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Medical Applications of 3D Printing
CHAPTER 21
Medical Applications of 3D Printing William K. Durfee1 and Paul A. Iaizzo2 1
Department of Mechanical Engineering, University of Minnesota, Minneapolis, MN, United States Department of Surgery, Institute for Engineering in Medicine, University of Minnesota, Minneapolis, MN, United States
2
21.1 INTRODUCTION 3D printing is defined as an additive manufacturing method that can build objects directly from a computational model. Unlike traditional manufacturing methods such as milling and molding, 3D printing can construct models of arbitrary complexity in relatively fast time frames. Typically, computer models can be an original design or they can be derived from scanned objects that exist or even processed from medical images. 3D printing is a powerful tool for visualizing complex human or animal anatomies and can be used for surgical planning, physician and patient education, medical procedure training, medical device prototyping, and personalized medical device manufacturing. 3D printing technology is rapidly evolving with advances in materials, resolution, and speed thus enabling greater realism and higher accuracy; this in turn enables new medical applications. To meet such needs at the University of Minnesota (Minneapolis, MN, USA), the Institute for Engineering in Medicine developed a 3D Modeling and Printing Core to serve associated members; this core is currently under the direction of Professor William Durfee. The pace of development within 3D printing technologies moves so rapidly that, by the time you read this chapter, nearly all current technologies will be out of date. For example, one recent review on the 3D printing industry noted over 350 articles reporting on clinical trials where 3D printing has played a role.1 Therefore, the objective of this chapter is not to review the latest 3D printing medical applications technology, but rather to provide the reader with a background in what 3D printing could do for you, a brief description of how the majority of current 3D printers work, and how printing has been (and could be) used in various medical applications. For additional information, the reader can consult recent reviews.115
21.1.1 A brief history of 3D printing The modern era of 3D printing is generally considered to have started in 1984, when Hull16 filed his patent for stereolithography, and later cofounded 3D Systems, the start of commercial 3D printing. Hull also invented the STL file format that is now Engineering in Medicine DOI: https://doi.org/10.1016/B978-0-12-813068-1.00021-X
r 2019 Elsevier Inc. All rights reserved.
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universally used by many in the 3D printing business. Another milestone was reached in the late 1980s when fused deposition modeling was developed by Scott Crump, who later founded Stratasys to commercialize these technologies. Much later, the RepRap printing community developed open-source designs for fused deposition 3D printers. The RepRap methodologies, and eventual expiration of Crump’s key patent,17 in turn led to the current explosion in low-cost desktop printers that have fueled the broader “maker” community. Inkjet power printing started at Massachusetts Institute of Technology in the mid-1990s. Ely Sachs was the key developer who spun off Z Corporation (acquired by 3D Systems in 2012) to commercialize these technologies. It should also be noted that in Germany, EOS GmbH was founded in 1989 and, after some time, perfected and commercialized direct metal laser sintering, one of the leading technologies for metal 3D printing. A bit later, Arcam was founded in the mid-1990s and perfected electron beam melting, another key metal 3D printing technology. Now we are in the middle of a chaotic, active, and exciting period where low-end 3D printing has flooded the maker community and (1) 3D printing is routinely utilized for product prototyping (still the most common use of printing); (2) the capabilities of printing continue to evolve, particularly in material choices, speed, and resolution; and (3) some inroads are being made in manufacturing applications, particularly for low-volume, complex parts. In the midst of this, medical applications of 3D printing are just starting to emerge as shown in Fig. 21.1, which charts the growth of citations (papers) one can find by searching for “3D printing” on PubMed.
Figure 21.1 Number of PubMed papers with “3D printing” as a keyword. There were almost 1500 such papers in 2017 compared to just 6 in 2000.
Medical Applications of 3D Printing
For the individual attempting to stay current in the field, it should be noted that the terminology for 3D printing has evolved along with the technology. Twenty years ago, the term “rapid prototyping” was common, reflecting the primary use of 3D printing in product prototyping, where printing was rapid compared to traditional machining and molding processes. With the increase in applications, “additive manufacturing” and “3D printing” are now synonymous terms used almost exclusively to describe these technologies.
21.1.2 Technology Several types of 3D printing technology are currently available, with machines coming in a broad range of prices. Table 21.1 provides information about the most common technologies, and the reader is encouraged to look at online sources for additional details. Table 21.1 3D printing technologies Technology Description (acronym)
FFF
FDM SLA SLS
DMLS
EBM
IJP PJET
Uses a continuous, small-diameter filament of thermoplastic that is heated and extruded to form a layer. Common materials are ABS and PLA. Most low-cost desktop printers use this technology A trademark for the FFF process used by Stratasys Uses an ultraviolet laser to photopolymerize a liquid resin. Parts can be built from the top or bottom Uses a laser to sinter powdered material, typically polymers such as nylon or polyamide, to form the structure. Sintering is the process of forming a solid by heat or pressure without liquefaction. Does not require supports because the structure is always surrounded by the unbound power One of two processes for 3D printing in metal. A type of SLS technology that sinters powered metal. Materials include stainless steel, aluminum, cobaltchrome, Inconel, and titanium The second process for 3D printing in metal. An electron beam micro welds powdered metal to form the structure, all in a vacuum environment. Materials include cobaltchrome, titanium, and nickel alloy Also known as powder bed printing. Uses an inkjet printer head to precisely release a liquid binding agent onto a bed of powered material Uses an inkjet heat to deposit drops of liquid photopolymer that solidify when exposed to UV light. Multiple materials with varying hardness and color can be deposited while making one part. PJET is a trademark of Objet/Stratasys
FFF, Fused filament fabrication; FDM, Fused deposition modeling; SLA, Stereolithography; SLS, Selective laser sintering; DMLS, Direct metal laser sintering; EBM, Electron beam melting; IJP, Inkjet printing, PJET, PolyJet, ABS, Acrylonitrile butadiene styrene; PLA, Polylactic acid.
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21.2 MEDICAL 3D PRINTING PROCESS The process of printing a physical 3D print from a medical image includes several steps, as shown in Fig. 21.2. The first step is to acquire a high-resolution medical image, commonly from a computed tomography (CT) scan or from magnetic resonance imaging (MRI). The former is generally higher resolution than the latter, although this is changing as MRI technologies improve. Today, the comparatively low spatial resolution of readily available clinical 3D ultrasound imaging limits its applications for 3D printing. Nevertheless, ultrasound scanning has been used for printing abnormal anatomies of a fetus,18 and services are beginning to emerge that enable parents to hold a 3D printed model of their growing baby, based on an ultrasound scan. Medical images come in the format of a DICOM (Digital Imaging and Communications in Medicine) file or data set, the current standard for storing and transmitting medical images. In other words, for an anatomic scan, the DICOM file is a set of stacked 2D images, each making up a cross section (slice) through a given anatomic region of the body. The next step in the process is to create 3D surface models from the 2D data set, a process known as segmentation, typically performed using a software tool such as Mimics (Materialise, Leuven, Belgium) or itk-SNAP. During segmentation, a label is assigned to each pixel or voxel. For example, when segmenting an image of the heart, one pixel in one image slice might be assigned the label “heart wall” while the neighboring pixel might be “blood.” The typical outputs of the segmentation process are 3D structures of all the voxels that share the same anatomic label. Not surprisingly, segmentation is the step that takes the most time in the overall 3D printing process and generally requires manual intervention by an expert user to precisely define various anatomic structures and thus determine the exact boundaries separating one specific structure from a neighboring structure. In a manual segmentation process, the user brings up one 2D image slice and then draws the contour around a candidate structure using a mouse or digital drawing pen. The process
Figure 21.2 Workflow process for creating a 3D printed physical model from a patient-specific image data set.
