3D Printing of Bioactive Devices for ClinicalMedicine Applications

Antwine W. McFarland JR, Yangyang Lou, Anusha Elumulai,Ahmed Humayun, and David K. Mills

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2The Need for Customized and Personalized Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Promise of 3D Printing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4A Brief Overview of 3D Printing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Fused Deposition Modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7Applications in Dental and Orthopedic Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83D Printing Polymer Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83D-Printed Bioactive Medical Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Functionalization of 3D-Printed Medical Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Commercial Development: 3D-Printed Medical Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14Commercial Development: Regulatory Hurdles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Overview of the Regulatory Landscape . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Current Regulation Regarding 3D-Printed Medical Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Further Regulatory Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

How 3D Printing will Shape our Future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Abstract3D printing is rapidly improving the effectiveness of medical practice and willcreate many new treatment options including “personalized medical solutions”over the next decade. This future is certain as improvements in 3D printers anda growing portfolio of new materials are being leveraged to rapidly expand the

A. W. McFarland · Y. Lou · A. Elumulai · A. HumayunMolecular Science and Nanotechnology, Louisiana Tech University, Ruston, LA, USAe-mail: awm011@latech.edu; ylu003@latech.edu; Ael026@latech.edu; Ahu005@latech.edu

D. K. Mills (*)Biological Sciences and Biomedical Engineering, Louisiana Tech University, Ruston, LA, USAe-mail: dkmills@latech.edu

© Springer Nature Switzerland AG 2019C. M. Hussain, S. Thomas (eds.), Handbook of Polymer and Ceramic Nanotechnology,https://doi.org/10.1007/978-3-030-10614-0_41-1

1

impact of additive manufacturing. 3D printing’s ability to make optimized andcustomized parts that are very precise and complex will usher in an era ofimproved and novel biomedical and clinical applications. Fused depositionmodeling (FDM) is an additive manufacturing technique that uses readily mold-able materials such as thermopolymers. It is also possible to additively manufac-ture metals and ceramics; however, fabrication methods must evolve to enableprinting of all three categories of materials interchangeably. 3D printing ofbiomedical constructs is primarily done using various thermoplastic polymers.The ability to extrude thermoplastic filaments for FDM fabrication methods hasled to the creation of customized and bioactive filaments. This book chapter willfocus on current advances in 3D printing of medical devices with an emphasis ondevice functionalization directed toward specific diseases and disorders. Specificsections will address the medical applications of 3D printing biomaterials andtechnologies; 3D-printed biomaterials in clinical applications; the state-of-the-artdevelopments in dental and orthopedic surgery; the commercial development ofmaterials, tools, their applications, and future developments; and how 3D printingwill impact our future.

KeywordsAdditive manufacturing · 3D printing · Bioactive devices · Bioplastics ·Customized medicine · Medical applications

Introduction

Historically, the application of 3D printing to fabricate and screen prototypesperfectly encapsulates the current needs of scientists and engineers toward theproduction of biomaterial scaffolds (Wong and Hernandez 2012). Biomaterialsresearchers have never had more materials at their disposal given the currentadvances in available metals, ceramics, polymers, and composites. 3D printingaffords the ability to construct these materials in any desired shape and size, eitherwith porosity or as solid materials and with increasingly high resolution as fabrica-tion processes are improved (Jijotiya and Verma 2013).

Advances in 3D printing materials, equipment, and techniques are enabling on-demand and highly customized patient treatments. 3D printing technologies rangefrom extrusion-based printing to laser-based approaches and are able to print arange biomaterials (Fig. 1 depicting 3D printing types and materials). Historically,3D printing has been used to fabricate and test scaffold prototypes with anemphasis on the properties of the biomaterial used in the printing process(Ventola 2014). As a result, this field now employs the use of ceramics, metals,polymers, and composites with the ability to construct high-resolution biomedicaldevices in any desired shape and size, either with porosity or as solid materials,complex internal architecture, and novel surface features (Guo and Leu 2013;Ventola 2014).

