In vascularized composite allotransplantation (VCA), the integration and long-term viability of complex, multi-tissue grafts is impacted by a range of immunological, functional, and regenerative challenges (1–5). While surgical advancements and immunosuppressive protocols have improved graft survival, issues related to tissue regeneration, biomimicry, and host-graft interface healing continue to limit broader clinical adoption and long-term success (1, 3, 4, 6).

Biopolymers, naturally-derived or bioengineered polymeric materials, have emerged as promising adjuncts in VCA, offering diverse applications across immunomodulation, tissue scaffolding, wound healing, and drug delivery (7, 8). Their tunable physicochemical properties, biodegradability, and potential for bioactive modification position them as ideal candidates to support composite tissue integration and functional recovery. In particular, the use of biopolymers as immunosuppressive carriers, nerve conduits, vascular scaffolds, and dermal substitutes has shown encouraging results in preclinical models and select clinical applications (9–14).

Furthermore, insights from solid organ transplantation (SOT), where biopolymers have successfully been used for targeted immunosuppression and bioscaffold support in heart, liver, kidney, pancreas and small intestine transplantation, may help inform and accelerate their application in the more complex, multi-tissue context of VCA (15, 16). Despite this promise, the role of biopolymers in VCA remains fragmented across a heterogeneous body of literature, with limited clinical translation and few standardized approaches (17). Key challenges include the optimization of polymer composition for specific tissue types, ensuring biocompatibility with allograft components, and integrating controlled-release systems within complex vascularized constructs. Furthermore, regulatory barriers and variability in transplant protocols have hindered the systematic evaluation of biopolymer-based interventions (18–20).

Given these considerations, a comprehensive synthesis of current evidence is needed to evaluate the roles, mechanisms, and therapeutic potential of biopolymers in VCA. Therefore, this systematic review aims to consolidate existing research, assess reported outcomes, and highlight opportunities for translational innovation, ultimately informing future clinical strategies and bioengineered solutions in composite tissue transplantation. To ensure a comprehensive overview, this includes not only the direct application of biopolymers but also the assessment of emerging approaches such as ex vivo modifications, in vitro and in vivo bio-boosting of allotransplants, and deep structural modifications of grafts, including decellularization and recellularization techniques designed to enhance graft integration, immune compatibility, and long-term function.

This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Due to the anticipated variability in study methodologies and reported outcomes, a narrative synthesis was employed in place of a meta-analysis. The review protocol was prospectively registered in the PROSPERO database (ID: CRD420251039845).

Systematic Search

A systematic literature search was carried out across PubMed/MEDLINE, EMBASE, the Cochrane Library, Web of Science, and Google Scholar (first 25 pages) for all studies published up to April 20^th, 2025. The search strategy centered on two main conceptual domains, combined with the Boolean operator “AND”: (i) “vascularized composite allotransplantation (VCA)” and (ii) “biopolymers.” Within each domain, relevant synonyms and MeSH terms were utilized to maximize search sensitivity and comprehensiveness. The full search strings for each database are presented in Supplementary Digital Content 1. Additionally, the reference lists of all included articles were reviewed to capture any further eligible studies.

Studies were included if they explored the use, mechanism, or therapeutic impact of biopolymers in the context of VCA, employing clinical data, preclinical animal models, or in vitro systems relevant to composite tissue transplantation. All original, peer-reviewed article types—regardless of study design—were considered, provided they were published in English and available as full-text articles. Exclusion criteria comprised non-peer-reviewed literature, articles lacking original data (such as reviews or editorials), or studies evaluating biopolymers outside the scope of VCA or its relevant composite tissue elements.

Title and abstract screening were independently conducted by three reviewers (T.N., T.S., V.M.), followed by full-text assessment for eligibility. Any disagreements were resolved through consensus discussion with a senior reviewer (L.K.). The study selection process is illustrated in the PRISMA 2020 flow diagram provided in Figure 1.

Quality assessment

The methodological quality of included studies was appraised using validated tools based on study design. Clinical studies were assessed using the Newcastle-Ottawa Scale (NOS), which evaluates methodological rigor across three domains: (i) selection of study groups, (ii) comparability of cohorts, and (iii) ascertainment of outcomes. A maximum of nine stars indicates the highest quality. The mean and standard deviation (SD) of studies included were calculated and reported in the results section (21). For preclinical animal studies, the SYRCLE Risk of Bias tool was employed to evaluate internal validity across key domains such as selection, performance, detection, and reporting bias (22).

In addition, the Oxford Centre for Evidence-Based Medicine (OCEBM) Levels of Evidence (LOE) framework was applied to stratify the strength of evidence (23). Randomized controlled trials and systematic reviews were classified as Level I, while observational studies and preclinical data were ranked according to their design and translational applicability. Detailed results of the quality assessments are provided in Supplementary Digital Content 2–4.