Medical Applications of 3D Printing
is repeated for each successive image slice in the stack until all slices (possibly hundreds) that contain the structure are processed. More advanced software tools automate much of this process, but no tool is completely automatic. Advances in AI (artificial intelligence) are being developed to provide greater automation. Once the image set has been segmented into anatomic structures, smoothing and/or interpolation is sometimes needed to fix deficiencies from the original image files. This can be accomplished with tools such as 3-matic (Materialise) or Meshmixer (Autodesk, Inc., San Rafael, CA, USA) For example, the CT scan data might have a hole in the data due to an artifact, which can be filled by interpolation. Or the scan may have a coarse surface, resulting from a low-resolution MRI scan, which can be smoothed out. After applying fixes, the mesh file is converted into a CAD or STL file, both universal file formats for 3D printing. Note that an STL format describes surfaces as sets of adjacent triangles with no scale or unit information. The next step is to ultimately prepare the STL file for 3D printing, which is done with slicing software that is supported by the printer being used. These tools enable the user to select (1) scale of the printed part, (2) print orientation, (3) material and infill if used, (4) printing speed, and (5) many other printer-specific parameters. After all parameters are set, the file is sent to the printer drivers. Depending on the machine, tiny parts with simple features can be printed in a few minutes but larger parts, including full-scale anatomic structures, can take several hours or even a day or more to print, particularly if the print is done at high (submillimeter) resolution. Once the print is completed, some post-processing may be needed such as cleaning to remove residual debris and support material or sanding if a smooth surface is desired.
21.3 EXAMPLES 21.3.1 Cardiac 3D printing Cardiovascular medicine represents one of the fastest growing applications of medical 3D printing, and it encompasses printing for (1) patient and clinician education, (2) pre-procedure planning, and (3) medical device innovation and prototyping.4,15 Images can be obtained from CT, MRI, or 3D echocardiography scans, and semiautomatic segmentation algorithms have been tailored to identify cardiac structures. Complex segmentation of an entire heart, including the internal structures, can take many hours to develop needed resolutions. While traditional plastic models of a generic heart have long been used for teaching, 3D printing enables models of patient-specific hearts, for example, those with specific cardiac conditions or congenital defects.19 Because the geometry of cardiac structures can be highly dependent on the condition of a specific heart, a collection of 3D models representing real disease states offers critical and needed education opportunities (Fig. 21.3).
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Figure 21.3 3D printed hearts, showing a range of heart conditions, used for education (Visible Heart Laboratory, University of Minnesota). Image from University of Minnesota Medical Bulletin. (https://www.med.umn.edu/news-events/medical-bulletin/made-order). Permission to use needed.
Because complex procedures to treat advanced heart disease often involve a heart with unique anatomic features that are challenging to interpret from flat CT or MRI files, 3D printing can be a valuable tool for planning interventional procedures.2022 For example, in a left ventricular assist device procedure, the 3D model can be used to visualize cannula placement, and/or 3D models can help clinicians determine the optimal surgical approach for removing cardiac tumors. Hospitals around the world are creating in-house 3D printing service labs, with the expectation that a good share of the service activity will revolve around cardiac cases and that such models are printed in a timely manner. In one recent example at the University of Minnesota, surgeons used a combination of a virtualreality immersive display and 3D printing for surgical planning to separate conjoined twins. The newborn sisters were attached from chest to navel, a condition known as thoraco-omphalopagus, and were separated in a 9-h procedure. The University of Minnesota’s Earl E. Bakken Medical Devices Center provided the virtual reality visualization resources, and Alex Mattson, PhD candidate in the Visible Heart Laboratory, created 3D printed models of the two hearts (Fig. 21.4). These tools revealed a previously unseen connection between the two hearts, causing the surgeons to completely reevaluate and change their direction of surgical approach.
Medical Applications of 3D Printing
Figure 21.4 Model of hearts of conjoined twins used to plan surgical approach for separating the babies (University of Minnesota). Image from University of Minnesota Health (https://www.mhealth. org/blog/2017/july-2017/conjoined-twins-separated-at-university-of-minnesota-masonic-childrens-hospital). Permission to use needed.
Currently, a barrier to widespread adoption of utilizing 3D printing for cardiovascular pre-procedure planning is the lack of an efficient means for validating every step used to produce the physical models. Unlike creating a model for teaching purposes, if an error is made when segmenting a pre-procedure MRI image, including a false positive or false negative identification of a vessel, the consequences can be devastating. It should be noted that software used for such purposes will require FDA approval. Innovative cardiovascular medical devices are continuing to be developed at a rapid pace, and the overall design process can benefit from various 3D printed models (Fig. 21.5). Many cardiovascular devices, including stents, valves, and annuloplasty rings, must be sized to create a precise fit to the patient’s anatomy. That anatomy can vary widely, so an important question is, What range of sizes must be designed to cover the full array of possible human anatomies? This is not a question that can be answered by a single cadaver study but instead can more easily be addressed by printing models of normal and diseased hearts from an image library. The ability to print 3D models with multiple flexible materials that match the compliance parameters of the real heart can provide further insights to the medical device designer.
21.3.2 Low-cost limb prosthetics and orthotics In another exciting use of technological advances, patient specific, low-cost arm and hand prosthetics can be fabricated with ordinary 3D printing approaches; some
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Figure 21.5 3D printed stent inside a 3D printed vessel to examine fit and function (Visible Heart Laboratory, University of Minnesota).
models have been popularized worldwide through traditional and social media.2325 One example is the Cyborg beast, a prosthetic hand for children that was intentionally designed to look like a robotic hand (Fig. 21.6).26 A strong grassroots community, eNABLE (enablingthefuture.org), has emerged as a collaborative organization for refining and disseminating open-source designs for printed prosthetics. In addition, gravity-assist orthoses for children with muscular diseases are now a reality with 3D printed links that allow easy customization for children of different sizes, or device modifications as the child grows. One such device, the Wilmington Robotic Exoskeleton, stemmed from research at the Nemours/Alfred I. duPont Hospital for Children in Wilmington, Delaware.27 Furthermore, the ability to self-print prosthetics and orthotics offers user control over the device, and user-specific modifications of designs are now common. While controlled trials to determine the effectiveness of low-cost printed devices compared to traditional prosthetics have not been completed, these low-cost devices have gained considerable traction within the user community. Importantly, this will also allow for global application of such therapies in countries where medical support is marginal.
Medical Applications of 3D Printing
Figure 21.6 The Cyborg beast, a 3D printed hand for children (e-NABLE). Image from e-NABLE (http://enablingthefuture.org/current-design-files/cyborg-beast-hand/). Permission to use needed.
