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Emerging nano-scale delivery systems for the treatment of osteoporosis. 用于治疗骨质疏松症的新兴纳米级输送系统。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-07-13 DOI: 10.1186/s40824-023-00413-7
Anoop Puthiyoth Dayanandan, Woong Jin Cho, Hyemin Kang, Alvin Bacero Bello, Byoung Ju Kim, Yoshie Arai, Soo-Hong Lee

Osteoporosis is a pathological condition characterized by an accelerated bone resorption rate, resulting in decreased bone density and increased susceptibility to fractures, particularly among the elderly population. While conventional treatments for osteoporosis have shown efficacy, they are associated with certain limitations, including limited drug bioavailability, non-specific administration, and the occurrence of adverse effects. In recent years, nanoparticle-based drug delivery systems have emerged as a promising approach for managing osteoporosis. Nanoparticles possess unique physicochemical properties, such as a small size, large surface area-to-volume ratio, and tunable surface characteristics, which enable them to overcome the limitations of conventional therapies. These nanoparticles offer several advantages, including enhanced drug stability, controlled release kinetics, targeted bone tissue delivery, and improved drug bioavailability. This comprehensive review aims to provide insights into the recent advancements in nanoparticle-based therapy for osteoporosis. It elucidates the various types of nanoparticles employed in this context, including silica, polymeric, solid lipid, and metallic nanoparticles, along with their specific processing techniques and inherent properties that render them suitable as potential drug carriers for osteoporosis treatment. Furthermore, this review discusses the challenges and future suggestions associated with the development and translation of nanoparticle drug delivery systems for clinical use. These challenges encompass issues such as scalability, safety assessment, and regulatory considerations. However, despite these challenges, the utilization of nanoparticle-based drug delivery systems holds immense promise in revolutionizing the field of osteoporosis management by enabling more effective and targeted therapies, ultimately leading to improved patient outcomes.

骨质疏松症是一种病理状态,其特点是骨吸收速度加快,导致骨密度降低,增加骨折的易感性,尤其是在老年人群中。传统的骨质疏松症治疗方法虽然有一定的疗效,但也存在一定的局限性,包括药物生物利用度有限、非特异性给药以及不良反应的发生。近年来,以纳米颗粒为基础的给药系统成为治疗骨质疏松症的一种很有前景的方法。纳米颗粒具有独特的物理化学特性,如体积小、表面积与体积比大、表面特性可调等,这些特性使其能够克服传统疗法的局限性。这些纳米颗粒具有多种优势,包括增强药物稳定性、控制释放动力学、靶向骨组织给药和提高药物生物利用度。本综述旨在深入探讨基于纳米颗粒的骨质疏松症疗法的最新进展。它阐明了在此背景下采用的各种类型的纳米颗粒,包括二氧化硅、聚合物、固体脂质和金属纳米颗粒,以及它们的特定加工技术和固有特性,这些技术和特性使它们成为治疗骨质疏松症的潜在药物载体。此外,本综述还讨论了与纳米颗粒给药系统的开发和临床应用相关的挑战和未来建议。这些挑战包括可扩展性、安全性评估和监管考虑等问题。然而,尽管存在这些挑战,利用基于纳米颗粒的给药系统仍有望通过更有效和更有针对性的疗法彻底改变骨质疏松症治疗领域,最终改善患者的预后。
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引用次数: 0
Engineering considerations of iPSC-based personalized medicine. 基于ipsc的个性化医疗的工程考虑。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-07-07 DOI: 10.1186/s40824-023-00382-x
Sangbae Park, Yonghyun Gwon, Shahidul Ahmed Khan, Kyoung-Je Jang, Jangho Kim

Personalized medicine aims to provide tailored medical treatment that considers the clinical, genetic, and environmental characteristics of patients. iPSCs have attracted considerable attention in the field of personalized medicine; however, the inherent limitations of iPSCs prevent their widespread use in clinical applications. That is, it would be important to develop notable engineering strategies to overcome the current limitations of iPSCs. Such engineering approaches could lead to significant advances in iPSC-based personalized therapy by offering innovative solutions to existing challenges, from iPSC preparation to clinical applications. In this review, we summarize how engineering strategies have been used to advance iPSC-based personalized medicine by categorizing the development process into three distinctive steps: 1) the production of therapeutic iPSCs; 2) engineering of therapeutic iPSCs; and 3) clinical applications of engineered iPSCs. Specifically, we focus on engineering strategies and their implications for each step in the development of iPSC-based personalized medicine.

个性化医疗旨在根据患者的临床、遗传和环境特征提供量身定制的医疗。诱导多能干细胞在个性化医疗领域引起了相当大的关注;然而,多能干细胞的固有局限性阻碍了其在临床应用中的广泛应用。也就是说,开发显著的工程策略来克服目前iPSCs的局限性是很重要的。这种工程方法可以为从iPSC制备到临床应用的现有挑战提供创新的解决方案,从而导致基于iPSC的个性化治疗取得重大进展。在这篇综述中,我们通过将开发过程分为三个不同的步骤,总结了如何使用工程策略来推进基于ipsc的个性化医疗:1)治疗性ipsc的生产;2)治疗性iPSCs的工程化;3)工程诱导多能干细胞的临床应用。具体来说,我们关注的是工程策略及其对基于ipsc的个性化医疗发展的每一步的影响。
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引用次数: 1
Oxygen-loaded microbubble-mediated sonoperfusion and oxygenation for neuroprotection after ischemic stroke reperfusion. 载氧微泡介导的超声灌注和氧合对缺血性脑卒中再灌注后神经保护的作用。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-07-06 DOI: 10.1186/s40824-023-00400-y
Yi-Ju Ho, Hsiang-Lung Cheng, Lun-De Liao, Yu-Chun Lin, Hong-Chieh Tsai, Chih-Kuang Yeh

Background: Ischemic stroke-reperfusion (S/R) injury is a crucial issue in the protection of brain function after thrombolysis. The vasodilation induced by ultrasound (US)-stimulated microbubble cavitation has been applied to reduce S/R injury through sonoperfusion. The present study uses oxygen-loaded microbubbles (OMBs) with US stimulation to provide sonoperfusion and local oxygen therapy for the reduction of brain infarct size and neuroprotection after S/R.

