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Advancing tumor microenvironment and lymphoid tissue research through 3D bioprinting and biofabrication 通过生物3D打印和生物制造推进肿瘤微环境和淋巴组织的研究
IF 15.2 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 DOI: 10.1016/j.addr.2024.115485
Corrado Mazzaglia , Yan Yan Shery Huang , Jacqueline D. Shields
Cancer progression is significantly influenced by the complex interactions within the tumor microenvironment (TME). Immune cells, in particular, play a critical role by infiltrating tumors from the circulation and surrounding lymphoid tissues in an attempt to control their spread. However, they often fail in this task. Current in vivo and in vitro preclinical models struggle to fully capture these intricate interactions affecting our ability to understand immune evasion and predict drugs behaviour in the clinic. To address this challenge, biofabrication and particularly 3D bioprinting has emerged as a promising tool for modeling both tumors and the immune system. Its ability to incorporate multiple cell types into 3D matrices, enable tissue compartmentalization with high spatial accuracy, and integrate vasculature makes it a valuable approach. Nevertheless, limited research has focused on capturing the complex tumor-immune interplay in vitro. This review highlights the composition and significance of the TME, the architecture and function of lymphoid tissues, and innovative approaches to modeling their interactions in vitro, while proposing the concept of an extended TME.
肿瘤微环境(TME)内复杂的相互作用显著影响肿瘤的进展。特别是免疫细胞,通过从循环和周围淋巴组织浸润肿瘤,试图控制其扩散,发挥关键作用。然而,他们经常在这项任务中失败。目前的体内和体外临床前模型很难完全捕捉到这些复杂的相互作用,这些相互作用影响了我们理解免疫逃避和预测临床药物行为的能力。为了应对这一挑战,生物制造,特别是3D生物打印已经成为一种有前途的工具,用于模拟肿瘤和免疫系统。它能够将多种细胞类型整合到3D矩阵中,使组织分区具有高空间精度,并整合脉管系统,使其成为一种有价值的方法。然而,有限的研究集中在体外捕获复杂的肿瘤免疫相互作用。本文重点介绍了TME的组成和意义,淋巴组织的结构和功能,以及在体外模拟它们相互作用的创新方法,同时提出了扩展TME的概念。
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引用次数: 0
Droplet-based 3D bioprinting for drug delivery and screening 用于药物输送和筛选的基于液滴的3D生物打印
IF 15.2 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 DOI: 10.1016/j.addr.2024.115486
Heqi Xu , Shaokun Zhang , Kaidong Song , Huayong Yang , Jun Yin , Yong Huang
Recently, the conventional criterion of “one-size-fits-all” is not qualified for each individual patient, requiring precision medicine for enhanced therapeutic effects. Besides, drug screening is a high-cost and time-consuming process which requires innovative approaches to facilitate drug development rate. Benefiting from consistent technical advances in 3D bioprinting techniques, droplet-based 3D bioprinting techniques have been broadly utilized in pharmaceutics due to the noncontact printing mechanism and precise control on the deposition position of droplets. More specifically, cell-free/cell-laden bioinks which are deposited for the fabrication of drug carriers/3D tissue constructs have been broadly utilized for precise drug delivery and high throughput drug screening, respectively. This review summarizes the mechanism of various droplet-based 3D bioprinting techniques and the most up-to-date applications in drug delivery and screening and discusses the potential improvements of droplet-based 3D bioprinting techniques from both technical and material aspects. Through technical innovations, materials development, and the assistance from artificial intelligence, the formation process of drug carriers will be more stable and accurately controlled guaranteeing precise drug delivery. Meanwhile, the shape fidelity and uniformity of the printed tissue models will be significantly improved ensuring drug screening efficiency and efficacy.
