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Immunometabolic cues recompose and reprogram the microenvironment around implanted biomaterials 免疫代谢线索对植入生物材料周围的微环境进行重组和重编程
IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-04 DOI: 10.1038/s41551-024-01260-0
Chima V. Maduka, Axel D. Schmitter-Sánchez, Ashley V. Makela, Evran Ural, Katlin B. Stivers, Hunter Pope, Maxwell M. Kuhnert, Oluwatosin M. Habeeb, Anthony Tundo, Mohammed Alhaj, Artem Kiselev, Shoue Chen, Alexis Donneys, Wade P. Winton, Jenelle Stauff, Peter J. H. Scott, Andrew J. Olive, Kurt D. Hankenson, Ramani Narayan, Sangbum Park, Jennifer H. Elisseeff, Christopher H. Contag
Circulating monocytes infiltrate and coordinate immune responses in tissues surrounding implanted biomaterials and in other inflamed tissues. Here we show that immunometabolic cues in the biomaterial microenvironment govern the trafficking of immune cells, including neutrophils and monocytes, in a manner dependent on the chemokine receptor 2 (CCR2) and the C-X3-C motif chemokine receptor 1 (CX3CR1). This affects the composition and activation states of macrophage and dendritic cell populations, ultimately orchestrating the relative composition of pro-inflammatory, transitory and anti-inflammatory CCR2+, CX3CR1+ and CCR2+ CX3CR1+ immune cell populations. In amorphous polylactide implants, modifying immunometabolism by glycolytic inhibition drives a pro-regenerative microenvironment principally by myeloid cells. In crystalline polylactide implants, together with arginase-1-expressing myeloid cells, T helper 2 cells and γδ+ T cells producing interleukin-4 substantially contribute to shaping the metabolically reprogrammed pro-regenerative microenvironment. Our findings inform the premise that local metabolic states regulate inflammatory processes in the biomaterial microenvironment. Immunometabolic cues surrounding implanted biomaterials govern the trafficking of subsets of neutrophils, monocytes and other immune cells, and determine the relative composition of pro-inflammatory and anti-inflammatory immune cell populations.
循环中的单核细胞在植入的生物材料周围组织和其他发炎组织中浸润并协调免疫反应。在这里,我们展示了生物材料微环境中的免疫代谢线索以一种依赖于趋化因子受体 2(CCR2)和 C-X3-C motif 趋化因子受体 1(CX3CR1)的方式控制着包括中性粒细胞和单核细胞在内的免疫细胞的迁移。这会影响巨噬细胞和树突状细胞群的组成和活化状态,最终协调促炎性、暂时性和抗炎性 CCR2+、CX3CR1+ 和 CCR2+ CX3CR1+ 免疫细胞群的相对组成。在无定形聚乳酸植入物中,通过抑制糖酵解来改变免疫代谢,从而主要通过髓系细胞来推动有利于再生的微环境。在结晶聚乳酸植入物中,T辅助2细胞和产生白细胞介素-4的γδ+ T细胞与表达精氨酸酶-1的髓系细胞一起,为塑造代谢重编程的促再生微环境做出了重大贡献。我们的研究结果证明了一个前提,即局部代谢状态可调节生物材料微环境中的炎症过程。
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引用次数: 0
Accurate prediction of disease-risk factors from volumetric medical scans by a deep vision model pre-trained with 2D scans 用二维扫描预训练的深度视觉模型从体积医学扫描中准确预测疾病风险因素
IF 28.1 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-01 DOI: 10.1038/s41551-024-01257-9
Oren Avram, Berkin Durmus, Nadav Rakocz, Giulia Corradetti, Ulzee An, Muneeswar G. Nittala, Prerit Terway, Akos Rudas, Zeyuan Johnson Chen, Yu Wakatsuki, Kazutaka Hirabayashi, Swetha Velaga, Liran Tiosano, Federico Corvi, Aditya Verma, Ayesha Karamat, Sophiana Lindenberg, Deniz Oncel, Louay Almidani, Victoria Hull, Sohaib Fasih-Ahmad, Houri Esmaeilkhanian, Maxime Cannesson, Charles C. Wykoff, Elior Rahmani, Corey W. Arnold, Bolei Zhou, Noah Zaitlen, Ilan Gronau, Sriram Sankararaman, Jeffrey N. Chiang, Srinivas R. Sadda, Eran Halperin

