3D bioprinting in liver transplantation: from organ replacement to transplantable functional support

Liver transplantation remains the most effective treatment for patients with end-stage liver disease, acute liver failure, and unresectable liver cancer. Yet the field continues to face a persistent mismatch between the clinical demand for transplantable hepatic function and the availability of suitable donor organs. Against this background, 3D bioprinting has often been presented as a future route to the acquisition of donor liver. This prospect is compelling, but it may also shape the translational question too narrowly. The whole human liver is not merely a shaped mass of hepatocytes; it is a highly perfused, zonated, immunologically active, metabolically specialized, and biliary-drained organ (1). Reproducing these features at transplantable scale remains beyond the immediate reach of current bioprinting platforms. The more urgent question, therefore, may not be whether 3D bioprinting can replace liver transplantation in the near future, but what type of hepatic graft could first become clinically meaningful. Recent studies have shown that bioprinted hepatic constructs can provide functional benefit after transplantation in mouse models of liver failure (2,3). These findings suggest that the first translational product may not be a whole organ substitute, but a transplantable hepatic support unit: an implantable, vascularizable, and functionally active construct designed to bridge patients to transplantation, support endogenous regeneration, or stabilize marginal graft function (4).

Beyond early proof-of-concept transplantation studies, recent work has begun to broaden the cellular and architectural basis of implantable hepatic constructs. Human induced hepatocyte-like cell-derived hepatorganoids (5), lobule-like bioprinted constructs intended for orthotopic implantation, and prevascularized hepatic tissues illustrate three complementary priorities: clinically expandable cell sources (6), liver-inspired spatial organization (7), and perfusion-oriented graft design (8). These advances should not be viewed as isolated technical refinements, but as part of a broader shift from maintaining liver-like tissue in vitro to engineering constructs capable of survival, integration, and functional support after implantation. In this sense, the field is moving from proof-of-viability toward transplantation-relevant graft design.

A major gap in the field is not only technological, but clinical: the first intended use of a bioprinted hepatic graft remains insufficiently defined. If 3D bioprinting is judged solely against the benchmark of whole liver replacement, current constructs will inevitably appear immature. Yet liver transplantation is not a single operative event, but a clinical continuum that spans waiting-list deterioration, acute decompensation, donor shortage, marginal graft utilization, early allograft dysfunction, and post-transplant recovery (4,9-11). Within this continuum, several unmet needs may be more realistic and clinically actionable than complete organ substitution.

For patients with acute liver failure or acute-on-chronic liver failure, a bioprinted hepatic graft could serve as a bridge to transplantation by extending the therapeutic window (10), stabilizing metabolic function (12), and potentially reducing waiting-list mortality (13). In patients with residual regenerative potential, the same strategy could function as a bridge to recovery, providing time-limited hepatic support while endogenous repair mechanisms regain control of systemic inflammation, ammonia accumulation, coagulopathy, and metabolic collapse. Beyond liver failure, partial restoration of specific hepatic functions may also be valuable for selected inherited or acquired metabolic liver diseases, where full organ replacement may not be necessary to achieve clinical benefit (14). In the transplant setting itself, bioprinted hepatic constructs might support small-for-size grafts, marginal donors, donation-after-circulatory-death grafts, or early graft dysfunction, where temporary functional assistance could improve perioperative stability and graft recovery. These potential applications share a common principle: the goal is not to create an anatomically complete liver, but to deliver sufficient, safe, and durable hepatic function at the right clinical moment. Thus, the central translational question should shift from “Can we print a whole liver?” to “What level of printed hepatic function is sufficient to change transplant decision-making?”

