KR20210007624A - Modularized multi-organ-on-a-chip system with oxygen controlled parallelized fluid circuit - Google Patents
Modularized multi-organ-on-a-chip system with oxygen controlled parallelized fluid circuit Download PDFInfo
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Abstract
Description
본 발명은 산소 조절이 가능한 병렬 유체회로를 갖는 모듈화된 다중 장기 칩 시스템에 관한 것으로, 더욱 상세하게는 산소 조절이 가능하고 병렬 유체회로를 가지는 시스템에 관한 것이다.The present invention relates to a modularized multi-organ chip system having a parallel fluid circuit capable of controlling oxygen, and more particularly, to a system capable of controlling oxygen and having a parallel fluid circuit.
도 1은 종래의 장기 칩을 설명하기 위한 도면이고, 도 2는 종래의 다중 장기 칩을 설명하기 위한 도면이다.1 is a diagram illustrating a conventional organ chip, and FIG. 2 is a diagram illustrating a conventional multi-organ chip.
도 1에 도시(출처 : www.elveflow.com)된 바와 같은, 미세유체 시스템 내부에 세포를 배양하여 특정 장기를 모사한는 장기 칩(Organ On a chip, OOC) 기술은 지속해서 발전해 오고 있다.As shown in FIG. 1 (source: www.elveflow.com), an organ on a chip (OOC) technology that simulates a specific organ by culturing cells inside a microfluidic system has been continuously developed.
최근에는 도 2에 도시(출처 : www.elveflow.com)된 바와 같이, 단일 장기를 모사하는 것에서 다중의 장기를 하나의 시스템에 구현하는 다중 장기 칩(Multi Organ On a chip) 기술과 관련된 연구가 활발히 진행되고 있다.Recently, as shown in Fig. 2 (source: www.elveflow.com), research related to a multi-organ chip (Multi Organ On a chip) technology that implements multiple organs in one system from simulating a single organ has been conducted. It is actively progressing.
하지만, 기존의 다중 장기 칩에서는 장기들이 직렬로 연결되어 있고, 장기별로 요구되는 배양액의 양과 산소 농도가 다름에도 불구하고, 일괄적으로 동일한 미세 환경이 구현되는 문제가 있다.However, in a conventional multi-organ chip, the organs are connected in series, and although the amount of the culture medium and the oxygen concentration required for each organ are different, there is a problem that the same microenvironment is implemented at once.
본 발명이 이루고자 하는 기술적 과제는, 인체의 혈액 순환 구조와 유사한 병렬화된 유체 회로 시스템으로 이루어지고, 각 장기별로 요구되는 알맞은 배양액 양과 산소 농도의 제어가 가능한 산소 조절이 가능한 병렬 유체회로를 갖는 모듈화된 다중 장기 칩 시스템을 제공하는 데 있다.The technical problem to be achieved by the present invention is made of a parallel fluid circuit system similar to the blood circulation structure of the human body, and a modularized fluid circuit having a parallel fluid circuit capable of controlling oxygen capable of controlling an appropriate amount of culture medium and oxygen concentration required for each organ. It is to provide a multi-organ chip system.
상기의 기술적 과제를 달성하기 위한 본 발명에 따른 산소 조절이 가능한 병렬 유체회로를 갖는 모듈화된 다중 장기 칩 시스템은, 인체의 혈액 순환 구조와 유사한 병렬화된 유체 회로 시스템을 가지고, 각 장기별로 요구되는 알맞은 배양액 양과 산소 농도의 제어가 가능하다.The modularized multi-organ chip system having a parallel fluid circuit capable of controlling oxygen according to the present invention for achieving the above technical problem has a paralleled fluid circuit system similar to the blood circulation structure of the human body, and is required for each organ. It is possible to control the amount of culture medium and the oxygen concentration.
본 발명에 따른 산소 조절이 가능한 병렬 유체회로를 갖는 모듈화된 다중 장기 칩 시스템에 의하면, 실제 인체에서 일어나는 장기들의 상호작용을 모사할 수 있고, 산소와 관련된 생리적/병리적 현상을 재현 및 기전을 확인할 수 있다.According to the modularized multi-organ chip system having parallel fluid circuits capable of controlling oxygen according to the present invention, it is possible to simulate the interaction of organs occurring in the actual human body, reproduce physiological/pathological phenomena related to oxygen, and confirm the mechanism. I can.