The application of machine learning to tasks involving volumetric biomedical imaging is constrained by the limited availability of annotated datasets of three-dimensional (3D) scans for model training. Here we report a deep-learning model pre-trained on 2D scans (for which annotated data are relatively abundant) that accurately predicts disease-risk factors from 3D medical-scan modalities. The model, which we named SLIViT (for ‘slice integration by vision transformer’), preprocesses a given volumetric scan into 2D images, extracts their feature map and integrates it into a single prediction. We evaluated the model in eight different learning tasks, including classification and regression for six datasets involving four volumetric imaging modalities (computed tomography, magnetic resonance imaging, optical coherence tomography and ultrasound). SLIViT consistently outperformed domain-specific state-of-the-art models and was typically as accurate as clinical specialists who had spent considerable time manually annotating the analysed scans. Automating diagnosis tasks involving volumetric scans may save valuable clinician hours, reduce data acquisition costs and duration, and help expedite medical research and clinical applications.

由于用于模型训练的三维(3D)扫描注释数据集有限,机器学习在涉及容积生物医学成像任务中的应用受到限制。在此,我们报告了一种在二维扫描(注释数据相对丰富)上预先训练的深度学习模型,该模型能从三维医学扫描模式中准确预测疾病风险因素。我们将该模型命名为 SLIViT(意为 "通过视觉转换器进行切片整合"),它将给定的容积扫描预处理为二维图像,提取其特征图,并将其整合为一个预测结果。我们在八个不同的学习任务中对该模型进行了评估,包括涉及四种容积成像模式(计算机断层扫描、磁共振成像、光学相干断层扫描和超声波)的六个数据集的分类和回归。SLIViT 的表现始终优于特定领域的最先进模型,其准确性通常不亚于花费大量时间手动标注分析扫描结果的临床专家。将涉及容积扫描的诊断任务自动化,可以节省临床医生的宝贵时间,降低数据采集成本,缩短数据采集时间,并有助于加快医学研究和临床应用。
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引用次数: 0
A fast all-optical 3D photoacoustic scanner for clinical vascular imaging 用于临床血管成像的快速全光三维光声扫描仪
IF 28.1 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-09-30 DOI: 10.1038/s41551-024-01247-x
N. T. Huynh, E. Zhang, O. Francies, F. Kuklis, T. Allen, J. Zhu, O. Abeyakoon, F. Lucka, M. Betcke, J. Jaros, S. Arridge, B. Cox, A. A. Plumb, P. Beard

The clinical assessment of microvascular pathologies (in diabetes and in inflammatory skin diseases, for example) requires the visualization of superficial vascular anatomy. Photoacoustic tomography (PAT) scanners based on an all-optical Fabry–Perot ultrasound sensor can provide highly detailed 3D microvascular images, but minutes-long acquisition times have precluded their clinical use. Here we show that scan times can be reduced to a few seconds and even hundreds of milliseconds by parallelizing the optical architecture of the sensor readout, by using excitation lasers with high pulse-repetition frequencies and by exploiting compressed sensing. A PAT scanner with such fast acquisition minimizes motion-related artefacts and allows for the volumetric visualization of individual arterioles, venules, venous valves and millimetre-scale arteries and veins to depths approaching 15 mm, as well as for dynamic 3D images of time-varying tissue perfusion and other haemodynamic events. In exploratory case studies, we used the scanner to visualize and quantify microvascular changes associated with peripheral vascular disease, skin inflammation and rheumatoid arthritis. Fast all-optical PAT may prove useful in cardiovascular medicine, oncology, dermatology and rheumatology.