Methods: The murine S/R model was established by photodynamic thrombosis and thrombolysis at the remote branch of the anterior cerebral artery. In vivo blood flow, partial oxygen pressure (pO2), and brain infarct staining were examined to analyze the validity of the animal model and OMB treatment results. The animal behaviors and measurement of the brain infarct area were used to evaluate long-term recovery of brain function.

Results: The percentage of blood flow was 45 ± 3%, 70 ± 3%, and 86 ± 2% after 60 min stroke, 20 min reperfusion, and 10 min OMB treatment, respectively, demonstrating sonoperfusion, and the corresponding pO2 level was 60 ± 1%, 76 ± 2%, and 79 ± 4%, showing reoxygenation. After 14 days of treatment, a 87 ± 3% reduction in brain infarction and recovery of limb coordination were observed in S/R mice. The expression of NF-κB, HIF-1α, IL-1β, and MMP-9 was inhibited and that of eNOS, BDNF, Bcl2, and IL-10 was enhanced, indicating activation of anti-inflammatory and anti-apoptosis responses and neuroprotection. Our study demonstrated that OMB treatment combines the beneficial effects of sonoperfusion and local oxygen therapy to reduce brain infarction and activate neuroprotection to prevent S/R injury.

背景:缺血性脑卒中再灌注(S/R)损伤是溶栓后脑功能保护的关键问题。超声刺激微泡空化引起的血管舒张已被应用于超声灌注减轻S/R损伤。本研究使用载氧微泡(OMBs)与US刺激提供超声灌注和局部氧治疗,以减少脑梗死面积和S/R后的神经保护。方法:采用光动力血栓和脑前动脉远端支溶栓法建立小鼠S/R模型。检测动物体内血流量、氧分压(pO2)和脑梗死染色,分析动物模型和OMB治疗结果的有效性。用动物行为学和脑梗死面积测量来评估脑功能的长期恢复。结果:脑卒中60 min、再灌注20 min、OMB治疗10 min后血流量百分比分别为45±3%、70±3%、86±2%,表现为超声灌注,相应的pO2水平分别为60±1%、76±2%、79±4%,表现为再氧合。治疗14天后,S/R小鼠脑梗死减少87±3%,肢体协调能力恢复。抑制NF-κB、HIF-1α、IL-1β和MMP-9的表达,增强eNOS、BDNF、Bcl2和IL-10的表达,提示其具有激活抗炎、抗凋亡反应和神经保护作用。我们的研究表明,OMB治疗结合了超声灌注和局部氧疗的有益作用,可以减少脑梗死,激活神经保护,防止S/R损伤。
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引用次数: 1
Ratiometric and discriminative visualization of autophagic processes with a novel dual-responded lysosome-specific fluorescent probe. 一种新型双反应溶酶体特异性荧光探针对自噬过程的比例和判别可视化。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-07-06 DOI: 10.1186/s40824-023-00409-3
Fan Zheng, Yeshuo Ma, Jipeng Ding, Shuai Huang, Shengwang Zhang, Xueyan Huang, Bin Feng, Hongliang Zeng, Fei Chen, Wenbin Zeng

Background: Autophagy is a critical self-eating pathway involved in numerous physiological and pathological processes. Lysosomal degradation of dysfunctional organelles and invading microorganisms is central to the autophagy mechanism and essential for combating disease-related conditions. Therefore, monitoring fluctuations in the lysosomal microenvironment is vital for tracking the dynamic process of autophagy. Although much effort has been put into designing probes for measuring lysosomal viscosity or pH separately, there is a need to validate the concurrent imaging of the two elements to enhance the understanding of the dynamic progression of autophagy.

Methods: Probe HFI was synthesized in three steps and was developed to visualize changes in viscosity and pH within lysosomes for real-time autophagy tracking. Then, the spectrometric determination was carried out. Next, the probe was applied to image autophagy in cells under nutrient-deprivation or external stress. Additionally, the performance of HFI to monitor autophagy was employed to evaluate acetaminophen-induced liver injury.

Results: We constructed a ratiometric dual-responsive probe, HFI, with a large Stokes shift over 200 nm, dual-wavelength emission, and small background interference. The ratiometric fluorescent signal (R = I 610/I 460) of HFI had an excellent correlation with both viscosity and pH. More importantly, high viscosity and low pH had a synergistic promotion effect on the emission intensity of HFI, which enabled it to specially lit lysosomes without disturbing the inherent microenvironment. We then successfully used HFI to monitor intracellular autophagy induced by starvation or drugs in real-time. Interestingly, HFI also enabled us to visualize the occurrence of autophagy in the liver tissue of a DILI model, as well as the reversible effect of hepatoprotective drugs on this event.

