author | Wayne
Zebian | Yi Hong
micro physiological system (MPS) , microfluidic The organ chip (microfluidic organs-on-chips) has rapidly developed into a promising in vitro tool that reproduces human physiology by reproducing key biological processes and disease states. However, their value to drug development is only now becoming clear. By combining microsystem engineering and cell biology, MPS has established a cell culture model that can display three-dimensional structure, multi-cell interaction, tissue-tissue interface, fluid flow, and organ-level mechanical characteristics. For example, they can integrate the respiratory mechanics of the human lung [1] , immune cells transported by capillary perfusion, [2] , microbiota [3] 9 integrate with other organs [4, 5] .They have also become new tools to identify treatments for potential diseases, including COVID-19 [6] . These features enable the human multi-cell culture system to replicate complex tissue and organ functions better than traditional cell culture. MPS has received widespread attention as an in vitro tool that can better predict drug efficacy and potential adverse reactions before patients adopt drug treatment.
On September 17, 2021, the Swiss Roche company Adrian Roth and other researchers published the title in Science _strong8span span 66 For drug development , proposes that organ chips can be used to evaluate the effectiveness of drugs and promote personalized medicine.
MPS technology may provide a way to better understand and resolve the main causes of early failures in clinical trial projects.Lack of efficacy or severe side effects cannot be predicted in animals or simpler cell systems . The key advantage provided by MPS is the establishment of more human organ models related to physiological functions (Figure 1) These models can produce data on the effect of drugs and are better than animal models or traditional cell system data. Transform into human beings. Due to the physiological differences of different species, research data from animals cannot always be transformed into human data, and traditional human in vitro models lack three-dimensional, tissue-tissue interface and mechanical factors, which lead to dedifferentiation of cultured cells and thus Weakened the correlation between in vitro model data and human physiology. Although most of the current MPS is in the exploratory stage, the pharmaceutical and biotechnology industries have a high degree of acceptance of the technology, and its long-term goal is to eventually replace the animal model as much as possible. At the same time, academic circles and many biotechnology companies are developing increasingly sophisticated MPS models to meet the needs and quality standards required for drug development, including scalability and robustness.
Figure 1. The microfluidic system can connect multiple types of human tissues and mimic various aspects of human physiology, thereby improving the evaluation of drug response.
- What can MPS do?
So far, MPS is mainly used for pre-clinical safety (pharmacotoxicology and metabolism) ,And some test systems have met the requirements of internal decision-making in the pharmaceutical industry [7] . MPS is also used to resolve the differences between different preclinical animal models and between animals and humans. For example, liver chip organs of rats, dogs, and humans have been shown to reproduce the toxicity of specific species observed by pharmaceutical companies in the past, while also providing new insights into the underlying toxicity mechanism. [8] . Regarding the drug effects observed in preclinical animal species, it is not clear whether it can be transformed and applied to humans. Toxic factors may prompt developers to select sub-optimal drug candidates for further development. Therefore, the human drug toxicity assessment system can greatly help promote the most promising drug candidates into the clinic.
MPS is also used to simulate and test other toxicity conditions, including situations where there is no suitable animal model or the animal model cannot predict human response. For example, the human blood vessel chip reproduces the thrombotic toxicity that caused a therapeutic monoclonal antibody to fail in human clinical trials, and this toxicity has never been found in animal preclinical trials. [9] . A vascularized human bone marrow chip that supports the differentiation and maturation of multiple blood cell lines also reproduces the toxicity of bone marrow red blood cells after exposure to chemotherapeutics and ionizing radiation, as well as the bone marrow recovery after drug-induced bone marrow function suppression [10] . In addition, the MPS model composed of bone tissue was exposed to cobalt and chromium solubles related to hip implants, and the concentration was set at the clinical reference value. This clarified the direct cytotoxic effect and successfully verified the chromium and cancellous bone The integration of chromium and interosseous matrix chromium combination previously found in patients [11] .
- What is the new direction of MPS?
Although solving preclinical safety testing is the early focus of MPS research, the new research focus is now gradually shifting to efficacy testing. For example, a human lung airway chip with interface endothelium was used to test the response of anti-inflammatory compounds, and was recently used to evaluate the impact of existing and potential antiviral therapies on SARS-CoV-2 infection and host inflammatory response. [6] . The bone marrow chip is also used to simulate a rare genetic disease (Shwachman-Diamond syndrome) , using cells isolated from the patient, the key hematopoietic defect of this disease can be reproduced [10] . By optimizing the treatment of patients’ cells, has demonstrated the potential value of using MPS to develop personalized therapies and may assist in the design of clinical trials. This is particularly useful for patients with very rare diseases, which are difficult to carry out systematically with traditional methods. Preclinical drug testing.
The complex physiological processes of the human body usually involve more than one organ. Therefore, MPS researchers have begun to establish multi-organ interaction models to better study disease biology or drug effects. For example, multi-organ MPS is used to study neuroactive drugs, such as methamphetamine,Explore how it crosses the blood-brain barrier and affects brain neurons [12] . The first pharmacokinetics composed of connected human liver, kidney and intestinal organ chips model combined with calculation model to quantitatively predict the pharmacokinetic and pharmacodynamic characteristics of drugs 【 4] . The integrated MPS model that connects the intestine, liver, brain, and kidney uses induced pluripotent stem cells from a single donor to differentiate [13] , which may achieve donor-specific individualization in the future Organ research and drug testing. If combined with patient-derived stem cells or organoid methods, [14] , this model can provide tailor-made precision medical tools at the individual patient level.
Different from commonly used immunodeficiency or semi-humanized animal models, human MPS is suitable for tumor transplantation. It has special advantages for human-specific viruses. However, due to the lack of sufficient verification and experience for this emerging technology, so far, no MPS detection method has been used for drug approval [7] . Therefore, how to leap from a research-level MPS detection method to a proven and reliable drug development tool and produce results that meet the regulatory review requirements is an important challenge for current research . Since drug development is increasingly focusing on the development of highly engineered therapeutic molecules, these molecules will not cross-react with the target in any animal model, so there is often no other choice other than the use of human in vitro models. Due to the shortage of supplies, it has become more difficult to use non-human primates for drug and vaccine testing (for example, COVID-19 vaccine testing) , in addition to the ethical issues that follow. Therefore, it is now more necessary than ever to use human cells to replace in vitro tests in preclinical models.
- To meet the rapid development of the pandemic virus, for example, it can also promote the rapid development of new pandemic RNA therapies. (mRNA) vaccine or chimeric antigen receptor (CAR) T cell cancer immunotherapy. Although these therapies have been approved by traditional methods, this innovative drug model often requires follow-up studies after approval to expand the safety and efficacy database. The MPS model has great potential value. If the data obtained on this chip model is jointly analyzed with real-world data, a more accurate model can be established for prediction. By incorporating the recommendations of relevant regulatory authorities into the design of (on-chip trial) ,The success of this method will be further strengthened. For example, the U.S. Food and Drug Administration (US FDA) 's drug development tool qualification certification program can be used, just like the biomarker is used to verify the biomarker , and the development of MPS can be used as a new drug innovation technology method (ISTAND) is part of the pilot program (the program aims to promote the development of new methods in drug development) . combines advanced data analysis, computer modeling and simulation, and repeatedly explores a specific scenario (such as a specific disease and treatment) each time. MPS can finally provide regulatory agencies with a usable data set, and its predictive ability may be better than Previously, the data set generated with animal models was higher. Once the proof of concept of a case is successful, other solutions will follow.
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