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器官芯片-未來的迷你器官?

【?2019-2-14 發布?】 美迪醫訊

到目前為止,體外方法和動物實驗已被用于確定疾病的原因,研究治療方法和預測藥物的作用。現在,器官芯片模型提供了更準確和符合道德標準的替代方案。美迪醫訊將帶您了解有關模型,它們的優勢和未來發展的更多信息。
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     體外過程和動物試驗用于開發新的藥物和新的治療方法。然而,動物試驗引起了重要的倫理問題。器官芯片模型有望成為一種可行的替代方案。在智能手機大小的系統中,器官通過人工循環連接。

器官芯片可用于研究藥物的影響,以及疾病和治療方法的原因。它們不僅具有成本效益,而且在動物實驗和體外方法方面也是道德上合理的替代品。

在治療和藥物批準用于治療和用于患者之前,仍然需要進行動物試驗。這些測試旨在預測藥物的活性和毒性及其對人體器官的影響。它們還使研究人員能夠確定疾病的原因并開發新的治療方法。醫療行業通過提供確保人類健康的經濟有效的選擇,從動物實驗中受益。然而,盡管動物實驗為醫療行業提供了優勢,但它不僅符合大多數人的最佳利益,而且也符合研究公司的最佳利益,即取代動物試驗或盡可能減少這些試驗。但這怎么可能成為可行的選擇?

智能手機大小的人體組織到目前進展如何?

作為動物實驗的替代方案,科學家依靠培養器皿培養細胞。細胞嵌入二維環境中,甚至遠不能與器官的自然生理環境相比。這使得幾乎不可能準確地預測藥物的效果。醫學進展 - 其中包括干細胞研究 - 使得器官芯片系統成為可能。這些三維細胞和組織模型能夠連續實時體外監測細胞群。器官芯片模型的關鍵優勢在于它們以微觀尺度復制特定器官和組織中人體細胞中發現的自然環境。到目前為止,“2-Organ-Chip”模型(2-OC)和“4-Organ-Chip”模型(4-OC)已經在醫療市場上取得了成功。前者根據兩個器官和疾病的原因監測藥物療效和有效性和疾病,而后者研究四種類器官。然而,兩種模型僅允許研究兩個或四個器官的細胞,并且不能排除對其他類型細胞的不利影響。

來自3D打印機的器官芯片

3D打印技術使得“器官芯片”模型或芯片的制造成為可能。科學家們還必須擁有他們可以研究的器官細胞。這些細胞來自組織,該組織是來自手術或捐贈的醫療廢物。然后將作為器官的最小功能單元的細胞分層施加到芯片上。細胞或類器官在該三維支架上生長并使用人工循環連接。循環由芯片的微通道組成,其由營養液灌注。泵模擬心臟的功能和節律,并通過芯片的通道傳輸營養液。后者的運作方式與人體血管相似。

當研究人員想要監測藥物和毒素對器官的影響時,他們會將相應的物質注入組織并研究其影響。為此,必須徹底解剖器官碎片,以便監測細胞功能。劍橋大學的研究人員現已開發出一種將電極附著在細胞上的器官芯片模型。它們不是由金屬制成,而是由導電聚合物海綿制成。這允許細胞通過電信號彼此通信,確保連續實時監測微型器官模型。與其他器官芯片系統不同,劍橋模型有助于長期實驗。


微型器官的利弊

三維器官芯片模型是醫學技術的重大進步,代表了二維細胞培養后的下一代。3D技術和基于細胞的分析使得不僅可以更仔細地檢查人體器官和組織的生理學 - 例如它們受到藥物和病原體的影響 - 而且還可以讓研究人員清楚地了解治療的類型。應該被接受或避免。另一個優點是,根據所涉及的器官,您可以將兩個或更多器官組織結合起來,對靶器官進行有效的研究。同時,缺點是4-OC模型還不能正常工作,因為模擬血流非常困難。盡管由于細胞功能的實時監測,器官芯片加速了新藥的開發,但目前這還不是技術上成熟的過程。海德堡大學醫學院生理學和病理生理學研究所所長Thomas Korff教授警告說,“這里的危險就是概括事物。當我在一個結合肺部的器官芯片系統中測試一種物質時,肝臟,腎臟和腸道細胞,我沒有發現任何不良反應,我只能得出結論,它在這個特定的系統和這些細胞中沒有任何有害影響。錯誤的結論是推斷不會對其他細胞產生副作用細胞類型。“ 話雖如此,要記住的一個重要方面是器官芯片解決了動物實驗的倫理問題。雖然它們仍然無法完全取代動物測試,但它們至少可以顯著降低它。更重要的是,這些系統大大推進了個性化醫療。

芯片患者的未來?

