Additive Manufacturing of Biomaterials, Tissues, and Organs
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The introduction of additive manufacturing (AM), often referred to as three-dimensional (3D) printing, has initiated what some believe to be a manufacturing revolution, and has expedited the development of the field of biofabrication. Moreover, recent advances in AM have facilitated further development of patient-specific healthcare solutions. Customization of many healthcare products and services, such as implants, drug delivery devices, medical instruments, prosthetics, and in vitro models, would have been extremely challenging—if not impossible—without AM technologies. The current special issue of the Annals of Biomedical Engineering presents the latest trends in application of AM techniques to healthcare-related areas of research. As a prelude to this special issue, we review here the most important areas of biomedical research and clinical practice that have benefited from recent developments in additive manufacturing techniques. This editorial, therefore, aims to sketch the research landscape within which the other contributions of the special issue can be better understood and positioned. In what follows, we briefly review the application of additive manufacturing techniques in studies addressing biomaterials, (re)generation of tissues and organs, disease models, drug delivery systems, implants, medical instruments, prosthetics, orthotics, and AM objects used for medical visualization and communication.
KeywordsBioprinting Biofabrication Biomaterials Drug delivery Medical devices Tissue regeneration
Additive manufacturing (AM), also known as 3D printing, has emerged during recent years as a flexible and powerful technique for advanced manufacturing in healthcare. Even though the underlying technology has been in development for more than two decades, the level of maturity and perfection required for real-world applications has been achieved only recently. Most importantly, a wide range of biomedical materials can now be processed using additive manufacturing techniques with increasing accuracy. Moreover, a number of AM processes and the resulting products have already been approved by regulatory bodies for (routine) clinical use, and a draft version of FDA guidance for additively manufactured devices has already been published.1 At the same time, AM technology has been applied for (re)generation of living tissue structures that could be applied as regenerative implants and disease models. This field of “biofabrication”28 is developing exponentially, underscoring the potential of applying AM in healthcare. Some other areas, such as pharmacology, oncology, surgery, and rehabilitation have also provided interesting clinical and research applications for additive manufacturing.
Additive Manufacturing of Biomaterials
Various categories of AM techniques (Fig. 1) have been used for processing a wide range of polymeric, metallic, and ceramic biomaterials. As far as polymeric materials are concerned, AM techniques based on vat polymerization, such as stereolithography (SLA), those based on material extrusion techniques such as fused deposition modeling (FDM), those based on powder bed fusion technologies such as selective laser sintering (SLS), and material jetting alternatives, such as inkjet printing, are commonly used (Fig. 1). The most widely used techniques for processing metallic biomaterials are currently based on powder bed fusion, such as selective laser melting (SLM) and electron beam melting (EBM) (Fig. 2). A large number of studies using AM techniques for processing of ceramic-based biomaterials applied binder jetting, material extrusion, powder bed fusion, or vat polymerization.1,64 However, indirect AM32 is another, particularly interesting approach, where biomaterials are not made through direct AM but are fabricated through a medium that is additively manufactured; For example, the negative of an intended biomaterial structure may be additively manufactured to allow for casting of the desired biomaterial. Direct and indirect methods can also be combined to enable fabrication of more complex biomaterial components.
There are two major challenges that need to be addressed to utilize the maximum potential of AM techniques for improving the performance of biomaterials. First, the optimal microarchitecture for the performance of each biomaterial is often unclear. Analytical and multiphysics computational modeling techniques need to be used to determine the best microarchitecture for any specific application. Ideally, all relevant mechanical, physical, and biological properties of the biomaterial should be considered simultaneously when designing the microarchitecture. Secondly, there is still limited availability of materials that are compatible with AM processes. Traditionally used biomaterials can often not be processed with AM techniques, whilst the best-performing materials in AM machines, in terms of accuracy and functionality, are not biocompatible or do not exhibit the required biodegradation behavior. It is, therefore, essential not only to improve the arsenal of available biomaterials, but also to adapt current AM technologies to better process the best available biomaterials. In view of this, developments in both AM materials and systems is required to utilize the potential of AM to its full extent.
Tissue and Organ Equivalents
Nevertheless, it still remains a challenge to ensure that the generated bioprinted tissue structures properly match the structure and properties of the native tissue. A current limitation is the limited availability of bioinks that possess appropriate physical properties for the printing process and simultaneously provide a suitable niche for the cells to differentiate towards the desired lineage. Different classes of hydrogels have been employed as parts of bioink systems used in tissue/organ bioprinting.41,43,45,55,62
A promising approach to simultaneously comply with the numerous requirements that AM techniques and bioinks must satisfy to guarantee optimal tissue quality and maximum tissue complexity is to combine various AM technologies and bioinks to benefit from the best aspects of different approaches. Recent application of this pragmatic approach has produced some promising results.36
Drugs and Drug Delivery
Computational modeling can aid prediction of release profiles from various drug delivery systems6,31,40 and may be of particular value for drug delivery systems based on AM structures. These computational models will provide insights into the effects of the geometrical design, microarchitecture, and spatial distributions of active and passive agents on the release profiles. The combination of AM techniques and computational models for achieving desired release profiles is a relatively unexplored area of research and is suggested to be an important area for future research.
AM has added a new dimension to the design and manufacturing of implants in general, and patient-specific implants in particular. Patient-specific implants,24,46,47 where the implant is designed to fit the anatomy or other requirements of a single patient, are one of the prime areas for routine clinical application of AM techniques. Recent advances close the loop in the pipeline that goes from image acquisition to image processing, implant design, and implant manufacturing, as the entire process can now be streamlined through CAD systems that integrate some or all of the required steps. The free-form nature of AM processes enables implants with anatomically complex geometries to be manufactured quickly, reliably, and cost-effectively. Companies that integrate the various aspects required for patient-specific AM are already active in the market, and their implants are already used in the clinic.