微血管病变(例如糖尿病和炎症性皮肤病)的临床评估需要表层血管解剖的可视化。基于全光学法布里-珀罗超声传感器的光声层析(PAT)扫描仪可以提供非常详细的三维微血管图像,但长达几分钟的采集时间使其无法用于临床。在这里,我们展示了通过并行化传感器读出的光学结构、使用高脉冲重复频率的激发激光器以及利用压缩传感技术,扫描时间可以缩短到几秒甚至几百毫秒。具有这种快速采集功能的 PAT 扫描仪能最大限度地减少与运动相关的伪影,并能对单个动脉血管、静脉、静脉瓣膜和毫米级的动脉和静脉(深度接近 15 毫米)进行容积可视化,以及对随时间变化的组织灌注和其他血流动力学事件进行动态三维成像。在探索性案例研究中,我们使用该扫描仪对与外周血管疾病、皮肤炎症和类风湿性关节炎相关的微血管变化进行了可视化和量化。快速全光 PAT 可能会在心血管医学、肿瘤学、皮肤病学和风湿病学领域大有用武之地。
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引用次数: 0
Meta-analysis of the make-up and properties of in vitro models of the healthy and diseased blood-brain barrier. 健康和患病血脑屏障体外模型的组成和特性的元分析。
IF 28.1 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-09-20 DOI: 10.1038/s41551-024-01250-2
James G Shamul,Zhiyuan Wang,Hyeyeon Gong,Wenquan Ou,Alisa M White,Diogo P Moniz-Garcia,Shuo Gu,Alisa Morss Clyne,Alfredo Quiñones-Hinojosa,Xiaoming He
In vitro models of the human blood-brain barrier (BBB) are increasingly used to develop therapeutics that can cross the BBB for treating diseases of the central nervous system. Here we report a meta-analysis of the make-up and properties of transwell and microfluidic models of the healthy BBB and of BBBs in glioblastoma, Alzheimer's disease, Parkinson's disease and inflammatory diseases. We found that the type of model, the culture method (static or dynamic), the cell types and cell ratios, and the biomaterials employed as extracellular matrix are all crucial to recapitulate the low permeability and high expression of tight-junction proteins of the BBB, and to obtain high trans-endothelial electrical resistance. Specifically, for models of the healthy BBB, the inclusion of endothelial cells and pericytes as well as physiological shear stresses (~10-20 dyne cm-2) are necessary, and when astrocytes are added, astrocytes or pericytes should outnumber endothelial cells. We expect this meta-analysis to facilitate the design of increasingly physiological models of the BBB.
人体血脑屏障(BBB)的体外模型越来越多地被用于开发能穿过BBB治疗中枢神经系统疾病的疗法。在此,我们报告了对健康血脑屏障以及胶质母细胞瘤、阿尔茨海默病、帕金森病和炎症性疾病中的血脑屏障的transwell和微流控模型的组成和特性进行的荟萃分析。我们发现,模型的类型、培养方法(静态或动态)、细胞类型和细胞比例以及用作细胞外基质的生物材料对再现 BBB 的低通透性和高表达紧密连接蛋白以及获得高跨内皮电阻都至关重要。具体来说,对于健康的 BBB 模型,内皮细胞和周细胞的加入以及生理剪切应力(约 10-20 达因厘米-2)是必要的,当加入星形胶质细胞时,星形胶质细胞或周细胞的数量应多于内皮细胞。我们希望这项荟萃分析能促进设计越来越多的 BBB 生理模型。
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引用次数: 0
Non-viral targeted insertion of large payloads into T cells 以非病毒为靶向将大型有效载荷植入 T 细胞
IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-09-16 DOI: 10.1038/s41551-024-01252-0
Zsuzsanna Izsvák
The nuclease Cas9 and DNA-repair pathway homology-mediated end joining can be leveraged to efficiently and non-virally integrate large DNA payloads into genomic target sites in primary T cells.
