(Le contexte est présenté en français. Le reste du document est en anglais)
Dans les années 1980, Charles Hull a déposé le premier brevet d’impression 3D (I3D)1. Depuis lors, le battage médiatique considérable et une demande croissante pour ce type de technologie ont provoqué un espoir de changement fondamental dans l’industrie de la production biomédicale2,5. Des solutions médicales prometteuses ont été conçues, comme des membres bioniques, des organes de remplacement et des systèmes avancés de de libération de médicaments. Cependant, les défis techniques, scientifiques et règlementaires persistent. Alors que certaines applications médicales de l’I3D s’insèrent dans la pratique, plusieurs en sont encore aux étapes de recherche et développement exploratoire6. Ce bulletin donne un aperçu des applications cliniques de l’I3D et de la bioimpression, y compris le contexte actuel au Canada et dans les autres pays, les nouveaux développements technologiques, les problèmes potentiels de mise en œuvre et les défis de l’évaluation et l’examen des technologies d’I3D.
Qu’est-ce que l’impression 3D?
La fabrication additive ou impression en 3 dimensions est le processus par lequel des objets tridimensionnels sont créés, couche par couche, en utilisant des matières premières et guidés par un fichier numérique7-10. Bien qu’il y a des désaccords dans la terminologie de l’I3D11, le terme fabrication additive décrit généralement les imprimantes de qualité industrielle à grande échelle utilisées à l’impression pour usage commercial, tandis que l’I3D décrit une impression à plus petite échelle utilisant des imprimantes de qualité dédiées aux consommateurs (p. ex. pour le maquettage rapide ou les modèles)7. Ce bulletin utilise le terme I3D pour décrire ces deux approches.
En soins de santé, les cliniciens, les administrateurs et les fabricants s’intéressent à l’I3D, en tant qu’outil, parce qu’elle peut aider à :
- visualiser et planifier des interventions complexes;
- créer des dispositifs personnalisés et adaptés aux besoins particuliers du patient;
- construire des dispositifs de forme et de structure internes et externes complexes à partir de matériaux biocompatibles;
- produire des dispositifs ou des matériaux sur place au besoin;
- alléger la chaine d’approvisionnement;
- réduire les besoins en inventaire; et
- réduire les couts de la main-d’œuvre.
L’I3D peut également être intéressante pour les prestataires de soins de santé qui utilisent régulièrement de petites pièces pour lesquelles l’I3D pourrait être utile (p. ex. les couronnes dentaires)15 et ainsi permettre aux soins de santé de passer d’une approche uniformisée à des dispositifs médicaux en petite quantité ou encore adaptés aux besoins particuliers d’un patient16.
L’I3D est un domaine où la recherche est active et où plusieurs études sont en cours. Lorsque nous avons effectué une recherche de la littérature grise pour la rédaction de ce bulletin, plus de 100 essais cliniques touchant aux applications de l’I3D répertoriés dans le Système d’enregistrement international des essais cliniques17 et sur ClinicalTrials.gov18 étaient en cours ou à l’étape du recrutement, et 14 revues systématiques des applications de l’I3D en soins de santé étaient enregistrées dans PROSPERO19.
Qu’est-ce que la bioimpression?
Faisant partie d’un processus complexe appelé la biofabrication, la bioimpression est une technique d’I3D qui combine des cellules vivantes (par exemple, les cellules souches) et des biomatériaux de soutien (p. ex. des échafaudages sur lesquels les cellules peuvent se développer) dans ce qu’on appelle « bioinks »13,2,21. Ces bioinks sont imprimés dans des modèles préétablis générés par ordinateur dans le but de les voir graduellement maturer dans certains tissus,20,21.
Motivées en partie par un manque de donneurs de tissus et d’organes22, les avancées en « instrumentation de bioimpression; en précision et rapidité d’impression; en conservation des cellules vivantes pré et post impression; en impression de plusieurs bioinks assemblés; et les innovations dans les formulations de matériaux de soutien et de bioinks permettant l’impression des matériaux de tissu flexible doux »23 contribuent aux progrès de la recherche et développement dans ce domaine.
Alors que les travaux in vivo en médecine régénérative sont encore dans les toutes premières étapes de la recherche23 — la greffe d’organes complets étant considérée comme l’objectif à long terme — un certain nombre d’entreprises du monde entier travaillent activement à l’amélioration de la bioimpression en cherchant à élargir les types de matériaux et à optimiser les approches technologiques24.
En 2016, l’ACMTS a produit une analyse prospective brève des applications de l’I3D en soins de santé25. Ce bulletin se penche sur ce travail, en se concentrant principalement sur les applications cliniques de l’impression 3D et de la bioimpression. On considère également certaines autres applications en soins de santé de l’impression 3D et de la bioimpression, y compris l’I3D de produits pharmaceutiques.
CADTH Horizon Scanning bulletins are not systematic reviews and do not involve critical appraisal or include a detailed summary of study findings. Rather, they present an overview of the technology and available evidence. They are not intended to provide recommendations for or against a particular technology.
Literature Search Strategy
A series of limited literature searches were conducted using the following bibliographic databases: MEDLINE, Embase, and the Cochrane Library. Grey literature was identified by searching relevant sections of the Grey Matters checklist (https://www.cadth.ca/grey-matters). The searches were completed on October 2018 and limited to English-language documents published after January 1, 2008. Regular alerts updated the search until project completion. Conference abstracts were excluded from the search results.
One author screened the literature search results and reviewed the full text of all potentially relevant studies. Studies were considered for inclusion if the intervention was a clinical application of 3-D printing or bioprinting. The final selection focused primarily on existing evidence syntheses including systematic reviews and meta-analyses. Studies providing direct cost data, narrative reviews, and expert commentaries were also included. Grey literature was included when it provided additional information not available in the published studies selected.
A draft version of this bulletin was peer-reviewed by a clinical expert.
A draft version of this bulletin was posted publicly for stakeholder review.
3-DP objects and bioprinted objects can be created using a number of different production techniques that, in general, share the following common components:7,14,26
- data (e.g., images) for the design software to use
- computer software for modelling, designing, and translating digital models into printer instructions
- a computer-controlled printer
- appropriate layering materials for producing the desired object.
Common production techniques for 3-DP and bioprinting used in clinical applications are described in Table 1.
Table 1: Description of Common Production Techniques for 3-D Printing and Bioprinting
|3-DP Techniquesa||Description and Considerations7,21,26-31|
|Stereolithography (SLA)27,28||The oldest method of 3-DP. Uses a scanning laser to scan a reservoir of photosensitive liquid polymer (resin), selectively solidifying layers from the surface of the liquid based on the design data. As layers are hardened, a movable build platform descends to increase the depth of the material. The process uses software-generated supports, which have to be removed from the finished product.|
|Selective laser sintering (SLS)28||Uses a laser or electron beam to trace a 2-D slice in a bed of fine thermoplastic powder composed of a variety of materials (e.g., nylon, metals), heating the powder to the point that it fuses together. Once the 2-D slice is traced, a new layer of powder is added to repeat the process until the object is formed. Referred to as direct metal laser sintering when the process is applied to metal alloys.|
|Selective laser melting (SLM)29||Similar to SLS, but the powder is heated by the laser to the point that it fully melts, creating a homogenous part. It may be used if you are only using a single metal powder. The material is stronger but the porosity cannot be controlled.|
|Selective heat sintering (SHS)32||Similar to SLS but uses a thermal print head as opposed to a laser to sinter the powder. It allows the printer to be smaller in size.|
|Fused filament fabrication (FFF)28b||Forms an object using a computer-controlled extrusion nozzle to deposit layers of heat-softened polymer melted from a filament.|
|Polyjet30||Uses inkjet technology to deposit photopolymer with an inkjet head that moves in the x- and y-axes. Each layer is cured, and successive layers are printed over top and fused. Products have high resolution but may be weaker than other techniques.|
|Bioprinting Techniques||Description and Considerations7,21,26-31|
|Extrusion-based21||Uses a robotic system to continuously extrude bioinks in one long filament onto a scaffold. Forces created by the extrusion may impede cell survival, but the resulting structures are more mechanically robust than other methods.|
|Droplet-based21||Bioinks are placed, drop-by-drop, into precise positions, using a variety of techniques to form a 3-D shape. Cells have good viability and the technique is relatively rapid and with high resolution. Limitations include the potential for variation in droplet size and clogging of the nozzle.|
|Laser-based21,31||Uses laser energy absorption to propel cell hydrogel droplets onto a surface. Compared with other methods, it has good cell viability and minimal clogging but is more expensive and time-consuming to do it in high resolution.|
2-D = two-dimensional; 3-D = three dimensional; 3-DP = 3-dimensional printing.
a This is not a comprehensive list of 3-D printing technologies; rather, some examples of approaches used in clinical applications.
b Also referred to as fused deposition modelling (FDM).