To move the field toward clinical translation, it may be more useful to define a minimal viable hepatic graft than to pursue an idealized whole liver as the immediate benchmark. Such a graft would not need to reproduce the full anatomy of the native liver. Instead, it should deliver a clinically meaningful degree of hepatic function, remain viable after implantation, and be manufactured reproducibly under conditions compatible with future clinical use. Several core attributes should define this concept. A candidate graft must contain sufficient functional hepatic cell mass to generate measurable systemic effects (15), including albumin secretion, urea synthesis, ammonia detoxification, bilirubin handling, and drug-metabolizing activity. Because hepatic tissue is highly oxygen-dependent, clinically relevant scale will also require rapid nutrient and oxygen supply after implantation. Diffusion alone is unlikely to be adequate; predesigned channels, vascular-inductive architectures, or host vascular integration will therefore be essential. Safety and controllability are equally important, particularly when stem-cell-derived or reprogrammed cells are used. Uncontrolled proliferation, ectopic tissue formation, thrombosis, severe inflammation, and tumorigenicity must be avoided before such constructs can be considered transplant relevant. The implantation strategy should also be clinically realistic. In early-phase translation, a retrievable or monitorable implantation site may be preferable, as it would allow safety surveillance, graft biopsy, functional assessment, and removal if necessary. Equally important is the need for scalability and standardization. Current studies vary widely in cell sources, bioinks, printing parameters, maturation protocols, implantation sites, and functional readouts. Without harmonized benchmarks, it will remain difficult to compare constructs or determine whether a bioprinted graft has achieved transplant-relevant performance. The concept of a minimal viable hepatic graft therefore reframes the field. The goal is not to ask whether a printed construct looks like a liver, but whether it can safely deliver enough hepatic function for long enough to affect a defined clinical scenario.

A clinically oriented assessment strategy is needed to determine when a bioprinted hepatic graft becomes relevant to transplantation. The field should move beyond demonstrating histological resemblance or short-term hepatocyte viability and adopt an evaluation approach that reflects the logic of transplant medicine (11). This approach should begin with reproducible biological function. A candidate graft should demonstrate hepatic activity in vitro, including albumin secretion, urea synthesis, ammonia clearance, bile acid transport, and cytochrome P450-mediated drug metabolism (5,6). These assays should not be reported as isolated endpoints; instead, they should be normalized to cell number, construct size, culture duration, and clinically interpretable thresholds. Functional output must then be tested in the context of implantation. After implantation, the graft should remain viable, avoid central necrosis, integrate with host vasculature, maintain functional activity, and show no evidence of uncontrolled proliferation, thrombosis, or severe inflammatory reaction. In early translation, retrievability and longitudinal monitoring may be as important as functional potency. Ultimately, the value of a bioprinted hepatic graft should be tested against transplant-relevant efficacy rather than technical feasibility alone. Clinically meaningful models should include liver failure, small-for-size syndrome, marginal graft injury, and metabolic liver disease. Relevant outcomes should include survival, duration of functional support, improvement in ammonia, bilirubin, coagulation parameters, systemic inflammation, and extension of the bridge-to-transplant or bridge-to-regeneration window. Large-animal studies will be essential before clinical testing, because rodent models cannot adequately capture the scale, hemodynamics, immune response, and surgical constraints of human transplantation (14).

Whole liver bioprinting remains an aspirational goal, limited by scale, vascular hierarchy, biliary drainage, immune compatibility, manufacturing reproducibility, and long-term safety. Yet these barriers should not obscure a nearer and more actionable opportunity: the use of bioprinted hepatic constructs as transplantable functional support rather than complete organ substitutes (12). This reframing has practical implications. It redirects attention toward achievable clinical scenarios, including bridging to transplantation, supporting endogenous regeneration, providing auxiliary metabolic function, and stabilizing marginal or small-for-size grafts. It also changes how success should be judged. The critical benchmark is not whether a construct reproduces every anatomical feature of the native liver, but whether it can deliver clinically meaningful hepatic function with acceptable safety, durability, retrievability, and scalability.

The first clinically meaningful 3D-bioprinted liver product may therefore not replace liver transplantation. Instead, it may reshape transplantation by converting otherwise irreversible deterioration into a controllable therapeutic window. To reach this stage, future studies should move beyond proof-of-concept printing and be designed around transplant-relevant endpoints, standardized functional benchmarks, and clinically realistic implantation models (15). The question is no longer simply whether we can print a liver, but whether we can print enough liver function to change the outcome of patients waiting for one.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article did not undergo external peer review.

Funding: This work was supported by the National Key R&D Program of China (No. 2024YFB4607800) and National High Level Hospital Clinical Research Funding (No. 2025-PUMCH-C-028).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2026-0610/coif). S.D. serves as an unpaid editorial board member of HepatoBiliary Surgery and Nutrition. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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