LABORATORIES Because every test matters.* Sales: 801-280-7502 Aeon Unt ot Sara nema ‘Service: 801-280-7500 \wworu.nelsonlabs.com Sterilization and Biocompatibility of 3D-Printed Orthopedic Devices: Testing Considerations Authors: Matthew R Jorgensen, PhD ‘Senior Scientist (Nelo Lbortores LG 2036NELSON LABORATORIES Because every test matters Orthopedic medical devices fabricated using D-printing methods, also known as additive manufacturing, are gaining attention and popularity due to their potential for enhanced biocompatiblily, customizablity, and cost-effectiveness. A major orthopedic-implant giant, for instance, received FDA 810(k) clearance for an additively manufactured posterior lumbar cage in April 2016, and in 2015 the company started integrating additively manufac: tured tibial baseplates and patellas into a line of knee-replacement products. As of Decem ber 2015, FDA has cleared more than 85 3D-printed medical devices, with more regulatory clearances on the horizon, One of the advantages of using 3D printing to fabricate orthopedic devices is the capability to produce intricate surface textures and interior geometries during manufacturing that are not feasible using machining processes. Additionally, additive manufacturing makes possi ble the abilty to custom manufacture a device to match an MRI image, to nearly perfectly fit ‘a patient's anatomy. Finally, 3D printing reduces material waste, using only the material needed to build the device. This is in contrast to milling, for instance, which results in a great deal of material being removed and often discarded. ‘These advantages, however, come with a unique set of challenges as well, specifically in the areas of sterilization and biocompatibility, The same characteristics of 3D-printed devic es that promote their incorporation into body tissues can also make cleaning and sterlizing the devices somewhat difficult With knowledge and understanding of the special considerations surrounding 3D-printed orthopedic devices, manufacturers can make more-informed planning decisions as they take advantage of this exciting technology. Sterilizing 3D-Printed Orthopedic Devices One of the major benefits of 3D printing a medical device is the relative ease with which complex, intricate geometries can be created, Some of these geometries are built inside the devices and some onto device surfaces, In most instances, these external geometries (and often, the internal geometries) are intended to make contact with human tissue and fluids. Because of these complex geometries, sterlant gasses (eg, ethylene oxide [EO], steam, and hydrogen-peroxide vapor) might require more time to penetrate and sterilize the device, and more time to exit the device as well, Due to these complexities, manufacturers might need to plan for potentially longer sterilization processes.NELSON LABORATORIES Because every test matters Sterilizing 3D-Printed Orthopedic Devices (continued) Microvoids on the surface of, and throughout, a 8D-printed orthopedic device must also be considered, particularly with EO gas. These tiny spaces, while offering plenty of surface area for tissue growth and integration, can trap EO gas during sterilization, and, as a result, the sterilization cycle may require a longer aeration phase. Longer aeration time is not necessarily a prohibitive problem ift has been planned and accounted for ahead of time. Some 3D-printed orthopedic devices made from polymers are sterilized via radiation (e.g gamma or electron beam), and crosslinking and curing need to be addressed, Manufactur- ers planning to sterilize @ polymer-based, 3D-printed device via radiation are advised to select their material wisely, particulatly if the device's size and shape are critical-as with customized implants, It should not be assumed that if a molded or milled polymer is accept able for radiation sterlization, the same polymer in a 3D-printing scenario will be equally acceptable. In this type of situation, material selection, sterilization-method selection, and product functionality testing must be carefully performed to ensure the 3D-printed material does not undergo unacceptable crosslinking. Also, it should be verified that subtle alteration to device configuration has not occurred, as it can result in a device that improper Iy fits the patient or does not function optimally. Differences in Stes ization Validation Validating the sterilization of $D-printed devices is sometimes different than traditional sterilization validations. For example, the conventional samples-per-batch model doesn’t always apply. Fortunately, flexible solutions for validating 3D-printed devices are available, In traditional radiation sterilization validations, for instance, a manufacturer is asked to send 10 samples from 3 different batches of a particular orthopedic device for bioburden testing (ISO 11137-2). Usually an additional 10 to 20 samples from one of those batches is subse- quently sent for the test of steriy. In these typical instances, which assume the device was, milled or injection-molded, a “batch” may comprise hundreds of the same device, In 8D printing, however, the concept of a “batch” is quite different because the batch size might be a single product. A manufacturer might have specifications