2 A. W. McFarland JR et al.

The Need for Customized and Personalized Treatments

Advances in 3D printing materials, equipment, and techniques are enabling on-demand and highly customized patient treatments. Advancements in filament extru-sion enables small batches of a desired filament with a variety of additives to bemade, allowing for conservation of fabrication material and drugs, thus 3D printingconstructs with desired specifications can be produced without the need for complexindustrial facilities. This method enables the complete customization of the dopantsadded without inhibiting extruder or 3D printer functionality. Constructs withdifferent infill ratios, orientations and architectures can be printed and with 3Dprinters with multiple heads. In this manner, 3D printing is rapidly improving theeffectiveness of medical practice and will create many new treatment optionsincluding “patient-specific medical solutions” over the next decade. The feasibilityof this future is certain as improvements in 3D printers and a growing portfolio ofnew materials are being leveraged to rapidly expand the impact of additivemanufacturing. 3D printing’s ability to make optimized and customized parts thatare very precise and complex will usher in an era of new and novel biomedical andclinical applications.

Fused deposition modeling (FDM) is an additive manufacturing technique thatuses readily moldable materials such as thermopolymers (Weisman et al. 2014; Zeinet al. 2002). It is also possible to additively manufacture metals and ceramics;

0% 10% 25%

50%a b

c

75%

Gentamicin/PLA catheters and beads Methotrexate /PLA catheters and beads

100%

X axis Y axis

Z axis

Fig. 1 (a) FDM-printed PLA disks with different infill rations. (b) Calcium phosphate/poly-caprolactone-printed constructs. (c) 3D-printed bioactive PLA constructs

3D Printing of Bioactive Devices for Clinical Medicine Applications 3

however, fabrication methods must evolve to enable printing of all three categoriesof materials interchangeably. 3D printing of biomedical constructs is primarily doneusing various thermoplastic polymers. The ability to extrude thermoplastic filamentsfor FDM fabrication methods has led to the creation of customized filaments. Thisbook chapter will focus on current advances in 3D printing of medical devices withan emphasis on device functionalization directed toward specific diseases anddisorders. Specific chapters will address the medical applications of 3D printingbiomaterials and technologies; 3D-printed biomaterials in clinical applications; thestate-of-the-art developments in dental and orthopedic surgery; the commercialdevelopment of materials, tools, their applications, and future developments; andhow 3D printing will design our future.

Promise of 3D Printing

As 3D printing continues to become more widely used in clinical domains, there aremany potential medical applications. 3D printing enables a variety of medicalconditions to be replicated for the purpose of educating dental, medical, nursingstudents and other health practitioners. Patient-specific models with anatomicalfidelity created from imaging dataset have the potential to significantly improvethe knowledge and skills of a new generation of surgeons (Garcia et al. 2018).

The printing of anatomical objects will enhance the teaching and learning envi-ronment for undergraduate students in the study of anatomy. In medical education,sophisticated anatomical models and pathological conditions can be created allo-wing the practice of cadaveric dissection as a means of medical education to becomea thing of the past.

3D printing uses computed tomography (CT), magnetic resonance imaging(MRI), and other medical imaging modalities to generate a three-dimensional solidobject from a digital data file, which can be used to create highly detailed andpatient-specific models for surgical planning (Abdullah et al. 2018). Moreover, withthe demand for more accurate custom models and the advent of more sophisticatedprinters and rendering software, 3D printing offers differentiated, anatomicallyprecise colors and varied textures within a single model, closely approximatingindividual patients and surgical cases (Whitaker 2014).

With 3D-printed models, surgical planning permits engagement with fully real-ized models capable of displaying complex articulation. The tactile, physical natureof 3D-printed models enables clinicians to conduct thorough preoperative prepara-tion, manipulate accurate relational representations of case anatomies, and identifyunusual physiologies and comorbidities whose early discovery can improve surgicalefficiency and effectiveness (Wu et al. 2018).

Manufacturing custom implantables, prosthetics, and surgical instruments ispossible due to the advancement in the field of medical 3D printing that allows forthe production of implantable prosthetics that utilize 3D CAD software in thefacilitation of surgical procedures while improving implant quality and reducingrisks associated with the surgery (Ventola 2014). Additionally, these 3D-printed

4 A. W. McFarland JR et al.

prosthetics can be designed to have the size, shape, and mechanical properties thatare patient specific and give the desired functionality for a variety of applications.

