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A wound-friendly antibacterial hyaluronic acid dressing with on-demand removability for infected wound healing. 一种伤口友好的抗菌透明质酸敷料,可按需去除,用于感染伤口愈合。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-05-01 DOI: 10.1186/s40824-023-00340-7
Datao Hu, Jinpeng Wen, Xinxin Zhao, Kailai Liu, Yuchen Zhang, Yizhuo Bu, Ke Wang

Background: Antibacterial activity and on-demand removability are key characteristics governing the effectiveness of clinic wound dressing. However, the excellent tissue adhesion of new dressings is often overemphasized without a detailed discussion of dressing replacement. Besides, the inherent antibacterial ability of dressings is beneficial for promoting the healing of infected wound. Therefore, we rationally design an injectable antibacterial wound dressing with on-demand removability to accelerate infected wound healing.

Method: We design this wound dressing with a simple and feasible method based on the electrostatic self-assembly of hyaluronic acid and ε-polylysine. We investigated the efficacy of this dressing in terms of its microtopography, rheology, self-healing performance, adhesive ability, antimicrobial, hemostatic, on-demand removal properties, and wound healing promotion through various tests.

Results: The prepared dressing possesses injectability, self-healing ability and antibacterial activity, showing NaCl-triggered on-demand dissolution due to the disruption of electrostatic interactions. When used as dressings for healing full-thickness wounds, it could effectively accelerate wound healing by killing bacteria, downregulating inflammation, promoting collagen deposition, enhancing keratinocyte migration and angiogenesis due to its excellent adhesion ability, favorable hemostatic property, and potent antibacterial performance.

Conclusion: All results indicate that this is a simple and practical dressing for clinical application. This strategy provides a novel idea for developing on-demand removal dressings with antibacterial and injectable properties.

背景:抗菌活性和按需去除性是控制临床伤口敷料有效性的关键特征。然而,新敷料良好的组织粘附性往往被过分强调,而没有详细讨论敷料更换。此外,敷料固有的抗菌能力有利于促进感染伤口的愈合。因此,我们合理设计了一种可按需去除的可注射抗菌创面敷料,以加速感染创面的愈合。方法:利用透明质酸和ε-聚赖氨酸的静电自组装,设计一种简单可行的创面敷料。我们通过各种试验,从微形貌、流变学、自愈性能、粘附能力、抗菌、止血、按需去除性能和促进伤口愈合等方面考察了这种敷料的功效。结果:制备的敷料具有可注射性、自愈性和抗菌活性,由于静电相互作用的破坏,表现出nacl触发的按需溶解。作为全层创面的敷料,其优异的粘附能力、良好的止血性能和较强的抗菌性能,能有效地促进创面愈合,杀灭细菌、下调炎症、促进胶原沉积、促进角质细胞迁移和血管生成。结论:本发明是一种简便实用的临床敷料。该策略为开发具有抗菌和注射性能的按需去除敷料提供了新的思路。
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引用次数: 1
A systematic study on the use of multifunctional nanodiamonds for neuritogenesis and super-resolution imaging. 多功能纳米金刚石在神经发育和超分辨率成像中的应用系统研究。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-04-27 DOI: 10.1186/s40824-023-00384-9
Jaeheung Kim, Moon Sung Kang, Seung Won Jun, Hyo Jung Jo, Dong-Wook Han, Chang-Seok Kim

Background: Regeneration of defective neurons in central nervous system is a highlighted issue for neurodegenerative disease treatment. Various tissue engineering approaches have focused on neuritogenesis to achieve the regeneration of damaged neuronal cells because damaged neurons often fail to achieve spontaneous restoration of neonatal neurites. Meanwhile, owing to the demand for a better diagnosis, studies of super-resolution imaging techniques in fluorescence microscopy have triggered the technological development to surpass the classical resolution dictated by the optical diffraction limit for precise observations of neuronal behaviors. Herein, the multifunctional nanodiamonds (NDs) as neuritogenesis promoters and super-resolution imaging probes were studied.

Methods: To investigate the neuritogenesis-inducing capability of NDs, ND-containing growing medium and differentiation medium were added to the HT-22 hippocampal neuronal cells and incubated for 10 d. In vitro and ex vivo images were visualized through custom-built two-photon microscopy using NDs as imaging probes and the direct stochastic optical reconstruction microscopy (dSTORM) process was performed for the super-resolution reconstruction owing to the photoblinking properties of NDs. Moreover, ex vivo imaging of the mouse brain was performed 24 h after the intravenous injection of NDs.

