Bridging clinical integration and regulatory compliance in 3D printing: a hybrid model for university-based manufacturing of custom-made medical devices

The rapid expansion of 3D printing in healthcare has enabled new paradigms in personalized medicine, particularly in the development of custom-made medical devices. However, in the European context, the integration of point-of-care additive manufacturing into routine clinical practice remains limited by the complexity of the Medical Devices Regulation (EU) 2017/745 (MDR), which poses significant challenges for hospital- and university-based laboratories in achieving regulatory compliance while preserving clinical integration. This study describes a real-world implementation of a hybrid organizational and regulatory model within the 3D Innovation Lab of Humanitas University (Milan, Italy), designed to bridge the gap between clinically embedded 3D printing activities and regulated medical device manufacturing. A top-down, regulatory-driven approach was adopted, based on the interpretation of MDR requirements and the implementation of ISO 13485 and ISO 14971 standards within a fully digital Quality Management System (QMS). The model integrates structured regulatory decision-making, formalized roles and responsibilities, and adapted design control, risk management, validation, and production processes tailored to a clinician-driven, custom-made workflow. The implementation resulted in ISO 13485 certification and formal registration as a manufacturer of custom-made medical devices under Annex XIII MDR. Key outcomes include: (i) the implementation of a regulatory decision framework enabling the systematic classification of in-house, custom-made, and CE-marked regulatory pathways within the broader point-of-care manufacturing landscape; (ii) the integration of clinical and manufacturing processes within a unified QMS, ensuring traceability and regulatory compliance across the device lifecycle; (iii) the ability to design, manufacture, and supply Class I and IIa custom-made devices to both internal and external healthcare institutions. Moreover, preliminary observations of this system have demonstrated clinical relevance in complex surgical scenarios, improving preoperative planning accuracy and enabling advanced patient-specific applications with a high precision surgical act, however comparative effectiveness data demonstration is still ongoing. These findings demonstrate the feasibility of combining clinical integration and regulated manufacturing within a single governance structure. The proposed hybrid model represents a structured and potentially replicable framework for advancing regulatory maturity in university-based 3D printing, supporting the transition from experimental point-of-care activities to sustainable, compliant medical device production.

The rapid diffusion of 3D printing in healthcare has substantially expanded the possibilities of personalized medicine, particularly in surgical planning, anatomical modelling, and in the development of custom-made devices (Mansour et al., 2025a; Beitler et al., 2022; Schulze et al., 2024). Over the last decade, point-of care 3D printing labs have increasingly demonstrated their clinical value by enabling close interaction between engineers and clinicians and by reducing the distance between design and bedside application (Mansour et al., 2025a; Beitler et al., 2022). The increasing diffusion of 3D printing point-of-care laboratories reflects the broader evolution toward personalized medicine, an approach that moves beyond the traditional “one-size-fits-all” paradigm and instead promotes the development of patient-centered and patient-specific healthcare solutions (Vaz and Kumar, 2021).

Typical applications addressed within this context include custom-made anatomical models for surgical planning and custom-made surgical guides, developed for complex clinical scenarios such as orthopedic, oncological, hepatic and cardiovascular surgery. These applications often require close clinician–engineer interaction and rapid iterative design processes, making them particularly relevant for point-of-care and university-based manufacturing environments (Helmer et al., 2023).

However, in Europe, the full clinical and organizational deployment of these activities remains constrained by the complexity of the regulatory framework established by the Medical Devices Regulation (MDR) 2017/745 (EU) (Garnier and Maingon, 2017; Adalbert et al., 2022; Cecc et al., 2026), especially when additive manufacturing is performed within healthcare institutions rather than by traditional industrial manufacturers (European Parliament and the Council of the European Union, 2017). In particular, Article 5 (5) of the MDR defines the conditions under which health institutions can manufacture and use medical devices in-house, while Annex XIII regulates custom-made medical devices, introducing specific requirements in terms of documentation, traceability, and compliance (European Parliament and the Council of the European Union, 2017).

Under the MDR framework, a clear distinction must be made between custom-made, patient-matched and adapted medical devices. According to Article 2 (3) MDR, a custom-made device is specifically manufactured in accordance with a written prescription from an authorized healthcare professional and intended to address the particular anatomical or pathological conditions of an individual patient (European Parliament and the Council of the European Union, 2017). Patient-matched devices, as clarified in MDCG 2021–3, are medical devices manufactured using patient-specific data within a predefined design and manufacturing process (European Commission and Medical Device Coordination Group, 2021). Adapted devices, by contrast, are existing medical devices modified after production without creating a completely new device. These distinctions are particularly relevant in the context of point-of-care 3D printing, where personalized geometries alone are not sufficient to define a device as custom-made. In this setting, regulatory qualification depends on the role of the clinician in defining the patient-specific requirements and on the extent to which the design and manufacturing workflow remains individualized rather than standardized. In parallel, Article 5 (5) MDR regulates the conditions under which healthcare institutions may manufacture and use devices in-house, representing a regulatory pathway distinct from the custom-made framework described in Annex XIII MDR (European Parliament and the Council of the European Union, 2017).