3D printing of case-specific models for surgical planning is a technologicaladvancement that aids in many surgeries. One such example is brain surgery.Spottiswoode et al. (2013) explains that an MRI has the ability for differentiatebetween healthy and non-healthy brain tissue, mapping what needs to be removedwhich is difficult to do with the human eye. The information gathered from the MRIis then used in conjunction with CAD software to create the program for the 3D-printed model. Ultimately, the 3D-printed, scale model can be used in planning andpracticing the surgery so that surgeons can make precise resections with an accuracyestimated at 0.5 mm.

A Brief Overview of 3D Printing

Additive manufacturing is the fabrication of an object using information fromcomputer-aided design (CAD) software that converts the design to a stereo-lithographic (.STL) file in order to physically fabricate an object through a machine(Sachs et al. 1994). Though this is very useful in rapid prototyping and noveltydesign, additive manufacturing techniques, primarily 3D printing, are rapidlycoming to the forefront of engineering and scientific research and industrialapplications (Zhang et al. 2012). The majority of basic additive manufacturingtechniques use readily moldable materials such as plastics. It is also possible toadditively manufacture metals and ceramics; however, fabrication methodsmust evolve to enable printing of all three categories of materials interchangeably(Zhang et al. 2012).

Additive manufacturing falls into three categories depending on the state of thematerial used: solid based, liquid based, and powder based. Liquid based additivemanufacturing uses precise and sufficiently powered UV laser beam to solidifyphoto-reactive polymer resins. The layers of liquid polymer are sequentially stackeduntil the desired artifact is built; however before each successive layer, the currentlayer must be polymerized so its form is preserved (Mahamood et al. 2014). Solidadditive manufacturing is primarily restricted to laminated object manufacturingwherein sheets of material are fused through pressure and heat and then cut tothe desired shape using a carbon dioxide laser (Feygin and Hsieh 1991). Thoughthis method is applicable to metals and ceramics, it generates large amounts of wastematerials, as the object is made. Wide varieties of this method exist; however, oneprimary technology that is widely known is selective laser sintering wherein a layerof powder is laid down, sintered using a laser, and then another layer is laid downatop the previously sintered layer and subsequently sintered (Kruth et al. 2005).

One of the major advantages of 3D printing in biomedical field is the significantdegree of freedom to fabricate customized medical devices (Ventola 2014). 3D-printed scaffolds are being actively studied in conjunction with 3D bioprinting withthe goal to produce living tissues, 3D-printed anatomical models for surgery, andpatient goal implants and prostheses (Chung et al. 2013; Ventola 2014). In tissue

3D Printing of Bioactive Devices for Clinical Medicine Applications 5

engineering, the approach most often utilized is to isolate primary and stem cells,multiplied in vivo by adding external growth factors, seeded onto scaffolds, and celldifferentiation induced with aim of producing a functioning tissue. 3D bioprintingand 3D culture systems offer the potential of recapitulating native tissue form andfunction. Many design parameters can be customized including the precise place-ment of cells, cell concentration, the use of multiple cell types, drop volume anddiameter of printed cells, and bioink composition (Chung et al. 2013). A keyconsideration in this area is the choice of bioplastic scaffolding and its composition(architecture, degradation rate, thickness, porosity, etc.). For example, if thebioprinted tissue has a thickness greater than 200 μm, the oxygen diffusion betweenthe host and transplanted tissue will be limited. To avoid this, a means to vascularizethe composite scaffold with a vascular network is required and has not yet beenaccomplished (Yu et al. 2009).

Traditionally used metallic implants have been proved clinically efficacious,but they are excessively stiff, stay at the site of implantation permanently, needsecondary revisions, and may require surgical removal upon healing (Derby 2012).Biopolymers, on the other hand, do not necessitate secondary surgery and can beengineered to degrade at the rate of new tissue formation, transforming the loadgradually from implant to newly formed tissue (Wuisman and Smit 2006). Severalbiopolymers, such as polycaprolactone (PCL), polylactic acid (PLA), hydroxyapa-tite (HA), and natural polymers (collagen, chitin), have been investigated fortissue engineering applications due to their biodegradability and bioresorbability(Vert et al. 1992). Additionally, they are available in various forms (solid, gel, fiber),easily molded into different shapes and compositions and do not cause anyinflammatory effects inside the body. Due to these properties, the applicabilityof biopolymers in 3D printing for medical applications has been increased(Derby 2012).