利用核酸酶 Cas9 和 DNA 修复途径同源物介导的末端连接,可以高效、非病毒性地将大 DNA 有效载荷整合到原代 T 细胞的基因组靶位点。
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引用次数: 0
In situ formation of biomolecular condensates as intracellular drug reservoirs for augmenting chemotherapy 原位形成生物分子凝聚物,作为细胞内药物库,用于增强化疗效果
IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-09-13 DOI: 10.1038/s41551-024-01254-y
Tingxizi Liang, Yuxiang Dong, Irina Cheng, Ping Wen, Fengqin Li, Feng Liu, Qing Wu, En Ren, Peifeng Liu, Hongjun Li, Zhen Gu
Biomolecular condensates, which arise from liquid–liquid phase separation within cells, may provide a means of enriching and prolonging the retention of small-molecule drugs within cells. Here we report a method for the controlled in situ formation of biomolecular condensates as reservoirs for the enrichment and retention of chemotherapeutics in cancer cells, and show that the approach can be leveraged to enhance antitumour efficacies in mice with drug-resistant tumours. The method involves histones as positively charged proteins and doxorubicin-intercalated DNA strands bioorthogonally linked via a click-to-release reaction between trans-cyclooctene and tetrazine groups. The reaction temporarily impaired the phase separation of histones in vitro, favoured the initiation of liquid–liquid phase separation within cells and led to the formation of biomolecular condensates that were sufficiently large to be retained within tumour cells. The controlled formation of biomolecular condensates as drug reservoirs within cells may offer new options for boosting the efficacies of cancer therapies. The controlled in situ formation of biomolecular condensates as intracellular reservoirs for the enrichment and retention of a chemotherapeutic in cancer cells enhanced antitumour activities in mice with drug-resistant tumours.
由细胞内液-液相分离产生的生物分子凝聚物可为富集和延长小分子药物在细胞内的保留时间提供一种方法。在这里,我们报告了一种原位受控形成生物分子凝聚体的方法,这种凝聚体是富集和保留癌细胞中化疗药物的贮库,并表明这种方法可用于提高抗药性肿瘤小鼠的抗肿瘤疗效。该方法通过反式环辛烯和四嗪基团之间的点击释放反应,将组蛋白作为带正电荷的蛋白质与多柔比星插入的 DNA 链生物正交连接起来。这种反应暂时阻碍了组蛋白在体外的相分离,有利于启动细胞内的液-液相分离,并导致生物分子凝聚物的形成,这种凝聚物足够大,可以保留在肿瘤细胞内。在细胞内可控地形成生物分子凝聚物作为药物储存库,可为提高癌症疗法的疗效提供新的选择。
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引用次数: 0
Learning what keeps nanomedicines in tumours 了解让纳米药物留在肿瘤中的原因
IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-09-13 DOI: 10.1038/s41551-024-01251-1
Yifan Wang, Benjamin R. Schrank, Wen Jiang, Betty Y. S. Kim
An analysis of histopathological data from mouse and human tumours via machine learning reveals that the densities of blood vessels and tumour-associated macrophages are predictive features of the degree of tumoural accumulation of polymeric and liposomal nanomedicines.