도 1은 종래의 장기 칩을 설명하기 위한 도면이다.
도 2는 종래의 다중 장기 칩을 설명하기 위한 도면이다.
도 3은 본 발명의 바람직한 실시예에 따른 산소 조절이 가능한 병렬 유체회로를 갖는 모듈화된 다중 장기 칩 시스템을 설명하기 위한 도면이다.1 is a diagram for explaining a conventional organ chip.
2 is a diagram illustrating a conventional multi-organ chip.
3 is a view for explaining a modularized multi-organ chip system having a parallel fluid circuit capable of controlling oxygen according to a preferred embodiment of the present invention.
이하에서 첨부한 도면을 참조하여 본 발명에 따른 산소 조절이 가능한 병렬 유체회로를 갖는 모듈화된 다중 장기 칩 시스템의 바람직한 실시예에 대해 상세하게 설명한다.Hereinafter, preferred embodiments of a modularized multi-organ chip system having a parallel fluid circuit capable of controlling oxygen according to the present invention will be described in detail with reference to the accompanying drawings.
먼저, 도 3을 참조하여 본 발명의 바람직한 실시예에 따른 산소 조절이 가능한 병렬 유체회로를 갖는 모듈화된 다중 장기 칩 시스템에 대하여 설명한다.First, a modularized multi-organ chip system having a parallel fluid circuit capable of controlling oxygen according to a preferred embodiment of the present invention will be described with reference to FIG. 3.
도 3은 본 발명의 바람직한 실시예에 따른 산소 조절이 가능한 병렬 유체회로를 갖는 모듈화된 다중 장기 칩 시스템을 설명하기 위한 도면이다.3 is a diagram for explaining a modularized multi-organ chip system having a parallel fluid circuit capable of controlling oxygen according to a preferred embodiment of the present invention.
도 3을 참조하면, 본 발명의 바람직한 실시예에 따른 산소 조절이 가능한 병렬 유체회로를 갖는 모듈화된 다중 장기 칩 시스템(이하 '다중 장기 칩 시스템'이라 한다)은, 종래의 다중 장기 칩 시스템보다 실제 인체와 더 유사한 시스템을 가지고 있다.Referring to FIG. 3, a modularized multi-organ chip system (hereinafter referred to as'multi-organ chip system') having a parallel fluid circuit capable of oxygen control according to a preferred embodiment of the present invention is more practical than a conventional multi-organ chip system. It has a system more similar to the human body.
즉, 본 발명에 따른 다중 장기 칩 시스템은, 인체의 혈액 순환 구조와 유사한 병렬화된 유체 회로 시스템으로 이루어진다.That is, the multi-organ chip system according to the present invention consists of a paralleled fluid circuit system similar to the blood circulation structure of the human body.
그리고, 본 발명에 따른 다중 장기 칩 시스템은, 각 장기별로 요구되는 알맞은 배양액 양과 산소 농도의 제어가 가능한 시스템으로 이루어진다.In addition, the multi-organ chip system according to the present invention includes a system capable of controlling an appropriate amount of culture medium and oxygen concentration required for each organ.
병렬 혈액순환 시스템의 설계/구축/최적화Design/build/optimization of parallel blood circulation system
본 발명에 따른 다중 장기 칩 시스템은, 생체 적합성 소재를 활용하여 실제 체내환경과의 유사성을 향상시킬 수 있다. 또한, 본 발명에 따른 다중 장기 칩 시스템은, 개별 장기를 모듈화함으로써, 용이하게 개별 장기 모듈을 결합/탈착할 수 있다. 이에, 본 발명에 따른 다중 장기 칩 시스템은 사용자의 요구사항에 따라 필요한 장기들로 이루어질 수 있다. 즉, 모듈화된 개별 장기로 인해, 그때그때 필요에 따라 개별 장기들의 조합을 달리할 수 있다.The multi-organ chip system according to the present invention can improve the similarity with the actual body environment by using a biocompatible material. Further, in the multi-organ chip system according to the present invention, individual organ modules can be easily coupled/detached by modularizing individual organs. Accordingly, the multi-organ chip system according to the present invention can be made of necessary organs according to user requirements. In other words, due to the modularized individual organs, combinations of individual organs can be varied as needed.