Conclusions: In this study, we developed the first ratiometric dual-responsive fluorescent probe, HFI, for real-time revealing autophagic details. It could image lysosomes with minimal perturbation to their inherent pH, allowing us to track changes in lysosomal viscosity and pH in living cells. Ultimately, HFI has great potential to serve as a useful indicator for autophagic changes in viscosity and pH in complex biological samples and can also be used to assess drug safety.

背景:自噬是一种重要的自食途径,参与许多生理和病理过程。功能失调细胞器和入侵微生物的溶酶体降解是自噬机制的核心,也是对抗疾病相关病症的必要条件。因此,监测溶酶体微环境的波动对于跟踪自噬的动态过程至关重要。尽管在设计分别测量溶酶体粘度或pH的探针方面已经付出了很多努力,但仍需要验证这两个元素的同时成像,以增强对自噬动态进展的理解。方法:探针HFI分三步合成,用于可视化溶酶体内粘度和pH的变化,实时跟踪自噬。然后进行光谱测定。接下来,应用探针成像细胞在营养剥夺或外部应激下的自噬。此外,采用HFI监测自噬的性能来评估对乙酰氨基酚诱导的肝损伤。结果:我们构建了一个比例双响应探针,HFI,在200 nm范围内具有大的Stokes位移,双波长发射,小背景干扰。HFI的比值荧光信号(R = I 610/I 460)与黏度和pH值均具有良好的相关性。更重要的是,高黏度和低pH值对HFI的发射强度有协同促进作用,使其能够在不干扰固有微环境的情况下特异性地照亮溶酶体。然后,我们成功地利用HFI实时监测饥饿或药物诱导的细胞内自噬。有趣的是,HFI还使我们能够可视化DILI模型肝组织中自噬的发生,以及肝保护药物对这一事件的可逆作用。结论:在这项研究中,我们开发了第一个比例双响应荧光探针HFI,用于实时显示自噬的细节。它可以在对溶酶体固有pH值进行最小扰动的情况下对溶酶体进行成像,使我们能够跟踪活细胞中溶酶体粘度和pH值的变化。最终,HFI具有很大的潜力,可作为复杂生物样品中粘度和pH自噬变化的有用指标,也可用于评估药物安全性。
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引用次数: 1
Non-interfacial self-assembly of synthetic protocells. 合成原细胞的非界面自组装。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-07-03 DOI: 10.1186/s40824-023-00402-w
Xiaolin Xu, Wencai Guan, Xiaolei Yu, Guoxiong Xu, Chenglong Wang

Background: Protocell refers to the basic unit of life and synthetic molecular assembly with cell structure and function. The protocells have great applications in the field of biomedical technology. Simulating the morphology and function of cells is the key to the preparation of protocells. However, some organic solvents used in the preparation process of protocells would damage the function of the bioactive substance. Perfluorocarbon, which has no toxic effect on bioactive substances, is an ideal solvent for protocell preparation. However, perfluorocarbon cannot be emulsified with water because of its inertia.

Methods: Spheroids can be formed in nature even without emulsification, since liquid can reshape the morphology of the solid phase through the scouring action, even if there is no stable interface between the two phases. Inspired by the formation of natural spheroids such as pebbles, we developed non-interfacial self-assembly (NISA) of microdroplets as a step toward synthetic protocells, in which the inert perfluorocarbon was utilized to reshape the hydrogel through the scouring action.

Results: The synthetic protocells were successfully obtained by using NISA-based protocell techniques, with the morphology very similar to native cells. Then we simulated the cell transcription process in the synthetic protocell and used the protocell as an mRNA carrier to transfect 293T cells. The results showed that protocells delivered mRNAs, and successfully expressed proteins in 293T cells. Further, we used the NISA method to fabricate an artificial cell by extracting and reassembling the membrane, proteins, and genomes of ovarian cancer cells. The results showed that the recombination of tumor cells was successfully achieved with similar morphology as tumor cells. In addition, the synthetic protocell prepared by the NISA method was used to reverse cancer chemoresistance by restoring cellular calcium homeostasis, which verified the application value of the synthetic protocell as a drug carrier.

Conclusion: This synthetic protocell fabricated by the NISA method simulates the occurrence and development process of primitive life, which has great potential application value in mRNA vaccine, cancer immunotherapy, and drug delivery.

