏主动推力来实现有效的经皮给药和肿瘤内穿透。方法:本研究采用“一步微成型”的方法,将泡腾组分(CaCO3和NaHCO3)与基于CBD的固体分散体(CBD- sd)相结合,制备出泡腾大麻二酚固体分散体掺杂溶解微针(Ef/CBD-SD@DMNs),促进大麻二酚(CBD)的透皮和肿瘤给药。结果:Ef/CBD-SD@DMNs压入皮肤后,通过质子消除快速产生CO2气泡,显著增强CBD的皮肤渗透性和肿瘤渗透性。Ef/CBD-SD@DMNs到达肿瘤后,可激活瞬时受体电位香兰素1 (TRPV1),增加Ca2+内流,抑制下游NFATc1-ATF3信号,诱导细胞凋亡。此外,Ef/CBD-SD@DMNs升高肿瘤内pH环境触发肿瘤微环境(TME)的工程化,包括肿瘤相关巨噬细胞(tam)的M1极化和T细胞浸润的增加。Ca2+的引入不仅可以放大泡腾效应,还可以为CBD提供足够的Ca2+,从而增强抗黑色素瘤的功效。这种“一石二鸟”的策略结合了透皮给药泡腾效应和TME调节的优势,为CBD在体外和体内获得更强的黑色素瘤生长抑制创造了有利的治疗条件。结论:本研究在经皮给药CBD治疗黑色素瘤方面具有良好的潜力,为皮肤肿瘤的经皮治疗提供了一种简便的工具。
{"title":"Effervescent cannabidiol solid dispersion-doped dissolving microneedles for boosted melanoma therapy via the \"TRPV1-NFATc1-ATF3\" pathway and tumor microenvironment engineering.","authors":"Jiachen Shi,&nbsp;Qiuling Ma,&nbsp;Wenting Su,&nbsp;Congyan Liu,&nbsp;Huangqin Zhang,&nbsp;Yuping Liu,&nbsp;Xiaoqi Li,&nbsp;Xi Jiang,&nbsp;Chang Ge,&nbsp;Fei Kong,&nbsp;Yan Chen,&nbsp;Ding Qu","doi":"10.1186/s40824-023-00390-x","DOIUrl":"https://doi.org/10.1186/s40824-023-00390-x","url":null,"abstract":"<p><strong>Background: </strong>Conventional dissolving microneedles (DMNs) face significant challenges in anti-melanoma therapy due to the lack of active thrust to achieve efficient transdermal drug delivery and intra-tumoral penetration.</p><p><strong>Methods: </strong>In this study, the effervescent cannabidiol solid dispersion-doped dissolving microneedles (Ef/CBD-SD@DMNs) composed of the combined effervescent components (CaCO<sub>3</sub> & NaHCO<sub>3</sub>) and CBD-based solid dispersion (CBD-SD) were facilely fabricated by the \"one-step micro-molding\" method for boosted transdermal and tumoral delivery of cannabidiol (CBD).</p><p><strong>Results: </strong>Upon pressing into the skin, Ef/CBD-SD@DMNs rapidly produce CO<sub>2</sub> bubbles through proton elimination, significantly enhancing the skin permeation and tumoral penetration of CBD. Once reaching the tumors, Ef/CBD-SD@DMNs can activate transient receptor potential vanilloid 1 (TRPV1) to increase Ca<sup>2+</sup> influx and inhibit the downstream NFATc1-ATF3 signal to induce cell apoptosis. Additionally, Ef/CBD-SD@DMNs raise intra-tumoral pH environment to trigger the engineering of the tumor microenvironment (TME), including the M1 polarization of tumor-associated macrophages (TAMs) and increase of T cells infiltration. The introduction of Ca<sup>2+</sup> can not only amplify the effervescent effect but also provide sufficient Ca<sup>2+</sup> with CBD to potentiate the anti-melanoma efficacy. Such a \"one stone, two birds\" strategy combines the advantages of effervescent effects on transdermal delivery and TME regulation, creating favorable therapeutic conditions for CBD to obtain stronger inhibition of melanoma growth in vitro and in vivo.</p><p><strong>Conclusions: </strong>This study holds promising potential in the transdermal delivery of CBD for melanoma therapy and offers a facile tool for transdermal therapies of skin tumors.</p>","PeriodicalId":9079,"journal":{"name":"Biomaterials Research","volume":null,"pages":null},"PeriodicalIF":11.3,"publicationDate":"2023-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10193696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9825183","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}
引用次数: 0
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Biomaterials Research
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