In response to marketplace demand, 3D printing technology has rapidly advancedin recent years (Wong and Hernandez 2012). A typical printing setup uses a .STL fileto generate nearly any desired shape so long as the volume of the object is less thanthe printer’s capability. Gaining insight into a patient’s anatomy prior to a surgicalprocedure is of utmost importance for a successful surgery. Current imagingprocedures such as MRI, CT scans, and X-rays, which are viewed in 2D, are theonly source to study and simulate surgery. Cadavers are also used for this purpose,but they lack appropriate pathology and provide more of an anatomy lesson thana representation of surgical procedure (Flowers and Moniz 2002). Recent advancesin 3D CAD modeling have enabled use of these primary imaging techniques to beconverted into 3D models, which later can be 3D printed into tangible constructs thatrender the patient’s specific and detailed anatomy (Flowers and Moniz 2002).As researchers seek to further customize this manufacturing method for rapidprototyping, a wider array of materials, and the ability to specially tailor theproperties of those materials, will be required. Additionally, there is a need fornew methods to ensure consistent dispersion of additives in the host polymer,while maintaining printability. Finally, by using these methods in commerciallyavailable devices that offer cost advantages, not industrial grade equipment is alsohighly desired.

6 A. W. McFarland JR et al.

Fused Deposition Modeling

Fused deposition modeling (FDM) printers typically use a plastic or polymerfilament to build a three-dimensional construct in a layered manner. For industrialprototyping, materials such as acrylonitrile butadiene styrene (ABS), polycarbonate(PC), polystyrene (PS), and polyethylether ketone (PEEK) are widely used.Bioplastics such as polylactic acid (PLA) and polycaprolactone (PCL) are usedfor medical applications due to their biocompatibility (Domingos et al. 2013).The consumer version of these printers operates at resolutions ranging from 50to 400 microns. Most printers use a plastic filament of 1.75–3 mm diameter througha heated print head with a narrow nozzle around 0.4 mm, melting the plastic andpassing it through the nozzle as the print head continues moving along the print path.As the print head temperature, infill ratio, and resolution are easily modified, highlyvariable designs of the same construct can be obtained. By altering the infill ratio ofthe construct, the porosity and mechanical strength of the construct can be custom-ized (Zein et al. 2002).

The drive for customized filament creation has also led to the design of person-alized filament extruders. Different processing techniques have been developedto fabricate filaments of required polymer type. Lactide-based polymers, such asPLA, PCL, and PLGA, are widely investigated for fused deposition modeling(FDM)-based fabrication due to their flexibility, low sensitivity to environmentalconditions such as temperature and humidity, complete bioresorbability, and FDAapproval.(Zein et al. 2002; Ballard et al. 2018; Weisman et al. 2014).

In FDM, extrusion of filaments with unique material properties that also providesa consistent dispersion of an additive without disrupting 3D printing capabilities isa major challenge. Weisman et al. (2015) developed a method enabling the rapidproduction of customized filaments at varying weight percentages using a commer-cially available filament extruder and 3D printer. The method applied silicone oil as asuspension media for powdered additives coated on the surface of standard polymerpoly(lactic acid) (PLA) and polycaprolactone (PCL) plastic pellets. This stepenabled filament extrusion with a minimal loss of additive throughout the process.Additives used in later work ranged from metals to ceramics to antibiotics (genta-micin, kanamycin, vancomycin), chemotherapeutics (methotrexate), and hormones(estrogen) and required minimal adjustment to the fabrication process.

An ideal implant should have a proper balance of mechanical and physicalproperties. The optimization of properties such as hardness, elasticity, yield stress,wearability, and time of degradation completely depends on the type and function-ality of the implant. Scaffolds with different infill ratios and different orientationswere printed as shown in Fig. 1. Such a design enables printing an internal archi-tecture for aided load absorption and distribution as well as regulating drug release.