Results: NDs were endocytosed by the cells and promoted spontaneous neuritogenesis without any differentiation factors, where NDs exhibited no significant toxicity with their outstanding biocompatibility. The images of ND-endocytosed cells were reconstructed into super-resolution images through dSTORM, thereby addressing the problem of image distortion due to nano-sized particles, including size expansion and the challenge in distinguishing the nearby located particles. Furthermore, the ex vivo images of NDs in mouse brain confirmed that NDs could penetrate the blood-brain barrier (BBB) and retain their photoblinking property for dSTORM application.

Conclusions: It was demonstrated that the NDs are capable of dSTORM super-resolution imaging, neuritogenic facilitation, and BBB penetration, suggesting their remarkable potential in biological applications.

背景:中枢神经系统缺陷神经元的再生是神经退行性疾病治疗的热点问题。由于受损的神经元往往无法实现新生神经突的自发修复,各种组织工程方法都集中在神经突发生上,以实现受损神经元细胞的再生。同时,由于对更好的诊断的需求,荧光显微镜超分辨率成像技术的研究引发了技术的发展,超越了由光学衍射极限决定的经典分辨率,以精确观察神经元的行为。本文研究了多功能纳米金刚石作为神经生成促进剂和超分辨率成像探针的作用。方法:在HT-22海马神经元细胞中加入含nd的生长培养基和分化培养基,培养10 d,研究nd诱导神经发生的能力。利用nd的光闪烁特性,利用定制的双光子显微镜观察nd的离体和离体图像,并进行直接随机光学重建显微镜(dSTORM)超分辨率重建。此外,在静脉注射NDs后24 h进行小鼠脑离体成像。结果:NDs能被细胞内吞,促进神经细胞的自发发生,无任何分化因子,具有良好的生物相容性,无明显毒性。通过dSTORM将nd -内吞噬细胞的图像重建为超分辨率图像,从而解决了纳米颗粒造成的图像失真问题,包括尺寸膨胀和难以区分附近位置的颗粒。此外,NDs在小鼠脑内的离体图像证实了NDs可以穿透血脑屏障(BBB)并保留其用于dSTORM的光闪烁特性。结论:NDs具有dSTORM超分辨率成像、神经生成促进和血脑屏障穿透等功能,具有显著的生物学应用潜力。
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引用次数: 1
Advanced polymer hydrogels that promote diabetic ulcer healing: mechanisms, classifications, and medical applications. 促进糖尿病溃疡愈合的先进聚合物水凝胶:机制、分类和医学应用。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-04-26 DOI: 10.1186/s40824-023-00379-6
Yamei Xu, Qiyuan Hu, Zongyun Wei, Yi Ou, Youde Cao, Hang Zhou, Mengna Wang, Kexiao Yu, Bing Liang

Diabetic ulcers (DUs) are one of the most serious complications of diabetes mellitus. The application of a functional dressing is a crucial step in DU treatment and is associated with the patient's recovery and prognosis. However, traditional dressings with a simple structure and a single function cannot meet clinical requirements. Therefore, researchers have turned their attention to advanced polymer dressings and hydrogels to solve the therapeutic bottleneck of DU treatment. Hydrogels are a class of gels with a three-dimensional network structure that have good moisturizing properties and permeability and promote autolytic debridement and material exchange. Moreover, hydrogels mimic the natural environment of the extracellular matrix, providing suitable surroundings for cell proliferation. Thus, hydrogels with different mechanical strengths and biological properties have been extensively explored as DU dressing platforms. In this review, we define different types of hydrogels and elaborate the mechanisms by which they repair DUs. Moreover, we summarize the pathological process of DUs and review various additives used for their treatment. Finally, we examine the limitations and obstacles that exist in the development of the clinically relevant applications of these appealing technologies. This review defines different types of hydrogels and carefully elaborate the mechanisms by which they repair diabetic ulcers (DUs), summarizes the pathological process of DUs, and reviews various bioactivators used for their treatment.

糖尿病溃疡(DUs)是糖尿病最严重的并发症之一。功能敷料的应用是DU治疗的关键步骤,与患者的恢复和预后有关。传统敷料结构简单,功能单一,已不能满足临床需要。因此,研究人员将注意力转向了先进的聚合物敷料和水凝胶,以解决DU治疗的治疗瓶颈。水凝胶是一类具有三维网状结构的凝胶,具有良好的保湿性能和渗透性,促进自溶清创和物质交换。此外,水凝胶模拟了细胞外基质的自然环境,为细胞增殖提供了合适的环境。因此,具有不同机械强度和生物性能的水凝胶作为DU敷料平台被广泛探索。在这篇综述中,我们定义了不同类型的水凝胶,并阐述了它们修复DUs的机制。此外,我们还总结了DUs的病理过程,并对目前治疗DUs的各种添加剂进行了综述。最后,我们研究了这些吸引人的技术在临床相关应用的发展中存在的限制和障碍。本文对不同类型的水凝胶进行了定义,并详细阐述了它们修复糖尿病溃疡的机制,总结了糖尿病溃疡的病理过程,并综述了用于治疗糖尿病溃疡的各种生物激活剂。
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引用次数: 5
Advanced pathophysiology mimicking lung models for accelerated drug discovery. 先进的病理生理学模拟肺模型加速药物发现。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-04-26 DOI: 10.1186/s40824-023-00366-x
Thanh Huyen Phan, Huaikai Shi, Christopher E Denes, Alexander J Cole, Yiwei Wang, Yuen Yee Cheng, Daniel Hesselson, Susan H Roelofs, Graham Gregory Neely, Jun-Hyeog Jang, Wojciech Chrzanowski