Data extraction

Data extraction was performed through a blinded dual-review process to ensure accuracy and minimize bias. From each included study, the following parameters were systematically collected: Digital Object Identifier (24), study title, first author, year of publication, study type, sample size, recipient age and sex, donor age and sex, duration of follow-up, underlying cause of transplantation, type of VCA, study intervention, objective of intervention, biomaterial used, animal model (if applicable), comparison group (if applicable), and overall study outcome.

The systematic search initially identified n=1,356 studies. Following application of predefined inclusion and exclusion criteria, a total of n=11 (0.8%) studies met eligibility for final inclusion. Year of publication ranged from 2014 to 2024. The mean (SD) NOS-score was 7.4 (1.5), indicating moderate methodological rigor. The LOE ranged from Foundational Evidence to Level 1b.

Study designs encompassed randomized clinical trials, prospective clinical investigations, as well as preclinical in vivo and in vitro experimental models, reflecting a multidisciplinary exploration of biopolymer applications in VCA-related fields. Animal models included Wistar rats, Sprague Dawley rats, baboons, and sheep. Transplant types ranged from bone and soft tissue grafts to composite limbs and vascular grafts. Full insights on study designs and cohorts are shown in Table 1. A clear definition and classification of biopolymers in this context are provided in Table 2.

Biopolymers have emerged as promising preclinical adjuncts in VCA due to their biocompatibility, tunable degradation profiles, and potential for bioactive functionalization (Figure 2). In this field, where multi-tissue integration and long-term graft viability remain critical challenges, biopolymers offer unique opportunities to enhance outcomes through scaffold support, localized drug delivery, and immunomodulation. Their role spans across structural regeneration, infection prevention, and vascular or neural guidance within complex graft environments. Conversely, in tissue engineering, a major challenge lies in the effective recellularization of the scaffold, which can occur in vitro under controlled laboratory conditions or in vivo where the human body functions as a natural bioreactor (35). As research advances, biopolymers may serve as key enablers of next-generation, bioengineered solutions that improve both functional recovery and immunologic tolerance in VCA, which, to date, was only achieved in vivo through mixed chimerism (7, 8, 36–42).

In our study, biopolymers have shown significant versatility in VCA, supporting tissue-specific scaffold development for limb, facial, and vascular grafts through techniques like decellularization and surface modification. While materials such as COL/HA, PCL, and calcium alginate demonstrated strong regenerative or structural properties, others like chitosan faced limitations in load-bearing applications, though remained effective in drug delivery (Figure 3).

Current research increasingly highlighted the versatility of biopolymers in modulating immune responses, promoting graft integration, and supporting structural regeneration in transplant surgery (43, 44). Their tunable biodegradability, mechanical properties, and ability to carry bioactive molecules are further advantages (45, 46). In literature, the application of biopolymers in VCA ranges from localized drug delivery systems to structural scaffolds designed to promote cellular adhesion, angiogenesis, or tissue remodeling (47, 48). In this context, biopolymers were evaluated for their efficacy in drug delivery and regenerative capacity in specific tissues (49). Natural and synthetic polymers were incorporated into nerve conduits, vascular scaffolds, dermal replacements, and bone grafts. Literature supported their use in enhancing revascularization, modulating inflammatory responses at the host-graft interface, and creating composite scaffolds that mimicked the structural and biochemical features of native tissues (50, 51). However, biopolymer application faces various challenges. The structural demands of each tissue type meant that a single biopolymer system was rarely suitable across the entire graft (52). Furthermore, skin components oftentimes elicited particularly strong immune responses, making tolerance induction difficult (4, 53–55). Bone regeneration required load-bearing strength, while neural repair called for guidance conduits with bioactive cues, necessitating tailored, often multi-layered or composite polymer systems. The integration of these systems into a single, unified construct that could function in vivo remained a significant engineering challenge (56–59). Another issue was the relative scarcity of translational studies. While preclinical models showed encouraging results, clinical implementation lagged due to regulatory constraints, manufacturing scalability, and the need for long-term outcome data (60–63). This gap is particularly problematic because most preclinical studies observe grafts for only weeks to months, whereas VCA recipients require immunosuppression and graft surveillance over decades, creating a disconnect between experimental timelines and real-world clinical needs. In our review, follow-up periods were similarly short, highlighting the challenge of extrapolating short-term biomaterial performance to the lifelong immunosuppression demands faced by VCA patients These challenges are further amplified by the limited number of performed VCA transplants globally, which may have constrained the ability to perform large-scale clinical studies. Additionally, ethical considerations regarding the risk-benefit profile of VCA transplants complicated the evaluation of experimental adjuncts such as biopolymer systems (18, 53, 64). Moreover, biopolymers derived from natural sources often suffer from inherent batch-to-batch variability and structural complexity, making mass production for commercial clinical applications technically and economically challenging, posing a significant hurdle for widespread application (65, 66). Here, triglycerol monostearate (TGM) gels and other injectable hydrogel platforms loaded with tacrolimus emerged as potential alternatives and have shown promise as minimally invasive drug delivery systems due to their thermoresponsive properties, ability to form depots in situ, and responsiveness to inflammation-associated enzymatic triggers that enable on-demand drug release. However, challenges such as limited mechanical integrity, potential burst release, and the absence of intrinsic regenerative or structural functions restrict their standalone utility in the multi-tissue environment of VCA (7, 67, 68).

