Preclinical trials are an essential step in the development of drugs, acting as a bridge between basic science and human clinical trials. The traditional preclinical models that has been extensively used are performed in vitro and on animals for prediction of safety and efficacy of candidate drugs.
However, these methods have drawbacks such as ethical concerns surrounding toxicity in humans along with high costs and poor prediction. In order to address these issues, researchers and pharmaceutical companies are turning toward novel models that offer the flexibility, cost-savings, speed-to-market, and ethical standards not only for traditional efficacy testing but also for preclinical investigational safety testing. In this article, we dive deep into a few of the most exciting innovations.
1. Organoids & Organ-on-a-Chip Models
Organoids are in vitro grown three-dimensional, miniaturized organs that mimic organ structure and function. They replicate the features, form and function of its in vivo counterparts that consists a new generation tool to investigate mechanisms behind diseases and drug responses with precision. They can be generated from different tissues such as brain, liver, kidney or intestine and offer tissue specific model systems for preclinical drug testing.
Key Advantages:
The bigger picture: Because organoids are made from human cells rather than animal cells, they provide a model that is far more relevant for predicting how humans will respond.
Modelling Diseases: Useful to examine genetic diseases and cancer, providing insight into pathogenesis and responses to therapies.
In organ-on-a-chip technology, replicates physiological properties of human organs are carried out through microfluidic devices. These chips are outfitted with miniscule channels that contain living cells, an aggregate of which can closely replicate certain mechanical and biochemical functions of live tissues.
Physiological environment: Organ-on-a-chip models are more realistic than standard static cell culture systems, they can recreate dynamical behaviour such as blood circulation, nutrient exchange, mechanical forces.
Organ Connectivity: Multiple organ chips may be interconnected to model multi-organ interactions, generating an integrated prediction of drug effects and toxicities.
2. Artificial intelligence and advanced computational models
In Silico Modelling
Computational models are in silico way to predict drug behaviour or simulate biological processes using computational techniques. These models included molecular dynamics simulations, up to whole-body physiologically based pharmacokinetic (PBPK) models.
Key Advantages:
High Throughput: Computational models can quickly screen many thousands of small molecule candidates, consequently reducing laboratory testing that would otherwise be necessary.
Personalization: They can be tailored through individual characteristics such as genetic and metabolic information, advancing personalized medicine.
AI Machine Learning
Preclinical trials are the testing phase for a pharmacological or biological agent on cells, tissues, and/or animals before going ahead with human clinical trials and involve large datasets that now can be analysed by AI and machine learning (ML) to detect patterns that help predict outcomes. ML algorithms can help in maximizing this drug discovery process from target identification to understanding adverse effects.
Key Advantages:
AI Will Predict Clinical Outcomes: AI will develop meaningful predictive models using complex datasets for predicting drug efficacy and safety more accurately.
Cost Reduction: AI-based drug development increasingly reduces the cost of drug development by decreasing dependency on traditional experimental methods.
3. Humanized Animal Models
Species differences between traditional animal models and humans result in poor translations to human responses. Humanized animal models are created by genetic engineering of animals so that they synthesize, display or carry out human genes, proteins and cells providing a more reliable preclinical testing methodology.
Mouse models: These are genetically engineered mice that can have human immune systems or certain human genes and can be used to study infectious diseases, cancer and immune responses.
Human-for-animal Chimeric Models: These models are created by incorporating human cells into an animal embryo, thus creating animals with tissues that comprise of both human and animal cells.
Key Advantages:
Greater Relevance: Humanized models better recapitulate human biology and disease, leading to more predictive preclinical trials.
Ethical Implications: By reducing the use of higher-order animals in research studies these models can be used to better combat ethical concerns.
4. 3D Bioprinting
3D bioprinting is a simple concept that involves building biological structures layer-by-layer with cell and biomaterial-laden bioinks. The technology enables in vitro tissue models with complex organotypic and physiological levels simulating in vivo conditions.
Key Advantages:
Personalization: 3D bioprinting shows prospects for cultivating person-specific tissues as well, allow us with personalized medicine and regenerative treatments.
Complexity: It allows for the development of highly organized tissues, such as those containing vasculature or other vascular networks that are necessary to study drug delivery and toxicity.
5. Ex Vivo Models
Ex vivo models (tissue slice and organ culture) – using living tissue or organs that have been removed from an organism but kept alive in a controlled environment. The models maintain the structure and known mechanisms of the native tissue, making them one of the most genuine platforms regarding drug testing.
Precision-Cut Tissue Slices: These slices are cultured from human (and animal) tissues and ensure the retention of both cellular diversity and interactions present in original tissue for drug testing.
Perfusion Systems: circulating blood or nutrient solutions through organs such as the liver, kidney, is used to assess drug metabolism and toxicity in a human-relevant context.
Key Advantages:
Actual Response: Ex vivo systems are more complex compared to in vitro, they do reflect the complexity of the tissues and can give a realistic overview of whether or not it is tissue penetrating.
Ethical and Practical Advantages: These models reduce the dependence on live animal testing and can be constructed from tissues sourced from surgeries or biopsies.
Preclinical trial ecosystems, such as the one described here, have developed to capitalize on innovation in preclinical studies that bridges limitations of traditional models. While organoids, organs-on-a-chip, advanced computational models, humanized animal models as well as 3D bioprinting and ex vivo cell models have unique features by which they enhance predictive accuracy and increase efficiency in already commonly used techniques, standards for improved preclinical testing are ethically defined. As these technologies improve in precision, they stand ready to transform drug development and bring better and safer therapeutics to market more quickly and at less expense.
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