Background: Respiratory diseases are the 2nd leading cause of death globally. The current treatments for chronic lung diseases are only supportive. Very few new classes of therapeutics have been introduced for lung diseases in the last 40 years, due to the lack of reliable lung models that enable rapid, cost-effective, and high-throughput testing. To accelerate the development of new therapeutics for lung diseases, we established two classes of lung-mimicking models: (i) healthy, and (ii) diseased lungs - COPD.

Methods: To establish models that mimic the lung complexity to different extents, we used five design components: (i) cell type, (ii) membrane structure/constitution, (iii) environmental conditions, (iv) cellular arrangement, (v) substrate, matrix structure and composition. To determine whether the lung models are reproducible and reliable, we developed a quality control (QC) strategy, which integrated the real-time and end-point quantitative and qualitative measurements of cellular barrier function, permeability, tight junctions, tissue structure, tissue composition, and cytokine secretion.

Results: The healthy model is characterised by (i) continuous tight junctions, (ii) physiological cellular barrier function, (iii) a full thickness epithelium composed of multiple cell layers, and (iv) the presence of ciliated cells and goblet cells. Meanwhile, the disease model emulates human COPD disease: (i) dysfunctional cellular barrier function, (ii) depletion of ciliated cells, and (ii) overproduction of goblet cells. The models developed here have multiple competitive advantages when compared with existing in vitro lung models: (i) the macroscale enables multimodal and correlative characterisation of the same model system, (ii) the use of cells derived from patients that enables the creation of individual models for each patient for personalised medicine, (iii) the use of an extracellular matrix proteins interface, which promotes physiological cell adhesion and differentiation, (iv) media microcirculation that mimics the dynamic conditions in human lungs.

Conclusion: Our model can be utilised to test safety, efficacy, and superiority of new therapeutics as well as to test toxicity and injury induced by inhaled pollution or pathogens. It is envisaged that these models can also be used to test the protective function of new therapeutics for high-risk patients or workers exposed to occupational hazards.

背景:呼吸系统疾病是全球第二大死亡原因。目前对慢性肺病的治疗只是支持性的。在过去的40年里,由于缺乏可靠的肺模型,无法实现快速、经济、高通量的检测,很少有新的治疗方法被引入肺部疾病。为了加速肺部疾病新疗法的发展,我们建立了两类肺模拟模型:(i)健康肺,(ii)病变肺——COPD。方法:为了建立不同程度模拟肺复杂性的模型,我们使用了五个设计成分:(i)细胞类型,(ii)膜结构/组成,(iii)环境条件,(iv)细胞排列,(v)底物,基质结构和组成。为了确定肺模型是否具有可重复性和可靠性,我们开发了一种质量控制(QC)策略,该策略整合了细胞屏障功能、通透性、紧密连接、组织结构、组织成分和细胞因子分泌的实时和终点定量和定性测量。结果:健康模型的特征是(i)连续紧密连接,(ii)生理细胞屏障功能,(iii)由多层细胞组成的全层上皮,(iv)纤毛细胞和杯状细胞的存在。同时,该疾病模型模拟了人类慢性阻塞性肺病:(i)细胞屏障功能失调,(ii)纤毛细胞耗竭,(ii)杯状细胞过量产生。与现有体外肺模型相比,本研究开发的模型具有多种竞争优势:(i)宏观尺度使同一模型系统的多模态和相关特征成为可能,(ii)使用来自患者的细胞,可以为每个患者创建个性化药物的个体模型,(iii)使用细胞外基质蛋白质界面,促进生理细胞粘附和分化,(iv)模拟人体肺部动态条件的介质微循环。结论:该模型可用于检测新疗法的安全性、有效性和优越性,也可用于检测吸入污染或病原体引起的毒性和损伤。设想这些模型也可用于测试新疗法对高危患者或暴露于职业危害的工人的保护功能。
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引用次数: 0
A multi-targeting bionanomatrix coating to reduce capsular contracture development on silicone implants. 多靶点生物异常基质涂层减少硅胶植入物包膜挛缩的发展。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-04-22 DOI: 10.1186/s40824-023-00378-7
Patrick Hwang, Chung Min Shin, Jennifer A Sherwood, DongHo Kim, Vineeth M Vijayan, Krishna C Josyula, Reid C Millican, Donald Ho, Brigitta C Brott, Vinoy Thomas, Chul Hee Choi, Sang-Ha Oh, Dong Woon Kim, Ho-Wook Jun