for 30 different sizes or shapes of a product, but the products are only manufactured upon request. Devices manufactured on request may subsequently require further customization based on a partic: lar specification by a physician. This means that sterilization validations for these products might need a greater emphasis on validation of the process as opposed to validation of the finished product. In these cases, the concept of family grouping for sterilization validation is often implemented, This method involves evaluating a family of products rather than a particular device model, In this type ofLABORATORIES Because every test matters Difference: Sterilization Validation (continued) ‘grouping, one product type, with a specific configuration, is chosen as a “master product” that accurately represents the multiple configurations and processes of the family. Alter: nately, a testing “coupon,” which does not necessarily look lke the product but features the same materials, characteristics, handling, and cleaning processes, is justified and used for validation. This type of sterilization validation addresses the unique considerations of 3D printing while stil fulfing validation requirements. Assessing the Biocompatibility of 3D-Printed Orthopedic Devices ‘As mentioned, a key motivator for 3D printing orthopedic devices is essentially the limitless potential for creating surface textures that encourage and support tissue in-growth and integration, Because this is a primary reason for 3D printing, those surface textures should be carefully and thoroughly characterized-more so than is typically done for conventionally manufactured orthopedic devices. When evaluating a SD-printed orthopedic device's biocompatibility, scanning electron microscopy (SEM) and electron dispersive spectrosco: py (EDS) should be employed to ensure surface texture is appropriate. These evaluations wil provide critical data regarding porosity (size, spacing, and more), elemental composi: tion, and pillar height Microvoids and Biocompati ity As previously mentioned, microvoids are inherent to 3D printing, particularly with metal-ox ide powders, and offer both benefits and potential drawbacks. One possible negative outcome is pitting, which can decrease the device's hemocompatibilty inside the body and create unexpected implantation reactions, Another microvoid-related risk is the entrapment of chemicals, oils, and leachables, which can create a danger to the patient. (Planning not to do any post-manufacturing machining is a major step toward reducing these risks, but that is not always possible) aeNELSON LABORATORIES Because every test matters Microvoids and Biocompatibility (continued) Fortunately, these biocompatibility risks can al be satisfactorily evaluated by running various tosts, including basic chemistry tests, hemocompatibilty tests, implantation tests, toxicity evaluations, and more, Non-specific chemistry tests in particular, such as those looking for total organic carbon (TOC) and non-volatile residuals (NVR), can determine if production oils or other residuals are present on devices. The presence of residuals isa red flag indicat ing that further consideration is warranted, Residuals can be identified and quantified using ‘such methods as gas chromatography mass spectrometry (GC/MS). Biocompatibilty risks can be assessed by evaluating analytical chemistry results from a toxicological perspective. Laser Sintering, Residual Metal-Oxide Powders, and Biocompatibility. Another biocompatibility consideration for 3D-printed orthopedic devices laser sintered from metak-oxide powders is the sacrificial support material. During 3D printing, some of the metal-oxide powder acts as sacrificial support material for interior and hanging parts of a device. Because 3D printing by nature builds a device layer by layer “rom the ground up," sacrificial metatoxide powder is in heavy contact with the actual device. Depending on the geometry of the device, that sacrificial powder can potentially get stuck within holes, voids, ‘openings, and channels on and within the device, and be difficult to remove. These particu: lates can remain after the manufacturing process or shed from the device surface during Use, and they can be especially dangerous ifthe device is placed within blood flow or inside ‘a joint. The associated risks can and must be thoroughly and properly evaluated through testing or justification. 3D Printing of Orthopedic Devices: Enjoying the Advantages While Acknowledging the Unique Challenges 3D printing of orthopedic devices, including implants, represents an exciting technology with clear advantages to all stakeholders for biocompatibilty, customization, and cost effec: tiveness, Patients, physicians, and device manufacturers alike are realizing the benefits that, smaller-scale 3D printing can provide. Alongside these benefits are special considerations and challenges regarding sterilization ‘and biocompatibility: those related to surface texture, intricate device geometries, micro: voids, sacrificial support powders, and particulates. Manufacturers who are aware of these considerations and the potential risks they pose will be better positioned to take full advan- tage of 3D printing's truly remarkable capabilties.