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 Biomaterials Research 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
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引用次数: 0

摘要

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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Advanced pathophysiology mimicking lung models for accelerated drug discovery.

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.

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来源期刊
Biomaterials Research
Biomaterials Research Medicine-Medicine (miscellaneous)
CiteScore
10.20
自引率
3.50%
发文量
63
审稿时长
30 days
期刊介绍: Biomaterials Research, the official journal of the Korean Society for Biomaterials, is an open-access interdisciplinary publication that focuses on all aspects of biomaterials research. The journal covers a wide range of topics including novel biomaterials, advanced techniques for biomaterial synthesis and fabrication, and their application in biomedical fields. Specific areas of interest include functional biomaterials, drug and gene delivery systems, tissue engineering, nanomedicine, nano/micro-biotechnology, bio-imaging, regenerative medicine, medical devices, 3D printing, and stem cell research. By exploring these research areas, Biomaterials Research aims to provide valuable insights and promote advancements in the biomaterials field.
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