title: Quality by Design for the Development of Additively Manufactured Patient-Specific Bone Implants and Scaffolds
Creators: name: Martinez Marquez, Daniel
Publisher: name: Griffith University
Year: 2020
Subjects: subject: biomedical engineering
subject: orthopaedic products
subject: nano-coated patient-specific bone implants
subject: nano-coated patient-specific bone scaffolds

description: In recent decades, engineering and medical technology advancements have provided the means to design and develop innovative medical solutions to address various health issues. However, despite the tremendous progress in biomedical engineering, a reasonable proportion of patients that were subjected to joint reconstruction surgery are still not completely satisfied. Moreover, orthopaedic products such as knee and hip prostheses together rank as the fifth most recalled medical product. One of the main reasons for patient dissatisfaction and high rates of defective medical products, is due to the common practice in the medical device industry to designing complex, innovative products at the expense of long-term reliability and easily controlled manufacturing processes. Moreover, titanium bone implants manufactured by traditional methods fail to provide precise reconstructions of the injury location and are manufactured from bulk materials that do not match the mechanical properties of bone or the patient’s unique joint kinematics. However, the recent advent of additive manufacturing (AM) technologies, has provided a new path for the design and manufacture of patient-specific medical devices. Unlike subtractive manufacturing technologies, AM can fabricate complex shapes from the macro to the micro scale, thereby allowing the design of patient-specific implants following a biomimetic approach for the reconstruction of complex bone configurations. This design freedom opens the way for the use of AM in difficult clinical scenarios such as the reconstruction of bones with complex anatomical shapes in bone diseases, deformities and trauma. Moreover, to further augment its bioactivity, Ti surface modifications have been performed in the macro, micro and nano-scales. Briefly these include hydroxyapatite/polymer coating, protein immobilization and various topography modifications achieved by anodization or acid-etching. Nonetheless, numerous in-vitro and in-vivo investigations have established that nanoscale topography outperforms macro and micro-scale surface features towards augmenting cellular functions. Additionally, studies have also revealed immune-modulatory and antibacterial effects from various nano-scale surface modifications. Among the various nano-topographic modifications of Ti, electrochemically anodized (EA) TiO2 nanotubes (TNTs) stand out due to their enhanced bioactivity, and ability to achieve local drug elution. EA is a cost effective strategy to fabricate highly ordered TiO2 nanostructures with a great degree of control over their dimensions. In 2015, the global orthopaedic industry market was valued at USD 4.3 billion and is expected to reach USD 8.97 billion by 2025, with the Asia-Pacific region exhibiting the highest compound annual growth rate of 6.4%. This market growth provides the opportunity for introducing the next generation of orthopaedic implants that can overcome the current quality issues and patient dissatisfaction with traditional products. The advent of AM technologies and the prospects for mass customisation provides significant market opportunities, but also presents a serious challenge to regulatory bodies tasked with managing and assuring product quality and safety. Nevertheless, the complexity of patient-specific implants combined with the current limited expertise in reliability engineering and manufacturability in the AM sector is posing a number of quality performance challenges. Factors such as high design variability and changeable customer needs are re-shaping current medical standards and quality control strategies in this sector. Such factors necessitate the urgent formulation of comprehensive AM quality control procedures. Worldwide medical device regulatory bodies are facing increasing pressure to formulate adequate standards to ensure long-term patient safety and product performance. Therefore, successful industry transformation to this new design and manufacturing approach requires technology integration, concurrent multi-disciplinary collaboration, and a robust quality management framework. The overarching goal of this study was to develop an adaptation of the Quality by Design (QbD) system for nano-coated patient-specific bone implants and scaffolds produced by AM. Such a system would facilitate the development of the next generation of bone implants by integrating various innovative technologies, avoiding trial-and-error studies, accelerating research timelines, and reducing product development risks and cost in the early stages of the product development cycle. For this purpose, this study explored the different factors, technologies, and strategies that need to be considered in the design and fabrication of these products. To achieve the goal of this study, the developed QbD system was systematically tailored and refined through a sequential multi-stage mixed method research design consisting of five phases. The different phases of this study employed and integrated various data collection methods and risk management tools, including systematic literature reviews, an online-questionnaire survey, and face-to-face interviews with researchers, industry experts, and medical practitioners from different related fields. Moreover, exploratory case studies were undertaken with three medical device companies located in the USA, Germany, and Lithuania. Study phases 2-5 culminated into journal manuscripts. The first study phase involved an extensive literature review and gap analysis. The second phase of this exploratory study aimed to establish and validate the first steps (1–5.3) of a general adaptation of the QbD system. The main outcomes of this phase were the establishment of the quality target product profile from three quality perspectives, and the identification of 39 critical quality attributes (CQA) including their classification groups. Moreover, a comprehensive design and fabrication process flow diagram was developed in conjunction with the identification and categorisation of 86 risks and 178 potential effects on product quality associated with the design and fabrication processes of such products. The overall contribution of this research phase was the development of tailored steps of the QbD system, which founded the formulation of the following QbD steps. The third phase of this study focused on the Steps 5.4–5.7 of the QbD system, which consisted of the investigation and identification of the most critical risks and sensitive process areas in terms of product quality for the initial stages of the development process. The main outcomes include the development of a failure mode, effects, and critical analysis (FMECA) coupled with a 3D risk assessment approach. Research outcomes included the identification of 13 critical risks and a FMECA form containing 137 failure modes with AM materials, AM machine general, Fabrication, EBM machine, Finishing, and Design being as the most influential process areas in term of product quality. The novel 3D risk assessment approach provided a more accurate graphic representation of the three different factors used for risks rating, thus facilitating the presentation of risk assessment analysis to different stakeholders. The fourth phase of this research finalised the general adaptation of the QbD system for patient-specific bone implants and scaffolds produced by AM. This phase focused on adapting Steps 7 and 8 of the QbD system. The main outcome of this phase was the development of an integrated quality control procedure composed of 18 quality control gates. The procedure sought to help prepare the AM industry for the inevitable future tightening in related medical regulations. Moreover, this study revealed some critical success factors for companies developing additively manufactured patient-specific implants, including ongoing R&amp;D investment, investment in advanced technologies for controlling quality, and fostering a quality improvement organizational culture. Finally, the last phase of this study was conducted to develop the first two steps of the QbD system for nano engineered surfaces with titania nano tubes (TNT) for orthopaedic/dental applications. This phase produced a semi-qualitative estimate of the level of importance of the CQAs of TNTs-Ti implants, including the most optimal configuration of CQAs to satisfy the participants’ expert opinion. Moreover, the analysis procedure qualitatively determined the level of contribution of each TNT characteristic to the overall implant performance from three different perspectives; biological, physicochemical, and mechanical. This study phase demonstrated that the QbD system can better direct the design process for nano-engineered implant surfaces with TNTs by significantly reducing the need for costly and time-consuming trial-and-error studies. In summary, this PhD thesis has made significant theoretical, methodological and practical contributions, in the fields of quality management and AM product development within the biomedical context.