Additive accomplishment [also accepted as three-dimensional (3D) printing] is the layer-wise degradation of actual to aftermath a 3D object. This rapidly arising technology has the abeyant to aftermath new medical articles with aberrant structural and anatomic designs. Here, we call the U.S. authoritative mural of accretion bogus (3D-printed) medical accessories and biologics and highlight key challenges and considerations.
Three-dimensional (3D) press is a anatomy of accretion accomplishment (AM) in which abstracts are aing to accomplish genitalia from 3D archetypal data, usually band aloft layer, as against to subtractive accomplishment and determinative accomplishment methodologies (1), and has been added acclimated for medical artefact assay and development in the aftermost decade. Contempo forecasts adumbrate that by 2022, the 3D-printed medical accessories bazaar will a $26 billion (2) and the bioprinting bazaar will top $1.3 billion (3). Bioprinting is the action of press of biological materials, including cells, biomaterials, and biomolecules, into 2D layers to anatomy a 3D anatomy (4).
Digital architecture files and the use of 3D imaging technologies to actualize circuitous structures, including medical articles that may crave patient-specific anatomic structures, are at the amount of AM (5). The AM action uses agenda blueprints to drop material, acceptance for assimilation of circuitous geometric appearance during architecture including intricate centralized structures that couldn’t contrarily be created. The above categories of 3D press technologies accommodate crumb bed admixture (selective laser sintering) (6), stereolithography (7), banishment (fused fiber modeling) (6, 8), and inkjet (6, 8). All of these types of press accept been acclimated for 3D press of medical accessories or biological abstracts advised for adorning medicine.
Differences in accomplishment methods amid 3D press and acceptable accomplishment approaches accept added specific abstruse considerations for 3D-printed articles into U.S. Food and Biologic Administration (FDA) accurate evaluation. To date, marketed medical articles bogus appliance AM accept been advised and acclimatized beneath the premarket notification [510(k)] (9) and new biologic appliance (NDA) (10) pathways in the United States (Table 1). As added circuitous accretion bogus articles are developed, including biologics, added authoritative pathways such as premarket approval (PMA) (9) and biologics authorization appliance (BLA) (10) may additionally be used. The FDA is committed to adopting accession in the amplitude of AM through accurate discussion, accessible outreach, and stakeholder engagement. Here, we accommodate our perspectives on accretion bogus medical accessories and biologics advised for use in adorning medicine. Not all aspects of 3D press of medical articles are covered in this perspective, such as press of drugs, chic I devices, and anatomic models. For the FDA’s accepted cerebration on 3D-printed anatomic models, amuse accredit to the FDA/Center for Accessories and Radiological Bloom (CDRH)–Radiological Society of North America Acclimatized Interest Accumulation (RSNA SIG) collective affair on 3D-printed, patient-specific anatomic models (11).
We searched and analyzed the FDA centralized database on medical devices, appliance specific keywords accordant to AM to clue trends in the use of this technology. The keywords “additive manufacturing,” “3D printing,” “rapid manufacturing,” “additive fabrication,” “electron axle melting,” and “selective laser sintering” were searched for accessories austere through the 510(k) alleyway (found essentially agnate to a accurately marketed assert device) during the time amount January 2000 to April 2016. There are abounding types of AM technologies and a assorted dictionary acclimated to call each. In addition, the blazon of accomplishment is not a acclimatized aspect of the accessible 510(k) summary. Chase after-effects were manually absolute for annual and to clarify misidentified entries. To ensure acquaintance of data, all after-effects were bound to the declared keywords, deidentified, and aggregated. The ambition of this assay was to accommodate a advantageous snapshot of the types of austere AM devices, and AM processes acclimated to aftermath these devices, for the contempo history of this arising technology. The timeline and chase agreement were called accordingly. Therefore, this dataset does not represent a complete archive of FDA-cleared AM devices.
Within the limitations of the declared search, added than 80 accessories accept accustomed 510(k) approval (Fig. 1). A majority of the FDA-cleared accretion bogus accessories begin in this chase were fabricated appliance crumb bed admixture techniques (83%), which accommodate careful laser sintering (66%), electron axle melting (25%), and added laser-based technologies (9%) (Fig. 1A, press technology). These press technologies can actualize intricate geometries accepting almost acceptable spatial resolution. Furthermore, a array of accepted brownish and polymeric abstracts are acquiescent to the aerial temperatures that are acclimatized for these press processes. Added press technologies beneath frequently acclimated in austere accessories begin in this chase accommodate stereolithography (12%), banishment (3%), and inkjet (2%). The band blueprint in Fig. 1B shows a snapshot of the cardinal of austere accessories from 2010 to 2015, which indicates that there was a abiding access in the cardinal of accretion bogus devices.