21.3.3 Other recent examples of 3D printing applications At the University of Michigan, a research team designed, 3D printed, and implanted a bioresorbable airway splint in a 5-month-old baby who presented with tracheobronchomalacia, a life-threatening condition where a collapsed bronchus blocks airflow to the lungs (Fig. 21.7).28 The splint was designed based on a CT scan of the patient’s airway and fabricated from polycaprolactone. Ventilator support was discontinued 21 days post-implant, and the splint is expected to be resorbed by the body in about 3 years. Another interesting medical application for 3D printing is high-resolution patientcustomized bone prosthetics. More specifically, Oxford Performance Materials (South Windsor, CT, USA) uses a proprietary, high-performance polyetherketoneketone material to additively manufacture custom skull implants using a laser sintering process.29 The implants are designed using CT or MRI of the patient’s skull anatomy, and in 2013, the application was cleared by the FDA under the 510(k) process (number K121818), another example of a personalized medical therapy. Recently at the Mayo Clinic (Rochester, MN, USA), 3D printing is being used for the surgical treatment of patients with an abdominal aortic aneurysm (AAA), which is an asymptomatic, balloon-like enlargement of the aorta that occurs following a weakening of the vessel wall. Each year, 200,000 people in the United States are diagnosed with an AAA, and a ruptured AAA is the 15th leading cause of death in the United States alone. If a patient presents with a large and/or rapidly growing aneurysm, surgical repair is generally recommended. At the Mayo Clinic, some difficult AAA cases are treated with a complex stent placed via endovascular surgery. After CT imaging, the vessel is 3D printed so that before the actual surgery takes place,
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Figure 21.7 Bioresorbable airway splint used to treat collapsed bronchus in an infant (University of Michigan). Image from University of Michigan, Otolaryngology-Head and Neck Surgery. Website https://medicine.umich.edu/dept/otolaryngology/3d-airway-printed-splint. Permission to use needed.
surgeons can practice placing the stent using the 3D model; this pre-procedure planning is complete with a pump that delivers fluid through the vessel to mimic the relative pressures and flows of blood that the vessel could accommodate (Fig. 21.8). At the University of Minnesota, the Visible Heart Laboratory, led by Professor Paul Iaizzo and Drs. Tinen Iles and Michael Bateman, is the home of one the largest human heart libraries (perfusion-fixed specimens) in the world. Subsequently, their research team has generated high-resolution image (MRI and CT) DICOM data sets of more than 470 normal and diseased human hearts and heartlung blocs. The laboratory collaborates with LifeSource (Minneapolis, MN, USA), a nonprofit organ and tissue donation organization that serves the Upper Midwest. With the permission of family members, donor hearts or heart/lung blocs that are not viable for transplantation are provided to the laboratory for research via LifeSource. In addition, the laboratory has worked with the University of Minnesota’s Anatomy Bequest Program to obtain fresh heart and heartlung bloc specimens from various whole-body donors. All specimens are carefully prepared and scanned using high-resolution MRI or CT and/or micro-CT; importantly, we can employ scanning times and dosing that would not be safely used on living patients. Dozens of the library heart image sets have been segmented and then 3D printed. Routinely, these generated 3D models and subsequent 3D prints are being used by medical and bioengineering students to learn heart anatomy, as well as by cardiac medical device designers to better understand how device concepts could be implanted within a variety of complex anatomies associated with different disease states. Quite often, students in the laboratory have the unique opportunity to engage in learn-by-painting exercises, where they identify and paint structures on a 3D printed heart (Fig. 21.9). Researchers at Tulane University School of Medicine (New Orleans, LA, USA) conducted a study to determine if physical 3D printed models of a kidney containing renal lesions, based on patient imaging, would enhance the patient’s understanding of
Figure 21.8 3D printed model of an aortic aneurysm. The model contains the stent used to treat the aneurysm (Mayo Clinic). Image from Discovery’s Edge, Mayo Clinic’s Research Magazine. Website (https://discoverysedge.mayo.edu/2016/08/09/just-in-time-technology-saves-patients/). Permission to use needed.
Figure 21.9 Students learning heart anatomy by painting 3D models (Visible Heart Laboratory, University of Minnesota).
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their condition (Fig. 21.10).30 Urology clinicians frequently reported that their patients did not fully understand their medical status when shown 2D CT or MRI images. The kidney models were printed in a clear resin with red vessels and tumors. By having both patients and clinicians manipulate the physical model during visits,
Figure 21.10 (A) CT scan of patient. (B and C) Front and back views of 3D printed kidney model made from CT image. Vessels and renal mass are in red. CT, Computed tomography. Image from Silberstein JL, Maddox MM, Dorsey P, Feibus A, Thomas R, Lee BR. Physical models of renal malignancies using standard cross-sectional imaging and 3-dimensional printers: a pilot study. Urology 2014;84:26872. Permission to use needed. This is an Elsevier journal. Can also get permission for equivalent image from Tulane University.
Medical Applications of 3D Printing
the study found that patients and their families had a better understanding of the relative size and location of their tumor(s), as well as the surgical approach being planned to remove such tumors.
21.4 BIOPRINTING An exciting future application of 3D printing is the potential manufacturing of repair tissues and perhaps even organs, a field known as bioprinting (Fig. 21.11).14,3134 Inkjet printing technology has proven to be one of the most compatible means for laying down scaffolding and cells to create biomaterials from a wide range of bioinks, with multiple print head technologies enabling the fabrication of scaffolds with varying material properties and critical seeding layers with several types of cells. There is hope by some in the field that bioprinted organs may be the solution for the chronic shortage of human organs available for transplantation. One concept is to seed the bioprinted organ by taking cells from the patient’s own body, to minimize the risk of foreign body rejection, that is, minimizing immune responses. While cell seeding of
Figure 21.11 Bioprinting process. Image from Seol YJ, Kang HW, Lee SJ, Atala A, Yoo JJ. Bioprinting technology and its applications. Eur J Cardiothorac Surg 2014;46:3428. Permission to use needed.
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scaffolds has been an active area of research for decades, 3D printing adds the ability to fabricate a scaffold with complex geometry and to seed it with precisely placed cells of numerous types. Recent proof-of-concept examples of bioprinted organs include heart valves, blood vessels, bone, cartilage, nerve and muscle tissue, and skin. However, to date, all have been restricted to the research laboratory setting. Currently, one of the main challenges associated with bioprinting is the ability to achieve a biologic result that is compatible with native tissue. While it may be possible to generate a scaffolding that has the requisite structural properties, it may not be optimal for growing the cells needed to create the target organ. For example, organs such as liver and kidney are thick but need prolific vascularization to function effectively. That means a bioprinted organ must fabricate the equivalent vascularization, a technical hurdle that has yet to be overcome. Thus, printed substitute tissues/organs such as heart valves, which require little vascularization, may be a more viable option for bioprinting. Further research in printing techniques and bioinks will certainly advance the promising application of 3D bioprinting.