그리고, 본 발명에 따른 다중 장기 칩 시스템은, 유체의 흐름 조절이 용이하도록 유체주입 시스템의 설치 위치(내부/외부)를 선정하며, 중력/공압/연동펌프/전자석 모터 등의 방법을 확인평가 후 선택할 수 있다. 본 발명에 따른 다중 장기 칩 시스템은, 실제 체내에서 개별 장기로 유입되는 혈액 비율을 기준으로, 제어하고자 하는 유량의 범위 및 정밀도를 확인할 수 있다.In addition, the multi-organ chip system according to the present invention selects the installation location (internal/external) of the fluid injection system to facilitate fluid flow control, and confirms and evaluates methods such as gravity/pneumatic/interlocking pump/electromagnet motor, etc. You can choose. The multi-organ chip system according to the present invention can confirm the range and precision of the flow rate to be controlled based on the ratio of blood flowing into the individual organs from the actual body.
그리고, 본 발명에 따른 다중 장기 칩 시스템은, 시스템 내 유체의 압력 및 유동감지를 제어할 수 있다. 구체적으로, 본 발명에 따른 다중 장기 칩 시스템은, 체내에서 형성되는 혈압의 범위를 확인하고, 해당 범위내 유체 압력 조절이 가능한 내부 유체압력 감지센서를 구비할 수 있다. 또한, 본 발명에 따른 다중 장기 칩 시스템은, 감지되는 압력을 기반으로 적정 압력범위 내에서 제어되고 고정 압력값을 지속적으로 인가할 수 있는 압력조절 피드백 제어 시스템을 구비할 수 있다.Further, the multi-organ chip system according to the present invention can control the pressure and flow detection of the fluid in the system. Specifically, the multi-organ chip system according to the present invention may include an internal fluid pressure sensor capable of checking a range of blood pressure formed in the body and adjusting the fluid pressure within the range. In addition, the multi-organ chip system according to the present invention may have a pressure control feedback control system that is controlled within an appropriate pressure range based on the sensed pressure and can continuously apply a fixed pressure value.
그리고, 본 발명에 따른 다중 장기 칩 시스템은, 세부 설계조건에 따른 병렬 혈액순환 시스템을 구비하며, 시스템 최적화를 진행할 수 있다. 우선적으로 유체의 흐름, 속도, 압력제어 시스템이 정상 작동하는지 기능 검증을 진행한다. 특히, 미체유체시스템의 특성상 유체의 흐름에서 발생할 수 있는 기포발생 문제에 대한 방지대책 및 기포제거 모듈에 대한 고려도 함께 진행할 수 있다(예: debubbler). 또한, 전체 순환 시스템에 설정된 압력의 정상적 유지를 테스트하여 시스템의 안정성을 확인할 수 있다.Further, the multi-organ chip system according to the present invention has a parallel blood circulation system according to detailed design conditions, and system optimization can be performed. First of all, it performs functional verification that the fluid flow, velocity, and pressure control system is operating normally. Particularly, due to the nature of the microfluidic system, a countermeasure against the bubble generation problem that may occur in the flow of the fluid and the bubble removal module can be considered together (eg, debubbler). In addition, the stability of the system can be confirmed by testing the normal maintenance of the set pressure in the entire circulation system.
개별 장기 모듈 확립 및 배양조건 최적화Establishing individual organ modules and optimizing culture conditions
본 발명에 따른 다중 장기 칩 시스템은, 간조직의 생리학적 구조를 모사한 적층구조의 3차원 공배양 시스템 구축을 위해, 간모듈 내에 thiolated collagen/polyethylene diacrylate로 제작한 inter penetrating hydrogel(IPN)을 이용한 관상형 이중층 복합 구조(bilayered composite tubular construct)의 3차원 배양환경을 조성할 수 있다. 또한, 본 발명에 따른 다중 장기 칩 시스템은, 혈관 모세 채널을 통해 공급되는 산소 및 각종 생리활성/독성 물질의 농도에 따른 세포반응의 실시간 모니터링을 실시할 수 있다.The multi-organ chip system according to the present invention uses an inter penetrating hydrogel (IPN) made of thiolated collagen/polyethylene diacrylate in a liver module in order to construct a three-dimensional co-culture system of a layered structure that simulates the physiological structure of liver tissue. It is possible to create a three-dimensional culture environment of a bilayered composite tubular construct. In addition, the multi-organ chip system according to the present invention can perform real-time monitoring of cellular responses according to the concentration of oxygen and various physiologically active/toxic substances supplied through blood vessel capillary channels.
