Clinical translation of 3D-printed patient-specific bone implants: a consensus statement

Abstract

Background:

Extensive defects in long bones, resulting from trauma, disease, or other etiologies, impose significant morbidity on patients and may necessitate amputation, long-term disability, or premature mortality. While three-dimensional (3D)-printed, patient-specific implants offer promising regenerative solutions, their clinical implementation remains hindered by regulatory challenges, lack of standardized guidelines, and gaps in translational research. Addressing these barriers is critical to improving patient outcomes and optimizing healthcare resource utilization.

Materials and methods:

A multidisciplinary group of 29 experts – including clinicians (surgeons, anesthesiologists), biomaterial scientists, biomedical engineers, legal/regulatory professionals, health economists, meta-researchers, artificial intelligence experts, trialists, and biomaterial industry representatives – convened for the Consensus Meeting on 3D-printed patient-specific Bone Implants (CoMBI). Preceding the meeting, key questions were discussed in individual interviews and categorized into fundamental research, preclinical studies, and clinical trials and implementation (CoMBI themes). Experts presented on each theme, followed by structured discussions. Statements were synthesized, iteratively refined, and validated through open review.

Results:

The consensus meeting resulted in 20 key statements addressing the CoMBI themes, outlining a framework to advance regulatory compliance and facilitate the clinical adoption of 3D-printed implants. Key statements include the need for harmonized regulatory pathways, clear guidelines on preclinical validation, and innovative trial designs tailored to complex, patient-specific implants. Strengthening collaboration among policymakers, regulatory agencies, and clinicians is crucial to overcoming current implementation barriers and ensuring equitable patient access to these advanced technologies.

Conclusion:

This Consensus Statement presents 20 key statements across fundamental research, preclinical studies, and clinical trials and implementation, offering a roadmap for accelerating the regulatory and clinical translation of 3D-printed patient-specific bone implants. The findings emphasize the critical role of interdisciplinary collaboration in overcoming challenges, such as standardizing implant development and navigating complex regulatory landscapes. By addressing these barriers and outlining practical strategies, the consensus highlights actionable steps to bridge the gap between innovation and clinical application.

Introduction

Translating biomedical research and advances in biomaterials into real-world health solutions is a central driver of modern medical innovation^[1]. This process involves bridging findings from experimental biomedical research methods – such as in vitro, ex vivo, in vivo, and in silico studies – into improved treatment options for human diseases and enhancements in clinical practice, as well as progress in biomaterials science^[2]. Over the past 25 years, three-dimensional (3D) printing – a pioneering layer-by-layer biomaterials manufacturing technology – has gradually developed the potential to change the treatment of bone defects substantially^[3,4]. It enables personalized therapies with 3D-printed implants or “scaffolds” that are tailored to the specific needs of individual patients to regenerate complex (long) bone defects, amongst others, through the concept of scaffold-guided bone regeneration (SGBR)^[5]. The SGBR concept enables a patient-specific treatment approach for complex bone defects, which, due to their variability in clinical presentation, require customized treatment strategies^[5]. Despite promising preliminary clinical results with 3D-printed scaffolds for bone regeneration^[5–8], their widespread, standardized translation from the laboratory to bedside remains slow, and clinical research continues to fall short of expectations^[9,10]. There are numerous reasons for this, among them the fact that this emerging opportunity introduces a range of underexplored challenges. These include the need to establish guidelines for specific surgical applications, to design appropriate frameworks for international multicenter preclinical and clinical trials, and to address issues related to current medico-legal considerations and reimbursement policies^[11]. It is, for example, unclear which bone defect dimensions and anatomical locations are suitable for 3D-printed scaffold implantation, and accordingly, legal and ethical approval is required on a case-by-case basis^[12,13]. Innovations in the treatment of bone defects however, are urgently needed, as conventional standard procedures are associated with significant healthcare costs and patient morbidity as well as providing poor clinical outcomes^[11,14,15]. Historically – and continuing to the present – complex bone defects often necessitate the use of improvised or modified implants originally designed for different anatomical regions and indications^[11]. Modern state-of-the-art 3D printing technologies now enable the fabrication of patient-specific, customized scaffolds – both non-biodegradable and biodegradable – for SGBR, utilizing 3D-printable biomaterials produced via additive manufacturing principles^[5,16]. This personalized approach to long bone defect treatment offers several advantages: implants can be precisely tailored to the defect’s morphology, enabling the exploration of mechanobiologically optimized scaffold designs, and eliminating the need for additional bone resection during surgical implantation^[11].