This regulatory complexity has contributed to a gap between the practical growth of point-of-care 3D printing and the availability of operationally mature, fully compliant organizational models (Mansour et al., 2025a). These challenges are not limited to Europe but are observed globally in the regulatory integration of point-of-care 3D printing (Beitler et al., 2022; U.S. Food and Drug Administration FDA, 2021).

In this context, the adoption of structured quality management systems becomes essential. ISO 13485 represents the international standard for quality management systems in the medical device sector, providing a framework for design control, production processes, documentation, traceability, and post-market surveillance (Inte rnational Organization for Standardization). In parallel, ISO 14971 establishes the principles for risk management throughout the entire lifecycle of medical devices, ensuring a systematic approach to hazard identification, risk evaluation, and mitigation (International Organization for Standardization, 2016). The integration of these standards is particularly relevant in complex environments such as university-based 3D printing laboratories, where clinical, technical, and regulatory activities coexist (Mansour et al., 2025a).

This work aims to describe the implementation of a structured and operational strategy tailored to 3D printing facilities within or in close collaboration with healthcare institutions. This is based on what we define as a hybrid model within the 3D Innovation Lab, Humanitas University, Milan, Italy: a university-based facility closely integrated with the IRCCS Humanitas Research Hospital in Rozzano and part of a wider hospital network. Unlike a purely in-house model limited to a single site (which in our case would be Humanitas Rozzano), this approach enables the design and supply of custom-made solutions across multiple centers. The 3D Innovation Lab consists of a university-based laboratory, ISO 13485 certified, which operates as a manufacturer of custom-made medical devices in accordance with Annex XIII of the MDR, with the ability to design and supply custom-made solutions also to third-party healthcare institutions. Within this framework, the 3D Innovation Lab primarily operates as a manufacturer of custom-made medical devices under Annex XIII MDR, while the references to in-house and CE-marked pathways are intended to contextualize alternative regulatory and organizational models within the broader point-of-care manufacturing landscape. Furthermore, a close integration with clinical practice (analogous to that of an in-house setting), a clinical–academic collaboration, and a regulatory organization typical of a medical device manufacturer have been maintained.

The originality of this contribution lies in presenting not a theoretical framework, but a real organizational case in which quality, regulatory strategy, design control, production governance, and post-market processes have been concretely integrated into a functioning structure.

Study design and strategic planning

This study is a descriptive case study of the implementation of, to the best of our knowledge, the first Italian hybrid university-based model for custom-made medical devices within the 3D Innovation Lab of Humanitas University. The implementation started in December 2024 and was conceived as the progressive transformation of a university-based 3D printing laboratory into a regulated manufacturing environment capable of preserving direct clinical integration.

The project was not conceived as the creation of a separate industrial entity detached from the clinical environment, but rather as a model able to combine clinical proximity with regulatory and quality compliance.

The strategic direction of the project was defined through a qualitative evaluation of alternative organizational models, including. clinical investigations,

purely hospital-based (in-house) configurations,

fully industrial manufacturing approaches,

CE-marked devices.

This evaluation considered key parameters such as regulatory compliance, clinical integration, operational flexibility, and scalability.

The starting point of the methodology consisted in a detailed analysis of the European Medical Device Regulation (MDR 2017/745) (Cecc et al., 2026), MDCG guidance documents and the ISO 13485:2016 standard (Inte rnational Organization for Standardization), with particular attention to their implications when applied to custom-made medical devices. In parallel, ISO 14971 (International Organization for Standardization, 2018) was considered as the reference framework for risk management across the entire device lifecycle. The selection of the applicable regulatory pathway was based on the interpretation of MDR definitions and guidance documents, particularly Article 2 (3) MDR, Article 5 (5) MDR, Annex XIII MDR and MDCG 2021–3. The analysis considered the intended use of the device, the role of clinician prescriptions in defining patient-specific requirements, the degree of design individualization, the presence or absence of standardized design envelopes, and whether the device was intended exclusively for internal institutional use or also for external supply. Afterwards, for the Quality Management System (QMS) construction we were supported by an external consultant (QasE3D | Quality in medical 3D printing, Ittervoort, Netherlands), who assisted us in structuring digital documentation.

Quality management system construction

Based on this regulatory and normative analysis, the QMS was progressively designed and implemented with the objective of covering all processes relevant to the realization of custom-made medical devices, from design input definition to post-market activities.

Rather than replicating an industrial production model, the system was specifically structured to reconcile the requirements of ISO 13485 with the characteristics of a university-based, clinician-driven, custom-made workflow.