Regardless of the technique used for printing, the production of 3-DP objects (including medical devices) involves three general steps: pre-processing, printing, and post-processing.7,26,33 Bioprinting follows a similar production path but with some notable differences throughout the process.21,23 These production steps (with additional considerations for bioprinting) are described in more detail in Table 2.
Other factors that may also be taken into consideration when producing a 3-DP object include:
- material selection, which depends on both the needs of the object being printed and the requirements of the printing process and equipment being used26
- design considerations beyond the object itself, such as the support structures and the thickness of layered materials.26,33
Table 2: A General Approach to the Production of 3-D Printed Objects and Considerations for Bioprinting
|Production Step||3-D Printing||Bioprinting Considerations|
CT = computed tomography; MRI = magnetic resonance imaging.
a Note: Design files can also be informed using lessons learned from previous product design.16
While the aforementioned production steps describe a typical approach to building a 3-DP object itself, manufacturers can use 3-DP to build “negative” structures for use as casts or molds.13
Emergence of 3-D Printing and Bioprinting in Canada
A 2017 report from Canada’s Standing Senate Committee on Social Affairs, Science and Technology identified 3-DP as one of three areas anticipated to present challenges to the Canadian health care system.34 Presentations from Health Canada to the committee indicated that devices produced using 3-DP have already been approved for use in Canada.34
Our search of the grey literature identified many examples of research, development, and production in 3-DP for health in Canada.35-45 Examples of Canadian activities include hospital scale printing,40,46,47 academic initiatives and collaborations,37-39,44,48 not-for-profit initiatives,35,49 and for-profit start-ups and organizations.36,41-43,45,50-52 A network of private, public, academic, and not-for-profit organizations, Canada Makes — “dedicated to promoting the adoption and development of advanced and additive manufacturing (AM) in Canada” — includes a section dedicated to 3-DP in medicine and dentistry on its website.53
As emerging and potentially disruptive health technologies, 3-DP and bioprinting present challenges to existing regulatory frameworks. Decisions around these frameworks could affect the adoption of 3-DP within the health system.54 This section discusses approaches to 3-DP and bioprinting in Canada and around the world.
In Canada, medical devices produced using 3-DP are subject to the Medical Devices Regulations.55 In August 2018, Health Canada announced it was beginning to develop guidance for manufacturers wishing to obtain licences for 3-DP medical devices.54 A draft guidance document was released for comment in October 2018 and final guidance is expected in the spring of 2019.55 Feedback on the guidance issued has been posted publicly by some stakeholder groups.56 The guidance is intended for manufacturers (including hospitals producing 3-DP devices for distribution outside their organizations) of 3-DP Class III and Class IV implantable medical devices and is supplementary to existing evidence requirements for all Class III and Class IV devices.55 It does “not provide guidance on third-party software, custom-made devices, patient-specific anatomical models, devices manufactured at point-of-care, and devices with biological components.”55 The draft guidance is considered a first step for 3-DP policy in Canada and is intended to evolve, along with the technology.55
Health Canada’s draft guidance notes that the production of 3-DP devices presents some unique considerations for manufacturers and that, in addition to the data required for the approval of all Class III and Class IV medical devices, additional information may be required for the approval of 3-DP medical devices.55 For example:
- Manufacturers should specify the starting materials, any additives, and the 3-DP technique used for production.
- Manufacturers should indicate if all or part of the device is 3-D printed.
- Submissions should include a design philosophy explaining why 3-DP was the appropriate manufacturing approach.
- Records of printer maintenance and cleaning, validation of consistent performance, the accuracy of reproduction of patient-specific images, and the validation of printer-material combinations should be retained.
- The processes for removal and possible reuse or recycling of layering materials should be validated.
- Verification and validation of the software for design and printing is required.
- Biocompatibility testing should be conducted on finished devices.
- Processes for the post-processing removal of residues, and excess layering material and sterilization of 3-DP devices, should demonstrate that the bioburden is minimized and consider how sterilization may affect the final product.
In recognition of the wide range of 3-DP applications, the FDA regulates technologies as either medical devices, biologics, or drugs.9 As of December 2017, more than one hundred 3-DP devices currently on the market had been reviewed by the FDA.57
Initial FDA guidance for 3-DP medical devices was issued in 2017, acknowledging the unique design, manufacturing, and device testing requirements.10 Bioprinting is not included in this guidance.10 The document covers technical considerations for quality systems based on regulatory classification and associated regulation to which the device is subject, as well as manufacturing considerations, and the information required for regulatory notifications, and submissions.10 It is meant to supplement, not replace, other applicable regulatory guidance for medical devices.10 The FDA noted that this guidance would evolve as understanding develops on factors such as non-traditional manufacturing sites and supply chains, the use of biological printing material,20 and point-of-care device considerations.
The FDA also conducts primary research on 3-D printing at several sites to help understand its impact on the safety and quality of medical technologies.10 Findings from this research aim to inform policy development and guidance updates.10 Support for innovation and access is offered through the Emerging Technology Program,58 which allows early engagement with manufacturers hoping to bring their 3-DP technologies to market.10
In Europe, the regulation of 3-DP health technologies is complex and is governed, as of 2017, by three frameworks: the European Medical Devices Directive, the Invitro Diagnostic Medical Devices Directive, and the Active Implantable Medical Devices Directive.14 Regulation is dependent on the type of device being printed (i.e., patient-specific, customizable, or mass produced).14 Consideration must also be made for the printer, software, and materials used.14 Hospital-made devices are exempt from some regulations provided that no equivalent product exists, the hospital is not mass-producing items, and quality manufacturing standards are maintained.14
In Australia, consultations are underway on proposed changes to the regulation of medical devices to better address the introduction of personalized medical devices, including 3-DP devices.59 The proposed changes include:
- adopting international definitions (e.g., custom-made, patient-matched) developed by the International Medical Device Regulators Forum (IMDRF)60
- creating a framework to allow clinicians to produce low-risk devices without manufacturing certification
- regulating anatomic models in a way similar to diagnostic images
- regulating “medical devices with a human origin component” (e.g., bioprinted patient-specific implants) as medical devices and not as biologics.59
Lack of Fit-for-Purpose Regulatory Frameworks for Bioprinting
Bioprinting does not fit within existing regulatory frameworks or guidance.20 It spans several areas of health care — including but not limited to regenerative medicine, medical devices, and biologic drugs — making it difficult to apply existing systems.20 The customized single-patient-use nature of bioprinted interventions suggests the potential for exemption from, or the ability to circumvent, regulatory processes.20
The exclusion of bioprinting from existing 3-DP guidance and the lack of a dedicated regulatory framework pose challenges in understanding the applicability of current regulatory requirements and addressing the uncertainty of harms.20,61,62 Many countries have noted challenges in trying to develop a dedicated framework.20 It is unclear whether bioprinted interventions will receive balanced consideration of their efficacy and safety without the presence of a tailored regulatory process.20
Our literature search identified a number of other possible questions and considerations for the regulation of 3-DP medical devices; for example:
- What are the biocompatibility needs for materials used for 3-DP medical instruments (e.g., surgical guides)? If 3-DP medical instruments have less biocompatibility requirements than 3-DP implantable devices, does this open up the possibility of using different products and materials?13
- A 2016 systematic review of surgical applications of 3-DP noted that, for hospitals wishing to produce their own devices and equipment, regulatory requirements are a concern and might prevent 3-DP from being adopted.63
- If there are requirements to label and be able to track medical devices, how does this work for custom 3-DP devices?14
Who Might Benefit?
