Decellularized liver scaffolds for constructing drug-metabolically functional ex vivo human liver models

IF 18 1区 医学 Q1 ENGINEERING, BIOMEDICAL Bioactive Materials Pub Date : 2024-09-23 DOI:10.1016/j.bioactmat.2024.09.029
Juan Liu , Ariel Hanson , Wenzhen Yin , Qiao Wu , Eliane Wauthier , Jinmei Diao , Timothy Dinh , Jeff Macdonald , Ruihong Li , Masahiko Terajima , Mitsuo Yamauchi , Ziye Chen , Praveen Sethupathy , Jiahong Dong , Lola M. Reid , Yunfang Wang
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Abstract

The creation of ex vivo human liver models has long been a critical objective in academic, clinical, and pharmaceutical research, particularly for drug development, where accurate evaluation of hepatic metabolic dynamics is crucial. We have developed a bioengineered, perfused, organ-level human liver model that accurately replicates key liver functions, including metabolic activities, and protein synthesis, thus addressing some of the limitations associated with traditional liver monolayers, organoids, and matrix-embedded liver cells. Our approach utilizes liver-specific biomatrix scaffolds, prepared using an innovative protocol and fortified with matrix components that facilitate cellular interactions. These scaffolds, when seeded with human fetal liver cells or co-seeded with liver parenchymal and endothelial cell lines, enable the formation of three-dimensional (3D) human livers with enhanced cellular organization. The “recellularized tissue-engineered livers” (RCLs) have undergone various analyses, demonstrating the capability for establishing liver microenvironments ex vivo. Within 7–14 days, the RCLs exhibit evidence of liver differentiation and metabolic capabilities, underscoring the potential for use in drug metabolism and toxicity studies. Although our study represents a significant step forward, we acknowledge the need for direct comparisons with existing models and further research to fully elucidate the spectrum of regenerative responses. The high drug-metabolizing enzyme activity of RCLs, as demonstrated in our study, provides a promising avenue for investigating drug-induced liver injury mechanisms, contributing to a more detailed understanding of early drug discovery processes.

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用于构建药物代谢功能性体内外人体肝脏模型的脱细胞肝脏支架
长期以来,创建体外人体肝脏模型一直是学术、临床和制药研究的重要目标,尤其是在药物开发方面,准确评估肝脏代谢动态至关重要。我们开发了一种生物工程灌注器官级人体肝脏模型,它能准确复制肝脏的主要功能,包括代谢活动和蛋白质合成,从而解决了传统肝脏单层、器官组织和基质包埋肝细胞的一些局限性。我们的方法利用肝脏特异性生物基质支架,采用创新方案制备,并添加了促进细胞相互作用的基质成分。这些支架在接种人类胎儿肝细胞或与肝实质细胞系和内皮细胞系共同接种后,可形成具有增强细胞组织的三维(3D)人类肝脏。对 "再细胞化组织工程肝脏"(RCL)进行了各种分析,证明了其在体内外建立肝脏微环境的能力。在 7-14 天内,RCLs 显示出肝脏分化和新陈代谢能力的证据,突出了用于药物代谢和毒性研究的潜力。尽管我们的研究向前迈进了一大步,但我们承认还需要与现有模型进行直接比较,并开展进一步研究,以充分阐明再生反应的范围。我们的研究表明,RCL 具有很高的药物代谢酶活性,这为研究药物诱导的肝损伤机制提供了一个很有前景的途径,有助于更详细地了解早期药物发现过程。
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来源期刊
Bioactive Materials
Bioactive Materials Biochemistry, Genetics and Molecular Biology-Biotechnology
CiteScore
28.00
自引率
6.30%
发文量
436
审稿时长
20 days
期刊介绍: Bioactive Materials is a peer-reviewed research publication that focuses on advancements in bioactive materials. The journal accepts research papers, reviews, and rapid communications in the field of next-generation biomaterials that interact with cells, tissues, and organs in various living organisms. The primary goal of Bioactive Materials is to promote the science and engineering of biomaterials that exhibit adaptiveness to the biological environment. These materials are specifically designed to stimulate or direct appropriate cell and tissue responses or regulate interactions with microorganisms. The journal covers a wide range of bioactive materials, including those that are engineered or designed in terms of their physical form (e.g. particulate, fiber), topology (e.g. porosity, surface roughness), or dimensions (ranging from macro to nano-scales). Contributions are sought from the following categories of bioactive materials: Bioactive metals and alloys Bioactive inorganics: ceramics, glasses, and carbon-based materials Bioactive polymers and gels Bioactive materials derived from natural sources Bioactive composites These materials find applications in human and veterinary medicine, such as implants, tissue engineering scaffolds, cell/drug/gene carriers, as well as imaging and sensing devices.
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