A key methodological choice was the development of a fully digital QMS architecture. A document management system (Confluence, Atlassian, Australia) was adopted not only for document control, but as an integrated environment for managing procedures, records, quality objectives, reviews, and continuous improvement actions. This approach enabled the transformation of compliance from a static set of documents into a dynamic and traceable system, in which updates, revisions, and process feedback are continuously integrated.

To ensure independent verification of QMS implementation and compliance with ISO 13485:2016 requirements, the notified body IMQ (Istituto italiano del marchio Qualità, Milano, Italy) was engaged to conduct a comprehensive third-party audit of the system. The audit was structured according to ISO 13485:2016 certification requirements and comprised two distinct stages, each designed to verify different aspects of QMS maturity and operational implementation.

Phase 1: Document Review. In the first stage, the notified body conducted a desk-top review of all QMS documentation to assess the completeness and adequacy of documented procedures and processes. This stage included evaluation of design control procedures, risk management approach, manufacturing specifications, post-market surveillance plans, and organizational procedures for complaint handling and CAPA (Corrective and Preventive Action).

Phase 2: On-Site Verification. In the second stage, and auditor team identified by the notified body conducted an on-site visit to the facilities to verify that the documented QMS was operationally implemented and functioning effectively.

To ensure QMS compliance with ISO 13485:2016 prior to certification, a structured workflow was implemented to identify, analyze and resolve any non-conformities or observations identified during the audit process. This documented workflow comprises five sequential phases: identification, registration, root cause analysis, corrective action planning and implementation, and verification. Identification: Multiple sources, including external and internal auditors during on-site audits and the internal Quality team during QMS implementation and internal process monitoring, identify aspects where the QMS fails to comply with established procedures, quality requirements, contractual obligations, or applicable standards, defined as non-conformities. All identified observations are documented in a formal Non-Conformity Report (NCR) template.

Assignment and Root Cause Analysis: Each non-conformity is assigned, based on the nature of the observation, to the appropriate department lead, which conducts formal root cause analysis to determine whether the non-conformity reflected a systemic QMS gap or an isolated implementation issue. Root cause analysis findings are documented.

Corrective Action Planning and Implementation: Based on root cause analysis, specific corrective actions are planned to address both the immediate non-conformity and underlying systemic factors. Corrective actions include procedure revisions, template modifications, training activities, and retroactive documentation updates. Implementation was performed according to documented timelines with evidence retained within the QMS.

Verification: The Quality Manager verifies that corrective actions are completed as planned and that implementation evidence supports closure. Non-conformities are formally closed in the NCR register only after verification. This structured approach ensures both regulatory compliance and identification of potential points of failure within the QMS framework for future prevention.

From an organizational perspective, the implementation required the formal definition of roles, responsibilities, and authorities in alignment with all the aspects required for custom made medical devices fabrication.

Process and clinical validation framework

To ensure the repeatability and reliability of the entire manufacturing workflow, a comprehensive, multi-stage validation framework was implemented within the QMS. At the technical level, critical phases of the workflow (including imaging segmentation, CAD design, 3D printing parameters, and post-processing quality control) undergo structured, documented validation protocols with explicit, predefined acceptance criteria. These process validations are established as essential components of the ISO 13485 QMS and are systematically maintained as design control records throughout the device lifecycle to guarantee that the equipment, software, and operators consistently produce devices within specifications.

To complement this technical infrastructure and assess the clinical outcome layer, a structured satisfaction questionnaire was developed to systematically collect prospective feedback from the treating surgeons upon device delivery and clinical use. This multi-layered approach ensures that both technical manufacturing precision and clinical performance are rigorously monitored.

Registration as manufacturer of custom-made medical devices

In parallel with the QMS implementation, a structured analysis of the requirements for qualification as a manufacturer of custom-made medical devices under the MDR was conducted. This included the identification of applicable regulatory obligations, documentation requirements, and organizational prerequisites, as well as national obligations such as registration in the Italian Ministry of Health list of custom-made manufacturers (Annex XIII MDR) (European Parliament and the Council of the European Union, 2017).

In Italy, manufacturers with legal headquarters in the country are required to register with the Ministry of Health and communicate information regarding custom-made medical devices placed on the market, according to the national implementation framework of Regulation (EU) 2017/745 established by Legislative Decree No. 137/2022 (Italian Government, 2022) and the requirements of the Italian Ministry of Health medical device registration system (Italian Ministry of Health, 2026), in alignment with Annex XIII MDR requirements. Prerequisites for registration included implementation of a documented QMS, compliance with Annex XIII MDR requirements regarding technical documentation, traceability, and post-market surveillance, and the designation of a Regulatory/Compliance Officer in accordance with Article 15 MDR (European Parliament and the Council of the European Union, 2017).