目前,传统的“一刀切”标准已不适合每个患者,需要精准医疗来提高治疗效果。此外,药物筛选是一个高成本和耗时的过程,需要创新的方法来提高药物的开发速度。得益于生物3D打印技术的不断进步,基于液滴的生物3D打印技术由于其非接触式打印机制和对液滴沉积位置的精确控制,在制药领域得到了广泛的应用。更具体地说,沉积用于制造药物载体/3D组织结构的无细胞/负载细胞生物墨水已被广泛用于精确药物传递和高通量药物筛选。本文综述了各种基于液滴的生物3D打印技术的机理以及在药物输送和筛选方面的最新应用,并从技术和材料两个方面讨论了基于液滴的生物3D打印技术的潜在改进。通过技术创新、材料开发和人工智能的辅助,药物载体的形成过程将更加稳定和精确地控制,保证药物的精确递送。同时,打印组织模型的形状保真度和均匀性将得到显著提高,保证了药物筛选的效率和功效。
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引用次数: 0
Applications of pharmacometrics in drug development 药物计量学在药物开发中的应用
IF 15.2 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 DOI: 10.1016/j.addr.2024.115503
Yuan Xiong , Mahesh N. Samtani , Daniele Ouellet
The last two decades have witnessed profound changes in how advanced computational tools can help leverage tons of data to improve our knowledge, and ultimately reduce cost and increase productivity in drug development. Pharmacometrics has demonstrated its impact through model-informed drug development (MIDD) approaches. It is now an indispensable component throughout the whole continuum of drug discovery, development, regulatory review, and approval. Today, applications of pharmacometrics are common in designing better trials and accelerating evidence-based decisions. Newly emerging technologies, especially those from data and computer sciences, are being integrated with existing computational tools used in the pharmaceutical industry at a remarkably fast pace. The new challenges faced by the pharmacometrics community are not what or how to contribute, but which optimal MIDD strategy should be adopted to maximize its value in the decision-making process. While we are embracing new innovative approaches and tools, this article discusses how a variety of existing modeling tools, with differentiated advantages and focus, can work in concert to inform drug development.
在过去的二十年里,先进的计算工具已经发生了深刻的变化,它们可以帮助利用大量的数据来提高我们的知识,并最终降低成本,提高药物开发的生产率。药物计量学已经通过模型知情药物开发(MIDD)方法证明了它的影响。它现在是整个药物发现、开发、监管审查和批准过程中不可或缺的组成部分。今天,药物计量学的应用在设计更好的试验和加速循证决策方面很常见。新兴技术,特别是来自数据和计算机科学的技术,正以惊人的速度与制药行业使用的现有计算工具相结合。药物计量学界面临的新挑战不是贡献什么或如何贡献,而是应该采用哪种最优的MIDD策略来最大化其在决策过程中的价值。当我们接受新的创新方法和工具时,本文讨论了各种现有的建模工具,具有不同的优势和重点,如何协同工作以通知药物开发。
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引用次数: 0
Seeing through the skin: Optical methods for visualizing transdermal drug delivery with microneedles 透过皮肤看世界:用光学方法观察微针透皮给药情况
IF 15.2 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 DOI: 10.1016/j.addr.2024.115478
Benchaphorn Limcharoen , Supason Wanichwecharungruang , Wijit Banlunara , Maxim E. Darvin
Optical methods play a pivotal role in advancing transdermal drug delivery research, particularly with the emergence of microneedle technology. This review presents a comprehensive analysis of optical methods used in studying transdermal drug delivery facilitated by microneedle technology. Beginning with an introduction to microneedle technology and skin anatomy and optical properties, the review explores the integration of optical methods for enhanced visualization. Optical imaging offers key advantages including real-time drug distribution visualization, non-invasive skin response monitoring, and quantitative drug penetration analysis. A spectrum of optical imaging modalities ranging from conventional dermoscopy and stereomicroscopy to advance techniques as fluorescence microscopy, laser scanning microscopy, in vivo imaging system, two-photon microscopy, fluorescence lifetime imaging microscopy, optical coherence tomography, Raman microspectroscopy, laser speckle contrast imaging, and photoacoustic microscopy is discussed. Challenges such as resolution and depth penetration limitations are addressed alongside potential breakthroughs and future directions in optical techniques development. The review underscores the importance of bridging the gap between preclinical and clinical studies, explores opportunities for integrating optical imaging and chemical sensing methods with drug delivery systems, and highlight the importance of non-invasive “optical biopsy” as a valuable alternative to conventional histology. Overall, this review provides insight into the role of optical methods in understanding transdermal drug delivery mechanisms with microneedles.