HIGHLIGHTS

• This consensus statement addresses a critical need in surgical practice by providing evidence-based recommendations for the clinical translation of three-dimensional (3D)-printed, patient-specific bone implants, a promising technology for treating long bone defects.

• The study underscores the critical role of interdisciplinary collaboration by integrating the expertise of surgeons with biomaterial scientists, engineers, and regulatory experts to overcome persistent barriers and accelerate the safe, effective adoption the widespread adoption of 3D-printed implants.

• This work offers practical guidance on harmonizing regulatory pathways, establishing preclinical validation guidelines, and designing innovative clinical trials, thereby contributing to the standardization and safe implementation of 3D-printed bone implants.

• By outlining actionable steps to bridge the gap between research and clinical application, this consensus statement aims to advance surgical techniques, improve patient outcomes, and optimize healthcare resource utilization in the management of complex bone defects.

Previous research has demonstrated that robust, transdisciplinary study designs and comprehensive data collections can lead to iterative improvements in interventions, therapies, or medical device applications. A sophisticated, multidisciplinary approach to study design enhances patient trial selection and validates results through a “back-to-bench-forward-to-bed approach” – also known as “refined translation” – to minimize risk and cultivate clinical implementation^[17,18]. Thus, to fully explore the possibilities offered by patient-specific 3D-printed scaffolds for the regeneration of large, long bone defects, open and honest exploration and detailed interaction among leading scientists and key stakeholders with expertise from very different research areas who would not come together at traditional discipline-specific conferences, are needed^[14,19,20]. This need echoes the concerns raised by C. P. Snow in his 1959 Rede Lecture at the University of Cambridge. In “The Two Cultures,” Snow highlighted the profound disconnect between individual academic disciplines – a divide that stifles collective progress and impedes applying comprehensive knowledge to real-world issues^[21,22]. Johann Wolfgang von Goethe captured the essence of this dilemma succinctly: “Knowing is not enough; we must apply. Willing is not enough; we must do.”

Guided by this insight, we organized a focused consensus meeting that fostered deep interdisciplinary collaboration and open debate among leaders from various research and clinical fields. This effort has created a unique opportunity to advance the clinical translation of patient-specific 3D-printed implants to regenerate long bone defects, exemplified by the SGBR concept.

Material and methods

The methods are reported in accordance with the Standards for Quality Improvement Reporting Excellence (SQUIRE 2.0) guidelines^[23]. In line with the TITAN Guidelines^[24], no artificial intelligence (AI) tools were used in the research and the manuscript development. Methods of data collection included a combination of research data derived from systematic literature reviews conducted by searching PubMed database (Supplemental Digital Content 1 and Supplemental Digital Content Table 1, available at: http://links.lww.com/JS9/E812), clinical trial registries and clinical guidelines, expert opinion and lived experience, with decision-making through a three-day in-person consensus meeting convened at the Herrenhausen Palace Hannover, Germany, preceded by iterative discussion of guiding questions and collaborative program design. The iterative discussion of the guiding questions and the collaborative program design involved individual meetings and using a website created specifically for the Consensus Meeting on 3D-printed patient-specific Bone Implants (CoMBI) project and accessible to all CoMBI members. Furthermore, the consensus meeting statement draft was distributed to working groups for open review, feedback, and final consensus following the meeting.

Working group

To stimulate disruptive progress in large-scale translation of patient-specific scaffolds for long bone defect treatment, it was sought to recruit a clinically and geographically diverse expert group. Working group members were chosen by the working group chairs to represent disciplines such as clinicians (surgeons and anesthesiologists), biomaterial scientists, biomedical engineers, physiologists, legal/regulatory professionals, health economists, meta-researchers, AI experts, methodologists, trialists, and biomaterial industry members. All members were asked to suggest further experts in their professional networks to participate in the CoMBI project. The selection criteria for achieving the desired group constellation included inviting key leaders based, inter alia, on scientific contribution in their specific specialized communities and academic activity and with relevant leadership roles in their professional associations while also attracting both renowned and aspiring younger experts to the interdisciplinary group. Experts were expected to participate actively in the preparation, execution, and subsequent iterative consensus-finding after the consensus meeting to become part of the expert group. The interdisciplinary working group comprised 34 experts from eight countries. A core project team coordinated and facilitated the project and undertook the supporting research. Disciplines of CoMBI project experts and CoMBI themes are shown in Figure 1.