Background: Capsular contracture is a critical complication of silicone implantation caused by fibrotic tissue formation from excessive foreign body responses. Various approaches have been applied, but targeting the mechanisms of capsule formation has not been completely solved. Myofibroblast differentiation through the transforming growth factor beta (TGF-β)/p-SMADs signaling is one of the key factors for capsular contracture development. In addition, biofilm formation on implants may result chronic inflammation promoting capsular fibrosis formation with subsequent contraction. To date, there have been no approaches targeting multi-facted mechanisms of capsular contracture development.

Methods: In this study, we developed a multi-targeting nitric oxide (NO) releasing bionanomatrix coating to reduce capsular contracture formation by targeting myofibroblast differentiation, inflammatory responses, and infections. First, we characterized the bionanomatrix coating on silicon implants by conducting rheology test, scanning electron microcsopy analysis, nanoindentation analysis, and NO release kinetics evaluation. In addition, differentiated monocyte adhesion and S. epidermidis biofilm formation on bionanomatrix coated silicone implants were evaluated in vitro. Bionanomatrix coated silicone and uncoated silicone groups were subcutaneously implanted into a mouse model for evaluation of capsular contracture development for a month. Fibrosis formation, capsule thickness, TGF-β/SMAD 2/3 signaling cascade, NO production, and inflammatory cytokine production were evaluated using histology, immunofluorescent imaging analysis, and gene and protein expression assays.

Results: The bionanomatrix coating maintained a uniform and smooth surface on the silicone even after mechanical stress conditions. In addition, the bionanomatrix coating showed sustained NO release for at least one month and reduction of differentiated monocyte adhesion and S. epidermidis biofilm formation on the silicone implants in vitro. In in vivo implantation studies, the bionanomatrix coated groups demonstrated significant reduction of capsule thickness surrounding the implants. This result was due to a decrease of myofibroblast differentiation and fibrous extracellular matrix production through inhibition of the TGF-β/p-SMADs signaling. Also, the bionanomatrix coated groups reduced gene expression of M1 macrophage markers and promoted M2 macrophage markers which indicated the bionanomatrix could reduce inflammation but promote healing process.

Conclusions: In conclusion, the bionanomatrix coating significantly reduced capsular contracture formation and promoted healing process on silicone implants by reducing myfibroblast differentiation, fibrotic tissue formation, and inflammation. A multi-targeting nitric oxide releasing bionanomatrix coating for silicone implant can reduce capsular contracture and im

背景:囊膜挛缩是硅胶植入的重要并发症,是由过多的异物反应引起的纤维化组织形成。各种方法已经被应用,但针对胶囊形成的机制尚未完全解决。肌成纤维细胞通过转化生长因子β (TGF-β)/p-SMADs信号分化是包膜挛缩发生的关键因素之一。此外,植入物上的生物膜形成可能导致慢性炎症,促进囊纤维化形成并随之收缩。到目前为止,还没有针对包膜挛缩发展的多因素机制的方法。方法:在这项研究中,我们开发了一种多靶向一氧化氮(NO)释放生物异常基质涂层,通过靶向肌成纤维细胞分化、炎症反应和感染来减少包膜挛缩的形成。首先,我们通过流变学测试、扫描电镜分析、纳米压痕分析和NO释放动力学评价来表征生物异常基质在硅植入物上的涂层。此外,我们还对生物异常基质包被硅胶植入物的分化单核细胞粘附和表皮葡萄球菌生物膜形成进行了体外评价。生物异常基质包被硅胶组和未包被硅胶组皮下植入小鼠模型一个月,观察包膜挛缩的发展情况。通过组织学、免疫荧光成像分析、基因和蛋白表达分析来评估纤维化形成、胶囊厚度、TGF-β/SMAD 2/3信号级联、NO产生和炎症细胞因子产生。结果:在机械应力条件下,生物异常基质涂层在有机硅表面仍保持均匀光滑。此外,生物异常基质涂层能持续释放一氧化氮至少一个月,并能减少硅胶植入体上分化单核细胞的粘附和表皮葡萄球菌生物膜的形成。在体内植入研究中,生物异常基质包被组显示出植入物周围包膜厚度的显著减少。这一结果是由于通过抑制TGF-β/p-SMADs信号传导减少了肌成纤维细胞分化和纤维细胞外基质的产生。此外,生物异常基质包被组降低了M1巨噬细胞标记物的基因表达,促进了M2巨噬细胞标记物的表达,这表明生物异常基质可以减轻炎症,促进愈合过程。结论:生物异常基质涂层通过减少成纤维细胞分化、纤维化组织形成和炎症,显著减少硅胶假体包膜挛缩形成,促进愈合过程。一种多靶点一氧化氮释放生物异常基质涂层用于硅胶植入物,可减少囊膜挛缩,改善愈合过程。在皮下小鼠模型中,生物异常基质涂层通过抑制TGF-β/SMADs信号级联,降低了胶囊厚度,α-平滑肌肌动蛋白和胶原合成,并减少了肌成纤维细胞的分化。
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引用次数: 0
Development of cell-laden multimodular Lego-like customizable endometrial tissue assembly for successful tissue regeneration. 开发细胞负载的多模块乐高样可定制子宫内膜组织组装成功的组织再生。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-04-21 DOI: 10.1186/s40824-023-00376-9
Se-Ra Park, Myung Geun Kook, Soo-Rim Kim, Jin Woo Lee, Chan Hum Park, Byung-Chul Oh, YunJae Jung, In-Sun Hong