It has been suggested that 3-DP will bring advantages to many aspects of health care such as diagnostics (using medical imaging to create models that aid in visualization), surgical planning, and personalized medicine.7 Applications of bioprinting may disrupt existing models of organ and tissue donation, although these applications are likely further in the future than other 3-DP applications.7 Many clinical areas are currently using, or investigating the use of, 3-DP. Because of this, 3-DP has the potential to affect Canadians living with many different health conditions.
Clinical Applications of 3-D Printing
Initially reserved for complex cases, 3-DP is becoming more common or routine in some clinical areas.64 A 2018 narrative review of registered clinical trials found orthopedics, dentistry, and maxillofacial surgery to be the most active areas of ongoing research.65
3-DP health care applications are generally categorized in the literature into the following applications:8,13,14,26,28,66,67
- anatomical models (e.g., for surgical preparation, planning, or to aid diagnosis)
- surgical guides
- tools and instruments
- implants and therapeutic devices
- tissues and organs
- dental applications.
3-DP medical devices can be further classified into three types, based on their degree of customization:14
- custom-made medical devices (i.e., devices unique to an individual)
- customizable medical devices (i.e., mass produced using a standard process and individualized to specific patients)
- standard medical devices (i.e., mass produced using 3-DP because of device complexity or to lower costs).
Information on applications of 3-DP in dentistry; prosthetics, orthotics, and assistive devices; and surgery are summarized. Because of overlap between clinical specialties (e.g., oral surgery and dentistry), some applications are discussed in more than one section of this report.
Advances in dental imaging (such as cone beam computed tomography [CT]) have resulted in increased interest in 3-DP for dentistry.68 3-DP applications in dentistry include :
- orthodontics7,69 (for making and positioning brackets, as well as aligners)
- dental crowns and partial dentures27,70
- removable complete dentures70,71
- oral surgery:69
- surgical guides placed over teeth to align drills27,68
- access guides for root canals68
- replica teeth to prepare autotransplantation sites68
- dental implants.69
Prosthetics, Orthotics, and Assistive Devices
The use of 3-DP in both prosthetics (devices that replace missing body parts) and orthotics (the design of external devices that modify the structure and function of the body) may be beneficial because of:13,64,72
- customization to offer a better fit and ability to adjust or increase device functionality
- lighter weight
- lower costs to make the devices available to a broader market.
These potential benefits are of particular interest for children who can quickly outgrow expensive devices.64
Other examples include using 3-DP to produce customized ear shells (devices that connect hearing instruments to a person’s ear canal) for hearing aids;15 and the printing of assistive devices, such as straw holders and key turners in occupational therapy.73
In surgery, 3-DP may provide surgeons with a better understanding of complex anatomy when planning surgeries, allow for customized or patient-specific implants and surgical guides, and ultimately reduce operating room time.63,74 Advantages may include shorter operative time and reduced costs, while disadvantages to 3-DP may include reactions to the material used and added planning time.
Surgical applications of 3-DP have been grouped into the following categories:28
- anatomic models67 (for preoperative planning)
- surgical instruments
- implants and prostheses, splints and external fixators.67
Imaging in surgical applications of 3-DP is conducted using CT and magnetic resonance imaging (MRI). As well, “a number of other 3D imaging options have been used in 3D printing, such as: cone beam CT, CTA [CT angiography], MRA [magnetic resonance angiography], PET [positron emission tomography], MRCP [magnetic resonance cholangiopancreatography], 3D echocardiography, 3D laser scanning systems, and even images captured on an iPhone.”67
Areas of research in surgical applications include surgical guides, models for surgical planning, or custom implants.74 Areas in development within surgical applications include orthopedics (particularly knee surgery), maxillofacial surgery (cranial and spinal surgery), dental surgery, cardiovascular surgery, cerebrovascular surgery, otolaryngology, and general surgery.74
Examples of surgical applications of 3-DP are discussed, by subspecialty, in the following sections.
In neurosurgery, advances in imaging have been beneficial to patient care by allowing clinicians to observe small and intricate structures inside the nervous system.75 3-DP offers the potential of improved visualization of the relationship between complex structures when planning a procedure.75 Because the spine has complex anatomy and is surrounded by delicate structures, 3-DP models and devices that help surgeons plan and accurately execute procedures could also help improve patient outcomes.76 It has been reported that, as case complexity increased, so did the benefits of using 3-DP such as reduced operative time and perioperative blood loss. 3-DP surgical guides were reported to help mitigate the risks of procedures.76
The use of 3-DP in neurosurgery75 includes the development of patient-specific anatomical models, the design of devices to assess and treat neurosurgical conditions, and biological tissue-engineered implants. In addition, subspecialty 3-D printing applications in neurosurgery are listed in Table 3.75,76
Table 3: Subspecialty Applications of 3-DP in Neurosurgery75
|Cerebrovascular75||Surgical planning and modelling||Cerebral aneurysm surgery|
|Neuro-oncology75||Surgical planning and modelling||Visualization of the relationship between skull, tissue, and tumour for resection — including incorporating information from fMRI|
|Neurosurgical devices||Proton range compensator — creates a conformal dose distribution to protect tissues surrounding the tumour|
|Functional75||Surgical planning and modelling||Placement of intracranial electrodes for treatment-resistant epilepsy|
|Neurosurgical devices||Patient-specific head casts to reduce movement when monitoring brain activity|
|Spinal75,76||Neurosurgical devices75,76||Patient-specific screw guides for optimizing the trajectory of pedicle screws used for spinal fixation|
|Custom implants||Used in complex cases (e.g., for congenital malformations or the replacement of whole vertebrae), where an individualized approach is important for the prognosis|
|Mass-produced implants76||Devices with improved geometry and control of porosity and roughness for better osteointegration|
|Biological implants75||Early research into implants to replace intervertebral disks instead of spinal fusion|
|Surgical planning and modelling76||Used to provide a more complete understanding of the pathology and to simulate the procedures|
Applications for 3-DP in orthopedics include using anatomical models to visualize and plan for fracture repairs,22,77 create implants for arthroplasty,22 prepare contour plates and surgical guides,64 and create lightweight, custom casts.22 Visualizing tibial plateau fractures can be difficult; it has been reported that 3-DP could help overcome preoperative planning challenges related to visualizing the injury. Outcomes reported included operating time, intraoperative blood loss, time to bone union, follow-up functional outcomes, and complications.77
3-DP has also been used in limb and pelvic injuries to help repair damage to many bones of both the upper and lower extremities, including those of the hands and feet.64
Vascular and Endovascular Surgery
In vascular and endovascular surgery, 3-DP applications focus on the visualization of anatomical structures.
3-DP models have been developed for infrarenal and juxtarenal arteries, abdominal aortic aneurysm, and thoracic aorta pathology and 3-DP of vessel pathologies have been used to better understand anatomy and post-surgical complications.78
Plastic and Reconstructive Surgery
3-DP is being studied and used in plastic and reconstructive surgery for procedural planning, the creation of surgical tools, and the customization of implants.
3-DP has been studied or used in maxillofacial surgery, dental implant surgery, mandibular reconstruction, orthognathic surgery, and midface reconstruction.79 Common applications include anatomic models, surgical guides (most common application), occlusal splints, patient-specific implants, and facial epithesis.79,80
The increased availability of affordable 3-D scanning technology may improve the ability of clinicians to make highly patient-specific products, which can be important in plastic and reconstructive surgery applications.81 Applications reported included surgical planning; upper limb and hand prosthetics; facial reconstruction; breast reconstruction; ear, nose, and cartilage reconstruction; and skin grafting.81 It has also been used in skull reconstruction, repairing orbital fractures, and in orthognathic procedures. 82
Applications of 3-DP in hepatobiliary surgery include models for surgical planning for liver surgery, including as a supplement to medical imaging. The clinical value and application of 3-DP in liver surgery may be in printing models to plan for surgery.83 It has been reported that printing time varies from 11 hours to 100 hours, and that some models take weeks to be printed and delivered.83
The production of models can be used as an adjunct or alternative to imaging because of the complex, unique anatomy involved in procedures such as liver transplant or cancer resection.84
Urology and Renal Surgery
In urology and renal surgery, 3-DP models are used for visualization to assist diagnosis; and in structural visualization to plan for surgery, transplantation, and other procedures.