Figure 1.

Disciplines of CoMBI project experts and CoMBI themes.

Decision-making process

The working group members were invited to join a consensus meeting for the CoMBI project (Supplemental Digital Content Table 2, available at: http://links.lww.com/JS9/E812). The CoMBI project was preregistered with Open Science Framework (OSF)^[25], a free, open-source platform created to help researchers manage, share, and collaborate on research projects across multiple disciplines, promoting transparency and reproducibility in science. First, individual interviews with the majority of the working group members were conducted by the core project team between October 2023 and January 2024. These interviews served to develop clearly defined guiding questions aimed at uncovering hidden barriers to the successful translation of 3D-printed implants for bone regeneration, such as the SGBR concept. In addition, the individual interviews were used to create the workshop program draft. All participants received a glossary of terms and a code of conduct to ensure consistency. The CoMBI project Code of Conduct was developed to ensure an inclusive, respectful, and bias-aware environment, enabling equitable participation across disciplines and backgrounds. In line with SQUIRE principles, it aimed to minimize dominance by any single expert group and foster open, constructive dialogue by promoting safety, mutual respect, and transparent communication throughout the consensus process. Before the consensus meeting, they were also provided with a list of guiding questions (Supplemental Digital Content Table 3, available at: http://links.lww.com/JS9/E812) and the program draft for review and comment to facilitate effective and aligned contributions to the workshop^[2]. Themes were then developed and clustered based on interview and feedback analysis, starting with intuitive, reflective associations among responses, and evolving into clusters of similar or conflicting responses to the guiding questions, or both eventually subsumed in the CoMBI themes. The consensus meeting’s internal website (via Confluence) featured short biographies of all attendees and the final program, which included three main themes: (1) fundamental research, (2) preclinical studies, and (3) clinical trials and implementation.

In the preparatory phase to the workshop, it was discussed if patients or patient representatives should also participate in the consensus meeting to include their opinions and perspectives. Several patient organizations, some from related disciplines such as oncology, were contacted to discuss possible participation (e.g. CCC Allianz WERA, EUPATI). Patient engagement is, however, not well established in orthopedic research^[26] and many researchers in this field and beyond in our interdisciplinary group are not familiar with this approach yet, which is why it was decided for this workshop not to invite patients or patient representatives. Rather it was decided to conduct a satellite workshop to introduce the topic “patient and stakeholder engagement” (PSE) to the participants and to include patients or patient representatives in a subsequent follow-up workshop. Thus, after a short introduction to definitions, models, approaches, and methods of PSE, the participants developed first ideas on the implementation of PSE in research on the treatment of bone defects, and its key findings assigned to the corresponding CoMBI theme.

During the consensus meeting, the participants engaged in small groups through guided group discussions, moderated by facilitators and a professional moderator, with note-takers ensuring all contributions were captured. After the consensus meeting, the core project team summarized all the contributions and identified the areas of tension and consensus. Open questions and opportunities for further research were identified. Based on the meeting minutes and the identified clusters, this consensus statement on CoMBI themes was drafted. The results were reported in the form of a manuscript with specific suggestions from a transdisciplinary perspective. The manuscript was sent to all the participants for review, who commented on and edited it in an iterative revision process. Subject-specific questions were answered by experts in the field, and concerns discussed with individual participants as requested. The quality of evidence pertaining to each of the CoMBI themes was not evaluated. Consensus was defined as agreement by the majority of the participants on the veracity or importance of a statement^[27].

Results

The results highlight a unified effort among working group members and consensus meeting participants to advance orthopaedic implant development, focusing on personalized solutions, interdisciplinary collaboration, and translating innovations from the laboratory to clinical practice (Table 1). The most important calls to action of the CoMBI themes for which consensus was reached are outlined here.

Table 1.