Background: The endometrium, the inner lining of the uterine cavity, plays essential roles in embryo implantation and its subsequent development. Although some positive results were preliminarily archived, the regeneration of damaged endometrial tissues by administrating stem cells only is very challenging due to the lack of specific microenvironments and their low attachment rates at the sites of injury. In this context, various biomaterial-based scaffolds have been used to overcome these limitations by providing simple structural support for cell attachment. However, these scaffold-based strategies also cannot properly reflect patient tissue-specific structural complexity and thus show only limited therapeutic effects.

Method: Therefore, in the present study, we developed a customizable Lego-like multimodular endometrial tissue architecture by assembling individually fabricated tissue blocks.

Results: Each tissue block was fabricated by incorporating biodegradable biomaterials and certain endometrial constituent cells. Each small tissue block was effectively fabricated by integrating conventional mold casting and 3D printing techniques. The fabricated individual tissue blocks were properly assembled into a larger customized tissue architecture. This structure not only properly mimics the patient-specific multicellular microenvironment of the endometrial tissue but also properly responds to key reproductive hormones in a manner similar to the physiological functions.

Conclusion: This customizable modular tissue assembly allows easy and scalable configuration of a complex patient-specific tissue microenvironment, thus accelerating various tissue regeneration procedures.

背景:子宫内膜是子宫腔的内层,在胚胎着床及其后续发育中起着至关重要的作用。虽然初步记录了一些积极的结果,但由于缺乏特定的微环境和损伤部位的低附着率,仅用干细胞再生受损子宫内膜组织非常具有挑战性。在这种情况下,各种基于生物材料的支架通过为细胞附着提供简单的结构支持来克服这些限制。然而,这些基于支架的策略也不能正确反映患者组织特异性结构的复杂性,因此仅显示有限的治疗效果。方法:因此,在本研究中,我们通过组装单独制造的组织块开发了一种可定制的乐高样多模块子宫内膜组织结构。结果:每个组织块都是由可生物降解的生物材料和一定的子宫内膜组成细胞组成的。每个小组织块通过集成传统的模具铸造和3D打印技术有效地制造。制造的单个组织块被适当地组装成一个更大的定制组织结构。这种结构不仅恰当地模拟了患者子宫内膜组织的特异性多细胞微环境,而且恰当地响应关键的生殖激素,其方式类似于生理功能。结论:这种可定制的模块化组织组件可以轻松和可扩展地配置复杂的患者特定组织微环境,从而加速各种组织再生程序。
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引用次数: 2
Stabilization and improved functionality of three-dimensional perfusable microvascular networks in microfluidic devices under macromolecular crowding. 大分子拥挤条件下微流控装置中三维可灌注微血管网络的稳定性和功能改善。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-04-19 DOI: 10.1186/s40824-023-00375-w
Ho-Ying Wan, Jack Chun Hin Chen, Qinru Xiao, Christy Wingtung Wong, Boguang Yang, Benjamin Cao, Rocky S Tuan, Susan K Nilsson, Yi-Ping Ho, Michael Raghunath, Roger D Kamm, Anna Blocki

Background: There is great interest to engineer in vitro models that allow the study of complex biological processes of the microvasculature with high spatiotemporal resolution. Microfluidic systems are currently used to engineer microvasculature in vitro, which consists of perfusable microvascular networks (MVNs). These are formed through spontaneous vasculogenesis and exhibit the closest resemblance to physiological microvasculature. Unfortunately, under standard culture conditions and in the absence of co-culture with auxiliary cells as well as protease inhibitors, pure MVNs suffer from a short-lived stability.