In renal surgery, 3-DP is used to visualize renal tumours for removal.85
In urology surgery, 3-DP applications include pre-surgical planning to remove renal masses, building molds to visualize the renal collection system for patients with kidney stones (to facilitate novel treatments), and producing models of a donor’s kidney and pelvic cavity to plan a kidney transplant.86 For prostate conditions, 3-DP models have been used alongside MRI to diagnose prostate cancers, to help plan prostate surgery, and to plan complex urologic surgeries.86
In urologic cancer, 3-DP has been applied to generate anatomical models for planning and surgical simulation.87
Surgical planning is noted as a potential application of 3-DP in cardiac surgery. The use of 3-DP heart models for surgical planning for people with congenital heart defects has been reported.88
3-DP has been used to produce anatomical models to preoperatively size airway devices and plan for airway management.89 Bioabsorbable airway splints have also been produced using 3-DP.89
Clinical Applications of Bioprinting
The development in the field of bioprinting is being driven largely by “[the medical needs of] aging populations; increasing unmet demand for organ donors; trends towards non-animal testing on therapeutics using 3-D cell culture platforms; clinical needs in wound care; and joint repair and replacement surgeries.”23
Bioprinting is being explored for the purposes of repair, replacement, or regeneration to develop an assortment of tissues including cartilage, bone, skin and periodontal tissues; other vascularized tissues; and cardiovascular tissues.13,90,91 Bioprinted tissues are being investigated as analogues for toxicity testing, disease modelling, and for patient-specific drug screening, with the potential to eliminate testing on animals.13
Bioprinting applications noted the following areas of inquiry in descending order of most to least developed and validated:23
- tissue modelling (drug discovery and development)
- toxicology testing (drug screening and cosmetics)
- engineered tissues (regenerative medicine, prosthetics, and dental applications)
- transplantation (full or partial organs as part of regenerative medicine).
Other Health-Related Applications of 3-D Printing and Bioprinting
3-D Printed Medications
The potential benefits of using 3-DP techniques for producing medications include the ability to personalize a medication dose, combine the delivery of medications, and avoid the use of bulking agents or fillers that a person may be intolerant to (such as lactose).16
One example is levetiracetam (a treatment for epilepsy), approved by FDA in 2015.7 This product is produced using a 3-DP technique called ZipDose that combines power and liquid printing to produce high-dose, quick-dissolving pills.92
A structured review of 3-DP of medications was published in 2013.93
Clinician Education and Training
Examples of using 3-DP models to educate and train clinicians are common in the literature. Clinical areas where 3-DP training and education models are in use include pathology, urology, neurosurgery, vascular and endovascular surgery, congenital heart disease, and anesthesia.67,75,78,86-89,94
In vascular and endovascular surgery, the use of 3-D printing has been discussed regarding the potential of moving from a traditional learning model of “see-one, do-one, teach one” to an approach that includes simulation using 3-DP models. 78
3-DP could also be used to build a library of pathologies for future education.28 However, the utility of practising on such models, particularly those made from a single material, might not accurately replicate the feel of actual human tissues.28 Advances in 3-DP now allow for models to include different tissue types, which may be more realistic as teaching models.94
While experienced clinicians may be able to clearly visualize internal structures, it is possible they could benefit from training using 3-DP anatomical models when preparing for complex interventions.13
Using 3-DP models may help patients understand their condition (e.g., visualizing anatomy in congenital heart disease88), understand complex anatomy and procedures (e.g., during the preparation for vascular surgery78 or liver cancer resections87), and improve shared understanding when seeking informed consent.28,82
3-DP is also used to produce phantoms — objects that are specially designed to be scanned or imaged — for testing imaging systems.95
The integration of 3-DP into routine clinical practice goes beyond the effectiveness and safety of individual technologies. There are several potential implementation considerations related to technical features, cost, legal and ethical issues, and patient-related factors.
There are a range of important considerations in the implementation of 3-DP related to factors such as the technological and manufacturing process, the materials used, and technical limitations of the technology.
3-DP requires a minimum level of image and resolution quality.26,82 Successful printing, which is especially challenging in specialized fields such as vascular surgery, can be highly dependent on the quality of imaging and printers available.78 There are also many software options available and care is needed to ensure errors do not occur when converting data from one file type to another.26 For 3-DP in craniofacial plastic surgery, it has been noted that the need for software specifically designed for these clinical applications was a barrier to uptake in the field.82 Issues with accuracy (poor image resolution) and artifacts (related to CT being unable to scan metal) were also noted.82
Uncertainty about the materials used for 3-DP has also been raised. For example, a review of prosthodontic applications of 3-DP noted that more research into the mechanical properties of materials used and the final products themselves was necessary.70 Concern has also been expressed about the limited availability of 3-DP compatible materials, which could limit the potential for its use in health care.13 That is, common biocompatible materials are often unsuitable for 3-DP and common materials used in 3-DP are often not biocompatible.13 Another issue raised is a need for a better understanding of what material microarchitectures, or internal structures, result in the best performance.13 It has been noted that 3-DP cannot replicate all surgically useful information (such as joint instability) and, unlike some types of imaging, cannot provide real-time information.76
In a report about 3-DP use in maxillofacial surgery, it was noted that although low-cost printers are available, 3-DP was more frequently being outsourced to a commercial medical devices manufacturer as opposed to being printed in-house.79 Less complex printing for items such as anatomical models may be more suitable for in-house 3-DP.79 In the case of self-printing, patients may not receive the support needed to maximize the safety and utility of such a device.72
Cost and Administration
The literature search aimed to identify cost-related information about 3-DP in health care. Few studies were identified that directly evaluated costs; however, many studies and reports discuss them indirectly.
Typical costs of 3-DP include the printer, software, high-resolution computer screens, high-powered computers, a high bandwidth computer network, printing materials, post-processing equipment, facility costs and upgrades (i.e., fume hoods, ventilation set-up), staff training, equipment maintenance contracts, and personnel salaries.67,96 Costs also depend on the type of manufacturing (i.e., consumer versus commercial).74 A 2018 systematic review of 3-DP in liver surgery noted that only a portion of included studies discussed costs and that what was reported was dependent on the technique and materials used.84 One pilot study of 3-DP in maxillofacial surgery considered procedural costs and associated variables such as operative time and surgical complications.97
A 2018 KCE (Belgium) report found there was not much information available on the cost-effectiveness of incorporating 3-DP into clinical practice and noted no studies were found that reported on cost utility.14 Similarly, a 2016 systematic review of studies on 3-DP applications in surgery noted that only about 10% of included studies discussed cost-effectiveness.74 However, the authors found mixed reporting about the costs of using 3-DP, with some reporting higher costs and some reporting lower costs associated with the use of the technology.74
While cost was identified as a barrier to 3-DP in many included studies, in a 2016 systematic review of surgical 3-DP, the authors noted that cost is a concern when introducing any new health technology.63 The value of 3-DP may also be difficult to assess. For example, while the time required for the 3-DP process may greatly exceed the time saved in the operating room by using a 3-DP model or device, the cumulative savings in operating room costs are likely greater than the additional expense required to produce 3-D printed tools.63 It may also be difficult to generalize costs across institutions because of different practices.63 3-DP may also allow for inexpensive production throughout the life of a device, with the first device costing a similar amount to the last — something that is uncommon with other forms of manufacturing where prototype models may involve substantial costs.81
A number of articles identified reported direct cost information and considerations. These examples are summarized in Table 4.
