體外過程和動(dòng)物試驗(yàn)用于開發(fā)新的藥物和新的治療方法。然而，動(dòng)物試驗(yàn)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(jī)大小的系統(tǒng)中，器官通過人工循環(huán)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(dòng)物實(shí)驗(yàn)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(zhǔn)用于治療和用于患者之前，仍然需要進(jìn)行動(dòng)物試驗(yàn)。這些測(cè)試旨在預(yù)測(cè)藥物的活性和毒性及其對(duì)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(fā)新的治療方法。醫(yī)療行業(yè)通過提供確保人類健康的經(jīng)濟(jì)有效的選擇，從動(dòng)物實(shí)驗(yàn)中受益。然而，盡管動(dòng)物實(shí)驗(yàn)為醫(yī)療行業(yè)提供了優(yōu)勢(shì)，但它不僅符合大多數(shù)人的最佳利益，而且也符合研究公司的最佳利益，即取代動(dòng)物試驗(yàn)或盡可能減少這些試驗(yàn)。但這怎么可能成為可行的選擇？

智能手機(jī)大小的人體組織到目前進(jìn)展如何？

作為動(dòng)物實(shí)驗(yàn)的替代方案，科學(xué)家依靠培養(yǎng)器皿培養(yǎng)細(xì)胞。細(xì)胞嵌入二維環(huán)境中，甚至遠(yuǎn)不能與器官的自然生理環(huán)境相比。這使得幾乎不可能準(zhǔn)確地預(yù)測(cè)藥物的效果。醫(yī)學(xué)進(jìn)展 - 其中包括干細(xì)胞研究 - 使得器官芯片系統(tǒng)成為可能。這些三維細(xì)胞和組織模型能夠連續(xù)實(shí)時(shí)體外監(jiān)測(cè)細(xì)胞群。器官芯片模型的關(guān)鍵優(yōu)勢(shì)在于它們以微觀尺度復(fù)制特定器官和組織中人體細(xì)胞中發(fā)現(xiàn)的自然環(huán)境。到目前為止，“2-Organ-Chip”模型（2-OC）和“4-Organ-Chip”模型（4-OC）已經(jīng)在醫(yī)療市場(chǎng)上取得了成功。前者根據(jù)兩個(gè)器官和疾病的原因監(jiān)測(cè)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(gè)或四個(gè)器官的細(xì)胞，并且不能排除對(duì)其他類型細(xì)胞的不利影響。

來自3D打印機(jī)的器官芯片

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

當(dāng)研究人員想要監(jiān)測(cè)藥物和毒素對(duì)器官的影響時(shí)，他們會(huì)將相應(yīng)的物質(zhì)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(jiān)測(cè)細(xì)胞功能。劍橋大學(xué)的研究人員現(xiàn)已開發(fā)出一種將電極附著在細(xì)胞上的器官芯片模型。它們不是由金屬制成，而是由導(dǎo)電聚合物海綿制成。這允許細(xì)胞通過電信號(hào)彼此通信，確保連續(xù)實(shí)時(shí)監(jiān)測(cè)微型器官模型。與其他器官芯片系統(tǒng)不同，劍橋模型有助于長期實(shí)驗(yàn)。

微型器官的利弊

三維器官芯片模型是醫(yī)學(xué)技術(shù)的重大進(jìn)步，代表了二維細(xì)胞培養(yǎng)后的下一代。3D技術(shù)和基于細(xì)胞的分析使得不僅可以更仔細(xì)地檢查人體器官和組織的生理學(xué) - 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(yīng)該被接受或避免。另一個(gè)優(yōu)點(diǎn)是，根據(jù)所涉及的器官，您可以將兩個(gè)或更多器官組織結(jié)合起來，對(duì)靶器官進(jìn)行有效的研究。同時(shí)，缺點(diǎn)是4-OC模型還不能正常工作，因?yàn)槟M血流非常困難。盡管由于細(xì)胞功能的實(shí)時(shí)監(jiān)測(cè)，器官芯片加速了新藥的開發(fā)，但目前這還不是技術(shù)上成熟的過程。海德堡大學(xué)醫(yī)學(xué)院生理學(xué)和病理生理學(xué)研究所所長Thomas Korff教授警告說，“這里的危險(xiǎn)就是概括事物。當(dāng)我在一個(gè)結(jié)合肺部的器官芯片系統(tǒng)中測(cè)試一種物質(zhì)時(shí)，肝臟，腎臟和腸道細(xì)胞，我沒有發(fā)現(xiàn)任何不良反應(yīng)，我只能得出結(jié)論，它在這個(gè)特定的系統(tǒng)和這些細(xì)胞中沒有任何有害影響。錯(cuò)誤的結(jié)論是推斷不會(huì)對(duì)其他細(xì)胞產(chǎn)生副作用細(xì)胞類型。“ 話雖如此，要記住的一個(gè)重要方面是器官芯片解決了動(dòng)物實(shí)驗(yàn)的倫理問題。雖然它們?nèi)匀粺o法完全取代動(dòng)物測(cè)試，但它們至少可以顯著降低它。更重要的是，這些系統(tǒng)大大推進(jìn)了個(gè)性化醫(yī)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(shí)際上是人體的替代品和復(fù)制品。該芯片結(jié)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(shè)是，未來'芯片患者'可以為大多數(shù)疾病模式生成有意義的數(shù)據(jù)，并隨后取代相應(yīng)的動(dòng)物實(shí)驗(yàn)，”柏林工業(yè)大學(xué)“多器官芯片”項(xiàng)目負(fù)責(zé)人Uwe Marx說。和TissUse GmbH的創(chuàng)始人。

另一個(gè)挑戰(zhàn)是肝臟和腦細(xì)胞不能被培養(yǎng)。肝細(xì)胞在短短幾天內(nèi)死亡，使得長期實(shí)驗(yàn)幾乎不可能。腦細(xì)胞每天繁殖需要一天才能通過稱為突觸的新結(jié)點(diǎn)傳遞信息。這就是為什么不可能準(zhǔn)確描述中央功能，如全身血壓和心臟和基底神經(jīng)節(jié)功能，從而使持續(xù)的動(dòng)物測(cè)試成為必要。話雖如此，研究的目的是避免將動(dòng)物用于未來的醫(yī)學(xué)實(shí)驗(yàn)，并將人類芯片系統(tǒng)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.