光学方法在推动透皮给药研究方面发挥着举足轻重的作用,尤其是随着微针技术的出现。本综述全面分析了用于研究微针技术促进透皮给药的光学方法。综述从介绍微针技术和皮肤解剖及光学特性开始,探讨了如何整合光学方法以增强可视化。光学成像具有实时药物分布可视化、无创皮肤反应监测和定量药物渗透分析等主要优势。本文讨论了一系列光学成像模式,从传统的皮肤镜和立体显微镜到荧光显微镜、激光扫描显微镜、活体成像系统、双光子显微镜、荧光寿命成像显微镜、光学相干断层扫描、拉曼显微光谱、激光斑点对比成像和光声显微镜等先进技术。在讨论分辨率和深度穿透限制等挑战的同时,还探讨了光学技术发展的潜在突破和未来方向。综述强调了缩小临床前研究与临床研究之间差距的重要性,探讨了将光学成像和化学传感方法与给药系统集成的机会,并强调了无创 "光学活检 "作为传统组织学重要替代方法的重要性。总之,本综述深入探讨了光学方法在了解微针透皮给药机制中的作用。
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引用次数: 0
Additive manufacturing in spatial patterning for spinal cord injury treatment
IF 15.2 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-27 DOI: 10.1016/j.addr.2025.115523
Christy Kwokdinata , Sing Yian Chew
Combinatorial treatments integrating cells and biomolecules within scaffolds have been investigated to address the multifactorial nature of spinal cord injury (SCI). Current regenerative treatments have been ineffective as they do not consider the spatial positions of various cell types to effectively form functional neural pathways. Emulating the complex heterogeneity of cells in the native spinal cord requires translating the existing biological understanding of spatial patterning in neural development, as well as the influence of biomolecule and mechanical patterning on regional specification and axonal regeneration, to engineer a scaffold for spinal cord regeneration. This review explores the potential of 3D bioprinting to precisely control material, cell and drug patterns in scaffolds, achieving spatial phenotype specification and providing axonal guidance to form appropriate connections. We also discuss the application of extrusion-based and digital light processing bioprinting in integrating mechanical, chemical and biological cues within a scaffold to advance spatially patterned 3D bioprinted scaffold, as well as current challenges and future perspectives in these bioengineering strategies.
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引用次数: 0
Clinical perspective on pluripotent stem cells derived cell therapies for the treatment of neurodegenerative diseases
IF 15.2 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-27 DOI: 10.1016/j.addr.2025.115525
Michal Izrael , Judith Chebath , Kfir Molakandov , Michel Revel
Self-renewal capacity and potential to differentiate into almost any cell type of the human body makes pluripotent stem cells a valuable starting material for manufacturing of clinical grade cell therapies. Neurodegenerative diseases are characterized by gradual loss of structure or function of neurons, often leading to neuronal death. This results in gradual decline of cognitive, motor, and physiological functions due to the degeneration of the central nervous systems. Over the past two decades, comprehensive preclinical efficacy (proof-of-concept) and safety studies have led to the initiation of First-in-Human phase I-II clinical trials for a range of neurodegenerative diseases. In this review, we explore the fundamentals and challenges of neural-cell therapies derived from pluripotent stem cells for treating neurodegenerative diseases. Additionally, we highlight key preclinical investigations that paved the way for regulatory approvals of these trials. Furthermore, we provide an overview on progress and status of clinical trials done so far in treating neurodegenerative diseases such as spinal cord injury (SCI), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), as well as advances in retina diseases such as Stargardt disease (a.k.a fundus flavimaculatus), retinitis pigmentosa (RP) and age-related macular degeneration (AMD). These trials will pave the way for the development of new cell-based therapies targeting additional neurological conditions, including Alzheimer’s disease and epilepsy.