Although administrative procedures may vary across European countries, including registration platforms, competent authorities responsible for adverse event communication, and language requirements for technical documentation, the overall regulatory framework remains harmonized under the MDR. Consequently, a manufacturer registered in one EU country may supply devices throughout the European Union in accordance with MDR requirements (European Parliament and the Council of the European Union, 2017).

On this basis, a stepwise plan was defined to ensure compliance with regulatory requirements, including the alignment of QMS processes, the implementation of technical documentation, and the establishment of traceability and post-market surveillance systems.

Overall, the methodology can be described as a top-down, regulatory-driven implementation, in which MDR requirements and ISO standards are first interpreted, then translated into quality procedures, and finally embedded into a digital and operational system tailored to a university-based context.

Outcome categorization

The implementation process described above led to a series of results that will be presented in the following paragraph. They are related to: regulatory and certification achievements; implementation of a lifecycle-based QMS and regulatory decision framework, including risk classification integration; organizational integration and digital QMS traceability; optimization of operational efficiency and expansion of external collaborations; clinical impact in terms of clinician feedback and improved surgical planning within a controlled manufacturing context.

Implementation of lifecycle-based QMS adaptation

A key result of the implementation was the successful adaptation of standard quality management principles to the specific requirements of custom-made medical device production in a clinically integrated environment. This adaptation was operationalized across the main phases of the device lifecycle, as summarized in Figure 1.

The figure also contextualizes a broader regulatory landscape, with pathways such as CE-marked device development (as documented in real-world implementations (Materialise, 2021; Pettersson et al., 2024)) and clinical investigation (outlined in regulatory guidance (BSI Group, 2021) and applied in various practical cases (ClinicalTrials.gov, 2026; European Commission, 2026)): although these were not selected as primary strategies in this implementation due to their lower compatibility with a flexible, case-driven, clinically integrated workflow.

At the same time, the implemented hybrid model incorporates selected elements from both university-based and industrial approaches. The result of the implementation was dual from the outset: on the one hand, to maintain the advantages of university-based additive manufacturing, namely, proximity to surgeons, rapid iteration, and translational flexibility; on the other hand, to introduce a level of quality, regulatory control and commercial potential comparable to that of an industrial manufacturer.

The entire workflow is shown in Figure 2.

In the intake and planning phase, clinical needs were systematically translated into formalized and traceable design inputs within the QMS framework.

During the design phase, the iterative clinician–engineer interaction typical of hospital settings was preserved, while being structured within formal design control processes. Clinical feedback was integrated into design review, verification, and change control activities aligning a flexible, case-driven process with ISO 13485 requirements.

In this workflow, clinicians played a central role in defining patient-specific anatomical and surgical requirements, directly guiding the individualized device development process. This differs from conventional industrial CE-marked manufacturing approaches, where device design is generally developed within predefined specifications and standardized production workflows.

For risk management and validation, the approach extended beyond a device-centered perspective to encompass the entire clinical–technical workflow, from imaging and segmentation to production and clinical application, enabling validation of the integrated process chain.

In the production and supplier control phase, industrial-level requirements such as material traceability, supplier qualification, and process control were implemented while maintaining the flexibility required for case-driven production.

For materials intended for the production of medical devices requiring patient contact, supplier qualification procedures also included verification of biocompatibility certifications according to ISO 10993 requirements (International Organization for Standardization, 2019), ensuring consistency between selected materials and their intended clinical application.

Finally, post-production activities, including device release, documentation, traceability, complaint handling, and CAPA processes, were integrated into a structured post-market surveillance system, incorporating direct clinical feedback.

Overall, this lifecycle-based adaptation demonstrates how a traditionally industrial QMS framework can be effectively translated into a clinician-driven, custom-made production environment.

Regulatory and certification outcomes

The implementation of the hybrid model, whose timeline is presented in Figure 3, resulted in the achievement of ISO 13485 certification (3 November 2025) and formal registration with the Italian Ministry of Health as a manufacturer of custom-made medical devices under Annex XIII MDR (5 November 2025).

ISO 13485:2016 certification was awarded by IMQ, a renowned Italian notified body accredited for quality management system audits. The certification audit process resulted in 0 major non-conformities, 0 minor non-conformities and two recommendations.

To the best of our knowledge, this represents one of the first documented Italian cases of a university-based 3D printing laboratory operating under a certified Quality Management System (QMS) while being authorized to manufacture and supply custom-made medical devices.

This regulatory positioning enables the design, production, and distribution of Class I and IIa devices both within the host institution and to external healthcare providers, extending the operational scope beyond the limitations of in-house manufacturing under Article 5 (5) MDR.

Implementation of a comparative regulatory framework

A structured regulatory decision logic was operationalized to translate MDR requirements into actionable workflows (Figure 4). Intended use was established as the primary decision node, enabling the classification of products into non-medical or medical categories. Medical devices were further stratified into three regulatory pathways. in-house devices (Article 5 (5) MDR),

custom-made devices (Annex XIII MDR),

CE-marked devices (general MDR framework).