Summary of consensus statements and relevant stakeholders

Fundamental research
The functionality of an implant determines its design characteristics.	Researchers, clinicians, professional societies, patients, patient organizations, state licensing boards, payers, FDA, EMA, CE marking
3D implants of hybrid materials should be patient-specific, (ideally) antimicrobial, osteoinductive, osteoconductive, controlled biodegradable, able to withstand partial loading, and have a porous surface structure – in addition to the general requirements for medical devices.	Researchers, clinicians, FDA, EMA, CE marking
Decentralizing and democratizing 3D printing facilities enable clinicians to adopt a bottom-up approach by exploring a variety of 3D-printed implant solutions at the point-of-care/bedside.	Clinicians, professional societies, policymakers, sponsors, hospital management
It is essential to classify 3D-printed implants according to existing standards.	FDA, EMA, researchers, clinicians, professional societies, industry/sponsors
Standardization of the 3D printing process and terminology among experts is necessary.	Researchers, clinicians, professional societies, FDA, EMA, CE marking, industry/sponsors
GLP-certified laboratories are required for translating 3D print designs.	Researchers, FDA, EMA, CE marking, sponsors, funding agencies
Future efforts should define standards to meet regulatory requirements.	Researchers, FDA, EMA, CE marking, professional societies, regulatory consultant agencies, industry/sponsors
Preclinical studies
More research is needed to understand the physico-bio-chemical processes on implant materials and their interface with tissue.	FDA, CE marking, clinicians, researchers, (industry) sponsors, professional societies
Clinicians should engage with research laboratories to discuss models, stimulate translational research, and foster exchanges	Clinicians, researchers, professional societies
The large animal sheep segmental defect model is current gold standard for assessment of 3D-printed implants for long bone regeneration (SGBR)	Researchers, clinicians, FDA, CE marking
Regarding data management and storage, it is advisable to implement the FAIR principle.	Researchers, sponsors, policymakers, professional societies, FDA, CE marking
Experts needed to plan and execute preclinical studies include biomedical scientists, engineers, clinicians, biostatisticians, regulatory scientists, and quality control personnel.	Researchers, clinicians, sponsors
Internal vs. external vs. translational validity are key factors to account for.	Researchers, clinicians, sponsors, FDA, EMA, CE marking, research funding societies
Patients, patient representatives, and care givers need to be engaged and involved in planning and execution phases of (pre)clinical research.	Clinicians, researchers, payers, professional societies, patients, patient organizations
Clinical trials and implementation
Interdisciplinary collaboration is essential to advance from laboratory research to clinical application.	Researchers, clinicians, training programs, professional societies
Multiprofessional exchanges are both a problem and a solution in clinical trials.	Clinicians, researchers, sponsors, professional societies, state licensing boards, patients, patient organizations
An evidence-based approach through multicenter studies is necessary for clinical proof of concept and guideline recommendations.	Researchers, clinicians, patients, patient organizations, sponsors, FDA, EMA, CE marking
Assessment of methodological feasibility is the first crucial step before planning a large trial.	Researchers, clinicians, sponsors, FDA, EMA, CE marking
It is advisable to set up a pilot or feasibility study within the trial design to test resources at individual clinical trial sites.	Researchers, clinicians, patients, patient organizations, sponsors, FDA, EMA, CE marking
A follow-up meeting with clinicians is required to discuss the target patient group and define clinical efficacy (according to PICO principle).	Clinicians, researchers, professional societies

Fundamental research

Existing bone reconstruction techniques, such as the Masquelet method, show limitations, including graft resorption and infection rates, which demand innovative approaches to enhance the osteo-environment and leverage natural bone growth processes. Thus, researchers have a consensus that significant advancements in the development of orthopedic implants are required to address the limitations of current solutions. Current implants often face challenges such as wear, corrosion, and infection, which necessitate the development of personalized, long-lasting alternatives. Utilizing computed-tomography data for 3D modeling has been identified as a key method for creating patient-specific implants that improve quality control during surgeries. To sustainably achieve high-quality 3D-printed implants, there is consensus on the need for standardization of terminology and printing processes across the industry to ensure consistency and reliability in implant production.