21.5 REGULATORY As with any medical device, those manufactured via 3D printing must also meet appropriate regulatory requirements. In the United States, the FDA’s Center for Devices and Radiologic Health regulates medical devices. In 2017, the FDA issued the Technical Considerations for Additive Manufactured Medical Devices guidance document that advises manufacturers on how to design, manufacture, and test medical devices that contain at least one 3D printed component.35 The document makes several points that need to be considered by device makers as well as innovators who are considering using 3D printing. Most importantly, additive manufactured (AM) medical devices are no different than any other medical devices; manufacturers must provide evidence to the FDA that the device is both safe and effective. In other words, AM is simply another manufacturing method rather than 3D printing being considered as a whole new type of medical device category. Yet, a special aspect of AM fabrication is that patientmatched devices can perhaps be easily made using images taken from the specific patient. Oftentimes, AM fabrication enables complex geometries that cannot be easily made with traditional manufacturing methods. Successful fabrication using AM is correlated to (1) materials utilized, (2) the 3D printing machine utilized, and (3) any additionally required post-printing processes. However, some of the remaining challenges include the layer-by-layer build process, which means the finished product lacks the strength of a product fabricated from bulk material, and the fact that there is no long-term data from AM medical devices because the technology is so new.
Medical Applications of 3D Printing
Because patient-matched devices are generally designed using CT or MRI images, the characteristics of the imaging process must be known, including the resolution and any necessary smoothing. Further, it is important to consider the time between taking the image and when the device is used/implanted, as the relative conditions of the patient can change over time. As described in the section on the 3D printing process, the software workflow involves several packages, often from different vendors, with the output of one step becoming the input of the next. Validations of file conversions are needed to ensure that the appropriate information is being passed without error, and these validations should be repeated each time a software package is updated. For example, the guidance document suggests using the Additive Manufacturing File format to store final build data, as this format is technologically independent and includes information on (1) surface textures, (2) materials, (3) color, (4) locations of objects in the build volume, and (5) high-resolution geometries, including curved patches. When it comes to 3D printing a medical device, control over fabrication parameters must also be known and documented. For examples, slicing thickness, infill density, and build path are all critical, as these parameters ultimately impact the device stiffness, hardness, and yield strength. Further, the mechanical anisotropic properties of the given device are a function of its build orientation. The size and placement of support structures also matter, particularly when the part has near-critical overhang geometries. Because support decisions are typically automatically handled by the machine software, the same part built on machines from two vendors generally will have different support structures, and ultimately different mechanical properties. Even the placement of the part in the build volume can make a difference, as 3D print machines tend to be well calibrated at the center of their build volume while maximum build uncertainty occurs at the perimeters, with the size of the uncertainty being machine dependent. Finally, the temperature and humidity of the build environment should be controlled for consistent prints. Controls must be established over the material used for printing, including the type, supplier, and storage conditions. The FDA approves finished medical devices and does not give blanket approvals for a specific material to be used in every device, which is why testing may be required even if the raw material has been used in a previous 3D printed/approved device. Furthermore, post-printing processes can affect the material properties of the finished part. For example, support material can be snapped off or dissolved in a bath, with each method producing a different surface finish. Surface finish can also be achieved with a polishing operation, but internal surfaces often cannot be reached for such polishing. In general, quality control over the 3D printing of medical devices can entail careful monitoring and control over the entire process, which could involve printing test coupons alongside the final part. In addition, mechanical and biocompatibility testing of the finished part will be necessary.
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21.6 CONCLUSIONS Medical applications of 3D printing are already extensive and growing rapidly. These technologies are routinely used for prototyping medical devices, particularly where prototyping in plastics is useful. Surgical applications are common where the most prevalent use is for creating custom guides to align surgical instruments, which reduces procedure times and increases surgical accuracy. Printing of difficult anatomies from patient imaging files, for planning complex surgery, is an emerging application that may soon become routine in numerous medical centers, as will printing of anatomical structures for surgical simulators. There are currently a few examples of patient-specific medical devices manufactured with 3D printing, with many more in the early and late research stages. To date, little objective research has been conducted on the relative costbenefit analyses of 3D printing in various medical settings. For example, while there are advantages for a surgeon holding a physical 3D representation of a patient’s organ in his/her hand, there is considerable cost in converting image files to a format that can be printed, mostly due to the costs and time of expert manual interventions to produce correct segmentations as well as printing. Further, these challenges currently prevent the use of this technology in complex procedures that must be done immediately (in the future, AI may be able to address this challenge). To move beyond the bias caused by excitement surrounding new 3D printing technologies, studies are needed to determine precisely whether 3D printed models and/or devices are cost effective and ultimately improve clinical outcomes before they become part of routine clinical practice. Even if widespread adoption does not occur, medical 3D printing may have advantages when used for complex cases.
REFERENCES 1. Diment LE, Thompson MS, Bergmann JHM. Clinical efficacy and effectiveness of 3D printing: a systematic review. BMJ Open 2017;7:e016891. 2. Martelli N, Serrano C, van den Brink H, et al. Advantages and disadvantages of 3-dimensional printing in surgery: a systematic review. Surgery. 2016;159:1485500. 3. 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;3:43343. 4. Vukicevic M, Mosadegh B, Min JK, Little SH. Cardiac 3D printing and its future directions. JACC Cardiovasc Imaging. 2017;10:17184. 5. Mitsouras D, Liacouras P, Imanzadeh A, et al. Medical 3D printing for the radiologist. Radiographics. 2015;35:196588. 6. Rengier F, Mehndiratta A, von Tengg-Kobligk H, et al. 3D printing based on imaging data: review of medical applications. Int J Comput Assist Radiol Surg. 2010;5:33541. 7. Alharbi N, Wismeijer D, Osman RB. Additive manufacturing techniques in prosthodontics: where do we currently stand? A critical review. Int J Prosthodont. 2017;30:47484. 8. Tack P, Victor J, Gemmel P, Annemans L. 3D-printing techniques in a medical setting: a systematic literature review. Biomed Eng Online. 2016;15:115. 9. Dawood A, Marti Marti B, Sauret-Jackson V, Darwood A. 3D printing in dentistry. Br Dent J. 2015;219:5219.