人體芯片或器官芯片是一種患者特異性芯片,實際上是人體的替代品和復制品。該芯片結合了所有人的器官,允許研究人員檢查藥物是否有幫助以及它如何影響特定患者。“我們的假設是,未來'芯片患者'可以為大多數疾病模式生成有意義的數據,并隨后取代相應的動物實驗,”柏林工業大學“多器官芯片”項目負責人Uwe Marx說。和TissUse GmbH的創始人。

另一個挑戰是肝臟和腦細胞不能被培養。肝細胞在短短幾天內死亡,使得長期實驗幾乎不可能。腦細胞每天繁殖需要一天才能通過稱為突觸的新結點傳遞信息。這就是為什么不可能準確描述中央功能,如全身血壓和心臟和基底神經節功能,從而使持續的動物測試成為必要。話雖如此,研究的目的是避免將動物用于未來的醫學實驗,并將人類芯片系統作為替代方案。


Organ-on-a-chip Organs in miniature format

In vitro processes and animal tests are used to develop new medications and novel therapeutic approaches. However, animal testing raises important ethical concerns. Organ-on-a-chip models promise to be a feasible alternative. In a system the size of a smartphone, organs are connected using artificial circulation.

The human organism in smartphone size and what has happened so far

As an alternative to animal experiments, scientist have relied on the Petri dish to grow or culture cells. The cells are embedded in a two-dimensional environment, which is not even remotely comparable to the natural physiological environment of organs. This makes it nearly impossible to accurately predict the effects of medication. Advances in medicine – among them stem cell research – have made organ-on-a-chip systems possible. These three-dimensional cell and tissue models enable continuous real-time in vitro monitoring of cell populations. The key advantage of organ-on-a-chip models is that they replicate the natural environment found in human cells in specific organs and tissues at microscale. So far, the "2-Organ-Chip" model (2-OC) and the "4-Organ-Chip" model (4-OC) have proven successful in the medical market. The former monitors drug efficacy and effectiveness and diseases based on two organs and the causes of diseases, while the latter studies four organoids. However, both models only allow studies of the cells of either two or four organs and are unable to rule out adverse effects on other types of cells.


Organs on chips from the 3D printer


3D printing technology makes the fabrication of the "organ-on-a-chip" models or chips possible. Scientists must also have the cells of the organs they aim to research at their disposal. These cells are obtained from tissue that was either medical waste from surgeries or a donation. The cells, which are the smallest functional unit of the organs, are then applied in layers onto the chip. The cells or organoids are grown on this three-dimensional scaffold and connected using artificial circulation. The circulation is made up of microchannels of the chip, which are perfused by a nutrient solution. A pump simulates the heart’s function and rhythm and transports the nutrient solution through the channels of the chip. The latter operate like human blood vessels. Cells can grow in three dimensions on the organ-on-a-chip the same way they do inside the human body.


When researchers want to monitor the effects of drugs and toxins on organs, they inject the respective substance into the tissue and study its impact. To do this, organ chips must be completely dissected, so that the cell function can be monitored. Researchers at the University of Cambridge have now developed an organ-on-a-chip model that attaches electrodes to cells. These are not made from metal but of conductive polymer sponge. This allows the cells to communicate with each other by electrical signals, ensuring continuous real-time monitoring of the miniature organ models. Unlike other organ-on-a-chip systems, the Cambridge model facilitates longer-term experiments.


Pros and cons of miniature organs


The three-dimensional organ-on-a-chip models are a substantial advancement in medical technology and represent the next generation following two-dimensional cell culture. 3D technology and cell-based assays make it possible to not only more closely examine the physiology of human organs and tissues -  as they are affected by pharmaceutical substances and pathogens for instance – but to also give researchers a clear indication of the types of therapies that should be either embraced or avoided. Another advantage is that, depending on the organs in question, you can combine two or more organ tissues to conduct effective research on the target organs. Meanwhile, the drawback is that the 4-OC models don’t function properly yet because it is very difficult to mimic blood flow. Even though organ chips speed up the development of new drugs thanks to real-time monitoring of cell function, this is not a technically mature process at this point. Professor Thomas Korff, Director of the Institute of Physiology and Pathophysiology at the Medical Faculty of the Heidelberg University cautions that "the danger here is to generalize things. When I test a substance in an organ-on-a-chip system that combines lung, liver, kidney and intestinal cells, and I do not detect any adverse effects, I can only conclude that it has no harmful effects in this particular system and these cells. A false conclusion would be to infer that there would be no side effects on other types of cells." Having said that, one important aspect to remember is that organ chips address the ethical issues of animal experimentation. And although they are still not able to completely replace animal testing, they can at least significantly reduce it. What’s more, these systems considerably advance personalized medicine.


Chip patient of the future?


The human-on-a-chip or body-on-a-chip is a challenge in organ chip development. This is a patient-specific chip that is virtually a stand-in and duplicate of the human body. The chip combines all of a person’s organs, allowing researchers to check whether a medication helps and how it affects the particular patient. "Our assumption is that future ’chip patients’ can generate meaningful data for the majority of disease patterns and subsequently replace the respective animal experiments," says Uwe Marx, Head of the  "Multi-Organ-Chip" program at the Technical University of Berlin and founder of TissUse GmbH.


Another challenge is that liver and brain cells cannot be cultivated. Liver cells die within a few short days, rendering long-term experiments nearly impossible. Brain cells, which reproduce every day take up to a day before they pass information via new junctions called synapses. That’s why it is impossible to accurately depict central functions such as systemic blood pressure and cardiac and basal ganglia function, thus making continued animal testing necessary. Having said that, research aims to spare animals from being used in medical experiments in the future and apply human-on-a-chip systems as an alternative.

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