Guideline committees, such as VDI 5708 on bioprinting^[28,29] are an example of how expert-driven standardization can serve as a basis for regulatory convergence. Harmonized regulatory pathways should include aligned definitions, shared evidence requirements, and coordinated efforts. Based on the input of complementary experts (e.g. research institutions, manufacturers, users, audit companies), standard-setting bodies such as ISO develop international standards that can be used by regulatory bodies to harmonize their regulations. EMA and FDA have to incorporate certain ISO standards into their regulatory frameworks where relevant.

Preclinical studies

The importance of optimizing preclinical studies through interdisciplinary collaboration is widely acknowledged. Researchers emphasize the need to understand (long-term) internal implant processes when exposed to the human biological environment. Furthermore, the necessity for effective data management, applying the FAIR principles – ensuring data is Findable, Accessible, Interoperable, and Reusable^[30] – was highlighted. Among the experts, there is consensus that to operationalize the FAIR principles, it is encouraged to utilize established metadata standards, publicly accessible data repositories, and persistent identifiers (e.g. DOIs) for datasets. For the practical implementation of FAIR principles, specific literature was referenced^[31]. Additionally, applying open-source data management tools and adhering to community-developed ontologies can significantly enhance data interoperability and reusability. Furthermore, experts agree on the necessity of incorporating biomedical scientists, engineers, trialists, veterinarians, and clinicians in study designs to increase the likelihood of success for translation, to improve translational validity and mitigate biases through proper randomization and control group usage. Additionally, engaging with patients and caregivers from the early stages of research is crucial for aligning study designs with clinical needs, enhancing mutual understanding, and improving recruitment outcomes.

Clinical trials and implementation

There is a shared understanding that interdisciplinary collaboration is essential for translating laboratory innovations into clinical practice. Effective communication between researchers and clinicians is identified as both a challenge and a potential solution for the development and successful execution of clinical trials. Multicenter studies are considered vital for establishing clinical proof of concept, with careful planning and feasibility assessments/trials being critical steps in advance of larger, confirmatory phase III trials. Experts advocate for the implementation of pilot phases to assess resource allocation and feasibility at individual trial sites, generating critical insights to inform the design and execution of larger clinical trials aimed at rigorously evaluating the efficacy of the proposed strategies. Furthermore, pragmatic trial designs, tailored to specific patient populations and consideration of the complex regulatory environment are essential. The role of international networks and collaborations is recognized as crucial for maximizing the success of such studies. These collaborations should address various operational, legal, economic, and regulatory challenges to ensure broad generalizability of received findings and facilitate the successful translation of 3D-printed implants for bone regeneration research into clinical practice. Engaging patients throughout the process and utilizing adaptive strategies to enhance trial outcomes are also emphasized as key components for long-term success and acceptance of novel implants from key stakeholders.

Discussion

Cultivating and deepening cross-disciplinary collaborations among experts from different fields willing to explore current options and future possibilities for treating (long) bone defects is critical to (cost-) effective healthcare. This is particularly significant considering that global spending on bone reconstruction is estimated to be around USD 17 billion annually^[32]. Moreover, the market for bone grafts and substitutes is expected to expand at a compound annual growth rate of 5.8% between 2021 and 2028, potentially reaching USD 4.3 billion by the end of that period^[33,34]. Different professional groups, such as surgeons and scientists, have expertise in very different areas based on their academic and practical training^[19]. The day-to-day work of both professions is equally specific, they regularly interact with working groups with different expertise and commercial interests from the healthcare sector and may even have different conceptual and scientific perspectives^[35]. In order to directly support the successful research and translation of innovations in the field of biomaterials and 3D-printed implants for bone defects such as the SGBR concept, our translational research CoMBI project working group organized a dedicated interdisciplinary consensus meeting and conducted it in February 2024^[20,25]. Thus, leading experts from diverse disciplines convened in a consensus meeting to collaboratively address translational challenges by contributing their perspectives and potential solutions, independent of institutional agendas or obligations, and outside the constraints of their routine professional responsibilities^[36,37]. Through an interdisciplinary approach in an open large group as well as in several guided small group discussions, the goals of the consensus meeting were achieved. These goals included identifying barriers and agreeing on measures to bridge the translational and implementation gaps in the field of patient-specific 3D-printed implants for bone regeneration. Identification of the (translational) challenges was facilitated by the interdisciplinary nature of the consensus meeting, where renowned experts from multiple fields identified and discussed the strengths, weaknesses, opportunities, and threats from their respective perspectives.

