生理学与病理生理学研究

隔离灌注化疗研究

  ↵

临床前药物测试

离体肿瘤切除手术研究

将器官移出体外、切除肿瘤后重新植入，为复杂解剖位置的肿瘤提供根治性切除可能。

非原位肿瘤切除技术最早于20世纪70年代应用于无法手术的肝肿瘤[2,9–14]。当肿瘤邻近主要血管或胆管、需复杂重建时，体外手术提供了无限制的视野和操作空间。研究显示，复杂肝脏恶性肿瘤的体外切除，R0切除率可达93.4%[15]。

机器灌注技术的引入，显著延长了体外手术的安全窗口，同时减轻了缺血再灌注损伤。该技术已成功应用于晚期中央型肺癌的肺叶保留手术、心脏肿瘤切除等领域。

体外器官支持系统

将同种或异种肝脏与患者循环系统连接，为急性肝功能衰竭患者争取自身恢复或等待移植的时间。

这一理念源于生物人工肝的研究。将完整肝脏（同种异体或异种）与患者循环连接，可作为急性肝功能衰竭的桥梁疗法，为患者自身肝脏修复或等待合适供体争取时间。

基因治疗与生物工程

在器官离体灌注期间进行基因修饰，可克服全身基因治疗的靶向与免疫挑战。

在机器灌注过程中进行基因治疗，可实现对目标器官的精准递送，避免全身暴露与免疫激活。病毒载体（慢病毒、腺病毒、腺相关病毒）与非病毒载体（细胞外囊泡、纳米颗粒等）均可通过灌注系统高效递送。CRISPR-Cas9等基因编辑工具已可在离体器官中实现靶向DNA修饰[16]。

当前，全身性腺相关病毒（AAV）介导的基因治疗虽在代谢性遗传病中展现前景，但免疫反应与肝脏内不均一表达仍是挑战。离体灌注可规避这些问题：治疗药物直接输送至隔离器官，最大限度减少全身暴露。未来，在自体器官移植前应用基因治疗纠正遗传缺陷，或可减少对供体器官的依赖。

细胞治疗与再生医学研究

在灌注期间输注健康细胞或干细胞，修复受损组织或调节免疫反应。

Sampaziotis等人使用胆道类器官，在常温机器灌注期间修复了DCD肝移植中受损的胆管[17]。间充质干细胞（MSCs）因其抗炎与诱导耐受特性，可在灌注期间输注以减轻缺血再灌注损伤或预防排斥反应。CAR-T细胞也可被改造以靶向特定免疫途径。

翟等人展示了在多器官灌注期间细胞治疗的一项进展：成功将同一供体的胰岛细胞移植给接受肝移植的糖尿病患者，改善了胰岛获取的流程与潜在的免疫学结果[18]。

外科培训与教育

机器灌注恢复器官血液循环，为外科医生提供接近生理状态的手术环境。

相比标本、离体模拟器或虚拟现实，机器灌注模型能模拟真实术中事件如出血或胆漏等。

引用文献

1. Y. Tang, J. Li, T. Zhang, et al., “The Establishment of Diseased Human Whole Organ Model by Normothermic Machine Perfusion Technique: Principle of Concept,” Artificial Organs 48, no. 9 (2024): 997–1007.

2. J. Iske, A. Schroeter, S. Knoedler, et al., “Pushing the Boundaries of Innovation: The Potential of Ex Vivo Organ Perfusion From an Interdis- ciplinary Point of View,” Frontiers in Cardiovascular Medicine 10 (2023): 1272945.

3. R. Todd, L. van Leeuwen, M. Holzner, et al., “Normothermic Ma- chine Perfusion of Explanted Livers: Exploratory Study of an Alterna- tive Translational Model for End-­ Stage Liver Disease,” Artificial Organs (2024).

4. J. P. Villeneuve, P. M. Huet, L. Gariepy, et al., “Isolated Perfused Cir- rhotic Human Liver Obtained From Liver Transplant Patients: A Feasi- bility Study,” Hepatology 12 (1990): 257.