背景:原细胞是指具有细胞结构和功能的生命和合成分子组装的基本单元。原细胞在生物医学技术领域有着广泛的应用。模拟细胞的形态和功能是制备原细胞的关键。然而,在原细胞的制备过程中使用的一些有机溶剂会破坏生物活性物质的功能。全氟碳对生物活性物质没有毒性作用,是制备原细胞的理想溶剂。然而,全氟碳化合物由于其惯性而不能与水乳化。方法:即使没有乳化,球形也可以在自然界中形成,因为液体可以通过冲刷作用重塑固相的形态,即使两相之间没有稳定的界面。受鹅卵石等天然球体形成的启发,我们开发了微滴的非界面自组装(NISA),作为合成原细胞的一步,其中惰性全氟碳化合物通过冲刷作用重塑水凝胶。结果:利用基于NISA的原细胞技术成功地获得了合成的原细胞,其形态与天然细胞非常相似。然后,我们模拟了合成原细胞中的细胞转录过程,并将原细胞作为信使核糖核酸载体转染293T细胞。结果表明,原代细胞可递送信使核糖核酸,并在293T细胞中成功表达蛋白质。此外,我们使用NISA方法通过提取和重组卵巢癌症细胞的膜、蛋白质和基因组来制造人工细胞。结果表明,成功实现了与肿瘤细胞形态相似的肿瘤细胞重组。此外,通过NISA方法制备的合成原细胞通过恢复细胞钙稳态来逆转癌症化疗耐药性,验证了合成原细胞作为药物载体的应用价值。结论:NISA方法制备的合成原细胞模拟了原始生命的发生和发展过程,在mRNA疫苗、癌症免疫治疗和药物递送等方面具有巨大的潜在应用价值。
{"title":"Non-interfacial self-assembly of synthetic protocells.","authors":"Xiaolin Xu, Wencai Guan, Xiaolei Yu, Guoxiong Xu, Chenglong Wang","doi":"10.1186/s40824-023-00402-w","DOIUrl":"10.1186/s40824-023-00402-w","url":null,"abstract":"<p><strong>Background: </strong>Protocell refers to the basic unit of life and synthetic molecular assembly with cell structure and function. The protocells have great applications in the field of biomedical technology. Simulating the morphology and function of cells is the key to the preparation of protocells. However, some organic solvents used in the preparation process of protocells would damage the function of the bioactive substance. Perfluorocarbon, which has no toxic effect on bioactive substances, is an ideal solvent for protocell preparation. However, perfluorocarbon cannot be emulsified with water because of its inertia.</p><p><strong>Methods: </strong>Spheroids can be formed in nature even without emulsification, since liquid can reshape the morphology of the solid phase through the scouring action, even if there is no stable interface between the two phases. Inspired by the formation of natural spheroids such as pebbles, we developed non-interfacial self-assembly (NISA) of microdroplets as a step toward synthetic protocells, in which the inert perfluorocarbon was utilized to reshape the hydrogel through the scouring action.</p><p><strong>Results: </strong>The synthetic protocells were successfully obtained by using NISA-based protocell techniques, with the morphology very similar to native cells. Then we simulated the cell transcription process in the synthetic protocell and used the protocell as an mRNA carrier to transfect 293T cells. The results showed that protocells delivered mRNAs, and successfully expressed proteins in 293T cells. Further, we used the NISA method to fabricate an artificial cell by extracting and reassembling the membrane, proteins, and genomes of ovarian cancer cells. The results showed that the recombination of tumor cells was successfully achieved with similar morphology as tumor cells. In addition, the synthetic protocell prepared by the NISA method was used to reverse cancer chemoresistance by restoring cellular calcium homeostasis, which verified the application value of the synthetic protocell as a drug carrier.</p><p><strong>Conclusion: </strong>This synthetic protocell fabricated by the NISA method simulates the occurrence and development process of primitive life, which has great potential application value in mRNA vaccine, cancer immunotherapy, and drug delivery.</p>","PeriodicalId":9079,"journal":{"name":"Biomaterials Research","volume":"27 1","pages":"64"},"PeriodicalIF":11.3,"publicationDate":"2023-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10318706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9758331","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
Fe3+-binding transferrin nanovesicles encapsulating sorafenib induce ferroptosis in hepatocellular carcinoma. 包裹索拉非尼的Fe3+结合转铁蛋白纳米囊泡诱导肝癌铁凋亡。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-07-01 DOI: 10.1186/s40824-023-00401-x
Youmei Xiao, Zhanxue Xu, Yuan Cheng, Rufan Huang, Yuan Xie, Hsiang-I Tsai, Hualian Zha, Lifang Xi, Kai Wang, Xiaoli Cheng, Yanfeng Gao, Changhua Zhang, Fang Cheng, Hongbo Chen

Background: Ferroptosis, iron-dependent cell death, is an established mechanism for cancer suppression, particularly in hepatocellular carcinoma (HCC). Sorafenib (SOR), a frontline drug for the treatment of HCC, induces ferroptosis by inhibiting the Solute Carrier family 7 member 11 (SLC7A11), with inadequate ferroptosis notably contributing to SOR resistance in tumor cells.

Methods: To further verify the biological targets associated with ferroptosis in HCC, an analysis of the Cancer Genome Atlas (TCGA) database was performed to find a significant co-upregulation of SLC7A11 and transferrin receptor (TFRC), Herein, cell membrane-derived transferrin nanovesicles (TF NVs) coupled with Fe3+ and encapsulated SOR (SOR@TF-Fe3+ NVs) were established to synergistically promote ferroptosis, which promoted the iron transport metabolism by TFRC/TF-Fe3+ and enhanced SOR efficacy by inhibiting the SLC7A11.

Results: In vivo and in vitro experiments revealed that SOR@TF-Fe3+ NVs predominantly accumulate in the liver, and specifically targeted HCC cells overexpressing TFRC. Various tests demonstrated SOR@TF-Fe3+ NVs accelerated Fe3+ absorption and transformation in HCC cells. Importantly, SOR@TF-Fe3+ NVs were more effective in promoting the accumulation of lipid peroxides (LPO), inhibiting tumor proliferation, and prolonging survival rates in HCC mouse model than SOR and TF- Fe3+ NVs alone.

Conclusions: The present work provides a promising therapeutic strategy for the targeted treatment of HCC.