Methods: Herein, we introduce a strategy for stabilization of MVNs through macromolecular crowding (MMC) based on a previously established mixture of Ficoll macromolecules. The biophysical principle of MMC is based on macromolecules occupying space, thus increasing the effective concentration of other components and thereby accelerating various biological processes, such as extracellular matrix deposition. We thus hypothesized that MMC will promote the accumulation of vascular ECM (basement membrane) components and lead to a stabilization of MVN with improved functionality.

Results: MMC promoted the enrichment of cellular junctions and basement membrane components, while reducing cellular contractility. The resulting advantageous balance of adhesive forces over cellular tension resulted in a significant stabilization of MVNs over time, as well as improved vascular barrier function, closely resembling that of in vivo microvasculature.

Conclusion: Application of MMC to MVNs in microfluidic devices provides a reliable, flexible and versatile approach to stabilize engineered microvessels under simulated physiological conditions.

背景:有很大的兴趣设计体外模型,允许研究微血管复杂的生物过程与高时空分辨率。微流体系统目前被用于体外微血管工程,它由可灌注微血管网络(MVNs)组成。它们是通过自发血管发生形成的,表现出与生理微血管最相似的特征。不幸的是,在标准培养条件下,在没有辅助细胞和蛋白酶抑制剂共同培养的情况下,纯MVNs的稳定性很短。方法:在此,我们介绍了一种基于先前建立的Ficoll大分子混合物的大分子拥挤(MMC)稳定MVNs的策略。MMC的生物物理原理是基于大分子占据空间,从而增加其他成分的有效浓度,从而加速各种生物过程,如细胞外基质沉积。因此,我们假设MMC会促进血管ECM(基底膜)成分的积累,并导致MVN的稳定和功能的改善。结果:MMC促进了细胞连接和基底膜成分的富集,同时降低了细胞的收缩性。随着时间的推移,粘附力与细胞张力之间的有利平衡导致了MVNs的显著稳定,并改善了血管屏障功能,与体内微血管非常相似。结论:将MMC应用于微流控装置的MVNs提供了一种可靠、灵活和通用的方法来稳定模拟生理条件下的工程微血管。
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引用次数: 3
Progress and emerging techniques for biomaterial-based derivation of mesenchymal stem cells (MSCs) from pluripotent stem cells (PSCs). 基于生物材料从多能干细胞(PSCs)衍生间充质干细胞(MSCs)的进展和新兴技术。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-04-18 DOI: 10.1186/s40824-023-00371-0
Nityanand Prakash, Jiseong Kim, Jieun Jeon, Siyeon Kim, Yoshie Arai, Alvin Bacero Bello, Hansoo Park, Soo-Hong Lee

The use of mesenchymal stem cells (MSCs) for clinical purposes has skyrocketed in the past decade. Their multilineage differentiation potentials and immunomodulatory properties have facilitated the discovery of therapies for various illnesses. MSCs can be isolated from infant and adult tissue sources, which means they are easily available. However, this raises concerns because of the heterogeneity among the various MSC sources, which limits their effective use. Variabilities arise from donor- and tissue-specific differences, such as age, sex, and tissue source. Moreover, adult-sourced MSCs have limited proliferation potentials, which hinders their long-term therapeutic efficacy. These limitations of adult MSCs have prompted researchers to develop a new method for generating MSCs. Pluripotent stem cells (PSCs), such as embryonic stem cells and induced PSCs (iPSCs), can differentiate into various types of cells. Herein, a thorough review of the characteristics, functions, and clinical importance of MSCs is presented. The existing sources of MSCs, including adult- and infant-based sources, are compared. The most recent techniques for deriving MSCs from iPSCs, with a focus on biomaterial-assisted methods in both two- and three-dimensional culture systems, are listed and elaborated. Finally, several opportunities to develop improved methods for efficiently producing MSCs with the aim of advancing their various clinical applications are described.