Table 4: Examples of Reported Costs of 3-DP Clinical Applications
|Clinical Specialty||Application||Reported Cost||Considerations|
|Plastic surgery81||Custom-printed implants||US$10,000 to US$15,000||
|Spinal surgery76||Anatomic models||US$300 to more than US$1,000||
|Vascular and endovascular surgery 78||Anatomical models||US$4 to US$2,360||
|Printers||US$2,210 to US$50,000||
|Renal surgery85||Anatomical models||US$100 to US$1,000||
|Congenital heart88||Anatomical models||US$55 to US$810||
3-DP = three dimensional printing; N/A = not applicable.
Moving away from costs, a 2017 systematic review of 3-DP in liver surgery noted that 3-D modelling use is not widespread because of a lack of technicians with specialist knowledge in interpreting medical imaging.84 Specialized knowledge needed by both radiologists and technicians includes: “anatomical structure segmentation (automatic, semiautomatic, or manual), virtual modeling, preparation for 3D printing, the printing process itself, and post-processing.”84
A 2018 review of the bioprinting process discusses affordability as a concern throughout production. The cost of bioinks depends on the materials used in their composition.21 For example, as the concentration of cells increases, so does the overall cost of bioinks.21 The high cost of current bioprinters may also be a barrier to the wider adoption of bioprinting in clinical use.21 The processes required for successful bioprinting — for example, sterility — may also contribute to the expensive cost.21 A 2018 review of bioprinting skin noted that costs included cells, scaffolds, and printers.91 Other costs associated with bioprinting include post-processing (e.g., the need for bioreactors to grow the tissues).21 Reported costs of bioprinters range from US$500 to US$200,000.21
Data Ownership and Privacy
3-DP (particularly for custom or patient-specific devices) requires individual patient data.14 The method of data collection and use must be taken into account when considering 3-DP as part of a patient’s care plan.14 The use of computer-aided design files may lead to intellectual property disputes and privacy concerns,98 and questions about a patient’s right to access and own their own data.14 It is not yet clear who will own the computer-aided designs, medical images, and final products, particularly when biological material is utilized.98 To ensure patient data are kept private, 3-DP systems must also have adequate cybersecurity protocols in place.26
3-DP deviates from standard chains of production, distribution, and use, making the question of who is the producer or manufacturer difficult to answer.14 It is unclear whether responsibility for custom-designed implant failure could fall to, for example, the surgeon who designed the implant, the software engineer who built the design software, the printer manufacturer, the manufacturer of the materials used for the final product, or a combination of those involved in its creation.14
Some of the novel features of 3-DP are associated with ethical questions or considerations. For instance, the ability of 3-DP to augment structures and functions of the human body suggests potential exploitation of this feature for human enhancement (e.g., proactively replacing bones with 3-DP alternative materials for function and performance).99 There is excitement and hope surrounding 3-DP, which may impact patient perceptions and expectations.100 This must be weighed against the uncertainty regarding safety and efficacy, and the ethics of offering experimental treatments.100
Another concern is the shift toward a decentralized manufacturing process.101 Current safety regulations rely on centralized manufacturing processes and may not be sufficient if manufacturing occurs at point-of-care.101 While some believe 3-DP may democratize access to personalized medicine, others believe complex 3-DP products — such as replacement organs, for example — may only be accessible by those with substantial resources.99 This may depend on the funding and reimbursement structure, and the type of product or application.
Ethical considerations, specifically related to the introduction of bioprinting, have been summarized in a review by Gilbert et al.20 The authors raise questions on several key topics including:20
- whether there should be restrictions on what (i.e., material and products) can be bioprinted
- the risks and challenges associated with testing bioprinted technologies in humans
- ethical questions about treatment irreversibility, loss of treatment opportunity, and treatment replicability
- the lack of guidance frameworks for the testing and regulation of bioprinting in humans.
Additional relevant ethical issues in bioprinting have been reviewed by others.101,102
Restrictions to Bioprinting Materials and Products
Bioprinting has generated interest for its potential role in reducing disease burden and health care costs,103 but there is also the potential for bioterrorism104 and unauthorized use by those with access to printing equipment.20 Gilbert et al. noted the conflicting desire to provide access to potentially lifesaving treatments while avoiding doing harm in the face of uncertainty.20 Further, the risks may differ depending on the product being printed and the bioink used for its creation.20 There may be ethical concerns with administering bioprinted treatments of animal or embryonic origin to those with religious or other ethical conflicts.20 The potential for donor coercion to supply biological materials was also noted.20 The authors also touched on the potential implications of the origin of the material and the possibility that certain materials may carry a higher risk of harm, such as disease transmission, than others. General ethical concerns with tissue engineering may also apply in the case of bioprinting.20
Risk of Testing Bioprinting in Humans
In studying or testing bioprinted products in humans, Gilbert et al. noted that, because of the nature of the bioprinted interventions, it is neither feasible nor ethical to conduct safety trials using the traditional approach of testing the intervention in multiple subjects.20 For each new application, the patient would likely be acting as the “guinea pig” for their personalized and thus experimental treatment.20 While it may be possible to standardize criteria and protocols, each treatment is unique and findings from one patient are not generalizable to the next.20 Gilbert et al. suggested that adding therapeutic efficacy end points to earlier stage clinical trials, particularly when patients have life-threatening conditions, could increase the value of investigations in this context.20 They also discussed the importance and challenge of obtaining transparent and comprehensive informed consent in an environment of substantial uncertainty, particularly given the hype and perception of lower risk when using autologous (whereby the patient is the donor) material.20,105
To help patients make informed decisions about 3-DP technologies, KCE Belgium recommended “giving the patient complete information on the existing alternatives and, as necessary, on the scientific uncertainty that the 3D-printed medical device concerned would be safer or more effective than the existing alternative.”14
Irreversibility, Loss of Opportunity for Future Treatment, and Limited Replicability of Treatment
Patients may not have the same opportunity to withdraw from a trial after the implantation of a bioprinted product.20 Procedures may have limited reversibility, particularly when cells are inserted into an existing biological structure.20 The inability to withdraw from a trial may limit the opportunity for access to future treatment, restricting patient autonomy.20,106 Gilbert et al. (also citing others) raised the question of whether it is morally appropriate to implant bioprinted materials for safety testing given the uncertainty regarding the risk-benefit profile.20,107-109 This is a concern given the current climate of extending experimental therapy opportunities in the regulatory context.20 Further, treatment effects may not be replicable from patient to patient, as the intervention will elicit a genetically, structurally, and phenotypically unique response.20
Considerations for Evaluation and Assessment of 3-D Printing and Bioprinting Technologies
Organizations conducting secondary research and evaluations of 3-DP technologies may encounter certain challenges and opportunities. Among these are the quality and maturity of the evidence, unique features of 3-DP that may warrant alternative study designs and data collection measures, challenges associated with the customized nature of the technology, and a lack of consensus on nomenclature.
Authors of literature reviewed for this bulletin often expressed concern with both the quality and quantity of available evidence (e.g., the lack of randomized controlled trials) for 3-DP in health, as well as a need for evaluation of relevant outcomes measures (e.g., the impact of 3-DP on surgical time and precision).8,14,76,79,84,97,110,111
The state of evidence may be a barrier to the adoption of 3-DP in health care.65 Surgical fields such as maxillofacial surgery, orthopedics, and cardiology have been suggested to be more developed than other clinical applications.65 A spike in registered 3-DP trials after 2015 has been reported, indicating the technology may be moving from a state of early ideas and research to one of more long-term study.65 As noted earlier, bioprinting is less developed than 3-DP, with much of the existing body of literature focusing on in vitro experimentation and conceptual exploration.21 In testimony to Canada’s Standing Senate Committee on Social Affairs, Science and Technology, presenters commented that traditional randomized controlled trials may not be the most appropriate approach for assessing the safety and efficacy of innovative technologies like 3-DP and that alternatives should be considered.34
The current quantity and quality of evidence, and unique features of 3-DP, may present challenges in conducting comprehensive evaluations of the technology. Specific challenges may exist for conducting health technology assessments. In a project description and planning document for a health technology assessment on a 3-DP topic, EUnetHTA made note of several relevant considerations. These included but were not limited to inconsistency in regulatory and market access requirements, questions around the type of data collection needed to monitor long-term safety outcomes, challenges identifying specific manufacturers and low manufacturer engagement, lack of standardization of the device due to customization, and the need for a technical expertise (in addition to clinical expertise) on the project.112
A 2017 review of taxonomy and terminology used in 3-DP research found that a wide range of terms are being used to describe these applications.11 The authors noted that a consistent, common set of language is necessary for collaborative research and eventually for reimbursement of 3-DP technologies, and proposed that “3D Printing” be adopted as the common term.11 The lack of consensus on terminology could present challenges when evaluating 3-DP technologies using epidemiological methods that rely on literature searching and review strategies, such as health technology assessments and systematic reviews.