A particularly challenging aspect of translational research is the disappointingly low success rate of translating preclinical models to human applications. A systematic review revealed that only around 33% of 67 highly cited animal research studies were successfully replicated in published randomized human clinical trials^[38]. Due to the uncertain nature of translational science, extrapolating results from animal research to human diseases should thus occur stepwise and be done cautiously when making claims about treatment approaches^[39]. Some even argue that the entire concept of predicting human outcomes from animal research is fundamentally flawed^[40]. This perspective is reinforced by distinct molecular, genetic, and physiological differences that cannot be experimentally bridged, along with philosophical reasoning that highlights the inherent unpredictability of complex systems such as animals and humans^[41]. Additionally, animal-to-human predictability has yet to be scientifically validated. Moreover, critics contend that animal models are outdated and irrelevant^[42], having been replaced by new and improved methods, such as digital twins, in silico physiology, and organ-on-chip test beds. Although there is not enough evidence to make a strong statement about these approaches being superior to animal models^[43].

Indeed, in line with the CoMBI consensus, literature^[44] shows that many medical research advances have heavily depended on predictable animal outcomes, demonstrating their importance in developing drugs and devices that benefit humans. However, it is important to recognize that many existing animal models used in biomedical research face criticism and scrutiny. Establishing clear criteria to assess the validity of improved models is crucial, and the research community has a responsibility to refine best practices for their implementation and ongoing advancement^[45,46]. For the specific context of the CoMBI project (3D-printed implants for bone regeneration focusing on long bones/SGBR), the sheep model with segmental bone defect has emerged as a useful instrument for a non-human study model, as it demonstrates similar mechanistic disease and healing signaling and regeneration pathways^[47,48]. It has been argued that both external validity (verified translation to other researchers and study groups) and internal validity (reproducible design, competent execution, critical analysis, and unbiased reporting) are essential. Therefore, the translational reliability of findings from animal models to humans depends on preclinical studies that establish both internal and external validity^[40,49]. There is consensus within the expert group that validated large animal models in sheep^[50–54] demonstrate good internal validity, though there is room for improvement in external validity. To address this, it is particularly recommended that multicenter preclinical in vivo studies need to be conducted^[36]. This approach aligns with current government funding strategies, where the allocation of third-party funds is increasingly linked to the funding of (confirmatory) large animal studies, among other initiatives^[55,56].

A comprehensive expert-level understanding of each medical challenge – its causes, progression, and the reliable translation of preclinical methodologies and data into clinically relevant contexts – is often necessary for progressing from preclinical testing to clinical validation^[2]. Notably, it is in line with the consensus of the CoMBI project that many clinical innovations now begin and evolve within academic labs, bringing new regulatory challenges^[57] and translational dimensions that need to be addressed. Future research activities on country-specific contexts developing tailored strategies would benefit from providing practical guidance on harmonizing regulatory pathways for the respective national implementation strategies. Thus, importantly, junior researchers should be trained specifically to develop the mindset and skills needed for translational medicine strategies and the associated regulatory components^[18,58]. Transforming healthcare to incorporate cultural changes, economic incentives, and necessary infrastructure demands substantial transformation^[59] rather than mere translation. Without such comprehensive change, as the broad opinion expressed at the consensus meeting, medical progress will be hindered, obstructing the translation of current biomedical advancements into future clinical realities. In order to achieve broad acceptance and affordability of patient-specific implant planning in a democratic and decentralized fashion, while considering the patient’s individual anatomy and biomechanics, initial software solution strategies are available^[12,13]. In the opinion of the experts, these strategies should be pursued, particularly with a focus on effectively implementing future multidisciplinary international clinical trials.

