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International Journal of Bioprinting 3D bioprinting for translational toxicology

1. Introduction By enabling layer-by-layer deposition of living cells,
biomaterials, and bioactive factors with micrometer-scale
Toxicity arises from adverse biological events triggered precision, bioprinting constructs physiologically relevant
by exposure to biological, physical, or chemical agents tissue architectures, such as vascularized liver lobules,
and manifests as reversible or irreversible dysfunctions, polarized renal tubules, and alveolar-capillary barriers,
ranging from transient cellular perturbations to severe that mirror native organ functionality. 17–20 Advanced
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organ failure and mortality. These outcomes are governed bioinks, including gelatin methacryloyl (GelMA) and
by the interplay between the absorption, distribution, decellularized ECM (dECM)-based hydrogels, provide
metabolism, and excretion (ADME) properties of tunable mechanical properties and biochemical niches
toxicants, as well as their interactions with cellular that maintain cell viability and phenotypic stability.
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macromolecules. Toxicology, as the scientific discipline Integrated microfluidic channels ensure sustained
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dedicated to evaluating toxicity mechanisms, severity, oxygenation and nutrient supply, thereby resolving
and frequency, has evolved into a cornerstone of modern necrosis issues in thick tissues. Notably, bioprinted models
pharmacology and chemical safety assessment. However, exhibit enhanced predictive accuracy for organ-specific
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the escalating demand for toxicity testing, fueled by the toxicities, as demonstrated by their ability to distinguish
annual introduction of over 2000 new chemicals across structural analogs such as trovafloxacin (hepatotoxic)
pharmaceuticals, cosmetics, and industrial sectors, has and levofloxacin (non-toxic), a feat unattainable with
revealed critical limitations in conventional approaches. 4 traditional models.
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Historically, animal testing served as the gold This review critically evaluates how 3D bioprinting
standard for toxicological evaluations. Although these addresses the limitations of existing in vitro toxicology
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models provide preliminary safety data, interspecies models. We first delineate the research trends and the
physiological disparities, such as divergent ADME profiles, technological evolution from animal testing to organ-
metabolic pathways, and lifespans, severely undermine on-a-chip systems, highlighting ongoing challenges in
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the translatability of animal-derived results to humans. physiological fidelity and scalability, as illustrated in
For instance, between 38% and 51% of drug-induced liver Figure 1. Next, we analyze advancements in bioprinting
injuries remain undetected during preclinical animal trials, modalities, such as extrusion, laser-assisted, and
culminating in costly late-stage clinical failures or post- stereolithography, as well as bioink design and
market withdrawals. Beyond ethical concerns, animal functional tissue fabrication. A central focus is placed
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models are characterized by low throughput, prolonged on organ-specific applications, such as liver, kidney,
testing cycles, and high operational costs, prompting an and lung toxicity assessments, where bioprinted models
urgent need for human-relevant alternatives. outperform conventional approaches in replicating
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The “Replacement, Reduction, Refinement” (3R) human pathophysiology. We also address unresolved
principles have catalyzed a paradigm shift toward in vitro controversies, including the lack of standardized
systems. 8–10 The global in vitro toxicology testing market, validation protocols and regulatory acceptance barriers.
valued at USD 10.1 billion in 2022, is projected to reach By synthesizing interdisciplinary innovations in materials
USD 17.1 billion by 2028, indicating a compound annual science, microfluidics, and artificial intelligence, this
growth rate of 9.5%. Early in vitro models, including work aims to outline a roadmap for translating bioprinted
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two-dimensional (2D) monocultures and static three- platforms into mainstream toxicological practice.
dimensional (3D) constructs, partially address ethical
and throughput challenges; however, they fail to replicate 2. A historical perspective on
the dynamic cell–cell and cell–extracellular matrix toxicological paradigms
(ECM) interactions and tissue-level complexity of human 2.1. The foundational era of toxicology
organs. 12,13 For example, 2D-cultured hepatocytes rapidly The nascent form of toxicology arose from rudimentary
dedifferentiate, losing cytochrome P450 activity within observations of natural phenomena and early experimental
hours, 14,15 whereas conventional 3D spheroids often develop inquiries. In the 16th century, Paracelsus introduced
hypoxic cores due to inadequate nutrient diffusion. Organ- the pivotal principle that “the dose makes the poison,”
on-a-chip platforms, which integrate microfluidics and thereby establishing the dose–response relationship as
mechanical cues, represent a significant leap forward but the cornerstone of toxicological science and laying the
encounter scalability issues and limited standardization. 7
groundwork for subsequent research in the field. By
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Three-dimensional bioprinting has emerged as a the late 18th century, British physician Percivall Pott’s
transformative technology to overcome these bottlenecks. investigation into scrotal cancer among chimney sweeps
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Volume 11 Issue 4 (2025) 100 doi: 10.36922/IJB025210209