Organ medicine: New concept of life sciences

Organs are fundamental anatomical entities within the human body, each performing distinct physiological functions and serving as sites for various pathological conditions. Current medical research and treatment focus primarily on the individual as a whole or on cellular and genetic levels. However, due to the absence of well-established in vitro organ culture techniques and models, research at the mesoscopic level of organs significantly lags behind microscopic and macroscopic investigations. This lag restricts the efficient translation of research outcomes and constrains the potential for regional research and precise treatment of diseased organs. Although murine models and cell lines contribute to the understanding of organ biology and associated diseases, they fail to replicate crucial aspects of human organ complexity and metabolic functions. Notably, failures in clinical trials have often been attributed to inaccurate modeling, particularly in animal models. Organoids, defined as 3D structures cultured in vitro from stem/progenitor cells or primary tissue, offer a possibility for exploration. However, organoids exhibit limitations in functionality and reproducibility and thus cannot fully replace actual organs. Therefore, establishing a platform for organ-level research and treatment becomes urgent to bridge the gap between foundational knowledge and clinical application. Our center has achieved significant milestones, pioneering a multiorgan bionic maintenance system and advancing multiple in vitro organ bionic maintenance techniques in China. This allows various organs (such as the liver, kidney, heart, lung, intestine, and brain) to sustain their normal physiological functions over extended durations post-isolation, providing a primary foundation for mesoscopic organ-level research. Based on these advancements, we propose the concept of “organ medicine,” a precise medical research and treatment paradigm conducted at the organ level and supported by an in vitro organ bionic maintenance technology platform. Organ medicine focuses primarily on studying physiological and metabolic functions at the organ level. The ex vivo perfusion platform has been applied to new fields of teaching, scientific research, and treatment. Concurrently, other international centers are rapidly advancing their organ medicine research, establishing a breakthrough trend across diverse areas. At our center, we have expanded the applications of machine perfusion beyond transplantation. Here, we systematically introduce our applications and research progress in organ medicine, including educational and training initiatives based on living organs, organ-focused research, organ transplantation, organ quarantine therapy (OQT), organ disease models, and extracorporeal liver support therapy.[1,2] Teaching and training on living organs: Organs can maintain normal vitality and extracorporeal physiological metabolism, making them invaluable teaching tools for various educational purposes, including anatomy and laparoscopic training. Acquiring laparoscopic surgical skills involves a learning curve, particularly in the initial phases of a surgeon’s training, underscoring the critical importance of training in skill mastery. Several models have been developed for laparoscopic training, including inanimate models such as cadavers, ex vivo simulators, and virtual reality (VR), each offering varying degrees of practicality. Our innovative multivisceral preservation system ensures a continuous supply of oxygen and nutrients to ex vivo organs. While animal models provide a more authentic experience, their widespread application is limited by costs, anesthetic requirements, and ethical approval. To address these challenges, we introduced a novel ex vivo simulator named Smagister for training purposes [Supplementary Figure 1, https://links.lww.com/CM9/C360]. The Smagister includes a normothermic machine perfusion platform, a multivisceral organ model of the porcine abdominal cavity (including the liver, gallbladder, pancreas, stomach, intestine, kidney, uterus, and bladder), a high-definition display, and a software system. This system uses pig viscera obtained from slaughterhouses to recreate common surgical conditions such as vascular bleeding, intestinal peristalsis, and bile secretion. This setup provides the most realistic training environment, significantly reducing the learning curve for endoscopy and enhancing the effectiveness of endoscopy teaching. In our previous study, we demonstrated that the combination of a live animal model and ex vivo simulation in Smagister captures the advantages of both ex vivo simulators and animal models.[3] This approach enhances the realism of surgical training scenarios, particularly those that benefit laparoscopic training. This approach overcomes the limitations of lifeless training models, which are often expensive and distorted, without requiring anesthesiologists. Additionally, it circumvents the constraints associated with live animal experiments, reducing both manpower and financial costs. Organ research: Medical research spans diverse magnitudes, engaging distinct methodologies tailored to different scopes of investigation. Population studies typically employ epidemiological research methods, including descriptive studies, case-control studies, and cohort studies. When examining individuals, clinical medical research methods such as blood tests, imaging tests, and pathological detection are commonly used. Investigations at the microscopic level, which focus on molecules or cells, usually employ techniques like cell culture, flow cytometry, and gene sequencing. However, research on human organs is hampered by the inaccessibility of human samples in vivo and inherent differences between animal models and human biology. The absence of research platforms and technologies facilitating organ-level research impedes the comprehensiveness of medical research. In our study, we successfully established a novel platform based on our multivisceral preservation system, enabling the in situ and ex situ functioning of the liver, kidney, heart, and intestine in vitro [Supplementary Figure 2, https://links.lww.com/CM9/C360]. For example, we utilized this platform to examine the metabolomic variances in donors’ livers between in