그리고, 본 발명에 따른 다중 장기 칩 시스템은, 신장조직의 해부학적 구조를 모사한 공배양 시스템을 구축하기 위해, 신장 모듈 유로 내에 신사구체와 근위곡세뇨관 세포의 부착 및 배양에 적합한 기질을 결정할 수 있다.And, the multi-organ chip system according to the present invention, in order to build a co-culture system that simulates the anatomical structure of kidney tissue, it is possible to determine a substrate suitable for adhesion and cultivation of glomerular and proximal tubule cells in the kidney module flow path have.
그리고, 본 발명에 따른 다중 장기 칩 시스템은, 각각의 장기 모듈이 유량 및 압력의 변화에 따른 세포의 생물학적 및 기능적 특성 변화를 확인하여 공배양에 최적화된 유량 및 압력을 탐색할 수 있다.In addition, in the multi-organ chip system according to the present invention, each organ module can search for a flow rate and pressure optimized for co-culture by confirming changes in biological and functional characteristics of cells according to changes in flow rate and pressure.
개별 장기 모듈의 구축 및 기능 평가 분석Construction and functional evaluation analysis of individual organ modules
본 발명에 따른 다중 장기 칩 시스템은, 개별 장기 모듈이 면역염색을 통하여 조직의 생존정도를 평가하고, 조직학적 분석을 수행할 수 있다. 간모듈의 세포내에 축적된 알부민 및 밀착연접의 구조적 분석은 면역조직학적 분석을 통해 수행할 수 있다. 신장 모듈 내의 배양 신사구체에서는 내피세포와 족세포(podocyte)를 각각의 특유의 마커인 CD31 및 synaptopodin, nephrin, podocin 항체를 이용한 면역염색법을 통하여 검증할 수 있다. 배양 근위곡세뇨관 조직은 면역염색을 이용하여 섬모의 발현(acetylated tubulin 항체), 세포접합 (K-cadherin 항체), 능동수송채널(Na/K ATPase, Aquaporin 1 항체)의 발현을 확인할 수 있다. 이외에도 주사전자현미경을 이용하여 세포의 접합정도 및 섬모의 길이 등의 해부학적 평가를 실시할 수 있다.In the multi-organ chip system according to the present invention, individual organ modules can evaluate the survival degree of tissues through immunostaining and perform histological analysis. Structural analysis of albumin and tight junctions accumulated in the cells of the liver module can be performed through immunohistochemical analysis. In the cultured glomerulus in the kidney module, endothelial cells and podocytes can be verified through immunostaining using antibodies of CD31, synaptopodin, nephrin, and podocin, which are specific markers. In the cultured proximal cannula tubular tissue, expression of cilia (acetylated tubulin antibody), cell conjugation (K-cadherin antibody), and active transport channels (Na/K ATPase, Aquaporin 1 antibody) can be confirmed using immunostaining. In addition, anatomical evaluation such as the degree of cell adhesion and the length of cilia can be performed using a scanning electron microscope.