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10. Ventola CL. Medical applications for 3D printing: current and projected uses. Pharm Ther. 2014;39:70411. 11. Malik HH, Darwood ARJ, Shaunak S, et al. Three-dimensional printing in surgery: a review of current surgical applications. J Surg Res. 2015;199:51222. 12. Mulford JS, Babazadeh S, Mackay N. Three-dimensional printing in orthopaedic surgery: review of current and future applications. ANZ J Surg. 2016;86:64853. 13. Li C, Cheung TF, Fan VC, Sin KM, Wong CWY, Leung GKK. Applications of three-dimensional printing in surgery. Surg Innov. 2017;24:828. 14. Zadpoor AA, Malda J. Additive manufacturing of biomaterials, tissues, and organs. Ann Biomed Eng. 2017;45:111. 15. Meier LM, Meineri M, Qua Hiansen J, Horlick EM. Structural and congenital heart disease interventions: the role of three-dimensional printing. Neth Heart J. 2017;25:6575. 16. Hull CW. Apparatus for production of three-dimensional objects by stereolithography. Patent US4575330A. 1986. hhttp://www.google.com/patents/US4575330i [accessed 18.03.27]. 17. Crump SS. Apparatus and method for creating three-dimensional objects. Patent US5121329A. 1992. hhttp://www.google.com/patents/US5121329i [accessed 18.03.27]. 18. VanKoevering KK, Morrison RJ, Prabhu SP, et al. Antenatal three-dimensional printing of aberrant facial anatomy. Pediatrics. 2015;136:e13825. 19. Bramlet M, Olivieri L, Farooqi K, Ripley B, Coakley M. Impact of three-dimensional printing on the study and treatment of congenital heart disease. Circ Res. 2017;120:9047. 20. Farooqi KM, Nielsen JC, Uppu SC, et al. Use of 3-dimensional printing to demonstrate complex intracardiac relationships in double-outlet right ventricle for surgical planning. Circ Cardiovasc Imaging. 2015;8:e003043. 21. Farooqi KM, Saeed O, Zaidi A, et al. 3D printing to guide ventricular assist device placement in adults with congenital heart disease and heart failure. JACC Heart Fail. 2016;4:30111. 22. Farooqi KM, Mahmood F. Innovations in preoperative planning: insights into another dimension using 3D printing for cardiac disease. J Cardiothorac Vasc Anesth. 2018;32:193745. 23. Mroz J. 3-D printing prosthetic hands that are anything but ordinary. NY Times February 16, 2015. hhttps://www.nytimes.com/2015/02/17/science/hand-of-a-superhero.htmli; [accessed 18.03.27]. 24. Tanaka KS, Lightdale-Miric N. Advances in 3D-printed pediatric prostheses for upper extremity differences. J Bone Joint Surg Am. 2016;98:13206. 25. Burn MB, Ta A, Gogola GR. Three-dimensional printing of prosthetic hands for children. J Hand Surg. 2016;41:e103109. 26. Zuniga J, Katsavelis D, Peck J, et al. Cyborg beast: a low-cost 3d-printed prosthetic hand for children with upper-limb differences. BMC Res Notes. 2015;8:10. 27. Haumont T, Rahman T, Sample W, et al. Wilmington robotic exoskeleton: a novel device to maintain arm improvement in muscular disease. J Pediatr Orthop. 2011;31:e4449. 28. Zopf DA, Hollister SJ, Nelson ME, Ohye RG, Green GE. Bioresorbable airway splint created with a three-dimensional printer. N Engl J Med. 2013;368:20435. 29. Oxford Performace Materials. Biomedical devices: OsteoFabs patient specific cranial device (OPSCD). , http://oxfordpm.com/cmf-orthopedics/osteofab-implants . [accessed 18.10.10]. 30. Silberstein JL, Maddox MM, Dorsey P, Feibus A, Thomas R, Lee BR. Physical models of renal malignancies using standard cross-sectional imaging and 3-dimensional printers: a pilot study. Urology. 2014;84:26872. 31. Cui H, Nowicki M, Fisher JP, Zhang LG. 3D bioprinting for organ regeneration. Adv. Healthc Mater. 2017;6. Available from: https://doi.org/10.1002/adhm.201601118. Epub 2016. 32. Mandrycky C, Wang Z, Kim K, Kim DH. 3D bioprinting for engineering complex tissues. Biotechnol Adv. 2016;34:42234. 33. Gao G, Cui X. Three-dimensional bioprinting in tissue engineering and regenerative medicine. Biotechnol Lett. 2016;38:20311. 34. Seol YJ, Kang HW, Lee SJ, Atala A, Yoo JJ. Bioprinting technology and its applications. Eur J Cardiothorac Surg. 2014;46:3428. 35. FDA. Technical considerations for additive manufactured medical devices. hhttps://www.fda.gov/downloads/ MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM499809.pdfi; 2017 [accessed 18.03.27].
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Medical Applications of 3D Printing William K. Durfee1 and Paul A. Iaizzo2 1
Department of Mechanical Engineering, University of Minnesota, Minneapolis, MN, United States Department of Surgery, Institute for Engineering in Medicine, University of Minnesota, Minneapolis, MN, United States
2
21.1 INTRODUCTION 3D printing is defined as an additive manufacturing method that can build objects directly from a computational model. Unlike traditional manufacturing methods such as milling and molding, 3D printing can construct models of arbitrary complexity in relatively fast time frames. Typically, computer models can be an original design or they can be derived from scanned objects that exist or even processed from medical images. 3D printing is a powerful tool for visualizing complex human or animal anatomies and can be used for surgical planning, physician and patient education, medical procedure training, medical device prototyping, and personalized medical device manufacturing. 3D printing technology is rapidly evolving with advances in materials, resolution, and speed thus enabling greater realism and higher accuracy; this in turn enables new medical applications. To meet such needs at the University of Minnesota (Minneapolis, MN, USA), the Institute for Engineering in Medicine developed a 3D Modeling and Printing Core to serve associated members; this core is currently under the direction of Professor William Durfee. The pace of development within 3D printing technologies moves so rapidly that, by the time you read this chapter, nearly all current technologies will be out of date. For example, one recent review on the 3D printing industry noted over 350 articles reporting on clinical trials where 3D printing has played a role.1 Therefore, the objective of this chapter is not to review the latest 3D printing medical applications technology, but rather to provide the reader with a background in what 3D printing could do for you, a brief description of how the majority of current 3D printers work, and how printing has been (and could be) used in various medical applications. For additional information, the reader can consult recent reviews.115
21.1.1 A brief history of 3D printing The modern era of 3D printing is generally considered to have started in 1984, when Hull16 filed his patent for stereolithography, and later cofounded 3D Systems, the start of commercial 3D printing. Hull also invented the STL file format that is now Engineering in Medicine DOI: https://doi.org/10.1016/B978-0-12-813068-1.00021-X
r 2019 Elsevier Inc. All rights reserved.
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universally used by many in the 3D printing business. Another milestone was reached in the late 1980s when fused deposition modeling was developed by Scott Crump, who later founded Stratasys to commercialize these technologies. Much later, the RepRap printing community developed open-source designs for fused deposition 3D printers. The RepRap methodologies, and eventual expiration of Crump’s key patent,17 in turn led to the current explosion in low-cost desktop printers that have fueled the broader “maker” community. Inkjet power printing started at Massachusetts Institute of Technology in the mid-1990s. Ely Sachs was the key developer who spun off Z Corporation (acquired by 3D Systems in 2012) to commercialize these technologies. It should also be noted that in Germany, EOS GmbH was founded in 1989 and, after some time, perfected and commercialized direct metal laser sintering, one of the leading technologies for metal 3D printing. A bit later, Arcam was founded in the mid-1990s and perfected electron beam melting, another key metal 3D printing technology. Now we are in the middle of a chaotic, active, and exciting period where low-end 3D printing has flooded the maker community and (1) 3D printing is routinely utilized for product prototyping (still the most common use of printing); (2) the capabilities of printing continue to evolve, particularly in material choices, speed, and resolution; and (3) some inroads are being made in manufacturing applications, particularly for low-volume, complex parts. In the midst of this, medical applications of 3D printing are just starting to emerge as shown in Fig. 21.1, which charts the growth of citations (papers) one can find by searching for “3D printing” on PubMed.
Figure 21.1 Number of PubMed papers with “3D printing” as a keyword. There were almost 1500 such papers in 2017 compared to just 6 in 2000.
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For the individual attempting to stay current in the field, it should be noted that the terminology for 3D printing has evolved along with the technology. Twenty years ago, the term “rapid prototyping” was common, reflecting the primary use of 3D printing in product prototyping, where printing was rapid compared to traditional machining and molding processes. With the increase in applications, “additive manufacturing” and “3D printing” are now synonymous terms used almost exclusively to describe these technologies.