In solid organ transplantation, biopolymers were mainly investigated for targeted immunosuppressive delivery, using microspheres, hydrogels, and nanoparticles to reduce systemic toxicity while enhancing graft-specific tolerance (47). They were also explored for cell encapsulation and early biosensing applications aimed at protecting donor tissue and monitoring graft health (69–72). However, persistent challenges, including incomplete local immunosuppression and the inability to prevent chronic, silent rejection, limited their clinical translation (73–78).

Nevertheless, research continues to explore more sophisticated biopolymer solutions, including stimuli-responsive systems, multi-functional coatings, and bioresorbable materials capable of temporally staged degradation. These innovations promised to enable the fine-tuned orchestration of immune modulation, structural support, and regenerative signaling, all key to advancing outcomes in both SOT and VCA (79–81). While the maturity of biopolymer applications in SOT was more advanced, the multifaceted demands of VCA offered a unique proving ground for next-generation biomaterial technologies.

For patients, biopolymer-enhanced grafts may offer future solutions that promote healing in hand, face, or limb transplants by supporting the regeneration of bone, nerve, and blood vessels while potentially reducing the need for lifelong systemic immunosuppression. For physicians, these platforms provide new potential tools for customizing graft design, ranging from load-bearing bone substitutes to localized drug delivery systems using agents. Although most studies remain in preclinical stages, early findings highlight the translational promise of biopolymers in improving functional outcomes, reducing complications, and expanding therapeutic options in VCA. Lastly, to further contextualize the future translational trajectory of biopolymer technologies in VCA, it is important to define what level of evidence would justify progression toward human application. At present, the available data remain insufficient to support early-phase clinical VCA trials, even at a Phase 0 exploratory or microdosing level, primarily due to short follow-up periods, limited safety reporting, and the absence of robust large-animal efficacy data. Meaningful translation will require well-designed, long-term studies in relevant large-animal VCA models that evaluate degradation behavior, immunologic safety, and functional integration under clinically realistic immunosuppression regimens. From a regulatory perspective, many biopolymer-based VCA adjuncts may be classified as combination products, integrating device, drug, or biologic components, which introduces additional requirements for manufacturing consistency, sterility validation, and dual-pathway oversight through FDA’s CDRH and CBER branches. Only once biopolymers demonstrate reproducible safety, predictable pharmacokinetics, and structural performance in validated large-animal models could regulatory agencies consider first-in-human exploratory use in VCA. As such, translation readiness remains preliminary and contingent upon both scientific and regulatory milestones yet to be achieved.

This systematic review was subject to several limitations that may affect the generalizability of its findings. First, the overall number of studies specifically addressing biopolymer use in VCA remains low, reflecting the nascent and exploratory stage of this field. Many of the included investigations were preclinical in nature, limiting the ability to extrapolate outcomes to human clinical settings. Additionally, heterogeneity in study design, graft type, animal models, and outcome measures hindered direct comparisons and precluded a quantitative meta-analysis. The diversity of polymer types, processing techniques, and application modes further introduced variability that may mask the relative effectiveness of specific biomaterials. Moreover, due to the scarcity of dedicated data, the boundary between biopolymer applications in established VCA, potential translation to VCA, or broader reconstructive contexts often remains blurred, complicating standard classification and comparative assessment. Importantly, reliable reporting on safety considerations, such as degradation products, foreign body responses, and long-term biocompatibility, was largely absent across studies, preventing a rigorous analysis of failure modes and raising the possibility of inadvertent positive-outcome bias, which in turn limits the translational readiness of the current evidence. Publication bias is also a concern, as studies demonstrating negative or inconclusive outcomes may be underrepresented in the literature. Lastly, regulatory, ethical, and logistical barriers specific to VCA constrain the availability of high-quality, large-scale clinical data, underscoring the need for standardized reporting frameworks and multicenter collaboration in future research.

Biopolymers hold substantial preclinical promise as multifunctional tools in vascularized composite allotransplantation, enabling progress in tissue-specific regeneration, immune modulation, and localized drug delivery. Across the preclinical studies reviewed, both natural and synthetic polymers demonstrated a capacity to enhance vascularization, reduce inflammation, and support structural integration within composite grafts. However, their successful clinical translation remains challenged by material-specific limitations, manufacturing complexity, and the need for tailored approaches based on tissue-specific demands. Insights from SOT, where biopolymers have shown value in controlling immunosuppression, could help inform the next generation of biomaterial strategies in VCA. Going forward, interdisciplinary collaboration among immunologists, biomaterial scientists, pharmacologists, and transplant surgeons is critical to optimizing these technologies. Continued efforts in translational research and standardized evaluation will be essential to unlock the full potential of biopolymers and integrate them into future clinical protocols for reconstructive transplantation.