通过机器学习分析小鼠和人类肿瘤的组织病理学数据发现,血管和肿瘤相关巨噬细胞的密度是聚合物和脂质体纳米药物在肿瘤中积累程度的预测特征。
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引用次数: 0
A pan-cancer dye for solid-tumour screening, resection and wound monitoring via short-wave and near-infrared fluorescence imaging 通过短波和近红外荧光成像进行实体瘤筛查、切除和伤口监测的泛癌症染料
IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-09-09 DOI: 10.1038/s41551-024-01248-w
Benedict Edward Mc Larney, Ali Yasin Sonay, Elana Apfelbaum, Nermin Mostafa, Sébastien Monette, Dana Goerzen, Nicole Aguirre, Rüdiger M. Exner, Christine Habjan, Elizabeth Isaac, Ngan Bao Phung, Magdalena Skubal, Mijin Kim, Anuja Ogirala, Darren Veach, Daniel A. Heller, Jan Grimm
The efficacy of fluorescence-guided surgery in facilitating the real-time delineation of tumours depends on the optical contrast of tumour tissue over healthy tissue. Here we show that CJ215—a commercially available, renally cleared carbocyanine dye sensitive to apoptosis, and with an absorption and emission spectra suitable for near-infrared fluorescence imaging (wavelengths of 650–900 nm) and shortwave infrared (SWIR) fluorescence imaging (900–1,700 nm)—can facilitate fluorescence-guided tumour screening, tumour resection and the assessment of wound healing. In tumour models of either murine or human-derived breast, prostate and colon cancers and of fibrosarcoma, and in a model of intraperitoneal carcinomatosis, imaging of CJ215 with ambient light allowed for the delineation of nearly all tumours within 24 h after intravenous injection of the dye, which was minimally taken up by healthy organs. At later timepoints, CJ215 provided tumour-to-muscle contrast ratios up to 100 and tumour-to-liver contrast ratios up to 18. SWIR fluorescence imaging with the dye also allowed for quantifiable non-contact wound monitoring through commercial bandages. CJ215 may be compatible with existing and emerging clinical solutions. A commercial near-infrared dye that is sensitive to apoptosis and that provides high tumour-to-muscle and tumour-to-liver contrast ratios facilitates fluorescence-guided tumour screening, tumour resection and the assessment of wound healing.
荧光引导手术在促进肿瘤实时分界方面的功效取决于肿瘤组织与健康组织的光学对比度。在这里,我们展示了 CJ215--一种对细胞凋亡敏感、吸收和发射光谱适合近红外荧光成像(波长为 650-900 纳米)和短波红外荧光成像(900-1700 纳米)的市售肾清除羰花青染料--可以促进荧光引导下的肿瘤筛查、肿瘤切除和伤口愈合评估。在小鼠或人源乳腺癌、前列腺癌、结肠癌和纤维肉瘤的肿瘤模型中,以及在腹膜内癌瘤病模型中,用环境光对 CJ215 进行成像,可在静脉注射染料后 24 小时内勾画出几乎所有肿瘤的轮廓,健康器官对染料的吸收极少。在较晚的时间点,CJ215 的肿瘤与肌肉对比度高达 100,肿瘤与肝脏对比度高达 18。使用该染料进行的西南红外荧光成像还可以通过商用绷带进行可量化的非接触式伤口监测。CJ215 可与现有和新兴的临床解决方案兼容。
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引用次数: 0
Virally delivered CMYA5 enhances the assembly of cardiac dyads 病毒递送的 CMYA5 可增强心脏二联体的组装
IF 28.1 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-09-05 DOI: 10.1038/s41551-024-01253-z
Fujian Lu, Carter Liou, Qing Ma, Zexuan Wu, Bingqing Xue, Yu Xia, Shutao Xia, Michael A. Trembley, Anna Ponek, Wenjun Xie, Kevin Shani, Raul H. Bortolin, Maksymilian Prondzynski, Paul Berkson, Xiaoran Zhang, Francisco J. Naya, Kenneth C. Bedi, Kenneth B. Margulies, Donghui Zhang, Kevin K. Parker, William T. Pu

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) lack nanoscale structures essential for efficient excitation–contraction coupling. Such nanostructures, known as dyads, are frequently disrupted in heart failure. Here we show that the reduced expression of cardiomyopathy-associated 5 (CMYA5), a master protein that establishes dyads, contributes to dyad disorganization in heart failure and to impaired dyad assembly in hiPSC-CMs, and that a miniaturized form of CMYA5 suitable for delivery via an adeno-associated virus substantially improved dyad architecture and normalized cardiac function under pressure overload. In hiPSC-CMs, the miniaturized form of CMYA5 increased contractile forces, improved Ca2+ handling and enhanced the alignment of sarcomere Z-lines with ryanodine receptor 2, a protein that mediates the sarcoplasmic release of stored Ca2+. Our findings clarify the mechanisms responsible for impaired dyad structure in diseased cardiomyocytes, and suggest strategies for promoting dyad assembly and stability in heart disease and during the derivation of hiPSC-CMs.