21.1.2 Technology Several types of 3D printing technology are currently available, with machines coming in a broad range of prices. Table 21.1 provides information about the most common technologies, and the reader is encouraged to look at online sources for additional details. Table 21.1 3D printing technologies Technology Description (acronym)
FFF
FDM SLA SLS
DMLS
EBM
IJP PJET
Uses a continuous, small-diameter filament of thermoplastic that is heated and extruded to form a layer. Common materials are ABS and PLA. Most low-cost desktop printers use this technology A trademark for the FFF process used by Stratasys Uses an ultraviolet laser to photopolymerize a liquid resin. Parts can be built from the top or bottom Uses a laser to sinter powdered material, typically polymers such as nylon or polyamide, to form the structure. Sintering is the process of forming a solid by heat or pressure without liquefaction. Does not require supports because the structure is always surrounded by the unbound power One of two processes for 3D printing in metal. A type of SLS technology that sinters powered metal. Materials include stainless steel, aluminum, cobaltchrome, Inconel, and titanium The second process for 3D printing in metal. An electron beam micro welds powdered metal to form the structure, all in a vacuum environment. Materials include cobaltchrome, titanium, and nickel alloy Also known as powder bed printing. Uses an inkjet printer head to precisely release a liquid binding agent onto a bed of powered material Uses an inkjet heat to deposit drops of liquid photopolymer that solidify when exposed to UV light. Multiple materials with varying hardness and color can be deposited while making one part. PJET is a trademark of Objet/Stratasys
FFF, Fused filament fabrication; FDM, Fused deposition modeling; SLA, Stereolithography; SLS, Selective laser sintering; DMLS, Direct metal laser sintering; EBM, Electron beam melting; IJP, Inkjet printing, PJET, PolyJet, ABS, Acrylonitrile butadiene styrene; PLA, Polylactic acid.
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21.2 MEDICAL 3D PRINTING PROCESS The process of printing a physical 3D print from a medical image includes several steps, as shown in Fig. 21.2. The first step is to acquire a high-resolution medical image, commonly from a computed tomography (CT) scan or from magnetic resonance imaging (MRI). The former is generally higher resolution than the latter, although this is changing as MRI technologies improve. Today, the comparatively low spatial resolution of readily available clinical 3D ultrasound imaging limits its applications for 3D printing. Nevertheless, ultrasound scanning has been used for printing abnormal anatomies of a fetus,18 and services are beginning to emerge that enable parents to hold a 3D printed model of their growing baby, based on an ultrasound scan. Medical images come in the format of a DICOM (Digital Imaging and Communications in Medicine) file or data set, the current standard for storing and transmitting medical images. In other words, for an anatomic scan, the DICOM file is a set of stacked 2D images, each making up a cross section (slice) through a given anatomic region of the body. The next step in the process is to create 3D surface models from the 2D data set, a process known as segmentation, typically performed using a software tool such as Mimics (Materialise, Leuven, Belgium) or itk-SNAP. During segmentation, a label is assigned to each pixel or voxel. For example, when segmenting an image of the heart, one pixel in one image slice might be assigned the label “heart wall” while the neighboring pixel might be “blood.” The typical outputs of the segmentation process are 3D structures of all the voxels that share the same anatomic label. Not surprisingly, segmentation is the step that takes the most time in the overall 3D printing process and generally requires manual intervention by an expert user to precisely define various anatomic structures and thus determine the exact boundaries separating one specific structure from a neighboring structure. In a manual segmentation process, the user brings up one 2D image slice and then draws the contour around a candidate structure using a mouse or digital drawing pen. The process
Figure 21.2 Workflow process for creating a 3D printed physical model from a patient-specific image data set.
Medical Applications of 3D Printing
is repeated for each successive image slice in the stack until all slices (possibly hundreds) that contain the structure are processed. More advanced software tools automate much of this process, but no tool is completely automatic. Advances in AI (artificial intelligence) are being developed to provide greater automation. Once the image set has been segmented into anatomic structures, smoothing and/or interpolation is sometimes needed to fix deficiencies from the original image files. This can be accomplished with tools such as 3-matic (Materialise) or Meshmixer (Autodesk, Inc., San Rafael, CA, USA) For example, the CT scan data might have a hole in the data due to an artifact, which can be filled by interpolation. Or the scan may have a coarse surface, resulting from a low-resolution MRI scan, which can be smoothed out. After applying fixes, the mesh file is converted into a CAD or STL file, both universal file formats for 3D printing. Note that an STL format describes surfaces as sets of adjacent triangles with no scale or unit information. The next step is to ultimately prepare the STL file for 3D printing, which is done with slicing software that is supported by the printer being used. These tools enable the user to select (1) scale of the printed part, (2) print orientation, (3) material and infill if used, (4) printing speed, and (5) many other printer-specific parameters. After all parameters are set, the file is sent to the printer drivers. Depending on the machine, tiny parts with simple features can be printed in a few minutes but larger parts, including full-scale anatomic structures, can take several hours or even a day or more to print, particularly if the print is done at high (submillimeter) resolution. Once the print is completed, some post-processing may be needed such as cleaning to remove residual debris and support material or sanding if a smooth surface is desired.
21.3 EXAMPLES 21.3.1 Cardiac 3D printing Cardiovascular medicine represents one of the fastest growing applications of medical 3D printing, and it encompasses printing for (1) patient and clinician education, (2) pre-procedure planning, and (3) medical device innovation and prototyping.4,15 Images can be obtained from CT, MRI, or 3D echocardiography scans, and semiautomatic segmentation algorithms have been tailored to identify cardiac structures. Complex segmentation of an entire heart, including the internal structures, can take many hours to develop needed resolutions. While traditional plastic models of a generic heart have long been used for teaching, 3D printing enables models of patient-specific hearts, for example, those with specific cardiac conditions or congenital defects.19 Because the geometry of cardiac structures can be highly dependent on the condition of a specific heart, a collection of 3D models representing real disease states offers critical and needed education opportunities (Fig. 21.3).
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Figure 21.3 3D printed hearts, showing a range of heart conditions, used for education (Visible Heart Laboratory, University of Minnesota). Image from University of Minnesota Medical Bulletin. (https://www.med.umn.edu/news-events/medical-bulletin/made-order). Permission to use needed.
Because complex procedures to treat advanced heart disease often involve a heart with unique anatomic features that are challenging to interpret from flat CT or MRI files, 3D printing can be a valuable tool for planning interventional procedures.2022 For example, in a left ventricular assist device procedure, the 3D model can be used to visualize cannula placement, and/or 3D models can help clinicians determine the optimal surgical approach for removing cardiac tumors. Hospitals around the world are creating in-house 3D printing service labs, with the expectation that a good share of the service activity will revolve around cardiac cases and that such models are printed in a timely manner. In one recent example at the University of Minnesota, surgeons used a combination of a virtualreality immersive display and 3D printing for surgical planning to separate conjoined twins. The newborn sisters were attached from chest to navel, a condition known as thoraco-omphalopagus, and were separated in a 9-h procedure. The University of Minnesota’s Earl E. Bakken Medical Devices Center provided the virtual reality visualization resources, and Alex Mattson, PhD candidate in the Visible Heart Laboratory, created 3D printed models of the two hearts (Fig. 21.4). These tools revealed a previously unseen connection between the two hearts, causing the surgeons to completely reevaluate and change their direction of surgical approach.