Another key consideration is the consistent dispersion of additives withdopant percentages of up to 25% by weight to allow for conservation of fabricationmaterial and supported the 3D printing of beads, catheters, pessaries, IUDs, andmedical implants with the desired specifications without the need for complexindustrial facilities (Weisman et al. 2014, 2015).

3D Printing of Bioactive Devices for Clinical Medicine Applications 7

Applications in Dental and Orthopedic Surgery

The etiology of many dental and orthopedic health conditions often stems frombiomechanical issues (broken bones, aging joints, and misaligned spines), implantfailure, and bacterial infection. These issues can be difficult to remedy because eachperson’s anatomy and physiology is uniquely shaped and a one-size-fits-all splint,implant, or back brace may not be optimal. 3D printers can deliver flexible, semi-rigid, bioactive, and bioresorbable structures with novel designs that can be customdesigned with a complexity more intricate than those manufactured using traditionalmethods.

3D Printing Polymer Types

Polymers can be divided into two categories, bioresorbable and non-bioresorbable.Bioresorbable polymers are polymers that, when exposed to biological conditions,begin to deteriorate through a process called hydrolysis. Polymer hydrolysis can becategorized in two ways, bulk and surface. Uhrich et al. (1999) explains that surfacehydrolysis dissolves from the surface and moves inward, while in bulk hydrolysis,water penetrates through the surface of the polymer and dissolves the polymer at anaccelerated rate in comparison. In each case, it is the ester bond that is cleaved thatfacilitates the polymer degradation (Vieira et al. 2010).

Polyglycolic acid (PGA) is one of the strongest bioactive polymers used tomanufacture medical devices. Its strength and rigidly makes it a viable optionto facilitate bone mending when used as a stabilization plate. Unfortunately, PGAtypically undergoes bulk hydrolysis, and its strength begins to diminish in vivoafter as few as 60 days (Nair and Laurencin 2007). Polyglycolic acid is broken downinto glycine which is absorbed by cells and used in the Krebs cycle (Nair andLaurencin 2007).

Comparatively, poly-L-lactic acid (PLLA) may be a better polymer whenconsidering bioresorbable thermoplastics for bone mending due to its slower degra-dation rate. Its ability to maintain the original strength of the bone fixation deviceis the leading rational behind this conclusion. While PLLA also undergoes bulkhydrolysis, it does so at a slower rate than PGA. Once PLLA is broken down intolactic acid, it is filtered out of the blood by either the liver and is convertedinto glucose or the kidneys and expelled in urine (Katz and Tayek 1998).

Polycaprolactone (PCL) is a relatively inexpensive bioresorbable polymer thathas a low melting point. PCL is the least rigid of the aforementioned polymers buthold its mass in vivo for up to twice as long as the other two polymers (Nair andLaurencin 2007). Its ability to resist degradation is ushering research in its ability tobecome a longer-term scaffold that can release drugs, vaccines, or steroids.

The desired characteristics of multiple polymers can be combined to makea thermoplastic that is superior to its constituents. A nanocomposite can beconstructed using a blend of multiple polymers in various ratios to make a polymerblend or copolymer. Polymer blends are constructed of two or more polymers that

8 A. W. McFarland JR et al.

have been simply blended together into a filament or solvent casted. A copolymeris similar, but with the addition of polymerizing the different polymers into a newtype of polymer.

Research on non-biodegradable polymers is less far reaching due to successfulcurrently available medical devices made of various FDA-approved polymers.Polyetheretherketone (PEEK), ultrahigh molecular weight polyethylene(UHMWPE), and polyvinyl alcohol (PVA) are all biologically safe polymers thatcan be used in prosthetics and a variety of medical applications where resorptionis not desired (Zhou et al. 2016). PEEK is being explored as an option to repairspinal injuries through the manufacturing of scaffolds (Kim et al. 2016).