过去十年间,间充质干细胞(MSCs)在临床上的应用急剧增加。间充质干细胞的多线分化潜能和免疫调节特性促进了各种疾病疗法的发现。间充质干细胞可从婴儿和成人组织来源中分离出来,这意味着它们很容易获得。然而,这也引起了人们的担忧,因为各种间充质干细胞来源的异质性限制了它们的有效利用。差异来自供体和组织的特异性差异,如年龄、性别和组织来源。此外,成人来源的间充质干细胞增殖潜力有限,阻碍了其长期疗效。成人间充质干细胞的这些局限性促使研究人员开发出一种生成间充质干细胞的新方法。多能干细胞(PSCs),如胚胎干细胞和诱导多能干细胞(iPSCs),可以分化成各种类型的细胞。本文对间充质干细胞的特点、功能和临床重要性进行了全面综述。比较了现有的间充质干细胞来源,包括成人和婴儿间充质干细胞来源。列举并阐述了从 iPSCs 中提取间充质干细胞的最新技术,重点是二维和三维培养系统中的生物材料辅助方法。最后,介绍了开发高效生产间充质干细胞改良方法的若干机会,目的是推进间充质干细胞的各种临床应用。
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引用次数: 0
Neutrophil-inspired photothermo-responsive drug delivery system for targeted treatment of bacterial infection and endotoxins neutralization. 中性粒细胞激发的光热反应药物传递系统用于细菌感染的靶向治疗和内毒素中和。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-04-15 DOI: 10.1186/s40824-023-00372-z
Chengnan Li, Yingying Gan, Zongshao Li, Mengjing Fu, Yuzhen Li, Xinran Peng, Yongqiang Yang, Guo-Bao Tian, Yi Yan Yang, Peiyan Yuan, Xin Ding

Background: P. aeruginosa, a highly virulent Gram-negative bacterium, can cause severe nosocomial infections, and it has developed resistance against most antibiotics. New therapeutic strategies are urgently needed to treat such bacterial infection and reduce its toxicity caused by endotoxin (lipopolysaccharide, LPS). Neutrophils have been proven to be able to target inflammation site and neutrophil membrane receptors such as Toll-like receptor-4 (TLR4) and CD14, and exhibit specific affinity to LPS. However, antibacterial delivery system based on the unique properties of neutrophils has not been reported.

Methods: A neutrophil-inspired antibacterial delivery system for targeted photothermal treatment, stimuli-responsive antibiotic release and endotoxin neutralization is reported in this study. Specifically, the photothermal reagent indocyanine green (ICG) and antibiotic rifampicin (RIF) are co-loaded into poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP-ICG/RIF), followed by coating with neutrophil membrane to obtain antibacterial delivery system (NM-NP-ICG/RIF). The inflammation targeting properties, synergistic antibacterial activity of photothermal therapy and antibiotic treatment, and endotoxin neutralization have been studied in vitro. A P. aeruginosa-induced murine skin abscess infection model has been used to evaluate the therapeutic efficacy of the NM-NP-ICG/RIF.

Results: Once irradiated by near-infrared lasers, the heat generated by NP-ICG/RIF triggers the release of RIF and ICG, resulting in a synergistic chemo-photothermal antibacterial effect against P. aeruginosa (~ 99.99% killing efficiency in 5 min). After coating with neutrophil-like cell membrane vesicles (NMVs), the nanoparticles (NM-NP-ICG/RIF) specifically bind to inflammatory vascular endothelial cells in infectious site, endowing the nanoparticles with an infection microenvironment targeting function to enhance retention time. Importantly, it is discovered for the first time that NMVs-coated nanoparticles are able to neutralize endotoxins. The P. aeruginosa murine skin abscess infection model further demonstrates the in vivo therapeutic efficacy of NM-NP-ICG/RIF.

Conclusion: The neutrophil-inspired antibacterial delivery system (NM-NP-ICG/RIF) is capable of targeting infection microenvironment, neutralizing endotoxin, and eradicating bacteria through a synergistic effect of photothermal therapy and antibiotic treatment. This drug delivery system made from FDA-approved compounds provides a promising approach to fighting against hard-to-treat bacterial infections.