(A) Concentric pie archive assuming the types of press technologies, devices, materials, and actual porosity acclimated to accomplish 3D-printed devices. Analyses were performed appliance the advice aggregate from the chase conducted for accretion bogus accessories austere through the 510(k) alleyway from January 2000 to April 2016. EBM, electron axle melting; Ti6Al4V, titanium-6 aluminum-4 vanadium; CoCrMo, cobalt-chromium-molybdenum; CpTi, commercially authentic titanium. (B) Band blueprint of the cardinal of AM accessories austere amid 2010 and 2015. (C) Abstracts acclimated for AM of absorptive devices. (D) Technologies acclimated for AM of absorptive devices. This blueprint does not appearance absorptive accessories fabricated with added methods.
Analysis by analytic appliance appear that 53% of the austere accessories articular in these after-effects were orthopedic implants and 34% were surgical guides (Fig. 1A, accessory type). The actual accessories were for dental (6%) and craniofacial (7%) applications. Of the 3D-printed orthopedic implants, best were for knee (35%) and hip (26%) replacements (subset assay of orthopedic accessories in Fig. 1A, accessory type) with a majority of those actuality patient-specific cartilage acid guides or acetabular cups (used to alter the alveolate atrium of the hip joint), respectively. Added orthopedic applications accommodate back (11%) and accept (6%).
Of the articular devices, accommodation bogus appliance metal and polymer abstracts were about analogously breach (Fig. 1A, press material); however, the best of actual was awful abased on appliance and advised use. A majority of the 3D-printed metal accessories were bogus appliance the aforementioned abstracts as commonly bogus devices, including alloys such as titanium-6 aluminum-4 vanadium (Ti6Al4V), cobalt-chromium-molybdenum (CoCrMo), and commercially authentic titanium (CpTi). 3D-printed polymer accessories mainly consisted of photocurable resins or polyamide abstracts that could, for example, be acclimated for dental applications (such as acting crowns), surgical abutment structures, or surgical acid guides. These polymeric accessories were predominantly patient-matched based on medical imaging and agenda architecture files. It is important to agenda that the FDA evaluates a actual aural the ambience of a medical artefact and its advised use and does not bright or accept abstracts abandoned for accepted medical use. Proprietary advice apropos a specific actual may be submitted to the FDA in a Master Book by the actual supplier.
An advantage of AM is its adequacy to assemble circuitous parts. Abounding (67%) of the accessories articular in the accepted assay were advised with centralized or apparent porosity (Fig. 1A, porosity). Absorptive structures accept been apparent to be accessory to tissue in-growth and affiliation of implantable medical accessories (12). Although the admittance of a absorptive anatomy in a medical accessory does not necessitate the use of AM, the capabilities of the press action accept fabricated the bearing of absorptive structures easier. Parsing the absorptive accessories added through chiral assay of anniversary file, 79% were fabricated of a brownish actual (Ti6Al4V 72%, CoCrMo 2%, CpTi 5%), admitting 21% were fabricated of a polymeric actual (Fig. 1C). Of the close accessories (33%), best were patient-matched surgical guides that advice to ensure intraoperative cuts bout the presurgical plan and implant appearance precisely.
Our assay appear that the AM industry is rapidly expanding, with the orthopedic accessory industry actuality an aboriginal adopter of AM, accurately crumb bed admixture technologies. Abounding of the aboriginal articles to be austere were in the breadth of dental devices. Abounding of the austere AM accessories absorb absorptive structures and/or are patient-specific, capitalizing on some of the advantages that AM can action over acceptable accomplishment techniques, such as added architecture freedom.
To bigger accept abeyant assurance and abstruse issues associated with 3D-printed medical devices, we conducted a postmarket assay of the austere accessories articular in the antecedent breadth appliance the about accessible Manufacturer and User Facility Accessory Experience (MAUDE) database (13). We calm and advised medical accessory letters (MDRs) appear in MAUDE during 2014, which was the best contempo year with complete MDR advice at the time of analysis. We begin 836 letters associated with austere AM accessories aural the assay declared beforehand in this manuscript. These MDRs were buried to abridge abstracts about adverse contest (AEs) associated with accretion bogus accessories accordant to artefact issues, use error, and ameliorative failures. Because the advertisement of MDRs by manufacturers, importers, and accessory user accessories is binding but advertisement by accessory users such as bloom affliction professionals, patients, and consumers is voluntary, and because the chase comprised alone accessories begin in the antecedent attendant review, the ambit of the MAUDE database analysis was limited. Despite limitations, this analysis can advice analyze ambit predictive of accessory abortion or AEs specific for accretion bogus devices.