The pathways presented in Figure 4 represent the broader regulatory landscape considered during the development of the hybrid model.

The proposed hybrid model should therefore not be interpreted as the simultaneous operational implementation of multiple regulatory pathways, but rather as a custom-made Annex XIII manufacturing framework strategically developed through the comparative evaluation of alternative organizational and regulatory approaches, including in-house and conventional CE-marked models.

Considering the class of devices designed and produced by the 3D Innovation Lab, anatomical model for surgical pre-planning and intra-operative surgical jigs designed from patient data, according to the definitions provided in the MDR and the additional means to define custom-made, patient-matched and adaptable medical devices, the only viable regulatory pathway is the one explained in Annex XIII, while in-house and CE-marked pathways were analyzed as alternative regulatory and organizational approaches for comparison and strategic positioning purposes.

This framework allowed the systematic identification of applicable regulatory obligations, documentation requirements and quality controls from the earliest stages of the design process, reducing ambiguity in regulatory classification and improving process standardization.

In the evaluation of in-house pathways under Article 5 (5) MDR, particular attention was given to the conditions limiting such devices to internal institutional use without market placement. Among the limitations imposed by the Article 5 (5) MDR that could not be applicable in the workflow of the 3D Innovation Lab, the most notable ones are: devices must not be transferred to another legal entity

the healthcare institution must justify in its documentation the fact that the specific needs of the targeted patient group cannot be met or cannot be met with results of the appropriate level by an equivalent device available on the market;

the health institution shall provide on request to its competent authority information regarding the use of such devices which includes a justification of their manufacture, modification and use;

The responsibility of the device, even though modified by mean of what decided by the surgeon, is on the manufacturer.

Additionally, since the implemented model included the manufacture and supply of custom-made devices to external healthcare institutions, the Article 5 (5) pathway was considered organizationally informative but not applicable as the primary regulatory framework. Consequently, Annex XIII MDR was selected as the operational regulatory pathway for the implemented model.

In particular, the qualification of devices as custom-made was based on case-specific clinician prescriptions and on the absence of predefined standardized design envelopes, consistently with Article 2 (3) MDR and MDCG 2021–3 guidance.

Integration of risk classification into operational workflows

Currently, the laboratory manages approximately 20 clinical cases per month, providing a high-volume output of personalized solutions. Within this operational context, risk classification according to Annex VIII MDR was embedded as a functional component of the decision-making process. Within the implemented model there can be found two categories of devices with two different risk classification: anatomical models were classified as Class I according to Rule 1,

surgical guides as Class IIa according to Rule 7.

Consistently with MDCG guidance (MDCG 2021–3 (European Commission and Medical Device Coordination Group, 2021)) on the distinction between patient-matched and custom-made devices, all devices included in this workflow were managed under the custom-made regulatory framework (Annex XIII MDR), as Article 5 (5) MDR is not applicable to custom-made devices.

This qualification was based on the presence of case-specific clinician prescriptions, individualized anatomical and surgical requirements, and iterative clinician–engineer co-design activities performed outside predefined standardized design envelopes. In particular, the clinical specialist defined the patient-specific surgical objectives, anatomical constraints, and intended surgical application, while biomedical engineers translated these clinical requirements into customized design and manufacturing specifications through a continuous bidirectional interaction process, as required for custom-made device development under the MDR framework.

Rather than serving solely as a regulatory label, risk class was used as a driver for defining: design control requirements,

risk management depth,

validation protocols,

documentation procedures.

This integration enabled a consistent alignment between regulatory classification and operational processes across different device categories.

Organizational integration and operational efficiency

The hybrid model enabled the integration of clinical, engineering and regulatory activities within a single QMS framework. This resulted in: explicit formalization of nine roles and responsibilities (Table 1) through a structured governance RACI-like model (some people have multiple roles due to the limited size of the facility),

end-to-end traceability from clinical need to device release, achieved through a GDPR-compliant (European Parliament and the Council of the European Union, 2016) case management system enabling secure handling of patients’ data (including patient data from external healthcare institutions),

standardization of design inputs, verification, validation and change control processes.

Moreover, the adoption of a fully digital QMS on Confluence based on a document management platform enabled. centralized control of procedures and records,

real-time updates and versioning,

integration of quality processes, reviews, and continuous improvement actions.

This approach transformed compliance from a static documentation requirement into a dynamic governance system, supporting traceability and lifecycle management of custom-made devices.

The effectiveness of the quality system was further supported by CAPA monitoring during the ISO 13485 certification audit process, with 31 non-conformities identified during the first months of activity of the QMS and 28 successfully resolved prior to certification, demonstrating effective implementation of corrective and preventive actions within the system.