背景:铁依赖性细胞死亡(Ferroptosis)是一种已知的肿瘤抑制机制,特别是在肝细胞癌(HCC)中。索拉非尼(Sorafenib, SOR)是治疗HCC的一线药物,通过抑制溶质载体家族7成员11 (SLC7A11)诱导铁下垂,而铁下垂不足是导致肿瘤细胞SOR耐药的重要原因。方法:为了进一步验证HCC中与铁死亡相关的生物学靶点,我们对癌症基因组图谱(TCGA)数据库进行了分析,发现SLC7A11和转铁蛋白受体(TFRC)存在显著的共上调。在此,我们建立了细胞膜源性转铁蛋白纳米囊泡(TF NVs)与Fe3+和封装的SOR (SOR@TF-Fe3+ NVs)结合,协同促进铁死亡。通过TFRC/TF-Fe3+促进铁转运代谢,并通过抑制SLC7A11增强SOR的功效。结果:体内和体外实验显示SOR@TF-Fe3+ NVs主要聚集在肝脏中,并特异性靶向过表达TFRC的HCC细胞。各种试验表明SOR@TF-Fe3+ NVs加速了肝癌细胞对Fe3+的吸收和转化。重要的是,在HCC小鼠模型中,SOR@TF-Fe3+ NVs在促进脂质过氧化物(LPO)积累、抑制肿瘤增殖和延长生存率方面比单独使用SOR和TF-Fe3+ NVs更有效。结论:本研究为肝癌的靶向治疗提供了一种有前景的治疗策略。
{"title":"Fe<sup>3+</sup>-binding transferrin nanovesicles encapsulating sorafenib induce ferroptosis in hepatocellular carcinoma.","authors":"Youmei Xiao,&nbsp;Zhanxue Xu,&nbsp;Yuan Cheng,&nbsp;Rufan Huang,&nbsp;Yuan Xie,&nbsp;Hsiang-I Tsai,&nbsp;Hualian Zha,&nbsp;Lifang Xi,&nbsp;Kai Wang,&nbsp;Xiaoli Cheng,&nbsp;Yanfeng Gao,&nbsp;Changhua Zhang,&nbsp;Fang Cheng,&nbsp;Hongbo Chen","doi":"10.1186/s40824-023-00401-x","DOIUrl":"https://doi.org/10.1186/s40824-023-00401-x","url":null,"abstract":"<p><strong>Background: </strong>Ferroptosis, iron-dependent cell death, is an established mechanism for cancer suppression, particularly in hepatocellular carcinoma (HCC). Sorafenib (SOR), a frontline drug for the treatment of HCC, induces ferroptosis by inhibiting the Solute Carrier family 7 member 11 (SLC7A11), with inadequate ferroptosis notably contributing to SOR resistance in tumor cells.</p><p><strong>Methods: </strong>To further verify the biological targets associated with ferroptosis in HCC, an analysis of the Cancer Genome Atlas (TCGA) database was performed to find a significant co-upregulation of SLC7A11 and transferrin receptor (TFRC), Herein, cell membrane-derived transferrin nanovesicles (TF NVs) coupled with Fe<sup>3+</sup> and encapsulated SOR (SOR@TF-Fe<sup>3+</sup> NVs) were established to synergistically promote ferroptosis, which promoted the iron transport metabolism by TFRC/TF-Fe<sup>3+</sup> and enhanced SOR efficacy by inhibiting the SLC7A11.</p><p><strong>Results: </strong>In vivo and in vitro experiments revealed that SOR@TF-Fe<sup>3+</sup> NVs predominantly accumulate in the liver, and specifically targeted HCC cells overexpressing TFRC. Various tests demonstrated SOR@TF-Fe<sup>3+</sup> NVs accelerated Fe<sup>3+</sup> absorption and transformation in HCC cells. Importantly, SOR@TF-Fe<sup>3+</sup> NVs were more effective in promoting the accumulation of lipid peroxides (LPO), inhibiting tumor proliferation, and prolonging survival rates in HCC mouse model than SOR and TF- Fe<sup>3+</sup> NVs alone.</p><p><strong>Conclusions: </strong>The present work provides a promising therapeutic strategy for the targeted treatment of HCC.</p>","PeriodicalId":9079,"journal":{"name":"Biomaterials Research","volume":"27 1","pages":"63"},"PeriodicalIF":11.3,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10314404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10120727","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
Regenerative capacity of trophoblast stem cell-derived extracellular vesicles on mesenchymal stem cells. 间充质干细胞上滋养层干细胞来源的细胞外囊泡的再生能力。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-06-27 DOI: 10.1186/s40824-023-00396-5
Yoon-Young Go, Chan-Mi Lee, Sung-Won Chae, Jae-Jun Song

Background: Human mesenchymal stem cells (MSCs) are therapeutic for clinical applications because of their excellent immunomodulatory and multiple lineage differentiation abilities at tissue injury sites. However, insufficient number of cells and lack of regenerative properties during in vitro expansion still limit the clinical applicability of MSC therapies. Here, we demonstrated a preconditioning strategy with trophoblast stem cell-derived extracellular vesicles (TSC-EVs) to boost the proliferation and regenerative capacity of MSCs.

Methods: We employed cell proliferation analyses such as CCK8 and BrdU assays to determine the proliferation-promoting role of TSC-EVs on MSCs. Osteogenic effects of TSC-EVs on MSCs were assessed by alkaline phosphatase (ALP) activity, calcium assays, and calvarial bone defect animal models. For skin regenerative effects, skin wound mice model was exploited to analyze wound-healing rate in this study, as well as immunofluorescence and histological staining evaluates. We also performed the small RNA profiling and RNA-sequencing analyzes to understand the cellular mechanism of TSC-EVs on MSCs.

Results: TSC-EVs significantly promoted MSC proliferation under xeno-free conditions and facilitated the therapeutic effects of MSCs, including osteogenesis, anti-senescence, and wound healing. Transcriptomic analysis also provided evidence that specific microRNAs in TSC-EVs and differentially expressed genes (DEGs) in TSC-EV-treated MSCs showed the possibility of TSC-EVs triggering the regenerative abilities of MSCs with cytokine interaction. Hence, we found that NGF/Akt signaling mediated the regenerative effects of TSC-EVs on MSCs as a particular cellular signaling pathway.