3D-Printed Bioactive Medical Devices

Technological advances in the medical field have given a rise to the possibilityof utilizing previously unused bioinert medical devices (Figure 2). 3D-printedmedical devices can be fabricated to replace or add function to tissues in the body(Manavitehrani et al. 2016). Bioactivity augments the usefulness of the medicaldevices by allowing for a secondary functionality to be taken advantage of overthe previously bioinert medical device. 3D-printed bioactive medical devices canprovide similar strength and function as its bioinert counterpart with the addedbenefit of having the ability to directly effect is microenvironment in a way thatis beneficial to the recipient. Bioactivity of a medical device can be tuned to theneeds of the specific patient and the circumstance of their need for implantationby varying factors such as polymer selection and additives (Porter et al. 2009).Fedorovich et al. (2011) explained how 3D-printed structures can be printedto specifications that allow multiple cell types in a single structure that wouldmimic the porosity and vascularity needed for the growth of implanted or migratedstem cells (Figs. 2 and 3).

3D-printed bioactive medical devices are not limited to bone growth. Ballard etal. (2018) wrote of the possibilities of using bioactive materials to create variousorgans such as the kidney, ovary, and cardiac tissues. There is a growing interest intheir utilization in the manufacturing of stents. Weisman et al. (2019) conductedstudies on 3D-printed catheters that have been given the ability to elute chemother-apeutic drugs, as well as antibiotics. They were able to show that 3D-printedcatheters are a viable option in fighting infection and inhibiting cancer cell progres-sion. Murgu and Colt (2007) explains that silicone airway stents have three maindrawbacks: mucus plugging, stent migration, and tissue granulation. The adventof a 3D-printed bioactive stent could be a replacement in the future that wouldeliminate these complications. By anchoring the bioactive medical device withbioactive sutures that could deter granulation, the bioactive 3D stent could see lessadverse effects than the silicone stent due to its ability to integrate itself with itssurrounding environment. Future studies could uncover more applications for 3D-printed medical devices.

3D Printing of Bioactive Devices for Clinical Medicine Applications 9

Functionalization of 3D-Printed Medical Devices

Due to its inherent high productivity, low-cost efficiency, and, most importantly, theability to produce customized medical equipment, 3D printing has been used in todevelop permanent implants, tissue-engineered scaffolds, drug-testing devices, anddrug-releasing models (Ventola 2014; Zhang et al. 2018).

Despite the multiple advantages and recent significant advances in 3D printing,the inherent limitations of biomaterials, and variability in the properties of targettissues, there exists a major challenge in fabricating patient-specific 3D scaffolds,

Fig. 2 For FDM 3D printing key constraints in creating a customized filament both in the materialproperties of the polymer to be used as well as the critical factors to be considered in fabricating abioactive device. The customized filament can then be used to print a variety of bioactive medicaldevices including (a), PLA screws, F, gentamicin-doped PLA, (b) estrogen-doped PLA IUD, (c)gentamicin-doped PMMA, (d) osteofixators, (e) nasal stent, (f) methotrexate-doped PLA micro-beads, (h) antibiotic-doped orthopedic brace, and (i) gentamicin-doped PLA microbeads

10 A. W. McFarland JR et al.

and often additional modifications are usually needed. For instance, porosity andpore size play a critical role in 3D scaffolds designed for bone regeneration. Saltleaching, gas foaming, phase separation, freeze-drying, and sintering are the mostcommon techniques used to fabricate porosity functionalized scaffolds. Smallpores (<100 μm) contain less oxygen and induce osteochondral formation beforeosteogenesis; in contrast, large pores (>100 μm) stimulate vascularization and resultin osteogenesis (Karageorgiou and Kaplan 2005). A recent report of surface-modi-fied scaffold has found that if the pore size of scaffold (nanostructure porous PCLscaffold – NSP PCL) was too small, even if it was pretreated with growth factors(BMP-2) or mononuclear cells, there was a significant inhibition for new boneformation; in addition, it caused a sustained inflammatory response (Jensen et al.2014).