그리고, 본 발명에 따른 다중 장기 칩 시스템은, 개별장기 모듈의 기능적 평가를 위하여, 간모듈에서는 단백질, DNA, RNA 분석을 통하여 여러 조건하에 세포로부터 분비 및 합성되는 간 특이적 기능 관련 바이오마커들(우레아 및 담즙산, 시토크롬 P450IA1)을 비교 분석할 수 있다. 밀착연접의 기능적 분석은 dye-coupling 방법을 이용하여 측정할 수 있다. 신장모듈에서는 형광물질이 부착된 이눌린, 소혈청알부민, IgG를 이용하여 신사구체의 여과 및 근위세뇨관의 재흡수 기능을 평가할 수 있다.In addition, the multi-organ chip system according to the present invention includes biomarkers related to liver-specific functions secreted and synthesized from cells under various conditions through protein, DNA, and RNA analysis in the liver module for functional evaluation of individual organ modules ( Urea and bile acids, cytochrome P450IA1) can be analyzed for comparison. Functional analysis of tight junctions can be measured using the dye-coupling method. In the renal module, inulin, bovine serum albumin, and IgG to which fluorescent substances are attached can be used to evaluate the filtration of glomerular and reabsorption functions of the proximal tubule.
이에 따라, 본 발명에 따른 다중 장기 칩 시스템을 통해, 실제 인체에서 일어나는 장기들의 상호작용을 모사할 수 있고, 산소와 관련된 생리적/병리적 현상을 재현 및 기전을 확인할 수 있다.Accordingly, through the multi-organ chip system according to the present invention, it is possible to simulate the interaction of the organs actually occurring in the human body, and to reproduce and confirm the mechanism of physiological/pathological phenomena related to oxygen.
나아가, 본 발명에 따른 다중 장기 칩 시스템을 이용하여 약물 테스트를 수행하는 시스템을 개발할 수 있다.Furthermore, it is possible to develop a system for performing a drug test using the multi-organ chip system according to the present invention.
본 발명은 또한 컴퓨터로 읽을 수 있는 기록 매체에 컴퓨터가 읽을 수 있는 코드로서 구현하는 것이 가능하다. 컴퓨터로 읽을 수 있는 기록 매체는 컴퓨터에 의하여 읽혀질 수 있는 데이터가 저장되는 모든 종류의 기록 장치를 포함한다. 컴퓨터가 읽을 수 있는 기록 매체의 예로는 롬(ROM), 램(RAM), 씨디-롬(CD-ROM), 자기 테이프, 플로피 디스크, 광 데이터 저장장치 등이 있다.The present invention can also be implemented as computer-readable codes on a computer-readable recording medium. The computer-readable recording medium includes all types of recording devices storing data that can be read by a computer. Examples of computer-readable recording media include ROM, RAM, CD-ROM, magnetic tapes, floppy disks, and optical data storage devices.
이상에서 본 발명의 바람직한 실시예에 대하여 상세하게 설명하였지만 본 발명은 상술한 특정의 바람직한 실시예에 한정되지 아니하며, 다음의 청구범위에서 청구하는 본 발명의 요지를 벗어남이 없이 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자라면 누구든지 다양한 변형 실시가 가능한 것은 물론이고, 그와 같은 변경은 청구범위 기재의 범위 내에 있게 된다.Although the preferred embodiments of the present invention have been described in detail above, the present invention is not limited to the specific preferred embodiments described above, and the technical field to which the present invention belongs without departing from the gist of the present invention claimed in the following claims. Anyone with ordinary knowledge can implement various modifications, as well as such changes are within the scope of the claims.
Claims (1)
각 장기별로 요구되는 알맞은 배양액 양과 산소 농도의 제어가 가능한,
산소 조절이 가능한 병렬 유체회로를 갖는 모듈화된 다중 장기 칩 시스템.
It has a parallelized fluid circuit system similar to the structure of human blood circulation,
It is possible to control the appropriate amount of culture medium and oxygen concentration required for each organ,
Modular multi-organ chip system with parallel fluid circuits capable of controlling oxygen.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20230109008A (en) | 2022-01-12 | 2023-07-19 | 경희대학교 산학협력단 | Microfluidic chip possible of mimicking hypoxia |
| WO2024113488A1 (en) * | 2022-11-30 | 2024-06-06 | 苏州大学 | Mini mammalian model for drug effect, toxicity and pharmacokinetic detection and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20230109008A (en) | 2022-01-12 | 2023-07-19 | 경희대학교 산학협력단 | Microfluidic chip possible of mimicking hypoxia |
| WO2024113488A1 (en) * | 2022-11-30 | 2024-06-06 | 苏州大学 | Mini mammalian model for drug effect, toxicity and pharmacokinetic detection and use thereof |
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