In particular, novel 3D-printed implants and SGBR concepts for (long) bone regeneration require clinical trials to address medical issues relevant to humans. It should be noted that national regulatory bodies require this evidence for approval of human use. Nowadays, randomized controlled trials represent the gold standard to evaluate the clinical evidence for new technological strategies and remain the preferred method for assessing the safety and efficacy of new interventions. However, the COVID-19 pandemic exposed many of the inherent limitations in conducting trials^[60] and forced the clinical trial research enterprise to re-evaluate all processes – disrupting, catalyzing, and then accelerating innovation in the field^[61,62]. Insights gained should guide researchers in designing and implementing the next generation of clinical trials with a focus on patient-centered approaches^[63]. Innovative approaches in clinical research that aim to improve the efficiency, flexibility, and effectiveness of studies are referred to as novel clinical trial designs^[64,65]. Importantly, any strategy to accelerate the evidence germination path should be supported. This can be facilitated in the future by utilizing real-world evidence and large registries^[66–69]. Within the CoMBI project, there is consensus that these concepts overcome some of the limitations of traditional clinical trials, such as high costs, long durations, and rigid structures, and facilitate adaptation to the complexity of modern medical research.

Moreover, ethical considerations are central to the clinical translation of (biodegradable) 3D-printed scaffolds for long bone defects, especially given the lack of sufficiently powered clinical trials registered to date^[11]. As Hollister and Murphy^[70] emphasize, large-scale studies require clear definitions of therapeutic goals and implant roles. Surgeons must demonstrate safety and added clinical value before human use^[11,71], and novel implants should undergo risk and needs assessments akin to phase III drug trials^[72–74]. Current literature highlights the growing importance of prospective trials for non-pharmacological interventions^[75], a perspective further supported by early clinical successes with 3D-printed scaffolds^[5,76–78]. The convergence of additive manufacturing and bone tissue engineering has initiated a new era in bone healthcare^[79], enabling the use of patient-specific, anatomically tailored 3D-printed implants – such as those applied in SGBR – for the customized restoration of defective or dysfunctional skeletal tissue. In this context, it is essential to investigate the long-term interplay between the biological degradation products and the therapeutic efficacy of biodegradable bone scaffolds in humans. In the field of bone tissue engineering, these novel therapeutic strategies are considered “experimental treatment approaches” that according to the expert’s consensus require the transparent involvement of all stakeholders, including patients and their family members, and formal and informal healthcare providers. Patient and Stakeholder Engagement (PSE) refers to the active and collaborative involvement of patients and relevant stakeholders – such as family members and healthcare providers – throughout the research process, ensuring that their unique experiences, values, and insights help guide research decisions in a meaningful and contextually relevant way^[80–83]. During the workshop, the concept of PSE was elaborated, and experts reached consensus that integrating PSE including patient representatives into the planning and conduct of future clinical trials as well as discussion of risks and benefits of specific novel implant technologies will be essential for ethical, evidence-based progress. Thus, future (pre)clinical studies should consider aspects of PSE throughout all project phases and novel design aspects such as adaptive trials, platform trials, basket trials, umbrella trials and pragmatic trials aiming to improve the speed, precision, and applicability of clinical research, making 3D-printed implants and SGBR concept projects more responsive to the evolving landscape of the needs of patients with complex (long) bone defect. The novel trial designs are particularly relevant for these patients, as they present less frequently and would therefore lead to a longer recruitment period^[84,85].

Strengths and limitations

We are confident that this study possesses several strengths. All consensus meeting participants were not only experts in their respective fields but also had access to preparatory information. They were actively involved in the decision-making process, ensuring a deep “immersion in the field” that enhanced the study’s credibility^[27]. Furthermore, input was actively solicited from all participants by the working group chairs and the professional moderator during discussions, capturing a diverse range of opinions. In particular, the guidance of the professional moderator ensured that each involved expert representing a certain discipline had an equal opportunity to contribute their expertise to the development of the consensus statements. The validity of the results was further reinforced through iterative member checks of the consensus statement. Moving forward, the working group will not only support other research groups in implementing the CoMBI theme action points but will also revise these statements as needed during future biennial update meetings. Future update meetings may refer to this interdisciplinary consensus statement paper, which contains specific recommendations for a diverse group of stakeholders and serves as a basis for proposals on multicenter international research collaborations and funding applications.

We also note limitations. Due to the professional contexts of the working group members and consensus meeting participants, the findings are predominantly relevant to Western, educated, industrialized, rich, and democratic settings. This work represents the initial phase of developing a framework to facilitate the clinical translation of 3D-printed, patient-specific bone implants; however, the project did not address the distinct management challenges inherent to such a complex endeavor. Moreover, ongoing dialogue should include a broader range of stakeholders, including government, patient organizations and the broader society representatives, to ensure more comprehensive representation from both public and private sector entities. Meanwhile, public funding agencies support not only national but also international funding for both public and private applicants, thereby facilitating multicenter international research collaborations among a broader range of diverse stakeholders.