Research on clinical applications of 3-DP and bioprinting has progressed, in both volume and stage of inquiry, with some applications exiting the exploratory phase and undergoing concrete clinical evaluation.8,65 In parallel, there has been growth in Canadian and international initiatives in 3-DP.35-45
Hospitals and clinics stand to benefit from more rigorous research into the effectiveness and safety of 3-DP technologies.8 Evidence could be made more robust through larger studies and greater consideration of the value of the technology.14 Adopting a formal model, such as IDEAL (Idea, Development, Exploration, Assessment and Long-term study), as suggested by KCE Belgium, may help address issues in data collection and help pave the way for further implementation and reimbursement of 3-DP in health care.14
Concepts that could help foster research and development in bioprinting include open sourcing of hardware and software, open innovation (greater use of external ideas and technologies for internal business, and greater sharing of internal ideas with external businesses),113 and developing a greater understanding of customer and market needs.23
Looking beyond the current state of 3-DP, 4-D printing — an approach that “adds a dimension of transformation over time, where printed products are sensitive to parameters like temperature, humidity, time etc.” — may offer additional advantages in the medical field as smart implants, tools, and devices become more common.114
- Hull CW, Inventor; US Patent US4,575,330, assignee. Apparatus for production of three-dimensional objects by stereolithography. 1986 Mar 11.
- Basiliere P, Shanler M. Hype cycle for 3D printing, 2018. Stamford (CT): Gartner; 2018: https://www.gartner.com/doc/3881825/hype-cycle-d-printing-. Accessed 2019 Jan 21.
- d’Aveni R. The 3-D printing revolution. Harv Bus Rev. 2015;93(5):40-48.
- Petrick IJ, Simpson TW. 3D printing disrupts manufacturing: how economies of one create new rules of competition. Res Technol Manag. 2013;56(6):12-16.
- Jamroz W, Szafraniec J, Kurek M, Jachowicz R. 3D printing in pharmaceutical and medical applications - Recent achievements and challenges. Pharm Res. 2018;35(9):176.
- Combellack E, Jessop ZM, Whitaker IS. The commercial 3D bioprinting industry. In: Thomas DJ, Jessop ZM, Whitaker IS, eds. 3D Bioprinting for Reconstructive Surgery. Cambridge (GB): Woodhead Publishing; 2018:413-421.
- Jagadeesh V. Medical applications of 3D printing. Pharma Times. 2018;50(5):9-17.
- Diment LE, Thompson MS, Bergmann JHM. Clinical efficacy and effectiveness of 3D printing: A systematic review. BMJ Open. 2017;7(12):e016891.
- 3D printing of medical devices. Silver Spring (MD): U.S. Food & Drug Administration; 2018: https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/3DPrintingofMedicalDevices/default.htm. Accessed 2018 Dec 21.
- Technical considerations for additive manufactured medical devices: guidance for industry and Food and Drug Administration staff. Silver Spring (MD): U.S. Food & Drug Administration; 2017: https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM499809.pdf. Accessed 2019 Jan 04.
- Chepelev L, Giannopoulos A, Tang A, Mitsouras D, Rybicki FJ. Medical 3D printing: methods to standardize terminology and report trends. 3D Print Med. 2017;3(1):4.
- The 3Rs of 3D printing: FDA's role. Silver Spring (MD): U.S. Food & Drug Administration; 2016: https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm533992.htm. Accessed 2019 Jan 04.
- Zadpoor AA, Malda J. Additive manufacturing of biomaterials, tissues, and organs. Ann Biomed Eng. 2017;45(1):1-11.
- Vinck I, Vijverman A, Vollebregt E, et al. Responsible use of high-risk medical devices: the example of 3D printed medical devices. Brussels: Belgian Health Care Knowledge Centre (KCE); 2018.
- Snyder GH, Cotteleer M, Kotrek B. 3D opportunity in medical technology : additive manufacturing comes to life. San Francisco (CA): Deloitte Touche Tohmatsu Limited; 2014: https://www2.deloitte.com/insights/us/en/focus/3d-opportunity/additive-manufacturing-3d-opportunity-in-medtech.html. Accessed 2019 Mar 14.
- Zema L, Melocchi A, Maroni A, Gazzaniga A. Three-dimensional printing of medicinal products and the challenge of personalized therapy. J Pharm Sci. 2017;106(7):1697-1705.
- International clinical trials registry platform search portal. http://apps.who.int/trialsearch/: Accessed 2019 Feb 04.
- Clinicaltrials.gov. https://clinicaltrials.gov/: Accessed 2019 Feb 04.
- PROSPERO: International prospective register of systematic reciews. https://www.crd.york.ac.uk/prospero/: Accessed 2019 Feb 03.
- Gilbert F, O’Connell CD, Mladenovska T, Dodds S. Print me an organ? Ethical and regulatory issues emerging from 3D bioprinting in medicine. Sci Eng Ethics. 2018;24(1):73-91.
- Datta P, Barui A, Wu Y, Ozbolat V, Moncal KK, Ozbolat IT. Essential steps in bioprinting: from pre- to post-bioprinting. Biotechnol Adv. 2018;36(5):1481-1504.
- Lieben L. Regenerative medicine: the future of 3D printing of human tissues is taking shape.[Erratum appears in Nat Rev Rheumatol. 2016 Apr;12(4):191]. Nat Rev Rheumatol. 2016;12(4):191.
- Thakur PC, Cabrera DD, DeCarolis N, Boni AA. Innovation and commercialization strategies for three-dimensional-bioprinting technology: a lean business model perspective. J Commer Biotechnol. 2018;24(1):78-87.
- Fraser A. 3D printing humans: a quick review of 3D bioprinters. 2018; http://bionics.ubc.ca/2018/08/03/3d-printing-humans-a-quick-review-of-3d-bioprinters/: Accessed 2019 Mar 13.
- Mason J. Focus on: 3-D printing. Health Technol Update. 2016(17).
- ECRI Institute. 3-D printing in medicine: an introduction. Health Devices. 2018.
- Dawood A, Marti Marti B, Sauret-Jackson V, Darwood A. 3D printing in dentistry. Br Dent J. 2015;219(11):521-529.
- Malik HH, Darwood AR, Shaunak S, et al. Three-dimensional printing in surgery: a review of current surgical applications. J Surg Res. 2015;199(2):512-522.
- Gokuldoss PK, Kolla S, Eckert J. Additive manufacturing processes: selective laser melting, electron beam melting and binder jetting-selection guidelines. Materials (Basel). 2017;10(6):672.
- Wong KV, Hernandez A. A review of additive manufacturing. ISRN Mechanical Eng. 2012.
- Turksen K. Bioprinting in regenerative medicine. Switzerland: Springer; 2015.
- Baumers M, Tuck C, Hague R. Selective heat sintering versus laser sintering: comparison of deposition rate, process energy consumption and cost performance. Paper presented at: Sold Freeform Fabrication Symposium, 2015; Austin (TX).
- Ripley B, Levin D, Kelil T, et al. 3D printing from MRI Data: harnessing strengths and minimizing weaknesses. J Magn Reson Imaging. 2017;45(3):635-645.
- Standing Senate Committee on Social Affairs, Science and Technology. Challenge ahead : integrating robotics, artificial intelligence and 3D printing technologies into Canada’s healthcare systems. Ottawa (ON): Canada Senate; 2017: http://publications.gc.ca/site/eng/9.846477/publication.html. Accessed 2018 May 24.
- The Victoria Hand Project. The Victoria hand project: prosthetics within reach. 2019; https://www.victoriahandproject.com/: Accessed 2019 Mar 13.