Metals are the materials most commonly used for AM of functional and load-bearing implants. Powder bed fusion processes including selective laser melting (SLM) and electron beam melting (EBM) are often used for this purpose.
Streamlined design and digital manufacturing of patient-specific implants and incorporation of complex geometrical features into the design of generic implants, as well as evaluation of the actual clinical performance of patient-specific implants and implants incorporating features such as hybrid design and functionally graded microarchitecture, are areas that require further research. In particular, sound design principles and computational platforms need to be developed to facilitate the design of the macroscale shape and microarchitecture of implants.
Similar to the case of implants, one of the unique applications of AM is fabrication of patient-specific instruments. An important example of patient-specific instruments are surgical guides,38 which could increase surgical accuracy. Moreover, they could shorten operating times, thereby also reducing the chance of surgery-related complications such as infections. In addition to numerous surgical procedures, where use of such guides could be of great value, patient-specific instruments could be combined with patient-specific implants to facilitate their positioning.
Both metallic and polymeric materials have been used for fabrication of medical instruments. The high-end AM techniques available for polymers such as stereolithography and two-photon lithography could usually achieve much higher accuracies as compared with techniques available for processing of metals. As a consequence, AM of high-end (steerable) medical instruments is currently possible only if polymeric materials are used. Some other categories of medical instruments such as many surgical guides require lower levels of accuracy and can also be manufactured from metals. On-demand fabrication of medical instruments in remote areas or in extreme conditions such as in areas hit by natural disasters or on the battlefield could only be done with low-end polymer processing techniques such as FDM and may only be realistic for the simplest medical instruments.
Prosthetics and Orthotics
Orthotics are no different from prosthetic devices in terms of how they could benefit from the possibilities offered by AM.16,52,63 Once more, orthotic devices could be tailored to perfectly fit the (correct) anatomy of the patient. Furthermore, materials with specific mechanical properties could be fabricated using AM using concepts similar to those used in the rational design of tissue engineering scaffolds and implants. The microarchitecture of certain parts of the orthotic device could be rationally designed so as to give rise to certain sets of desired mechanical properties; For example, AM has been used to design an ankle–foot orthosis with adjustable stiffness.63
Much research still needs to be done to fully utilize the potential of AM techniques for both the high- and low-end markets of prosthetics and orthotics. For the high-end market, advanced design and AM techniques need to be used for providing novel functionalities not currently possible in such devices, while parametric, easy-to-manufacture, and easy-to-assemble prosthetic and orthotic devices need to be developed for areas with inadequate healthcare coverage.
Models for Visualization, Education, and Communication
The same technology that enables image-based design and AM of implants, prosthetics, and orthotics could be used for a myriad of other purposes including communication with patients, education of medical students, visualization of malignancies, and preoperative planning. For most routine procedures, experienced clinicians can imagine anatomical features and malignancies and plan surgeries with the sole aid of two-dimensional images, not even requiring three-dimensional reconstructions of the images. The same clinicians may, however, benefit from three-dimensional reconstruction of images and physical AM models61,77 when planning complex surgeries, evaluating the suitability of certain clinical procedures for particular cases, and examining how well (patient-specific) implants fit the anatomy of the patient, which is also printed in the form of a physical object. The advantages might be even greater in the case of less experienced clinicians, suggesting that AM physical models could also be used as part of the learning curve of clinicians in training.74 Altogether, AM physical models might result in improved accuracy and shortened time when performing clinical procedures. Physical models might also be effective instruments when communicating with patients regarding their pathologies and the planned treatments.
Since visual aspects are of paramount importance in almost all the above-mentioned cases, multicolor and multimaterial AM techniques could be of tremendous value in fabrication of physical models aimed for visualization. Furthermore, the efficacy of physical models in improving the accuracy of clinical procedures, shortening the required time, improving the learning curve of clinicians in training, and management of patient anxiety should be thoroughly studied. There is currently not much data available to determine whether AM patient-specific physical models are actually capable of delivering the intended benefits.
Other Biomedical Areas
AM has been used in other areas of biomedical research as well. An important example is the use of AM in fabrication of microfluidic devices that have widespread applications in biomedical research. Microfluidic devices have traditionally been made using soft lithography, which is a slow, labor-intensive, and expensive process. AM enables automated, fast, and inexpensive development of microfluidic devices,7,30 potentially from biocompatible and transparent materials that allow for both unhindered cell culture and imaging.65 Advances in AM of microfluidic devices could have important implications for areas such as organ-on-a-chip research.
Imaging-based reconstruction of pathologies and subsequent AM of colored, subject-specific demonstrative replica have been proposed as effective methods for forensic medicine,20 not only because they could help improve understanding of pathologies but also because they are excellent instruments to facilitate communication in court rooms.
Finally, pioneering works on topics such as 3D printing of bacterial communities15 continue to appear in scientific literature and promise many more applications of AM techniques in biomedical and healthcare research.
AM has found numerous applications in many areas of biomedical research and clinical practice. The opportunities for further application areas are only increasing in number, complexity, and added value. Some of the most important areas of application were reviewed in this editorial to lay the ground for the research and review papers appearing in this special issue. Many topics touched upon in this editorial are further expanded on in the following contributions that try to present the state of the art in this exciting area of interdisciplinary biomedical research.
Food and Drug Administration (FDA), Technical Considerations for Additive Manufactured Devices—Draft Guidance for Industry and Food and Drug Administration Staff, Issued on May 10, 2016.
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