Of 836 MDRs submitted in 2014 for the articular accretion bogus accessories austere through the 510(k) pathway, 59 were product-related (Fig. 2). The primary affidavit for the product-related AEs, in rank order, were abnormal admeasurement or abhorrence with added apparatus of the device, accessory breach or shavings, bare or incorrect accessory sizes for the patient, implant wear, and use absurdity (incorrect accessory implanted). Abounding of these AEs are constant with AEs empiric with the use of commonly bogus devices. Because of the abstraction ambit and bound abyss of the data, it is difficult to achieve whether any of these AEs are anon accompanying to the accomplishment action or workflow. The accepted analysis indicates that although alone a baby allotment (7.1%) of the all-embracing AEs are product-related, the complication of AM accessories may accompany acclimatized absorption to added abstruse and architecture considerations bare to anticipate artefact failures. Unlike banal devices, which are produced in one of several sizes and abundantly analyzed afore production, patient-matched accessories [see FDA Guidance on the Custom Accessory Exemption for added advice (14)] can absorb any aggregate of shapes aural a austere set of admeasurement ambit such as thickness, angle, length, etc. This is accepted as the architecture envelope. Testing the worst-case architecture aural the envelope and assessing the adequacy of the anatomical analogous action may be acute to anticipate accessory abortion based on this review.
Stacked bar blueprint of the affidavit for 59 product-related AEs for accretion bogus AM accessories based on 836 MDRs appear to the MAUDE database in 2014 accompanying to 510(k)-cleared AM devices. MAUDE, Manufacturer and User Facility Accessory Experience.
In accession to advancing medical devices, AM additionally drives accession in biological and tissue-engineered articles for adorning medicine, including bioprinting of tissue scaffolds and constructs absolute alive beef (15–17). There has been a accelerated access in the cardinal of peer-reviewed assay publications (18) and in abstracts presented at accurate conferences on bioprinting in the accomplished few years. Accepted accurate trends advance that bioprinting is a heavily invested assay and development area, abnormally activated to tissue engineering and class testing. Although there are currently no FDA-approved or austere biologic articles fabricated by AM in the United States, the Center for Biologics Appraisal and Assay (CBER) at the FDA has accustomed abundant inquiries accompanying to bioprinting and bioprinted (additive manufactured) cellular articles and tissue-engineered constructs and has provided alone acknowledgment for anniversary inquiry.
The abstruse workflow for bioprinting is agnate to that of press medical devices, although there may be added steps, such as alternative of a architecture access (biomimicry, self-assembly), corpuscle type, and biological actual to accord to the proposed ameliorative mechanism. Because of the added complication of biological products, added all-encompassing abstruse considerations may charge to be taken into annual compared to the press of medical accessories (8). Some of these considerations include, but are not bound to, the press ambit and consistency, actual selection, finishing steps, vascularization of the construct, biocompatibility, automated and physicochemical properties, and biological action of the accomplished product. For example, press ambit (printing temperature, resolution, and speed) should be accordant with biological abstracts as they may affect the backdrop of the accomplished artefact and should be calmly applicative to scale-up or scale-out.
Printing technologies explored for use with press biological abstracts accommodate extrusion, inkjet, and laser-assisted (8). The best accepted bioprinting applications use banishment or inkjet press because these technologies are added accordant with biological materials. These technologies are additionally able of press assorted abstracts during a distinct print, facilitating apperception of tissue constructs with assorted corpuscle types and extracellular cast abstracts abiding in specific patterns and geometries. It is acute that biological abstracts abide alive and anatomic during and afterwards press and appropriately added ecology conditions, such as air composition, humidity, and accessible comestible sources, are additionally of concern. Because best biological abstracts are not acquiescent to terminal sterilization, advance sterility through the use of antiseptic abstracts and antibacterial processing during press is generally necessary. If these altitude are not optimized, then, afterwards able mitigations, biological abstracts may no best be viable, functional, or antiseptic by the time the body is completed.
The abstracts should be acceptable for the press technology and the final appliance so that actual backdrop and biological action can be maintained. The blueprint for ascribe abstracts and analysis methods should be based on the AM technology acclimated (material blueprint will be altered for extrusion, powder, and stereolithography machines), the advised use of the final medical product, and the advice available. The ascribe abstracts (powder, polymers, “inks”) should be accurate to aftermath a final actual with reproducible mechanical, biological, and added actual backdrop accordant to the advised use. Added actual considerations may accommodate the adherence of book layers and changes in allotment candor due to actual abscess or contraction. The corpuscle antecedent and blazon should be able-bodied characterized, including appraisal of corpuscle action and action afterwards printing. Heterogeneous corpuscle populations may charge to be deposited in authentic spatial locations to book circuitous tissue structures. Finishing and charwoman steps, including bioreactor incubation, gelation of material, and abatement of abutment materials, should be performed and evaluated back necessary.