Representative examples of non-conformities identified during the implementation phase are: a mismatch between the lot number reported on the filament spool and on the cardboard box was identified during incoming material inspection by the Production Engineer, resulting from incorrect supplier labeling. The non-conformity was resolved by identifying and marking the correct batch number, informing the supplier, and relabeling the material accordingly before release.

the Quality Team identified unclear sterilization instructions due to multiple materials and sterilization methods being reported within the same document without device-specific linkage. The non-conformity was resolved by clarifying the correct sterilization method with the sterilization provider and updating the documentation format to ensure unambiguous device-specific instructions.

Within this digital QMS, clinicians’ feedback is systematically collected and integrated into post-market surveillance, to guarantee a continuous improvement process. This configuration facilitated operational efficiency through rapid clarification of design inputs and a reduction in iterative design cycles. Indeed, clinical interaction (traditionally informal in point-of-care settings) was preserved but embedded within formal design control procedures, ensuring both flexibility and compliance. Moreover, this proximity to clinical practice enables the co-design of custom-made medical devices in direct collaboration with clinicians: it allows faster and more precise data collection, supported by qualitative clinical feedback through formalized questionnaires. These records enable us to quickly turn constructive feedback into immediate product improvements, ensuring a more streamlined and responsive custom-made device development process compared to traditional, more fragmented organizational models.

In addition, the collected feedback (7 clinicians submitted for surgical guides; nine clinicians submitted for anatomical models), shown in Figures 5, 6, highlight high satisfaction scores across both surgical guides and anatomical models. In particular: communication with the 3D Innovation Lab, discussions between colleagues, perceived improvement in surgical outcomes and overall surgery execution received the highest rating; ease of use, delivery time and likelihood of repurchasing also showed strong positive evaluations; lower—though still positive—scores were associated with time-saving aspects.

Economic sustainability and strategic advantages

It is also essential to evaluate the economic implications of the proposed regulatory strategy. The establishment of an in-house advanced manufacturing laboratory entails significant investments independently of the regulatory pathway adopted, but these costs should be interpreted in the context of the substantial strategic advantages offered by an internal production model compared with reliance on external suppliers. In particular, the availability of an internal point-of-care manufacturing platform enables complete device customization based on specific patient and clinician needs, positioning point-of-care labs in the broader picture of personalized medicine, while also supporting continuous need-driven clinical innovation generated by the direct interaction between advanced technological capabilities and everyday clinical practice. This close integration between engineering and clinical environments represents a major advantage over conventional outsourcing models, in which customization capacity and iterative clinical development are inherently more limited.

From an economic and organizational perspective, both the Article 5 (5) MDR framework and the Annex XIII custom-made device pathway require substantial institutional investment to establish and maintain a compliant manufacturing environment. Independently of the regulatory route selected, healthcare institutions must implement and maintain a robust QMS, develop validated manufacturing and traceability procedures, ensure personnel training, perform risk management activities, and sustain continuous documentation and internal audit processes. Additional costs derive from the acquisition and maintenance of dedicated technological infrastructure, software validation, process qualification, and regulatory oversight activities necessary to guarantee device quality and patient safety. Consequently, a considerable proportion of the economic effort is shared across both regulatory models and represents an unavoidable prerequisite for operating an advanced point-of-care manufacturing laboratory.

Within this framework, the adoption of the Annex XIII custom-made device pathway introduces a substantial economic advantage compared with a purely Article 5 (5)-based model. While Article 5 (5) restricts device use exclusively to the manufacturing healthcare institution, preventing commercialization and external distribution, the custom-made framework enables the supply of devices to third-party healthcare institutions and external customers. This creates the opportunity to generate revenue streams capable of partially compensating for the initial investments required for technological infrastructure, QMS implementation, certification activities, and long-term regulatory compliance. As a result, the financial burden associated with maintaining an internal manufacturing laboratory can be redistributed through external collaborations and product supply, improving the overall sustainability of the platform without compromising institutional regulatory control.

Beyond the economic implications, the hybrid custom-made model also enables broader clinical impact by extending patient-specific solutions beyond a single institution to multiple healthcare centers. Importantly, even within the Humanitas context itself, the intention to provide manufacturing services across multiple hospitals inherently excludes the applicability of the Article 5 (5) pathway, as the MDR exemption is limited to devices manufactured and used within the same healthcare institution. Furthermore, the model supports structured collaborations with external healthcare institutions and industrial partners while preserving design authority and QMS governance within the certified laboratory. It additionally strengthens post-market surveillance activities by enabling the collection of clinical and technical feedback from healthcare professionals operating across different institutions, thereby promoting continuous device optimization and wider translational adoption.

A key outcome of the hybrid model is the ability to supply custom-made devices to third-party healthcare institutions and collaborate with industrial partners while maintaining internal regulatory control.