- Precision ADM. Advanced digital manufacturing. 2019; https://www.precisionadm.com/: Accessed 2019 Mar 13.
- Living Cell Imaging Resource Lab. Living cell imaging resource laboratory. 2019; https://snyder.ucalgary.ca/imaging/: Accessed 2019 Mar 13.
- Kinsella Lab. Kinsella lab. 2018; http://kinsella.lab.mcgill.ca/: Accessed 2019 Mar 13.
- Institute for Reconstructive Sciences in Medicine. Institute for Reconstructive Sciences in Medicine (iRSM). 2016; https://www.covenanthealth.ca/media/122141/research-excellence-irsm-2016jan07.pdf: Accessed 2019 Mar 13.
- CBC News. Ottawa Hospital opens 1st medical 3D printing program of its kind in Canada. 2017; https://www.cbc.ca/news/canada/ottawa/ottawa-hospital-medical-3d-printing-1.3967350: Accessed 2019 Mar 13.
- Aspect Biosystems Ltd. 3D bioprinting and tissue engineering: creating human tissues on demand. 2019; https://www.aspectbiosystems.com/: Accessed 2019 Mar 13.
- Additive Design in Surgical Solutions Centre (ADEISS). Advanced medical and dental 3D metal printing solutions. 2019; http://adeiss.ca/: Accessed 2019 Mar 13.
- Adaptiiv. Adaptiiv: the key to any fight is a strong ally. 2019; https://www.adaptiiv.com/: Accessed 2019 Mar 13.
- Canada Makes. Quebec to open its frst medical 3D printing center. 2017; http://canadamakes.ca/quebec-open-first-medical-3d-printing-center/: Accessed 2019 Mar 13.
- Javelin Technologies Inc. Welcome to Javelin, Canada's largest 3D solution provider. 2019; https://www.javelin-tech.com/3d/: Accessed 2019 Mar 13.
- The Lynn and Arnold Irwin Advanced Perioperative Imaging Laboratory. The Lynn and Arnold Irwin advanced perioperative imaging laboratory. 2019; http://apil.ca/: Accessed 2019 Feb 22.
- Hospital SMs. 3D Printing. 2019; http://stmichaelshospitalresearch.ca/staff-services/research-facilities/facilities/microfabrication/3d-printing/: Accessed 2019 Feb 22.
- MED 3D Network. MED 3D network. 2019; https://www.munmed3dnetwork.ca/: Accessed 2019 Feb 22.
- Nia Technologies Inc. Nia. 2018; https://niatech.org/: Accessed 2019 Feb 22.
- 3D4MD Inc. Medical supplies made on-site: improving efficiency in healthcare. 2019; http://www.3d4md.com/: Accessed 2019 Feb 22.
- Medical Makers. Medical Makers: make healthcare better. 2019; https://www.medicalmakers.org/: Accessed 2019 Feb 22.
- TDL Systems Inc. O.L.T. footcare: 3D printed foot orthotics, AFO, orthotic sandals. 2019; https://www.oltfoot.com/: Accessed 2019 Feb 22.
- Canada Makes. About Canada Makes. 2019; http://canadamakes.ca/about/: Accessed 2019 Mar 14.
- Health Canada. Notice: upcoming guidance development on the licensing requirements for 3D-printed devices. 2018; https://www.canada.ca/en/health-canada/services/drugs-health-products/medical-devices/activities/announcements/3d-printing-notice.html: Accessed 2018 Aug 29.
- Health Canada. Draft guidance document - licensing requirements for implantable medical devices manufactured by 3D printing. 2018; https://www.canada.ca/en/health-canada/services/drugs-health-products/medical-devices/activities/announcements/notice-licensing-requirements-implantable-3d-printing/draft-guidance-document.html: Accessed 2019 Mar 14.
- Mulero A. AdvaMed calls for revisions to Health Canada guidance on 3D-printed implantable devices. Reg Focus. 2019;1.
- U.S. Food and Drug Administration. Statement by FDA Commissioner Scott Gottlieb, M.D., on FDA ushering in new era of 3D printing of medical products; provides guidance to manufacturers of medical devices. 2017; https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm587547.htm: Accessed 2019 Mar 14.
- U.S. Food and Drug Administration. About FDA: Emerging Technology Program. 2018; https://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm523228.htm: Accessed 2019 Jan 04.
- Therapeutics Goods Administration. Consultation: proposed regulatory scheme for personalised medical devices, including 3D-printed devices. 2019; https://www.tga.gov.au/consultation/consultation-proposed-regulatory-scheme-personalised-medical-devices-including-3d-printed-devices: Accessed 2019 Feb 25.
- IMDRF Personalized Medical Devices. Definitions for personalized medical devices. Canberra, Australia: Therapeutic Goods Administration; 2018: http://imdrf.org/docs/imdrf/final/technical/imdrf-tech-181018-pmd-definitions-n49.pdf. Accessed 2019 Mar 14.
- Davies C, Baird L, Jacobson M, et al. 3D printing of medical devices: when a novel technology meets traditional legal principles. New York (NY): Reed Smith, LLP; 2015.
- van Schothorst M, Weeda J, Schiffers K, et al. Study on the regulation of advanced therapies in selected jurisdictions. London, England: European Union; 2016: https://ec.europa.eu/health/sites/health/files/human-use/docs/20147306_rfs_chafea_2014_health_24_060516.pdf: Accessed 2019 Mar 14.
- Martelli N, Serrano C, van den Brink H, et al. Advantages and disadvantages of 3-dimensional printing in surgery: a systematic review. Surgery. 2016;159(6):1485-1500.
- Lal H, Patralekh MK. 3D printing and its applications in orthopaedic trauma: a technological marvel. J Clin Orthop Trauma. 2018;9(3):260-268.
- Witowski J, Sitkowski M, Zuzak T, et al. From ideas to long-term studies: 3D printing clinical trials review. Int J Comput Assist Radiol Surg. 2018;13(9):1473-1478.
- Trenfield SJ, Madla CM, Basit AW, Gaisford S. The shape of things to come: emerging applications of 3D printing in healthcare. In: Basit AW, Gaisford S, eds. 3D Printing of Pharmaceuticals. Switzerland: Springer; 2018:1-19.
- Hoang D, Perrault D, Stevanovic M, Ghiassi A. Surgical applications of three-dimensional printing: a review of the current literature & how to get started. Ann Transl Med. 2016;4(23):456.
- Anderson J, Wealleans J, Ray J. Endodontic applications of 3D printing. Int Endod J. 2018;51(9):1005-1018.
- Nayar S, Bhuminathan S, Bhat WM. Rapid prototyping and stereolithography in dentistry. J Pharm Bioallied Sci. 2015;7(Suppl 1):S216-219.
- Alharbi N, Wismeijer D, Osman RB. Additive manufacturing techniques in prosthodontics: where do we currently stand? A critical review. Int J Prosthodont,. 2017;30(5):474-484.
- Bilgin MS, Baytaroglu EN, Erdem A, Dilber E. A review of computer-aided design/computer-aided manufacture techniques for removable denture fabrication. Eur J Dent. 2016;10(2):286-291.
- Diment LE, Thompson MS, Bergmann JH. Three-dimensional printed upper-limb prostheses lack randomised controlled trials: a systematic review. Prosthet Orthot Int. 2018;42(1):7-13.
- Wagner JB, Scheinfeld L, Leeman B, Pardini K, Saragossi J, Flood K. Three professions come together for an interdisciplinary approach to 3D printing: occupational therapy, biomedical engineering, and medical librarianship. J Med Libr Assoc. 2018;106(3):370-376.
- Tack P, Victor J, Gemmel P, Annemans L. 3D-printing techniques in a medical setting: a systematic literature review. Biomed Eng Online. 2016;15(1).
- Randazzo M, Pisapia JM, Singh N, Thawani JP. 3D printing in neurosurgery: a systematic review. Surg Neurol Int. 2016;7(Suppl 33):S801-S809.
- Wilcox B, Mobbs RJ, Wu AM, Phan K. Systematic review of 3D printing in spinal surgery: the current state of play. J Spine Surg. 2017;3(3):433-443.