Conclusion: The results of this study demonstrated the functional properties of TSC-EVs on MSCs for MSC-based therapeutic applications, suggesting that TSC-EVs may serve as a potential preconditioning source for MSC therapy in the clinical field of regenerative medicine.

背景:人间充质干细胞(MSCs)因其在组织损伤部位具有良好的免疫调节和多谱系分化能力而被应用于临床治疗。然而,在体外扩增过程中细胞数量不足和缺乏再生特性仍然限制了间充质干细胞治疗的临床适用性。在这里,我们展示了滋养层干细胞衍生的细胞外囊泡(tsc - ev)的预处理策略,以促进间充质干细胞的增殖和再生能力。方法:我们采用CCK8和BrdU等细胞增殖分析来确定tsc - ev对MSCs的增殖促进作用。通过碱性磷酸酶(ALP)活性、钙含量测定和颅骨骨缺损动物模型评估tsc - ev对MSCs的成骨作用。在皮肤再生效果方面,本研究采用皮肤创面小鼠模型分析创面愈合率,并进行免疫荧光和组织学染色评价。我们还进行了小RNA分析和RNA测序分析,以了解tsc - ev对MSCs的细胞机制。结果:在无异种条件下,tsc - ev显著促进MSC增殖,促进MSCs的治疗作用,包括成骨、抗衰老和伤口愈合。转录组学分析也提供了证据,表明tsc - ev中的特异性microrna和tsc - ev处理的MSCs中的差异表达基因(DEGs)表明tsc - ev可能通过细胞因子相互作用触发MSCs的再生能力。因此,我们发现NGF/Akt信号通路作为一种特殊的细胞信号通路介导tsc - ev对MSCs的再生作用。结论:本研究结果证明了tsc - ev对MSC的功能特性,可用于基于MSC的治疗应用,提示tsc - ev可能在再生医学临床领域作为MSC治疗的潜在预处理源。
{"title":"Regenerative capacity of trophoblast stem cell-derived extracellular vesicles on mesenchymal stem cells.","authors":"Yoon-Young Go,&nbsp;Chan-Mi Lee,&nbsp;Sung-Won Chae,&nbsp;Jae-Jun Song","doi":"10.1186/s40824-023-00396-5","DOIUrl":"https://doi.org/10.1186/s40824-023-00396-5","url":null,"abstract":"<p><strong>Background: </strong>Human mesenchymal stem cells (MSCs) are therapeutic for clinical applications because of their excellent immunomodulatory and multiple lineage differentiation abilities at tissue injury sites. However, insufficient number of cells and lack of regenerative properties during in vitro expansion still limit the clinical applicability of MSC therapies. Here, we demonstrated a preconditioning strategy with trophoblast stem cell-derived extracellular vesicles (TSC-EVs) to boost the proliferation and regenerative capacity of MSCs.</p><p><strong>Methods: </strong>We employed cell proliferation analyses such as CCK8 and BrdU assays to determine the proliferation-promoting role of TSC-EVs on MSCs. Osteogenic effects of TSC-EVs on MSCs were assessed by alkaline phosphatase (ALP) activity, calcium assays, and calvarial bone defect animal models. For skin regenerative effects, skin wound mice model was exploited to analyze wound-healing rate in this study, as well as immunofluorescence and histological staining evaluates. We also performed the small RNA profiling and RNA-sequencing analyzes to understand the cellular mechanism of TSC-EVs on MSCs.</p><p><strong>Results: </strong>TSC-EVs significantly promoted MSC proliferation under xeno-free conditions and facilitated the therapeutic effects of MSCs, including osteogenesis, anti-senescence, and wound healing. Transcriptomic analysis also provided evidence that specific microRNAs in TSC-EVs and differentially expressed genes (DEGs) in TSC-EV-treated MSCs showed the possibility of TSC-EVs triggering the regenerative abilities of MSCs with cytokine interaction. Hence, we found that NGF/Akt signaling mediated the regenerative effects of TSC-EVs on MSCs as a particular cellular signaling pathway.</p><p><strong>Conclusion: </strong>The results of this study demonstrated the functional properties of TSC-EVs on MSCs for MSC-based therapeutic applications, suggesting that TSC-EVs may serve as a potential preconditioning source for MSC therapy in the clinical field of regenerative medicine.</p>","PeriodicalId":9079,"journal":{"name":"Biomaterials Research","volume":"27 1","pages":"62"},"PeriodicalIF":11.3,"publicationDate":"2023-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10304624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9720461","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
Polyetheretherketone implants with hierarchical porous structure for boosted osseointegration. 具有分层多孔结构的聚醚醚酮种植体促进骨整合。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-06-27 DOI: 10.1186/s40824-023-00407-5
Zhiyong Chen, Yu Chen, Yang Wang, JiaJia Deng, Xin Wang, Qingqing Wang, Yuehua Liu, Jiandong Ding, Lin Yu

Background: Good osseointegration is the key to the long-term stability of bone implants. Thermoplastic polyetheretherketone (PEEK) has been widely used in orthopedics; however, its inherent biological inertia causes fibrous tissue to wrap its surface, which leads to poor osseointegration and thus greatly limits its clinical applications.