Native tissues have complexity architectures and usually composed of multiplecells. Naked 3D-printed biomimetic scaffold is hard to achieve the precisely controlon cell spatial position, highly density distribution, and blood vessel orientation(Zhang et al. 2018). A control of spatiotemporal pattering of physical and biochem-ical factors is a potential strategy to overcome the barrier. Cell growth on two-dimensional (2D) patterns has been widely studied (Chen et al. 1998; Chen et al.2003) (Fig. 4). Instead of embedding growth factors with designed patterns, pat-terned microenvironments producing inside 3D scaffold are more complicated but

Fig. 3 A range of medical devices can be 3D printed including nasal stents, bone scaffolds, screwsand plates, orthobiologics, and osteofixators. These same devices can be 3D printed with bioactiveagents including antibiotics, chemotherapeutics, hormones, and growth factors

3D Printing of Bioactive Devices for Clinical Medicine Applications 11

more diverse. Different gradients of multiple growth factors could be distributedbased on specific spatial locations and temporal physiological condition. A precisespatial distribution of single and multiple molecules has been archived in a laser-based 3D scaffold. The functionalization with RGD and heparin enhanced celladhesion and orientation (Fig. 5).

Polymers used in 3D printing are chemically/biologically passive, and surfacefunctionalization becomes necessary; there are several chemical techniques forsurface modification of 3D-printed polymers including reacting with chemicalreagents, low-temperature plasma, or direct surface coating with chemicals ofinterest (Mapili 2005). Several studies have used alkaline hydrolysis which cova-lently introduces hydroxyl and carboxyl groups in poly(lactic acid) (PLA) bycleavage of the ester bond (Zhang 2017) (Fig. 6).

Similarly polydopamine (PDA) coating for introducing mussel adhesive proteinsmainly contain dihydroxyphenylalanine (DOPA) and lysine thus introduce hydroxyland amine functional groups respectively which subsequently results in increasedhydrophilicity translating into enhanced chemical and biological response. Theadded functional groups can also be used to immobilize charged species, moleculesof interest thus further increasing the functionality of the surface (Yeh et al. 2015).The 3D-printed surfaces can also be passivated using polyethylene glycol (PEG) forrendering surface hydrophobic and prevent microorganism attachment (Banerjee etal. 2011). Similarly antimicrobial agents embedded in polymeric surface help pre-vent bacterial growth (Zhang 2017).

Fig. 4 (a) 3D-printed bone scaffold by either FDM, robocasting, or SLA which contains therequired material properties and biodegradation properties. (b) Surface modification of this scaffoldby various methods can be used to provide a cell supportive surface (c). These agents can be usedfor enhanced cell adhesion, proliferation, and differentiation leading to tissue formation (d)

12 A. W. McFarland JR et al.

Fig. 5 Incorporation of RGD in the scaffold material allowed efficient cell attachment andspreading. SEM micrographs show top views of (a) scaffold without RGD modification and (b) ascaffold containing 5.0 mM RGD-PEG-acryl. OP-9 cells attached to coated scaffold and secretedECM-like materials on the scaffold. (c) and (d) Confocal fluorescence microscopy indicated thatcells only attached to RGD-functionalized scaffolds. (c) DAPI nuclei staining, and (d) cells pre-stained with CellTracerTM. The green staining seen in (d) is fluorescence from FITC-labeledparticles that were encapsulated during photopolymerization. (Reprinted from Reference 10)

O O

O

O

O

O

OX

OX

OH HO+

Alkaline

Hydrolysis

Poly (lactic acid) Carboxyl End Group Hydroxyl End Group

CH3

CH3CH3

CH3

CH3

CH3

O

On

Fig. 6 Hydrolysis of the ester bond in the PLA backbone results in carboxyl and hydroxyl endgroups. (Tham et al. 2014)

3D Printing of Bioactive Devices for Clinical Medicine Applications 13

Commercial Development: 3D-Printed Medical Devices

The global market in additive manufacturing achieved a high of $7.3 billion in 2017,with a compound annual growth rate of 21% (Columbus 2017). Of that, 11% was inmedical and dental technologies. GE Life Sciences, 3M, Medtronic, Stryker, andSmith & Nephew are medical companies that are making significant investments inthis space. Currently, FDM 3D printers can cost anywhere from $5,000 for a basicunit to $50,000 for a printer with enhanced functionality and structural integrity.For metal printing, the costs can be in the $1 million to $3 million range, and a largenumber of service companies have arisen to meet many manufacturing companies’current needs before making these companies a significant investment in 3D printingtechnology (Fig. 7).