Conclusion

Three-dimensional-printed, patient-specific bone implants have demonstrated the capacity to facilitate complete regeneration of extensive bone defects and restore full functional activity in affected patients. Nevertheless, the clinical translation of this innovative technology continues to fall short of expectations. Through the concerted efforts of the CoMBI project, this consensus statement presents a structured framework comprising 20 key statements across fundamental research, preclinical studies, and clinical trials and implementation, providing an urgently required roadmap to advance the translation of 3D-printed patient-specific bone implants into clinical practice. Thus, this paper is the first to present a comprehensive, multidisciplinary consensus on actionable strategies for bridging the translational gap in 3D-printed bone implant development, integrating perspectives from a uniquely broad expert panel. The findings emphasize the critical role of interdisciplinary collaboration in overcoming long-standing challenges, such as standardizing implant development and navigating complex regulatory landscapes. Looking ahead, advancing the clinical translation of 3D-printed patient-specific implants will require sustained investment in scalable manufacturing processes, harmonized regulatory frameworks, and high-quality clinical evidence generated through innovative, interdisciplinary trial designs. By addressing these barriers and outlining practical strategies, the consensus highlights actionable steps to bridge the gap between innovation and clinical application, offering transformative potential for treating patients with complex long bone defects.

Ethical approval

Not applicable.

Consent

Not applicable.

Sources of funding

Travel and meeting expenses for the consensus meeting held at the Xplanatorium Herrenhausen Palace, Hannover (Germany) were provided by the Volkswagen Foundation (funding scheme: “Scoping workshops”).

Author contributions

Dr Laubach had full access to all of the study’s data and took responsibility for its integrity and accuracy. concept and design: Dirnagl, Drude, Frankenbach-Désor, Holzapfel, Hutmacher, Laubach, Marmitt, van Griensven, Weimer, Wehrle, Weschke; acquisition, analysis, or interpretation of data: Baumgartner, Burgkart, Cheers, Cidonio, D’Este, Dirnagl, Eschweiler, Frankenbach-Désor, Friebe, Ganse, Hartmann, Hildebrand, Holzapfel, Hutmacher, Kim, Laubach, Łojkowski, Marmitt, Praster, Reimers, Schenke-Layland, Schulz, Spicher, Stoppe, Toelch, van Griensven, Weimer, Wehrle; drafting of the manuscript: Cheers, Frankenbach-Désor, Laubach, Weimer; critical review of the manuscript for important intellectual content: Baumgartner, Böcker, Burgkart, Cidonio, D’Este, Drude, Eschweiler, Friebe, Ganse, Hartmann, Hildebrand, Hoog Antink, Holzapfel, Hutmacher, Kim, Kneser, Mayer-Wagner, Łojkowski, Marmitt, Praster, Reimers, Schenke-Layland, Schulz, Spicher, Stoppe, Toelch, van Griensven, Wehrle, Weschke; obtained funding: Dirnagl, Drude, Ganse, Hoog Antink, Holzapfel, Hutmacher, Kneser, Laubach, Mayer-Wagner, Schenke-Layland, Stoppe, Weschke; administrative, technical, or material support: Baumgartner, Böcker, Hartmann, Holzapfel, Hutmacher, Laubach, Mayer-Wagner, Spicher, Weimer, Weschke; supervision: Dirnagl, Holzapfel, Hutmacher, Laubach, Mayer-Wagner.

Conflicts of interest disclosure

Prof. D. W. Hutmacher is a cofounder of both BellaSeno GmbH and Osteopore International. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest. The funder (Volkswagen Foundation) had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Research registration unique identifying number (UIN)

Not applicable, as this study did not involve human subjects. Nonetheless the CoMBI project was preregistered with OSF, a free, open-source platform created to help researchers manage, share, and collaborate on research projects across multiple disciplines, promoting transparency and reproducibility in science, https://osf.io/7jk2c.

Guarantor

Dr Markus Laubach had full access to all of the study’s data and took responsibility for its integrity and accuracy.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

The data supporting the findings of this study are available from the corresponding author upon reasonable request.