Methods: Herein, we developed a facile yet effective surface modification strategy. A commonly used sulfonation coupled with "cold pressing" treatment in the presence of porogenic agent formed a three-dimensional hierarchical porous structure on PEEK surface. Subsequently, the effects of porous surface on the in vitro adhesion, proliferation and differentiation of rat bone marrow-derived mesenchymal stem cells (BMSCs) were evaluated. Finally, the osteoinduction and osseointegration of surface-porous PEEK implant were examined in the rat distal femoral defect model.

Results: In vitro results showed that the surface modification did not significantly affect the mechanical performance and cytocompatibility of PEEK substance, and the porous structure on the modified PEEK substrate provided space for cellular ingrowth and enhanced osteogenic differentiation and mineralization of BMSCs. In vivo tests demonstrated that the surface-porous PEEK implant could effectively promote new bone formation and had higher bone-implant contact rate, thereby achieving good bone integration with the surrounding host bone. In addition, this modification technique was also successfully demonstrated on a medical PEEK interbody fusion cage.

Conclusion: The present study indicates that topological morphology plays a pivotal role in determining implant osseointegration and this facile and effective modification strategy developed by us is expected to achieve practical applications quickly.

背景:良好的骨融合是骨种植体长期稳定的关键。热塑性聚醚醚酮(PEEK)已广泛应用于骨科;但其固有的生物惰性导致纤维组织包裹其表面,导致骨整合性差,极大地限制了其临床应用。方法:在此,我们开发了一种简单有效的表面改性策略。在致孔剂存在的情况下,常用的磺化与“冷压”处理在PEEK表面形成三维分层多孔结构。随后,研究了多孔表面对大鼠骨髓间充质干细胞(BMSCs)体外粘附、增殖和分化的影响。最后,在大鼠股骨远端缺损模型中研究了表面多孔PEEK植入物的骨诱导和骨整合性。结果:体外实验结果表明,表面改性对PEEK物质的力学性能和细胞相容性没有明显影响,改性PEEK基质上的多孔结构为细胞向内生长提供了空间,增强了骨髓间充质干细胞的成骨分化和矿化。体内实验表明,表面多孔PEEK种植体可有效促进新骨形成,具有较高的骨-种植体接触率,从而与周围宿主骨实现良好的骨融合。此外,该改良技术也成功地在医用PEEK椎间融合器上进行了演示。结论:拓扑形态在种植体骨整合中起着关键作用,我们开发的这种简便有效的修复策略有望很快实现实际应用。
{"title":"Polyetheretherketone implants with hierarchical porous structure for boosted osseointegration.","authors":"Zhiyong Chen,&nbsp;Yu Chen,&nbsp;Yang Wang,&nbsp;JiaJia Deng,&nbsp;Xin Wang,&nbsp;Qingqing Wang,&nbsp;Yuehua Liu,&nbsp;Jiandong Ding,&nbsp;Lin Yu","doi":"10.1186/s40824-023-00407-5","DOIUrl":"https://doi.org/10.1186/s40824-023-00407-5","url":null,"abstract":"<p><strong>Background: </strong>Good osseointegration is the key to the long-term stability of bone implants. Thermoplastic polyetheretherketone (PEEK) has been widely used in orthopedics; however, its inherent biological inertia causes fibrous tissue to wrap its surface, which leads to poor osseointegration and thus greatly limits its clinical applications.</p><p><strong>Methods: </strong>Herein, we developed a facile yet effective surface modification strategy. A commonly used sulfonation coupled with \"cold pressing\" treatment in the presence of porogenic agent formed a three-dimensional hierarchical porous structure on PEEK surface. Subsequently, the effects of porous surface on the in vitro adhesion, proliferation and differentiation of rat bone marrow-derived mesenchymal stem cells (BMSCs) were evaluated. Finally, the osteoinduction and osseointegration of surface-porous PEEK implant were examined in the rat distal femoral defect model.</p><p><strong>Results: </strong>In vitro results showed that the surface modification did not significantly affect the mechanical performance and cytocompatibility of PEEK substance, and the porous structure on the modified PEEK substrate provided space for cellular ingrowth and enhanced osteogenic differentiation and mineralization of BMSCs. In vivo tests demonstrated that the surface-porous PEEK implant could effectively promote new bone formation and had higher bone-implant contact rate, thereby achieving good bone integration with the surrounding host bone. In addition, this modification technique was also successfully demonstrated on a medical PEEK interbody fusion cage.</p><p><strong>Conclusion: </strong>The present study indicates that topological morphology plays a pivotal role in determining implant osseointegration and this facile and effective modification strategy developed by us is expected to achieve practical applications quickly.</p>","PeriodicalId":9079,"journal":{"name":"Biomaterials Research","volume":"27 1","pages":"61"},"PeriodicalIF":11.3,"publicationDate":"2023-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10294516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9711369","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
NK cells encapsulated in micro/macropore-forming hydrogels via 3D bioprinting for tumor immunotherapy. 通过3D生物打印将NK细胞包封在微/大孔形成的水凝胶中用于肿瘤免疫治疗。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-06-22 DOI: 10.1186/s40824-023-00403-9
Dahong Kim, Seona Jo, Dongjin Lee, Seok-Min Kim, Ji Min Seok, Seon Ju Yeo, Jun Hee Lee, Jae Jong Lee, Kangwon Lee, Tae-Don Kim, Su A Park

Background: Patients face a serious threat if a solid tumor leaves behind partial residuals or cannot be completely removed after surgical resection. Immunotherapy has attracted attention as a method to prevent this condition. However, the conventional immunotherapy method targeting solid tumors, that is, intravenous injection, has limitations in homing in on the tumor and in vivo expansion and has not shown effective clinical results.