- Xie L, Chen C, Zhang Y, Zheng W, Chen H, Cai L. Three-dimensional printing assisted ORIF versus conventional ORIF for tibial plateau fractures: a systematic review and meta-analysis. Int J Surg. 2018;57:35-44.
- Tam CHA, Chan YC, Law Y, Cheng SWK. The Role of three-dimensional printing in contemporary vascular and endovascular surgery: a systematic review. Ann Vasc Surg. 2018;53:243-254.
- Louvrier A, Marty P, Barrabe A, et al. How useful is 3D printing in maxillofacial surgery? J Stomatol Oral Maxillofac Surg. 2017;118(4):206-212.
- Lin HH, Lonic D, Lo LJ. 3D printing in orthognathic surgery - a literature review. J Formos Med Assoc. 2018;02:02.
- Bauermeister AJ, Zuriarrain A, Newman MI. Three-dimensional printing in plastic and reconstructive surgery: a systematic review. Ann Plast Surg. 2016;77(5):569-576.
- Choi JW, Kim N. Clinical application of three-dimensional printing technology in craniofacial plastic surgery. Arch Plast Surg. 2015;42(3):267-277.
- Perica ER, Sun Z. A systematic review of three-dimensional printing in liver disease. J Digit Imaging. 2018;31(5):692-701.
- Witowski JS, Coles-Black J, Zuzak TZ, et al. 3D Printing in liver surgery: a systematic review. Telemed J E Health. 2017;23(12):943-947.
- Sun Z, Liu D. A systematic review of clinical value of three-dimensional printing in renal disease. Quant Imaging Med Surg. 2018;8(3):311-325.
- Parikh N, Sharma P. Three-dimensional printing in urology: history, current applications, and future directions. Urology. 2018;121:3-10.
- Manning TG, O'Brien JS, Christidis D, et al. Three dimensional models in uro-oncology: a future built with additive fabrication. World J Urol. 2018;36(4):557-563.
- Lau I, Sun Z. Three-dimensional printing in congenital heart disease: a systematic review. J Med Radiat Sci. 2018;65(3):226-236.
- Chao I, Young J, Coles-Black J, Chuen J, Weinberg L, Rachbuch C. The application of three-dimensional printing technology in anaesthesia: a systematic review. Anaesthesia. 2017;72(5):641-650.
- Trombetta R, Inzana JA, Schwarz EM, Kates SL, Awad HA. 3D printing of calcium phosphate ceramics for bone tissue engineering and drug delivery. Ann Biomed Eng. 2017;45(1):23-44.
- Tarassoli SP, Jessop ZM, Al-Sabah A, et al. Skin tissue engineering using 3D bioprinting: an evolving research field. J Plast Reconstr Aesthet Surg. 2018;71(5):615-623.
- Aprecia Pharmaceuticals LLC. Zipdose technology: the world's first 3DP dosage form. 2018; https://www.aprecia.com/technology/zipdose: Accessed 2019 Jan 08.
- Ursan ID, Chiu L, Pierce A. Three-dimensional drug printing: a structured review. J Am Pharm Assoc. 2013;53(2):136-144.
- Vakharia VN, Vakharia NN, Hill CS. Review of 3-dimensional printing on cranial neurosurgery simulation training. World Neurosurg. 2016;88:188-198.
- Filippou V, Tsoumpas C. Recent advances on the development of phantoms using 3D printing for imaging with CT, MRI, PET, SPECT, and ultrasound. Med Phys. 2018;22.
- Chen J, Gariel M. A roadmap from idea to implementation: 3D printing for pre-surgical application: operational management for 3D printing in surgery. 2016: https://www.sec.gov/Archives/edgar/data/1703997/000167025418000347/document_14.pdf: Accessed 2019 Mar 14.
- Rogers-Vizena CR, Sporn SF, Daniels KM, Padwa BL, Weinstock P. Cost-benefit analysis of three-dimensional craniofacial models for midfacial distraction: a pilot study. Cleft Palate Craniofac J. 2017;54(5):612-617.
- Mendis D, Lemley M, Rimmer M. The future of printcrime: intellectual property, innovation law, and 3D printing. 3D Printing and Beyond: The Intellectual Property and Legal Implications Surrounding 3D Printing and Emerging Technology. Cheltenham Glos (UK): Edward Elgar Publishing; 2019.
- Haddow G, Vermeulen N. So, what is not to like about 3D bioprinting? Journal of Medical Ethics Blog 2017; https://blogs.bmj.com/medical-ethics/2017/03/21/so-what-is-not-to-like-about-3d-bioprinting/: Accessed 2019 Mar 14.
- Gilbert F, Viana JNM, O'Connell CD, Dodds S. Enthusiastic portrayal of 3D bioprinting in the media: ethical side effects. Bioethics. 2018;32(2):94-102.
- Neely EL. The risks of revolution: ethical dilemmas in 3D printing from a US perspective. Sci Eng Ethics. 2016;22(5):1285-1297.
- Vermeulen N, Haddow G, Seymour T, Faulkner-Jones A, Shu W. 3D bioprint me: a socioethical view of bioprinting human organs and tissues. J Med Ethics. 2017;43(9):618-624.
- Marchioli G, van Gurp L, Van Krieken P, et al. Fabrication of three-dimensional bioplotted hydrogel scaffolds for islets of Langerhans transplantation. Biofabrication. 2015;7(2):025009.
- Wolinsky H. Printing organs cell‐by‐cell: 3‐D printing is growing in popularity, but how should we regulate the application of this new technology to health care? EMBO Rep. 2014;15(8):836-838.
- Munsie M, Hyun I. A question of ethics: selling autologous stem cell therapies flaunts professional standards. Stem Cell Res. 2014;13(3 Pt B):647-653.
- Gilbert F. A threat to autonomy? The intrusion of predictive brain implants. AJOB Neurosci. 2015;6(4):4-11.
- Gilbert F. The burden of normality: from ‘chronically ill’to ‘symptom free’. New ethical challenges for deep brain stimulation postoperative treatment. J Med Ethics. 2012;38(7):408-412.
- Bretzner F, Gilbert F, Baylis F, Brownstone RM. Target populations for first-in-human embryonic stem cell research in spinal cord injury. Cell Stem Cell. 2011;8(5):468-475.
- Hess P. Intracranial stem cell-based transplantation: reconsidering the ethics of phase 1 clinical trials in light of irreversible interventions in the brain. AJOB Neurosci. 2012;3(2):3-13.
- ECRI Institute. Use of three-dimensional printed anatomic models for cardiovascular and neurologic surgical planning. Plymouth Meeting (PA): ECRI Institute; 2018.
- AETNA. Stereolithography 2017; http://www.aetna.com/cpb/medical/data/600_699/0613.html: Acccessed 2019 Mar 14.
- EUnetHTA. Custom-made or customisable 3D printed implants and cutting guides versus non-3D printed standard implants and cutting guides for improving outcome in patients undergoing knee, maxillofacial, or cranial surgery. Netherlands: EUnetHTA; 2018: https://www.eunethta.eu/wp-content/uploads/2018/11/OTCA11_Final-Project-Plan_3D_printing.pdf: Accessed 2019 Mar 14.
- Chesbrough HW. Bringing open innovation to services. MIT Sloan Manag Rev 2011; https://sloanreview.mit.edu/article/bringing-open-innovation-to-services/: Accessed 2019 Mar 14.
- Javaid M, Haleem A. 4D printing applications in medical field: a brief review. Clin Epidemiol Global Health. 2018.
About this Document
Authors: Jeff Mason, Sarah Visintini, Teo Quay
Acknowledgments: Caitlyn Ford, Lesley Dunfield, Iryna Magega, Kinneret Globerman, Taralyn Carver, Glenda Proctor, and Charlene Argaez. CADTH thanks the external reviewers who kindly provided comments on an earlier draft of this bulletin.
Cite as: An Overview of Clinical Applications of 3-D Printing and Bioprinting. Ottawa: CADTH; 2019 Apr. (CADTH Issues in Emerging Health Technologies; Issue 175).
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