5. J. Hefler, B. A. Marfil-­ Garza, N. Dadheech, and A. M. J. Shapiro, “Machine Perfusion of the Liver: Applications Beyond Transplanta- tion,” Transplantation 104, no. 9 (2020): 1804–1812.

6. R. Czymek, D. Dinter, S. Löffler, et al., “Electrochemical Treatment: An Investigation of Dose-­ Response Relationships Using an Isolated Liver Perfusion Model,” Saudi Journal of Gastroenterology 17 (2011): 335–342.

7. B. G. Bruinsma, G. V. Sridharan, P. D. Weeder, et al., “Metabolic Pro- filing During Ex Vivo Machine Perfusion of the Human Liver,” Scien- tific Reports 6 (2016): 22415.

8. L. J. Stevens, J. Dubbeld, J. B. Doppenberg, et al., “Novel Explanted Human Liver Model to Assess Hepatic Extraction, Biliary Excretion and Transporter Function,” Clinical Pharmacology and Therapeutics 114, no. 1 (2023): 137–147.

9. J. Iske, C. A. Hinze, J. Salman, A. Haverich, S. G. Tullius, and F. Ius, “The Potential of Ex Vivo Lung Perfusion on Improving Organ Quality and Ameliorating Ischemia Reperfusion Injury,” American Journal of Transplantation 21, no. 12 (2021): 3831–3839, https:// doi. org/ 10. 1111/ ajt. 16784 .

10. R. Zulpaite, P. Miknevicius, B. Leber, K. Strupas, P. Stiegler, and P. Schemmer, “Ex-­ Vivo Kidney Machine Perfusion: Therapeutic Poten- tial,” Frontiers in Medicine 8 (2021): 808719, https:// doi. org/ 10. 3389/ fmed. 2021. 808719.

11. M. MacConmara, C. A. Feizpour, A. Shubin, and P. A. Vagefi, “The Role of Machine Perfusion in Liver Xenotransplantation,” Current Opinion in Organ Transplantation 25 (2020): 477–482, https:// doi. org/ 10. 1097/ MOT. 00000 00000 000799.

12. E. Forni and F. Meriggi, “Bench Surgery and Liver Autotransplanta- tion. Personal Experience and Technical Considerations,” Il Giornale di Chirurgia 16 (1995): 407–413.

13. T. Kato, R. Hwang, P. Liou, et al., “Ex Vivo Resection and Autotrans- plantation for Conventionally Unresectable Tumors—An 11year Single Center Experience,” Annals of Surgery 272 (2020): 766–772.

14. M. Zawistowski, J. Nowaczyk, M. Jakubczyk, and P. Domagała, “Outcomes of Ex Vivo Liver Resection and Autotransplantation: A Systematic Review and Meta-­ Analysis,” Surgery 168 (2020): 631–642, https:// doi. org/ 10. 1016/j. surg. 2020. 05. 036.

15. E. Gringeri, P. Auricchio, L. Perin, et al., “A Translational Approach to Standardization of Machine Perfusion Adoption in Ex Vivo Liver Re- section,” Annals of Surgical Oncology 27, no. 6 (2020): 1919, https:// doi. org/ 10. 1245/ s1043 4- 019- 08163 - 4.

16. J. A. Doudna and E. Charpentier, “The New Frontier of Genome En- gineering With CRISPR-­ Cas9,” Science 346, no. 6213 (2014): 1258096.

17. F. Sampaziotis, D. Muraro, O. C. Tysoe, et al., “Cholangiocyte Or- ganoids Can Repair Bile Ducts After Transplantation in the Human Liver,” Science 371, no. 6531 (2021): 839–846.

18. Q. Zhao, J. Li, Z. Lin, et al., “The First Case of Intra-­ Portal Islet Im- plantation During Liver Machine Perfusion Allowing Simultaneous Islet-­ Liver Transplantation in A Human: A New and Safe Treatment for End-­ Stage Liver Disease Combined With Diabetes Mellitus,” Annals of Surgery 281, no. 2 (2024): 177–184.