Method: To overcome these limitations, NK cells (Natural killer cells) were encapsulated in micro/macropore-forming hydrogels using 3D bioprinting to target solid tumors. Sodium alginate and gelatin were used to prepare micro-macroporous hydrogels. The gelatin contained in the alginate hydrogel was removed because of the thermal sensitivity of the gelatin, which can generate interconnected micropores where the gelatin was released. Therefore, macropores can be formed through bioprinting and micropores can be formed using thermally sensitive gelatin to make macroporous hydrogels.

Results: It was confirmed that intentionally formed micropores could help NK cells to aggregate easily, which enhances cell viability, lysis activity, and cytokine release. Macropores can be formed using 3D bioprinting, which enables NK cells to receive the essential elements. We also characterized the functionality of NK 92 and zEGFR-CAR-NK cells in the pore-forming hydrogel. The antitumor effects on leukemia and solid tumors were investigated using an in vitro model.

Conclusion: We demonstrated that the hydrogel encapsulating NK cells created an appropriate micro-macro environment for clinical applications of NK cell therapy for both leukemia and solid tumors via 3D bioprinting. 3D bioprinting makes macro-scale clinical applications possible, and the automatic process shows potential for development as an off-the-shelf immunotherapy product. This immunotherapy system could provide a clinical option for preventing tumor relapse and metastasis after tumor resection. Micro/macropore-forming hydrogel with NK cells fabricated by 3D bioprinting and implanted into the tumor site.

背景:如果实体瘤在手术切除后留下部分残余或不能完全切除,患者将面临严重的威胁。免疫疗法作为一种预防这种疾病的方法引起了人们的注意。然而,传统的针对实体瘤的免疫治疗方法,即静脉注射,在肿瘤的归巢和体内扩张方面存在局限性,尚未显示出有效的临床效果。方法:为了克服这些局限性,将NK细胞(自然杀伤细胞)包裹在微/大孔形成的水凝胶中,使用3D生物打印技术靶向实体肿瘤。采用海藻酸钠和明胶制备微大孔水凝胶。海藻酸盐水凝胶中含有的明胶被去除,因为明胶的热敏性,它可以产生相互连接的微孔,在那里明胶被释放。因此,可以通过生物打印形成大孔,利用热敏明胶形成微孔,制成大孔水凝胶。结果:证实有意形成的微孔有利于NK细胞聚集,提高细胞活力、裂解活性和细胞因子释放。使用3D生物打印技术可以形成大孔,使NK细胞能够接受必需的元素。我们还表征了NK 92和zEGFR-CAR-NK细胞在成孔水凝胶中的功能。采用体外模型研究其对白血病和实体瘤的抗肿瘤作用。结论:通过生物3D打印技术,我们证明了包裹NK细胞的水凝胶为NK细胞治疗白血病和实体瘤的临床应用创造了合适的微观宏观环境。3D生物打印使宏观临床应用成为可能,自动过程显示出作为现成的免疫治疗产品的发展潜力。该免疫治疗系统可为预防肿瘤切除术后复发和转移提供临床选择。利用生物3D打印技术制备含有NK细胞的微/大孔形成水凝胶并植入肿瘤部位。
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引用次数: 1
Polymeric biomaterial-inspired cell surface modulation for the development of novel anticancer therapeutics. 高分子生物材料激发的细胞表面调控用于新型抗癌疗法的发展。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-06-21 DOI: 10.1186/s40824-023-00404-8
Ashok Kumar Jangid, Sungjun Kim, Kyobum Kim

Immune cell-based therapies are a rapidly emerging class of new medicines that directly treat and prevent targeted cancer. However multiple biological barriers impede the activity of live immune cells, and therefore necessitate the use of surface-modified immune cells for cancer prevention. Synthetic and/or natural biomaterials represent the leading approach for immune cell surface modulation. Different types of biomaterials can be applied to cell surface membranes through hydrophobic insertion, layer-by-layer attachment, and covalent conjugations to acquire surface modification in mammalian cells. These biomaterials generate reciprocity to enable cell-cell interactions. In this review, we highlight the different biomaterials (lipidic and polymeric)-based advanced applications for cell-surface modulation, a few cell recognition moieties, and how their interplay in cell-cell interaction. We discuss the cancer-killing efficacy of NK cells, followed by their surface engineering for cancer treatment. Ultimately, this review connects biomaterials and biologically active NK cells that play key roles in cancer immunotherapy applications.

基于免疫细胞的疗法是一种迅速崛起的新型药物,可以直接治疗和预防靶向癌症。然而,多种生物屏障阻碍了活免疫细胞的活性,因此需要使用表面修饰的免疫细胞来预防癌症。合成和/或天然生物材料是免疫细胞表面调节的主要方法。在哺乳动物细胞中,不同类型的生物材料可以通过疏水插入、逐层附着、共价偶联等方式应用于细胞膜表面,从而获得表面修饰。这些生物材料产生互易性,使细胞间相互作用成为可能。在这篇综述中,我们重点介绍了不同的生物材料(脂质和聚合物)在细胞表面调制中的先进应用,一些细胞识别片段,以及它们在细胞-细胞相互作用中的相互作用。我们讨论了NK细胞的抗癌功效,然后讨论了NK细胞的表面工程用于癌症治疗。最后,本文综述了生物材料和具有生物活性的NK细胞在癌症免疫治疗应用中的关键作用。
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引用次数: 2
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Biomaterials Research
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