多能干细胞具有自我更新能力和分化成人体几乎所有细胞类型的潜力,因此是制造临床级细胞疗法的宝贵起始材料。神经退行性疾病的特点是神经元的结构或功能逐渐丧失,往往导致神经元死亡。中枢神经系统的退化会导致认知、运动和生理功能的逐渐衰退。在过去的二十年里,通过全面的临床前疗效(概念验证)和安全性研究,针对一系列神经退行性疾病的 I-II 期临床试验相继启动。在本综述中,我们将探讨多能干细胞神经细胞疗法治疗神经退行性疾病的基本原理和挑战。此外,我们还重点介绍了为这些试验获得监管部门批准铺平道路的关键临床前研究。此外,我们还概述了迄今为止在治疗脊髓损伤(SCI)、帕金森病(PD)和肌萎缩侧索硬化症(ALS)等神经退行性疾病方面所做临床试验的进展和现状,以及在治疗斯塔加特病(又称眼底黄斑病变)、视网膜色素变性(RP)和老年性黄斑变性(AMD)等视网膜疾病方面取得的进展。这些试验将为开发针对更多神经系统疾病(包括阿尔茨海默病和癫痫)的新型细胞疗法铺平道路。
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引用次数: 0
Breaking barriers in targeted Therapy: Advancing exosome Isolation, Engineering, and imaging 突破靶向治疗的障碍:推进外泌体分离、工程和成像
IF 15.2 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-22 DOI: 10.1016/j.addr.2025.115522
Anastasiya Kostyusheva , Eugenia Romano , Neng Yan , Manu Lopus , Andrey A. Zamyatnin Jr. , Alessandro Parodi
Exosomes have emerged as promising tools for targeted drug delivery in biomedical applications and medicine. This review delves into the scientific advancements, challenges, and future prospects specifically associated with these technologies. In this work, we trace the research milestones that led to the discovery and characterization of exosomes and extracellular vesicles, and discuss strategies for optimizing the synthetic yield and the loading of these particles with various therapeutics. In addition, we report the current major issues affecting the field and hampering the clinical translation of these technologies. Highlighting the pivotal role of imaging techniques, we explore how they drive exosome therapy and development by offering insights into biodistribution and cellular trafficking dynamics. Methodologies for vesicle isolation, characterization, loading, and delivery mechanisms are thoroughly examined, alongside strategies aimed at enhancing their therapeutic efficacy. Special emphasis was dedicated to their therapeutic properties, particularly to their ability to deliver biologics into the cytoplasm. Furthermore, we delve into the intricate balance between surface modifications and targeting properties including also transgenic methods aimed at their functionalization and visualization within biological systems. This review underscores the transformative potential of these carriers in targeted drug delivery and identifies crucial areas for further research and clinical translation.
外泌体已成为生物医学应用和医学中有前途的靶向药物递送工具。本文将深入探讨与这些技术相关的科学进展、挑战和未来前景。在这项工作中,我们追溯了导致外泌体和细胞外囊泡的发现和表征的研究里程碑,并讨论了优化合成产量和用各种治疗方法装载这些颗粒的策略。此外,我们报告了当前影响该领域和阻碍这些技术临床转化的主要问题。强调成像技术的关键作用,我们通过提供对生物分布和细胞运输动力学的见解,探索它们如何驱动外泌体治疗和发展。对囊泡分离、表征、装载和递送机制的方法进行了彻底的检查,以及旨在提高其治疗效果的策略。特别强调了它们的治疗特性,特别是它们将生物制剂输送到细胞质中的能力。此外,我们深入研究了表面修饰和靶向特性之间的复杂平衡,包括转基因方法,目的是在生物系统中实现其功能化和可视化。这篇综述强调了这些载体在靶向药物递送中的变革潜力,并确定了进一步研究和临床转化的关键领域。
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引用次数: 0
Fluorescence lifetime imaging in drug delivery research 荧光寿命成像在给药研究中的应用
IF 15.2 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-21 DOI: 10.1016/j.addr.2025.115521
Yiqing Lu , Parinaz Jabbari , Anton Mukhamedshin , Andrei V. Zvyagin
Once an exotic add-on to fluorescence microscopy for life science research, fluorescence lifetime imaging (FLIm) has become a powerful and increasingly utilised technique owing to its self-calibration nature, which affords superior quantification over conventional steady-state fluorescence imaging. This review focuses on the state-of-the-art implementation of FLIm related to the formulation, release, dosage, and mechanism of action of drugs aimed for innovative diagnostics and therapy. Quantitative measurements using FLIm have appeared instrumental for encapsulated drug delivery design, pharmacokinetics and pharmacodynamics, pathological investigations, early disease diagnosis, and evaluation of therapeutic efficacy. Attention is paid to the latest advances in lifetime-engineered nanomaterials and practical instrumentation, which begin to show preclinical and clinical translation potential beyond in vitro samples of cells and tissues. Finally, major challenges that need to be overcome in order to facilitate future perspectives are discussed.
