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refers to biological studies involving tissues, organs, or cells maintained outside their native [[organism]] under controlled laboratory conditions. By carefully managing factors such as temperature, oxygenation, nutrient delivery, and [[perfusing|Perfusion]] a nutrient solution through the tissue's [[vasculature]], researchers sustain function long enough to conduct experiments that would be difficult or unethical in a living body. ''Exvivo'' models occupy a middle ground between ''in vitro'' () models, which typically use isolated cells, and ''in vivo'' () studies conducted inside living organisms, offering both experimental control and physiological relevance.
Ex vivo platforms support pharmacologic screening, toxicology testing, transplant evaluation, developmental biology, and investigations of disease-mechanism research across medicine and biology, from cardiology and neuroscience to dermatology and orthopedics. Because they often use human tissues obtained from clinical procedures or , they can reduce reliance on Animal testing; their utility, however, is limited by finite viability, incomplete systemic integration, and post-mortem biochemical changes that accumulate over time. The earliest perfusion studies were conducted in the mid-19thcentury, and subsequent advances in sterilization, imaging, and microfluidics have facilitated broader adoption into the 20th and 21stcenturies. Regulatory oversight depends on specimen origin: human exvivo research is subject to informed consent, whereas animal-derived models fall under institutional animal care guidelines.
In the preclinical development of therapies for bone diseases, for example, in vitro cell studies are typically performed prior to in vivo testing in animal models, as the latter approach is more costly, time-intensive, and complex, requiring large sample sizes to yield statistically meaningful results. However, in vitro findings frequently fail to predict in vivo responses due to the absence of native tissue architecture, including the extracellular matrix (ECM), and the lack of physiologically relevant cell–cell as well as cell–matrix interactions. Ex vivo bone preserve these features by maintaining tissue integrity outside the organism, and reduce the complexity of in vivo testing by excluding systemic variables, enabling controlled investigation of specific biological or mechanical factors.
Another example is the use of ex vivo models during the preclinical evaluation of intestinal Drug delivery. Unlike in vivo studies, which rely on animal models and are affected by interspecies differences, ex vivo approaches can utilize resected human intestinal segments, more accurately representing human physiological conditions.
The boundary between exvivo and invitro models remains contested, particularly in the fields of regenerative medicine and tissue engineering, where the terms have been used interchangeably in many studies. Modern invitro systems have progressed from simple two-dimensional cell cultures to advanced three-dimensional constructs, such as and organ-on-a-chip devices, that replicate aspects of tissue architecture, further complicating the distinction. Klein and Hutmacher (2024) propose that a model may be classified as exvivo if it meets one or more of the following criteria: it preserves the native structure and composition of a cell, tissue, or organ without disrupting its cellular or extracellular components; it is used in therapeutic contexts where cells, organs, or tissues are removed and then reimplanted; or it links organs or tissues to artificial circulation via perfusion. According to these criteria, systems involving extensive reorganization or manipulation—including organoids, organ-on-a-chip, and organotypic cultures—are considered invitro, even when they replicate certain organ-level functions.
In general, invitro models are highly flexible and relatively inexpensive, making it easier to test new treatments quickly and adjust experimental parameters as needed. Exvivo systems are less adaptable but often provide a more reliable indication of how a treatment will work, and what it might cause, in the human body. Nonetheless, they are subject to inherent limitations, including post-mortem alterations in biophysical properties, progressive tissue degradation, limited viability duration, and, typically, the absence or artificial replication of circulation and innervation. These constraints can hinder the models' ability to reproduce long-term or systemic physiological effects. Some of these factors complicate direct comparisons with invivo systems; for example, studies measuring how behave in primate brain tissue during stimulation have found that results differ markedly between in vivo and ex vivo conditions—and the longer the tissue has been removed from the body, the greater the discrepancy, partly due to cooling and loss of normal biological function.
In cardiovascular research, a Langendorff heart preparation removes a heart and perfuses it with a nutrient solution, preserving structure and conduction pathways for investigation of or drug effects without the complexity of an in vivo model. Several ex vivo perfusion systems have been developed to reduce ischemic injury during the organ preservation phase. One such system is the Organ Care System (OCS), which maintains the heart in a non-beating but metabolically active state by circulating heparinized donor blood supplemented with a proprietary perfusate formulation. In translational pharmacology, perfusion platforms restore pulsatile blood flow in isolated human organs, enabling direct measurement of absorption, metabolism, and toxicity prior to first-in-human trials. By supplying pharmacokinetic data on viable human tissue rather than relying on animal models or cell assays, the platforms inform clinical trial decisions and may reduce animal testing.
Not all forms of organ perfusion are ex vivo; in situ perfusion techniques are employed during organ retrieval to restore blood flow to organs while they remain within the body, minimizing ischemic injury and preserving viability for transplantation. A related example is selective insitu perfusion during surgery, such as isolated hepatic perfusion (IHP), which is used for targeted chemotherapy.
Cell culture involves Cell isolation individual cells from tissues and growing them in a medium enriched with nutrients and . While these cultures retain some functional characteristics of their tissue of origin, they often exhibit changes in phenotype and gene expression when removed from their native environment. Primary cell cultures, derived directly from tissues, more closely resemble physiological conditions than immortalized cell lines, making them essential for studying cellular behavior, disease mechanisms, and drug effects.
Computed tomography (CT) is used in ex vivo research to produce non-destructive, high-resolution images of internal structures.