situ and ex situ conditions. Our analysis revealed that d-arginine and d-ornithine metabolism, as well as arginine and proline metabolism, were exclusively observed under in situ conditions. This platform facilitates the exploration of organ physiology and functions, both individually and in interorgan interactions. Notably, similar endeavors are underway in mainstream international research. Organ transplant: Ischemia-free organ transplantation (IFOT) exemplifies the application of organ medicine in transplantation. In IFOT, a continuous blood supply to the organs is maintained throughout the processes of procurement, preservation, and implantation. Consequently, ischemia-reperfusion injury (IRI) can be avoided, leading to optimized transplant outcomes. Compared with conventional liver transplantation, ischemia-free liver transplantation (IFLT) has demonstrated superior outcomes. Additionally, IFLT can improve the prognosis for extended criteria donors (ECDS), who are more susceptible to IRI after conventional transplantation.[2] A subsequent randomized clinical trial (RCT) supported the effectiveness of IFLT, showing a significant reduction in IRI-associated complications compared with conventional methods.[1] In addition to IFLT, our efforts have extended to include ischemia-free kidney transplantation (IFKT) and ischemia-free beating heart transplantation (IFBHT).[4] We have established a comprehensive IFOT system encompassing the liver, kidney, and heart, leading to an era of “warm organ transplantation.” OQT: OQT introduces a novel paradigm for organ therapy, enabling targeted treatment of specific organs while reducing systemic adverse effects. For example, in patients requiring chemotherapy for tumors, in situ, normothermic machine perfusion (NMP) can be employed for tumor-bearing organs, with chemotherapy drugs added to the perfusion solution for localized treatment. This approach has the potential to significantly reduce the total drug dose and minimize systemic toxicity, making OQT a safe, highly effective, and low-toxicity option. During the pioneering application of OQT in May 2023, patients with an abdominal aortic aneurysm (AAA) and a transplanted kidney were successfully treated.[5] Notably, in the resection of large AAAs and the replacement of artificial blood vessels, in situ renal mechanical perfusion at room temperature was adopted, avoiding the need for autologous kidney transplantation and mitigating renal IRI. Organ disease model: The selection of organ disease models is fundamental for understanding disease mechanisms. For example, studying hepatocellular carcinoma often involves examining tumor cells, adjacent cancer tissues, and normal control tissues or constructing tumor models through animal experiments. Although these methods can restore disease progression to some extent, they are time-consuming, labor-intensive, and not always intuitive. Traditionally, excised diseased organs are discarded after pathological examination, losing significant research value. By perfusing excised diseased organs post-pathology, we established preliminary disease models encompassing tumors, infectious diseases, and metabolic conditions such as liver cancer, diabetic nephropathy, and lower limb osteosarcoma [Supplementary Figure 3, https://links.lww.com/CM9/C360]. This innovative approach provides a more intuitive way of understanding disease progression and treatment response, presenting a promising avenue for drug screening. Our mechanistic study using an acute-on-chronic liver failure (ACLF) model revealed pyroptosis as the predominant mode of cell death in the livers of patients with hepatic B virus-related ACLF. Thus, organ disease models offer a promising framework for drug screening. Extracorporeal liver support therapy: Acute liver failure is a rare, acute, potentially reversible condition that results in severe liver impairment and rapid clinical deterioration in patients without preexisting liver disease. With effective treatment, the liver can recover its function after passing the critical period. We have established a novel extracorporeal liver perfusion support therapy that successfully sustains the lives of pigs with liver failure for up to three days. This involves connecting the liver to our perfusion device and linking it to the porcine body, creating an extracorporeal liver circulation system to function in place of the liver. The perfusion lasted 72 h, during which the liver provided essential metabolic synthesis. The pigs remained alive with stable physiological and metabolic indices. This approach, which was successful in preliminary animal experiments, holds promise for potential clinical applications [Supplementary Figure 4, https://links.lww.com/CM9/C360]. In conclusion, the concept of “organ medicine” has emerged as a remedial approach to address current limitations in medical research and treatment methodologies. Organ medicine stands to significantly advance emerging disciplines and industries related to the life sciences, facilitating the transformation of medical devices, innovative drug research and development, medical education, and the technological upgrading of the medical and pharmaceutical industries. Funding This work was supported by grants from China Postdoctoral Science Foundation, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (No. 2022M723604), National Natural Science Foundation of China (Nos. 822706886, 81570587 and 81700557), the Guangdong Provincial Key Laboratory Construction Projection on Organ Donation and Transplant Immunology (Nos. 2013A061401007 and 2017B030314018), Guangdong Provincial Natural Science Funds for Major Basic Science Culture Project (No. 2015A030308010), Guangdong Provincial Funds for High-end Medical Equipment (No. 2020B1111140003), Science and Technology Program of Guangzhou (No. 201704020150), the Natural Science Foundations of Guangdong Province (Nos. 2016A030310141 and 2020A1515010091), Young Teachers Training Project of Sun Yat-Sen University (No. K0401068), Colin New Star of Sun Yat-Sen University (No. R08027), and the Guangdong Science and Technology Innovation Strategy (Nos. pdjh2022b0010 and pdjh2023a0002). Conflicts of interest None. Data availability statement The data supporting the findings of this study are available from the corresponding author upon reasonable request.