This represents a significant extension beyond purely in-house models, enabling: broader clinical impact, by enabling the design and supply of custom-made solutions across multiple centers, instead of just in a single site (in our case, Humanitas Rozzano),

structured external collaborations,

retention of design authority and QMS governance within the certified laboratory,

access to post-market feedback not only from internal clinicians but also from healthcare professionals operating in external institutions,

the possibility to place products on the market and supply external customers, overcoming the limitations of point-of-care-only frameworks (Article 5 (5) MDR).

The present work suggests that the real added value of the hybrid model does not lie only in the coexistence of clinical and engineering activities, but in the establishment of a single quality governance framework according to standards comparable to those of industrial manufacturers. While the rapid expansion of point-of-care 3D printing has been widely documented, most literature describes how struggling it is to transition from setups operating under experimental or strictly in-house exemptions to certified medical device manufacturing (Boyle et al., 2024; de Jong et al., 2024). To overcome this issue, the strategic selection of the hybrid model based on Annex XIII was identified as the most suitable compromise among the different options that were initially considered. The results demonstrate that this strategic positioning was not only feasible, but also operationally effective. In this sense, the model supports what can be described as a CE-ready level of regulatory preparedness compatible with future CE-marking pathways, even while operating primarily in the regime of custom-made devices. The point is not that the laboratory is already functioning as a conventional CE-marked manufacturer for serial products, but that the discipline of the system has been designed in such a way that documentation, controls and responsibilities are managed with a level of rigor that prepares the organization for future regulatory evolution.

Moreover, a challenge in current literature is the lack of standardized protocols to ensure process reliability and traceability within clinical 3D printing workflows (Neussl et al., 2025). In contrast to this fragmented approach, our hybrid model establishes a unified quality governance framework that integrates clinical, engineering and operational activities under a single QMS. In this way, the model reduces ambiguity in responsibilities and establishes a controlled pathway from clinical need to medical device, improving traceability, document control and risk governance. The organizational discipline imposed by the QMS is therefore not in opposition to translational flexibility; rather, it is what makes that flexibility sustainable over time.

The effectiveness of this synergy is validated by the high levels of clinician satisfaction and the robustness of the feedback loop. However, as outlined in the methodology, the validation of this hybrid model extends far beyond clinical feedback questionnaires alone, relying on a multi-stage framework where technical process validation and clinical outcomes are deeply interconnected. In this architecture, the surgeon questionnaire feedback represents the clinical outcome layer, a functional confirmation that the structurally validated technical process (covering segmentation, CAD, and printing) successfully translates into custom made medical devices that meet specific surgical requirements. Overall, clinicians’ questionnaires confirm that the hybrid model effectively translates into clinical value, particularly through enhanced communication and close clinician–engineer collaboration, which are critical for custom-made devices such as surgical guides and anatomical models. High ratings in surgery execution and perceived outcome improvement suggest that formalized design control does not limit customization but rather improves reliability and usability. Slightly lower scores for time saved in the operating room may reflect the high complexity of the cases, where the advantages are less evident intraoperatively and become more apparent in other stages of the workflow. These findings are consistent with previous studies on point-of-care manufacturing reporting high clinician satisfaction and perceived improvements in surgical planning and execution (George et al., 2017; Martelli et al., 2016). Crucially, the total absence of adverse events combined with these high satisfaction scores provide cumulative evidence that the underlying, ISO 13485-validated manufacturing process reliably produces safe and effective custom-made devices. Furthermore, formal post-market surveillance mechanisms continue to monitor device performance and capture any real-world issues that would trigger corrective action processes, ensuring ongoing process reliability. Therefore, the results indicate that integrating structured feedback within the QMS supports both continuous improvement and user satisfaction, reinforcing the effectiveness of the point-of-care manufacturing model.

Furthermore, this clinician-engineers proximity ensures that qualitative insights and technical refinements are immediately captured and implemented. This permits us to overcome the limitation of purely industrial manufacturing, that often lacks the bedside agility required for highly complex, patient-specific scenarios (Sharma et al., 2026) and reinforce close collaboration with clinicians, allowing the development of tailored solutions rather than “off-the-shelf” products typical of industries. Indeed, the implemented pathway enabled the support of highly complex clinical scenarios.

In orthopedics, this translated into improved preoperative assessment, with custom-made 3D models showing higher agreement with intraoperative findings compared to conventional imaging, with an overall improvement of 30% (data from an internal study conducted within our institution (Zampedri, 2025)). However, these findings remain preliminary, as they were driven from a single-center thesis study focused primarily on diagnostic agreement and reproducibility. Therefore, the observed improvement of approximately 30% should be interpreted cautiously and warrants further validation. This capability extended to exceptional customized pre-planning contexts including. liver surgery case where a custom-made guide was tested on a 3D-printed phantom; the simulation demonstrated that using the guide the resection volume (33.89%) was nearly identical to the original preoperative plan (33.90%), corresponding to a volumetric agreement of 99.97% (Procopio et al., 2021),

cardiac oncology case where a custom-made model was used in a cadaveric setting to enable targeted surgical rehearsal in collaboration with an international team, ultimately supporting a successful intervention in an otherwise inoperable patient,

giant abdominal sarcoma case in which 3D reconstruction enabled preoperative planning and surgical procedure simulation, contributing to a limb-preserving and organ-preserving surgical outcome.

