Research review paperEnabling personalized implant and controllable biosystem development through 3D printing
Introduction
Additive manufacturing has been slowly pervading to all aspects of life and is a driving force in a silent revolution in how we design, develop and manufacture products. Since early 80s, following the footsteps of the stereolithography breakthrough by Charles W. Hull, the advances in the production of 3D structures with a wide range of technologies have been achieved that enabled the additive manufacturing of different forms of materials. As a highly regulated domain, medicine has been, up to now, slow in uptake of 3D printing technologies due to the particular restrictions in the materials that can be used. However, as 3D printing field matured, technologies for printing clinically relevant materials with the required precision have evolved (Murphy and Atala, 2014). Currently, there are dedicated instruments that can print medical grade ceramics, metals and polymers for medical uses. There are many occasions where 3D printed implants, although mostly anecdotal or in limited series, have been used clinically (Di Prima et al., 2015). Also the availability of the technology has brought further innovations for the use of 3D printed structures (such as surgical simulation). ASTM and ISO standards currently recognizes 7 processes for additive manufacturing all of which has been adapted for medical use to a certain extent: These processes are: powder bed fusion, material extrusion, material jetting, binder jetting, sheet lamination, direct energy deposition and vat photopolymerization (ISO). This wide range of available technologies together with those under development provides a positive outlook for further establishment of 3D printing techniques for biomedical devices field.
Still, the portion of medical devices in overall 3D market, which is on its way to become a multibillion $ market, is <5%. One of the biggest roadblocks that leads to this is the disruptive nature of 3D printing technology; the methods used for 3D printing do not conform well with the processes developed for validation and quality checks of medical devices in use. Establishing the necessary validation process regarding customized 3D printed products (for example an instrument and non-invasive sampling based validation process rather than implant lot based validation) is an important step that needs to be taken together by the regulatory actors and industry. This is particularly crucial for bioprinting applications for which the final products will be by default Class III products or ATMPs (Advanced Therapeutic Medicinal Products) and thus have higher levels of regulatory constraints (where ISO standard 10993 for biocompatibility needs to be observed for example for both FDA approval and for obtaining CE mark). Moreover, the patient-specific shape and architecture also complicate validation of certain design parameters. For example, for a set implant design the mechanical failure analyses can be done via simulation or experimentally but for a unique implant this needs to be repeated for each implant as the specific shape based on anatomical constraints can weaken the overall structure. As preparing several samples of each implant for each patient for just testing is untenable, reliable simulation-based verification means needs to be implemented. However, this route has not been fully embraced by the regulatory bodies yet. Moreover, most of the 3D printed structures will have intricate interior designs which needs to be validated post-printing with non-invasive but robust methods, for example micro-CT validation of interior dimension fidelity (Hollister et al., 2016). In addition, possible compromises with the sterility can be also linked with the architectural differences between the implants and assuring the sterility might require additional steps, which is not necessary for conventional implants. Readers are referred to the cited reference which explains the difficulties and requirements of such validation processes for a 3D printed tracheobronchial splint for pediatric use (Morrison et al., 2015b). However, it should be noted that tracheobronchial splint has a well-defined reference design where several parameters are changed to optimize the final implant for a specific patient. This will not be the case for filling of defects or partial organ replacement, for example, and can further complicate the verification and validation processes.
Also, there are significant logistics related problems particularly for ATMPs produced by 3D bioprinting as the sourcing of the cells of the patient, the location of the printing and the fragile nature of the final products require a tight synchronization of diagnosis, clinical decision, implantable structure production, delivery and implantation. However, in the view of potential benefits for patients, healthcare system and overall society, the required amount of work to achieve this is reasonable. Moreover, bioprinting driven research in hydrogel 3D printing can have other overarching effects as recently demonstrated. Additive manufacturing of hydrogels can be used for design and implementation of implantable microelectromechanical systems where stimuli responsive hydrogels can function as barriers, valves, pumps etc. (Zorlutuna et al., 2013). A recent elegant example demonstrates the potential of using 3D printing for development of devices with soft controllable components. Using iron oxide nanoparticle doped photopolymerisable poly(ethyleneglycol) diacryate (PEGDA) hydrogels, Chin et al. demonstrated a wirelessly activated drug payload system that contains movable mechanical components for triggered release (Chin et al., 2017). This system was demonstrated to be effective in controlled delivery of doxorubicin, a widely used anti-cancer drug, and shown to be efficient at concentrations 1/10th of that is used in clinical practice.
In this review, we aim to provide a state of the art overview of the currently available bioprinting techniques and bioink formulations that are under development. This will be followed by use of 3D printing technologies for implantable devices with examples of clinical applications. Finally, the use of bioprinted structures beyond medical devices and regenerative medicine with recent examples will be introduced.
Section snippets
Bioprinting applications
Bioprinting is the 3D printing of artificial tissues and organs by precisely assembling the cells and natural or synthetic cell matrices, layer-by-layer to achieve highly accurate biomimetic constructs (Mandrycky et al., 2016; Wu et al., 2016b). Currently used conventional tissue engineering techniques remain insufficient for fabricating completely functional, vascularized tissues and organs (Ozbolat et al., 2016). In this regard, bioprinting techniques have enabled rapid development of the
Implantable 3D printed structures
The advantages of 3D printing can be divided into several categories. Those related to implantable devices are based on personalization which will be helpful for non-standard size patients and pathology related unique anatomical conditions. Moreover, 3D printing enables the development of multicomponent structures with site specific physical and mechanical properties which is not achievable with molding and potential temporal control over the implant properties when degradable materials are
Biorobotics
Recently, advances in tissue engineering and microfabrication techniques have led to the development of a new research field that explores the possibility of hybrid biological machines called biorobots (Feinberg, 2015; Kim et al., 2013). These synthetic biological systems or devices are composed of a soft biological component, such as living cells or muscle explants, incorporated into an artificial mechanical support. Usually, elastomeric materials such as polydimethylsiloxane (PDMS) or
Future directions
For medical applications two important challenges still remain for 3D printing. First one is the heterogeneous nature of the tissues that contain composites of multiple materials with distinct physicochemical properties. Thus, for implantable structures and bioprinting, it is desirable to have simultaneous printing of multiple materials which is not a trivial problem. Recently, Liu et al. reported multimaterial extrusion printing using a digitally controlled printhead (Liu et al., 2017). The
Acknowledgements
This study has received funding from EU FP7 IMMODGEL (Grant No. 602694), EU Horizon 2020 PANBioRA (760921) and FUI FASSIL (AAP-22-FASSIL) project. This study was supported by NSF Grants CBET-1530884 and ECCS-1611083.
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