In biosensing and electroanalytical applications, ex vivo methods offer experimental flexibility unavailable in living systems. While many in vivo experiments favor micro- and nanoelectrodes to minimize invasiveness, larger are routinely used for specific purposes. Exvivo approaches, by contrast, permit custom electrode geometries that interface precisely with biological tissues under controlled conditions, without the same constraints on size and invasiveness. This adaptability enables detailed examination of biological and their physiological roles. Exvivo electroanalytical methods are applied in neuroscience, pharmacology, and biomedical engineering to study neurotransmitter dynamics, metabolic activity, and disease-associated .
In some cases, ex vivo electroporation, in which an electric field is applied to cells to facilitate the uptake of genetic material, is used to introduce DNA into cells within tissue slices, allowing researchers to study gene expression in a controlled environment.
In the 1880s, British physiologist Sydney Ringer developed a salt solution that sustained rhythmic contractions in the isolated frog heart. Later named Ringer's solution, it enabled extended observation of cardiac activity and supported controlled experimental studies on cardiac physiology in isolated preparations. In 1895, German physiologist Oskar Langendorff introduced a method for isolated heart perfusion involving retrograde flow through the aorta to supply the coronary circulation. The Langendorff preparation allowed for direct measurement of cardiac function and precise control of perfusion parameters while minimizing systemic confounders inherent to in vivo models. It became a widely used technique in the study of cardiac physiology and remains a standard method in cardiovascular research. At the turn of the 20thcentury, researchers initiated efforts to preserve animal tissues exvivo within laboratory settings. Early experiments involved isolating tissues from organisms and transferring them to external media to develop reliable cultivation techniques. These studies aimed not only to maintain cellular viability but also to stimulate tissue growth, often using blood plasma—typically sourced from the same animal—as the medium.
In 1935, French surgeon Alexis Carrel and American aviator Charles Lindbergh unveiled the first closed, sterile perfusion pump. The glass-enclosed, three-chamber device maintained a pulsatile flow of oxygenated perfusate through explanted animal , keeping them viable for up to three weeks in vitro. Their fragments were then transferred to , where they gave rise to proliferating cell colonies, verifying exvivo viability. By equalizing pressure and continuously recirculating the medium, the apparatus proved that long-term organ maintenance outside the body was feasible and laid the groundwork for modern perfusion culture techniques. In 1953, American surgeon John Heysham Gibbon successfully employed a heart–lung machine during open-heart surgery on a human patient. The procedure demonstrated that an artificial circuit with controlled oxygenation and temperature could temporarily maintain systemic circulation. Throughout the 20thcentury, exvivo techniques were adapted for a range of animal models. A notable refinement was the development of the working heart model, in which perfusate enters the left atrium and exits through the aorta, more closely replicating physiological flow conditions. Advances in instrumentation enabled detailed assessments of cardiac function, including pressure–volume relationships, oxygen consumption, and myocardial contractility. The artificial organ field contributed significantly to the advancement of exvivo systems; for example, the development of hemodialysis relied on a series of exvivo models designed to support and test extracorporeal circulation technologies.
Human tissues for exvivo models are typically obtained from clinical procedures, such as surgical discards, donations, biopsies, or through accredited . Tissues obtained shortly after death through autopsy are used in some cases, particularly for studies focused on maintaining structural integrity or assessing short-term functional properties. Although human tissues provide the highest degree of physiological relevance, their use is subject to inter-sample heterogeneity (e.g., age, gender, medication history, and diet), logistical challenges in obtaining region-specific samples, and ethical constraints. In many jurisdictions worldwide, the acquisition and research use of human tissues are regulated by ethical and legal frameworks that require informed consent. In Japan, the 人を対象とする生命科学・医学系研究に関する倫理指針, implemented in 2021, consolidate previous standards and mandate that researchers obtain informed consent when conducting studies involving human tissues. In Switzerland, the Federal Act on Research involving Human Beings (Human Research Act, HRA) stipulates that all research involving identifiable human tissue must be approved by an ethics committee. Researchers are required to obtain written informed consent from donors, and documentation concerning the origin of the tissue and the consent procedure must be submitted as part of the ethical review process.
In the United Kingdom, the legal framework governing the removal, storage, and use of human tissue for research varies by jurisdiction. In England, Wales, and Northern Ireland, the Human Tissue Act 2004 mandates that appropriate consent must be obtained for the removal and use of tissue from both the living and the deceased, unless specific statutory exemptions apply. The Act includes provisions introduced in response to public health scandals in the 1990s, such as the Alder Hey and Bristol Royal Infirmary cases, in which thousands of children's organs were retained without parental knowledge. In Scotland, the Human Tissue (Scotland) Act 2006 regulates the removal, retention, and use of human tissue for purposes including transplantation and research. Unlike the 2004 Act, which relies on "appropriate consent", the Scottish legislation is based on the principle of "authorisation" as the legal basis for the use of human tissue. The 2006 Act was subsequently amended by the Human Tissue (Authorisation) (Scotland) Act 2019, which introduced a system of deemed authorisation for organ and tissue donation after death. In Wales, the Human Transplantation (Wales) Act 2013 further diverged by introducing a system of deemed consent for post-mortem organ and tissue donation.
In the United States, federal regulations such as the Common Rule and those enforced by the Food and Drug Administration (FDA) stipulate that researchers must obtain informed consent when conducting studies involving human subjects, including the use of identifiable biological materials. The Health Insurance Portability and Accountability Act (HIPAA) further safeguards the confidentiality of personal health information, including data derived from tissue samples.
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