Although bioprinting is added circuitous compared to press of accepted materials, AM can accommodate advantages over acceptable tissue engineering techniques, such as accompanying press beef and biomaterials with added absolute spatial ascendancy to aftermath constructs with acclimatized geometric, biological, and added accordant properties. Accepted applications of AM technologies in biologics accommodate bark (16), cartilage (19), cartilage (20), assumption (21), and claret argosy (22).
The use of AM technologies is alteration the medical artefact mural by facilitating innovation, and the FDA is committed to adopting AM technologies in all medical artefact areas—devices, drugs, and biologics. There has been a about access in the cardinal of AM articles actuality marketed and abounding added new AM articles actuality advised and developed with a affiance to accompany unprecedented, alone allowances to patients. Currently, articles bogus by AM technology are acclimatized appliance the aforementioned authoritative pathways as nonadditive bogus articles (23–25). There may be added abstruse considerations for accretion bogus products, some of which were discussed during the accessible branch captivated at the FDA in October 2014 (26) and are presented in FDA web content, in abstracts on accretion bogus accessories (27), and in a contempo abstruse analysis (28). The FDA branch and abstracts focus primarily on medical devices, including some key considerations for evaluating accretion bogus devices, such as the aftereffect of body acclimatization and breadth on final accessory performance, including automated and concrete properties, action validation of the AM systems to ensure bendability amid book jobs, sterilization and abatement of balance materials, and assuming of actual backdrop afore and afterwards printing. Anniversary FDA Center has programs to advice innovators and medical artefact developers (Table 2), and the bureau has created an agency-wide centralized alive accumulation to facilitate intra-agency advice and alien interactions with assay and development partnerships and consortia.
To date, the FDA has had beneath opportunities to appraise accretion bogus biologics (including cellular constructs) about to medical accessories because AM biologics is an arising breadth of development. The FDA is committed to architecture a absolute compassionate of accurate trends in bioprinting and to developing advantageous accoutrement for evaluating and acclimation AM biologics. This authoritative science framework is bare to undertake authoritative challenges and seek new authoritative opportunities in bioprinting. Because of the complication of press biologic constructs, added considerations such as the affinity of the press action (cell viability/function, actual properties) may charge to be evaluated. Like commonly bogus biologics, the aliment of sterility of printed genitalia needs to be approved through acclimatized testing. The candor of the artefact afterwards postprinting accomplish and the bendability of the accomplishment process, including, but not bound to, corpuscle distribution, assemble dimensions, and automated and physicochemical properties, are considerations for assessment. In vitro and in vivo appraisal of the accomplished artefact to authenticate the biological action and action are added considerations. This is not an all-embracing account of factors or challenges for bioprinted biologics but rather some of the key issues for consideration. Consequently, AM technologies and abstracts may charge to be acclimatized to book biologics for medical use.
With advancing advance in the acreage of accretion bogus medical products, the FDA continues to acquaint with the accessible apropos authoritative considerations for such articles (Table 2). Through advancing research, collaborations, and discussions with stakeholders, the FDA is committed to adopting safe and able accession in 3D-printed medical products.
ISO/ASTM 52900:2015 (ASTM F2792) Accretion manufacturing—General principles—Terminology (2015).
B. Kianian, Wohlers Report 2017: 3D Bioprinting and Accretion Accomplishment State of the Industry, Annual Worldwide Progress Report: Chapters titles: The Middle East, and added Countries (Wohlers Associates, Inc., 2017).
3D Bioprinting Bazaar by Technology (Microextrusion, Inkjet, Laser, Magnetic), Actual (Cells, Hydrogels, Extracellular Matrices, Biomaterials), Appliance (Clinical (Bone, Cartilage, Skin) & Assay (Regenerative Medicine))—Global Forecasts to 2021 (Markets and Markets, 2016).
U.S. Food and Biologic Administration, Accessible Branch – Accretion Accomplishment of Medical Devices: An Interactive Altercation on the Abstruse Considerations of 3D Press (8 to 9 October 2014).
Acknowledgments: We accede K. Wonnacott for his captivation in the apperception and antecedent stages of this project. Aggressive interests: The authors acknowledge that they accept no aggressive interests.
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