Medical Applications of 3D Printing
Figure 21.4 Model of hearts of conjoined twins used to plan surgical approach for separating the babies (University of Minnesota). Image from University of Minnesota Health (https://www.mhealth. org/blog/2017/july-2017/conjoined-twins-separated-at-university-of-minnesota-masonic-childrens-hospital). Permission to use needed.
Currently, a barrier to widespread adoption of utilizing 3D printing for cardiovascular pre-procedure planning is the lack of an efficient means for validating every step used to produce the physical models. Unlike creating a model for teaching purposes, if an error is made when segmenting a pre-procedure MRI image, including a false positive or false negative identification of a vessel, the consequences can be devastating. It should be noted that software used for such purposes will require FDA approval. Innovative cardiovascular medical devices are continuing to be developed at a rapid pace, and the overall design process can benefit from various 3D printed models (Fig. 21.5). Many cardiovascular devices, including stents, valves, and annuloplasty rings, must be sized to create a precise fit to the patient’s anatomy. That anatomy can vary widely, so an important question is, What range of sizes must be designed to cover the full array of possible human anatomies? This is not a question that can be answered by a single cadaver study but instead can more easily be addressed by printing models of normal and diseased hearts from an image library. The ability to print 3D models with multiple flexible materials that match the compliance parameters of the real heart can provide further insights to the medical device designer.
21.3.2 Low-cost limb prosthetics and orthotics In another exciting use of technological advances, patient specific, low-cost arm and hand prosthetics can be fabricated with ordinary 3D printing approaches; some
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Figure 21.5 3D printed stent inside a 3D printed vessel to examine fit and function (Visible Heart Laboratory, University of Minnesota).
models have been popularized worldwide through traditional and social media.2325 One example is the Cyborg beast, a prosthetic hand for children that was intentionally designed to look like a robotic hand (Fig. 21.6).26 A strong grassroots community, eNABLE (enablingthefuture.org), has emerged as a collaborative organization for refining and disseminating open-source designs for printed prosthetics. In addition, gravity-assist orthoses for children with muscular diseases are now a reality with 3D printed links that allow easy customization for children of different sizes, or device modifications as the child grows. One such device, the Wilmington Robotic Exoskeleton, stemmed from research at the Nemours/Alfred I. duPont Hospital for Children in Wilmington, Delaware.27 Furthermore, the ability to self-print prosthetics and orthotics offers user control over the device, and user-specific modifications of designs are now common. While controlled trials to determine the effectiveness of low-cost printed devices compared to traditional prosthetics have not been completed, these low-cost devices have gained considerable traction within the user community. Importantly, this will also allow for global application of such therapies in countries where medical support is marginal.
Medical Applications of 3D Printing
Figure 21.6 The Cyborg beast, a 3D printed hand for children (e-NABLE). Image from e-NABLE (http://enablingthefuture.org/current-design-files/cyborg-beast-hand/). Permission to use needed.
21.3.3 Other recent examples of 3D printing applications At the University of Michigan, a research team designed, 3D printed, and implanted a bioresorbable airway splint in a 5-month-old baby who presented with tracheobronchomalacia, a life-threatening condition where a collapsed bronchus blocks airflow to the lungs (Fig. 21.7).28 The splint was designed based on a CT scan of the patient’s airway and fabricated from polycaprolactone. Ventilator support was discontinued 21 days post-implant, and the splint is expected to be resorbed by the body in about 3 years. Another interesting medical application for 3D printing is high-resolution patientcustomized bone prosthetics. More specifically, Oxford Performance Materials (South Windsor, CT, USA) uses a proprietary, high-performance polyetherketoneketone material to additively manufacture custom skull implants using a laser sintering process.29 The implants are designed using CT or MRI of the patient’s skull anatomy, and in 2013, the application was cleared by the FDA under the 510(k) process (number K121818), another example of a personalized medical therapy. Recently at the Mayo Clinic (Rochester, MN, USA), 3D printing is being used for the surgical treatment of patients with an abdominal aortic aneurysm (AAA), which is an asymptomatic, balloon-like enlargement of the aorta that occurs following a weakening of the vessel wall. Each year, 200,000 people in the United States are diagnosed with an AAA, and a ruptured AAA is the 15th leading cause of death in the United States alone. If a patient presents with a large and/or rapidly growing aneurysm, surgical repair is generally recommended. At the Mayo Clinic, some difficult AAA cases are treated with a complex stent placed via endovascular surgery. After CT imaging, the vessel is 3D printed so that before the actual surgery takes place,
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Figure 21.7 Bioresorbable airway splint used to treat collapsed bronchus in an infant (University of Michigan). Image from University of Michigan, Otolaryngology-Head and Neck Surgery. Website https://medicine.umich.edu/dept/otolaryngology/3d-airway-printed-splint. Permission to use needed.
surgeons can practice placing the stent using the 3D model; this pre-procedure planning is complete with a pump that delivers fluid through the vessel to mimic the relative pressures and flows of blood that the vessel could accommodate (Fig. 21.8). At the University of Minnesota, the Visible Heart Laboratory, led by Professor Paul Iaizzo and Drs. Tinen Iles and Michael Bateman, is the home of one the largest human heart libraries (perfusion-fixed specimens) in the world. Subsequently, their research team has generated high-resolution image (MRI and CT) DICOM data sets of more than 470 normal and diseased human hearts and heartlung blocs. The laboratory collaborates with LifeSource (Minneapolis, MN, USA), a nonprofit organ and tissue donation organization that serves the Upper Midwest. With the permission of family members, donor hearts or heart/lung blocs that are not viable for transplantation are provided to the laboratory for research via LifeSource. In addition, the laboratory has worked with the University of Minnesota’s Anatomy Bequest Program to obtain fresh heart and heartlung bloc specimens from various whole-body donors. All specimens are carefully prepared and scanned using high-resolution MRI or CT and/or micro-CT; importantly, we can employ scanning times and dosing that would not be safely used on living patients. Dozens of the library heart image sets have been segmented and then 3D printed. Routinely, these generated 3D models and subsequent 3D prints are being used by medical and bioengineering students to learn heart anatomy, as well as by cardiac medical device designers to better understand how device concepts could be implanted within a variety of complex anatomies associated with different disease states. Quite often, students in the laboratory have the unique opportunity to engage in learn-by-painting exercises, where they identify and paint structures on a 3D printed heart (Fig. 21.9). Researchers at Tulane University School of Medicine (New Orleans, LA, USA) conducted a study to determine if physical 3D printed models of a kidney containing renal lesions, based on patient imaging, would enhance the patient’s understanding of
Figure 21.8 3D printed model of an aortic aneurysm. The model contains the stent used to treat the aneurysm (Mayo Clinic). Image from Discovery’s Edge, Mayo Clinic’s Research Magazine. Website (https://discoverysedge.mayo.edu/2016/08/09/just-in-time-technology-saves-patients/). Permission to use needed.
Figure 21.9 Students learning heart anatomy by painting 3D models (Visible Heart Laboratory, University of Minnesota).