荧光寿命成像(FLIm)曾经是荧光显微镜用于生命科学研究的一种外来的附加技术,由于其自校准的性质,荧光寿命成像(FLIm)已经成为一种强大的、越来越多的应用技术,它比传统的稳态荧光成像提供了更好的定量。这篇综述的重点是最新的FLIm的实施相关的配方,释放,剂量和药物的作用机制,旨在创新的诊断和治疗。使用FLIm的定量测量已成为胶囊药物递送设计、药代动力学和药效学、病理调查、早期疾病诊断和治疗效果评估的工具。人们关注的是终身工程纳米材料和实用仪器的最新进展,它们开始在细胞和组织的体外样本中显示出临床前和临床转化的潜力。最后,讨论了为促进对未来的展望而需要克服的主要挑战。
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引用次数: 0
Light sheet fluorescence microscopy for monitoring drug delivery: Unlocking the developmental phases of embryos 用于监测药物输送的光片荧光显微镜:揭开胚胎发育阶段的神秘面纱
IF 15.2 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-20 DOI: 10.1016/j.addr.2025.115520
Gagan Raju , Aymeric Le Gratiet , Giuseppe Sancataldo , Guan-Yu Zhuo , Yury Kistenev , Subir Das , Ajeetkumar Patil , Nirmal Mazumder
Light sheet fluorescence microscopy (LSFM) has emerged as a transformative imaging technique in the study of drug delivery and embryonic development, offering high-resolution, real-time visualization with minimal phototoxicity. This review examines the application of LSFM in tracking drug pharmacokinetics, tissue-specific targeting, and drug efficacy during critical phases of embryonic development. Recent advancements in fluorescent labeling and machine learning integration have enabled more precise monitoring of drug release, distribution, and interaction with developing tissues. The ability of LSFM to capture long-term dynamics at single-cell resolution has revolutionized drug discovery, especially in nanomedicine and targeted therapies. By integrating LSFM with multimodal imaging and AI-driven data analysis, researchers are now better equipped to explore complex biological processes and optimize drug delivery in a highly controlled, minimally invasive manner. Finally, the review highlights the pivotal role of LSFM in advancing drug delivery research, addressing existing challenges, and unlocking new frontiers in clinical applications.
光片荧光显微镜(LSFM)作为一种革命性的成像技术,在药物传递和胚胎发育研究中出现,提供高分辨率,实时可视化和最小的光毒性。本文综述了LSFM在胚胎发育关键阶段药物药代动力学、组织特异性靶向和药物疗效跟踪方面的应用。荧光标记和机器学习集成的最新进展使更精确地监测药物释放、分布和与发育组织的相互作用成为可能。LSFM在单细胞分辨率下捕获长期动态的能力已经彻底改变了药物发现,特别是在纳米医学和靶向治疗方面。通过将LSFM与多模态成像和人工智能驱动的数据分析相结合,研究人员现在可以更好地探索复杂的生物过程,并以高度可控、微创的方式优化药物输送。最后,综述强调了LSFM在推进给药研究、解决现有挑战和开辟临床应用新领域方面的关键作用。
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引用次数: 0
Drug delivery systems for treating neurodevelopmental disorders 治疗神经发育障碍的给药系统。
IF 15.2 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 DOI: 10.1016/j.addr.2024.115473
Boaz Barak, Paolo Decuzzi
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引用次数: 0
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Advanced drug delivery reviews
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