These case studies also highlight the innovative dimension of the proposed model, in which advanced manufacturing techniques are not only applied, but strategically integrated within a regulated clinical workflow to enable solutions that would be difficult to achieve through conventional pathways alone (Micalizzi et al., 2026). In parallel, the framework proved compatible with sustainable and technically controlled production workflows: for example, a circular process based on recycled HDPE enabled 85% saving of filament production costs, together with a decrease in estimated environmental impact from 56.61 kgCO 2 /kg to 0.47 kgCO 2 /kg (Mansour et al., 2025b).

At the same time, the model is undeniably complex. Managing more than one operational regime within the same institutional ecosystem requires a much higher level of procedural clarity than would be necessary in a narrower setting. This complexity is consistent with recent literature highlighting how compliance with MDR requirements significantly increases organizational and documentation burdens for healthcare-based manufacturing environments (European Com mission). This is precisely why the comparative compliance mapping (Figure 4) described in this paper should be regarded as a core organizational tool rather than a secondary diagram.

From an international perspective, the proposed hybrid model also highlights important differences between the European and United States regulatory approaches to point-of-care 3D printing. In Europe, the MDR provides specific regulatory pathways for both in-house manufacturing and custom-made medical devices, allowing university- and hospital-based facilities to operate within a clearly defined framework. In contrast, the US approach is currently more heterogeneous and still evolving, particularly regarding the role of healthcare institutions acting as manufacturers. Recent FDA discussion papers on point-of-care manufacturing have emphasized the need for clearer definitions of responsibilities, quality management requirements, and regulatory oversight for healthcare institutions acting as manufacturers (U.S. Food and Drug Administration FDA, 2021). In this context, the present hybrid model may represent a structured example of how clinically integrated 3D printing activities can transition toward a regulated and quality-controlled manufacturing environment while maintaining close collaboration between engineers and clinicians.

A related challenge concerns post-market and external supply: once a laboratory extends beyond purely internal use and supplies custom-made devices to third-party institutions, obligations become more demanding. For this issue existing digital infrastructures can help, but they still require dedicated regulatory and quality competences. The same applies to supplier management, especially when collaboration with external manufacturers or technology partners is needed. Indeed, literature on medical 3D printing highlights supplier qualification and process validation as critical aspects when moving toward regulated production environments (Schlagintweit, 2021). The hybrid model therefore does not eliminate complexity; it organizes it within a coherent governance structure.

For this reason, the replicability of the model in other university-based contexts should be considered realistic but conditional. The present experience indicates that at least three prerequisites are essential: a mature ISO 13485, stable integration between clinicians and engineers, and a clear regulatory strategy. Without these prerequisites, the risk is to reproduce only the visible part of the model (the presence of a 3D printing laboratory) without reproducing the governance structure that actually makes the model compliant and scalable.

This study shows that a university-based laboratory can operate as a manufacturer of custom-made medical devices within a certified ISO 13485 QMS and with a strong governance structure. The significance of this result lies in demonstrating the feasibility of an advanced organizational model inside a clinically integrated academic environment, without requiring a full detachment into a conventional industrial structure. In this sense, to the best of our knowledge, the hybrid model represents the concrete answer to the current gap between university-based additive manufacturing practice and the need for robust regulatory compliance.

Beyond its organizational and regulatory value, the model has a direct impact on patient care by enabling a truly personalized medicine approach. Close and continuous interaction with clinicians allows the iterative co-design of custom-made devices, tailored to individual anatomical and surgical needs. In practice, this translates into rapid refinement cycles, improved surgical planning and devices that better match clinical requirements, ultimately contributing to improved procedural efficiency and potentially better clinical outcomes.

At the same time, the implementation of such a model requires high regulatory, organizational, and technical maturity, together with strong coordination among clinicians, engineers, and quality management professionals. It is therefore a demanding configuration, and not an immediately transferable one. However, it may serve as a structured framework for other university-based institutions that possess the necessary quality culture, institutional support, and interdisciplinary integration.

Looking forward, the model also opens a path toward further regulatory maturity. Future developments may include extension toward CE-marking pathways for selected device categories, possible expansion to more complex product types including implantable solutions, and deeper integration with external manufacturing capabilities while preserving internal design authority and QMS governance. The value of the hybrid model lies not only in what it already enables, but also in the regulatory and organizational trajectory that it makes possible.