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their condition (Fig. 21.10).30 Urology clinicians frequently reported that their patients did not fully understand their medical status when shown 2D CT or MRI images. The kidney models were printed in a clear resin with red vessels and tumors. By having both patients and clinicians manipulate the physical model during visits,
Figure 21.10 (A) CT scan of patient. (B and C) Front and back views of 3D printed kidney model made from CT image. Vessels and renal mass are in red. CT, Computed tomography. Image from Silberstein JL, Maddox MM, Dorsey P, Feibus A, Thomas R, Lee BR. Physical models of renal malignancies using standard cross-sectional imaging and 3-dimensional printers: a pilot study. Urology 2014;84:26872. Permission to use needed. This is an Elsevier journal. Can also get permission for equivalent image from Tulane University.
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the study found that patients and their families had a better understanding of the relative size and location of their tumor(s), as well as the surgical approach being planned to remove such tumors.
21.4 BIOPRINTING An exciting future application of 3D printing is the potential manufacturing of repair tissues and perhaps even organs, a field known as bioprinting (Fig. 21.11).14,3134 Inkjet printing technology has proven to be one of the most compatible means for laying down scaffolding and cells to create biomaterials from a wide range of bioinks, with multiple print head technologies enabling the fabrication of scaffolds with varying material properties and critical seeding layers with several types of cells. There is hope by some in the field that bioprinted organs may be the solution for the chronic shortage of human organs available for transplantation. One concept is to seed the bioprinted organ by taking cells from the patient’s own body, to minimize the risk of foreign body rejection, that is, minimizing immune responses. While cell seeding of
Figure 21.11 Bioprinting process. Image from Seol YJ, Kang HW, Lee SJ, Atala A, Yoo JJ. Bioprinting technology and its applications. Eur J Cardiothorac Surg 2014;46:3428. Permission to use needed.
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scaffolds has been an active area of research for decades, 3D printing adds the ability to fabricate a scaffold with complex geometry and to seed it with precisely placed cells of numerous types. Recent proof-of-concept examples of bioprinted organs include heart valves, blood vessels, bone, cartilage, nerve and muscle tissue, and skin. However, to date, all have been restricted to the research laboratory setting. Currently, one of the main challenges associated with bioprinting is the ability to achieve a biologic result that is compatible with native tissue. While it may be possible to generate a scaffolding that has the requisite structural properties, it may not be optimal for growing the cells needed to create the target organ. For example, organs such as liver and kidney are thick but need prolific vascularization to function effectively. That means a bioprinted organ must fabricate the equivalent vascularization, a technical hurdle that has yet to be overcome. Thus, printed substitute tissues/organs such as heart valves, which require little vascularization, may be a more viable option for bioprinting. Further research in printing techniques and bioinks will certainly advance the promising application of 3D bioprinting.
21.5 REGULATORY As with any medical device, those manufactured via 3D printing must also meet appropriate regulatory requirements. In the United States, the FDA’s Center for Devices and Radiologic Health regulates medical devices. In 2017, the FDA issued the Technical Considerations for Additive Manufactured Medical Devices guidance document that advises manufacturers on how to design, manufacture, and test medical devices that contain at least one 3D printed component.35 The document makes several points that need to be considered by device makers as well as innovators who are considering using 3D printing. Most importantly, additive manufactured (AM) medical devices are no different than any other medical devices; manufacturers must provide evidence to the FDA that the device is both safe and effective. In other words, AM is simply another manufacturing method rather than 3D printing being considered as a whole new type of medical device category. Yet, a special aspect of AM fabrication is that patientmatched devices can perhaps be easily made using images taken from the specific patient. Oftentimes, AM fabrication enables complex geometries that cannot be easily made with traditional manufacturing methods. Successful fabrication using AM is correlated to (1) materials utilized, (2) the 3D printing machine utilized, and (3) any additionally required post-printing processes. However, some of the remaining challenges include the layer-by-layer build process, which means the finished product lacks the strength of a product fabricated from bulk material, and the fact that there is no long-term data from AM medical devices because the technology is so new.
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Because patient-matched devices are generally designed using CT or MRI images, the characteristics of the imaging process must be known, including the resolution and any necessary smoothing. Further, it is important to consider the time between taking the image and when the device is used/implanted, as the relative conditions of the patient can change over time. As described in the section on the 3D printing process, the software workflow involves several packages, often from different vendors, with the output of one step becoming the input of the next. Validations of file conversions are needed to ensure that the appropriate information is being passed without error, and these validations should be repeated each time a software package is updated. For example, the guidance document suggests using the Additive Manufacturing File format to store final build data, as this format is technologically independent and includes information on (1) surface textures, (2) materials, (3) color, (4) locations of objects in the build volume, and (5) high-resolution geometries, including curved patches. When it comes to 3D printing a medical device, control over fabrication parameters must also be known and documented. For examples, slicing thickness, infill density, and build path are all critical, as these parameters ultimately impact the device stiffness, hardness, and yield strength. Further, the mechanical anisotropic properties of the given device are a function of its build orientation. The size and placement of support structures also matter, particularly when the part has near-critical overhang geometries. Because support decisions are typically automatically handled by the machine software, the same part built on machines from two vendors generally will have different support structures, and ultimately different mechanical properties. Even the placement of the part in the build volume can make a difference, as 3D print machines tend to be well calibrated at the center of their build volume while maximum build uncertainty occurs at the perimeters, with the size of the uncertainty being machine dependent. Finally, the temperature and humidity of the build environment should be controlled for consistent prints. Controls must be established over the material used for printing, including the type, supplier, and storage conditions. The FDA approves finished medical devices and does not give blanket approvals for a specific material to be used in every device, which is why testing may be required even if the raw material has been used in a previous 3D printed/approved device. Furthermore, post-printing processes can affect the material properties of the finished part. For example, support material can be snapped off or dissolved in a bath, with each method producing a different surface finish. Surface finish can also be achieved with a polishing operation, but internal surfaces often cannot be reached for such polishing. In general, quality control over the 3D printing of medical devices can entail careful monitoring and control over the entire process, which could involve printing test coupons alongside the final part. In addition, mechanical and biocompatibility testing of the finished part will be necessary.
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21.6 CONCLUSIONS Medical applications of 3D printing are already extensive and growing rapidly. These technologies are routinely used for prototyping medical devices, particularly where prototyping in plastics is useful. Surgical applications are common where the most prevalent use is for creating custom guides to align surgical instruments, which reduces procedure times and increases surgical accuracy. Printing of difficult anatomies from patient imaging files, for planning complex surgery, is an emerging application that may soon become routine in numerous medical centers, as will printing of anatomical structures for surgical simulators. There are currently a few examples of patient-specific medical devices manufactured with 3D printing, with many more in the early and late research stages. To date, little objective research has been conducted on the relative costbenefit analyses of 3D printing in various medical settings. For example, while there are advantages for a surgeon holding a physical 3D representation of a patient’s organ in his/her hand, there is considerable cost in converting image files to a format that can be printed, mostly due to the costs and time of expert manual interventions to produce correct segmentations as well as printing. Further, these challenges currently prevent the use of this technology in complex procedures that must be done immediately (in the future, AI may be able to address this challenge). To move beyond the bias caused by excitement surrounding new 3D printing technologies, studies are needed to determine precisely whether 3D printed models and/or devices are cost effective and ultimately improve clinical outcomes before they become part of routine clinical practice. Even if widespread adoption does not occur, medical 3D printing may have advantages when used for complex cases.
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