从人类诱导多能干细胞(hiPSC-CMs)中提取的心肌细胞缺乏高效激发-收缩耦合所必需的纳米级结构。这种被称为二联体的纳米结构在心力衰竭中经常被破坏。我们在这里发现,心肌病相关 5(CMYA5)--一种建立二联体的主蛋白--的表达减少导致了心衰中的二联体紊乱和 hiPSC-CMs 中的二联体组装受损,而一种适合通过腺相关病毒递送的小型化 CMYA5 能显著改善二联体结构,并使压力过载下的心脏功能恢复正常。在 hiPSC-CMs 中,小型化形式的 CMYA5 增加了收缩力,改善了 Ca2+ 处理,并增强了肌节 Z 线与雷诺丁受体 2(一种介导肌浆释放储存的 Ca2+ 的蛋白质)的排列。我们的研究结果阐明了病变心肌细胞中二联体结构受损的机制,并提出了在心脏病和 hiPSC-CMs 培育过程中促进二联体组装和稳定性的策略。
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引用次数: 0
Low-cost and scalable projected light-sheet microscopy for the high-resolution imaging of cleared tissue and living samples 低成本、可扩展的投射光片显微镜,用于对清除的组织和活体样本进行高分辨率成像
IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-08-29 DOI: 10.1038/s41551-024-01249-9
Yannan Chen, Shradha Chauhan, Cheng Gong, Hannah Dayton, Cong Xu, Estanislao Daniel De La Cruz, Yu-Young Wesley Tsai, Malika S. Datta, Gorazd B. Rosoklija, Andrew J. Dwork, J. John Mann, Maura Boldrini, Kam W. Leong, Lars E. P. Dietrich, Raju Tomer
Light-sheet fluorescence microscopy (LSFM) is a widely used technique for imaging cleared tissue and living samples. However, high-performance LSFM systems are typically expensive and not easily scalable. Here we introduce a low-cost, scalable and versatile LSFM framework, which we named ‘projected light-sheet microscopy’ (pLSM), with high imaging performance and small device and computational footprints. We characterized the capabilities of pLSM, which repurposes readily available consumer-grade components, optimized optics, over-network control architecture and software-driven light-sheet modulation, by performing high-resolution mapping of cleared mouse brains and of post-mortem pathological human brain samples, and via the molecular phenotyping of brain and blood-vessel organoids derived from human induced pluripotent stem cells. We also report a method that leverages pLSM for the live imaging of the dynamics of sparsely labelled multi-layered bacterial pellicle biofilms at an air–liquid interface. pLSM can make high-resolution LSFM for biomedical applications more accessible, affordable and scalable. A light-sheet fluorescence microscope leveraging consumer-grade components as well as optimized optics and software facilitates the high-resolution imaging of cleared and living samples at scale with lower costs.
光片荧光显微镜(LSFM)是一种广泛用于对清除的组织和活体样本进行成像的技术。然而,高性能 LSFM 系统通常价格昂贵且不易扩展。在这里,我们介绍了一种低成本、可扩展和多功能的 LSFM 框架,并将其命名为 "投射光片显微镜"(pLSM),它具有成像性能高、设备和计算占用空间小的特点。我们通过对清除的小鼠大脑和死后病理人脑样本进行高分辨率制图,以及对从人类诱导多能干细胞中提取的大脑和血管有机体进行分子表型,证明了投射光片显微镜的能力。我们还报告了一种利用 pLSM 对空气-液体界面上稀疏标记的多层细菌胶粒生物膜的动态进行实时成像的方法。pLSM 可以使生物医学应用中的高分辨率 LSFM 更容易获得、更经济实惠、更可扩展。
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引用次数: 0
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Nature Biomedical Engineering
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