背景:铜绿假单胞菌是一种高毒力的革兰氏阴性菌,可引起严重的医院感染,并对大多数抗生素产生耐药性。目前迫切需要新的治疗策略来治疗这种细菌感染,并降低内毒素(脂多糖,LPS)引起的毒性。中性粒细胞已被证明能够靶向炎症部位和中性粒细胞膜受体,如toll样受体-4 (TLR4)和CD14,并表现出对LPS的特异性亲和力。然而,基于中性粒细胞独特性质的抗菌递送系统尚未见报道。方法:本研究报道了一种中性粒细胞激发的靶向光热治疗、刺激反应性抗生素释放和内毒素中和的抗菌药物递送系统。将光热试剂吲哚菁绿(ICG)和抗生素利福平(RIF)共负载到聚乳酸-共乙醇酸(PLGA)纳米粒子(NP-ICG/RIF)中,再用中性粒细胞膜包裹,得到抗菌递送系统(NM-NP-ICG/RIF)。体外研究了光热疗法和抗生素治疗的炎症靶向性、协同抑菌活性以及内毒素中和作用。采用铜绿假单胞菌诱导的小鼠皮肤脓肿感染模型,评价纳米颗粒- np - icg /RIF的治疗效果。结果:NP-ICG/RIF经近红外激光照射后,产生的热量触发RIF和ICG的释放,对铜绿假单胞菌具有协同的化学-光热抗菌作用(5 min杀灭效率~ 99.99%)。纳米颗粒(NM-NP-ICG/RIF)包裹中性粒细胞样细胞膜囊泡(NMVs)后,特异性结合感染部位的炎症血管内皮细胞,使纳米颗粒具有感染微环境靶向功能,延长滞留时间。重要的是,这是第一次发现nmvs包被的纳米颗粒能够中和内毒素。铜绿假单胞菌小鼠皮肤脓肿感染模型进一步验证了NM-NP-ICG/RIF的体内治疗效果。结论:中性粒细胞激发的抗菌递送系统(NM-NP-ICG/RIF)通过光热治疗和抗生素治疗的协同作用,能够靶向感染微环境,中和内毒素,根除细菌。这种由fda批准的化合物制成的药物输送系统为对抗难以治疗的细菌感染提供了一种有希望的方法。
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引用次数: 0
Responsive manganese-based nanoplatform amplifying cGAS-STING activation for immunotherapy. 响应性锰基纳米平台扩增cGAS-STING激活用于免疫治疗。
IF 11.3 1区 医学 Q1 Medicine Pub Date : 2023-04-15 DOI: 10.1186/s40824-023-00374-x
Qingbin He, Runxiao Zheng, Junchi Ma, Luyang Zhao, Yafang Shi, Jianfeng Qiu

Background: The activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) signaling pathway has attracted great attention for its ability to up-regulate innate immune response and thus enhance cancer immunotherapy. However, many STING agonists limit the further advancement of immunotherapy due to weak tumor responsiveness or low activation efficiency. The responsive and effective activation of cGAS-STING signaling in tumors is a highly challenging process.

Methods: In this study, a manganese-based nanoplatform (MPCZ NPs) was constructed that could responsively and efficiently generate more manganese ions (Mn2+) and reactive oxygen species (ROS) to activate cGAS-STING signaling pathway. Briefly, manganese dioxide (MnO2) was loaded with zinc protoporphyrin IX (ZPP) molecule and coated by polydopamine (PDA) embedded with NH4HCO3 to obtain MPCZ NPs. Additionally, MPCZ NPs were evaluated in vitro and in vivo for their antitumor effects by methyl thiazolyl tetrazolium (MTT) assay and TUNEL assays, respectively.

Results: In this system, tumor responsiveness was achieved by exogenous (laser irradiation) and endogenous (high levels GSH) stimulation, which triggered the collapse or degradation of PDA and MnO2. Moreover, the release of Mn2+ augmented the cGAS-STING signaling pathway and enhanced the conversion of hydrogen peroxide (H2O2) to hydroxyl radical (·OH) under NIR laser irradiation. Furthermore, the release of ZPP and the elimination of GSH by MPCZ NPs inhibited HO-1 activity and prevented ROS consumption, respectively.

Conclusions: This adopted open source and reduce expenditure strategy to effectively generate more ROS and Mn2+ to responsively activate cGAS-STING signaling pathway, providing a new strategy for improving immunotherapy.

背景:环鸟苷单磷酸腺苷单磷酸合成酶干扰素基因刺激因子(cGAS-STING)信号通路的激活因其上调先天免疫应答从而增强肿瘤免疫治疗能力而备受关注。然而,许多STING激动剂由于肿瘤反应性弱或激活效率低,限制了免疫治疗的进一步发展。肿瘤中cGAS-STING信号的响应和有效激活是一个极具挑战性的过程。方法:本研究构建了锰基纳米平台(MPCZ NPs),该平台能够响应性、高效地生成更多的锰离子(Mn2+)和活性氧(ROS),激活cGAS-STING信号通路。简单地说,二氧化锰(MnO2)负载锌原卟啉IX (ZPP)分子,并包被含有NH4HCO3的聚多巴胺(PDA),得到MPCZ NPs。此外,采用甲基噻唑四氮唑(MTT)法和TUNEL法分别评价了MPCZ NPs的体外和体内抗肿瘤作用。结果:在该系统中,肿瘤反应性通过外源(激光照射)和内源(高水平GSH)刺激实现,触发PDA和MnO2的塌陷或降解。此外,在近红外激光照射下,Mn2+的释放增强了cGAS-STING信号通路,促进了过氧化氢(H2O2)向羟基自由基(·OH)的转化。此外,MPCZ NPs释放ZPP和消除GSH分别抑制HO-1活性和阻止ROS消耗。结论:采用开源节流策略,有效生成更多ROS和Mn2+响应性激活cGAS-STING信号通路,为改善免疫治疗提供了新的策略。
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引用次数: 1
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Biomaterials Research
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