3D printing technology has mainly targeted product development, prototyping,customized product development, and increase production flexibility. Other usesinclude reducing tooling investment, reducing demo product expenses, and improv-ing spare parts management (Columbus 2017). In a survey done by Columbus(2017), 90% of companies using 3D printing view it as competitive, and 71%of services companies will attain a higher ROI versus previous years. FDM is themost widely used technology, followed by SLS and finally SLA printing. Ease ofuse, cost, and availability of a range of printing filament types reflect the continuedmaturity of the market.

One exception is healthcare, where there is currently more private investmentbeing done with the perspective that 3D printing is a potential revenue stream thatwill help build a solid return on their investment. Rady Children’s Hospital in San

Air pressure

Dispenser

Dry

For 24h at RT

Grafting Dopamine

NH2

OH

• HCI

OH

Polydopamine

PCL scaffold

Tris-HCL,pH 8.5

Dopamine coatedPCL scaffold

3D PorousPCL scaffold

rhBMP2immobilization

rhBMP2

• Cell adhesion

• Osteogenesis Tris-HCL,pH 8.5

Nozzle

Scaffold

Fig. 7 3D printing of porous PCL scaffold with grafting of mussel-inspired polydopamine forimmobilization of rhBMP-2. (Lee et al. 2016)

14 A. W. McFarland JR et al.

Diego is among a growing number of hospitals investing in 3D printing in cardiacand radiology, and the hospital is developing a 3D printing hub to serve all itsdepartments. The new lab consists of six dedicated rooms. In addition to 3D printing,there will be virtual reality technology and space for types of manufacturingtechnologies, including casting technologies.

At the Mallinckrodt Institute of Radiology (MIR, https://www.mir.wustl.edu/research/research-support-facilities/3d-printing-lab-3dp), 3D printing lab has as itsmission unique research and educational experiences using 3D visualization, 3Dmodeling, and 3D printing technologies for multiple medical and surgical applica-tions. Using patient data (CT or MRI scans), the lab produced CAD models and3D models with high precision and accuracy. Patient-specific anatomical modelsare used for visualization, educational training, perioperative surgical planning,and simulations and for printing customized implants and biomedical devices.Their research arms offer fabrication of bioprinted scaffolds for tissue engineeringand drug delivery purposes. MIR 3D printing lab fosters a cross-disciplinaryapproach to research and education through its collaborations with various labgroups within and outside the Washington University. Dr. David Ballard of theMIR believes “3D printing is an innovative tool that allows our medical imagingto be transformed into haptic models that can be manipulated and visually inspectedby surgeons and proceduralists. Although anatomic models for preoperative plan-ning is the mainstay of 3D printing’s current use in medicine, other surgical andclinical uses include surgical guides, prosthetics, imaging phantoms, and surgicalpathology cutting guides. Moreover, the translational potentials of impregnatingdrugs and other bioactive agents into 3D-printed constructs and designing bioprintedtissue scaffolds are other exciting areas of investigation (Ballard et al. 2018, personalcommunication).”

Although the most significant hurdle with implementing 3D-printed products intoclinical use is the lack of or inadequate reimbursement, the upcoming AmericanMedical Association Current Procedural Terminology category III code is a signif-icant step forward toward reimbursement. Indeed, the current status and futureoutlook of 3D printing in medicine have yet to be written.

Commercial Development: Regulatory Hurdles

Overview of the Regulatory Landscape

The advent of 3D printing has revolutionized several industries with applicationsthat include regenerative medicine, dentistry, construction, aerospace, and automo-tive industries (Ahangar et al. 2019). There are currently numerous examples where3D-printed materials have been successfully implanted into patients, both in humansand animals (Ahangar et al. 2019). There has also been a surge of US Food and DrugAdministration (FDA) authorizations, with more than 100 3D-printed medicaldevices approved since the mid-2000s (https://www.fda.gov/medical-devices/3d-printing-medical-devices/medical-applications-3d-printing). These devices appear

3D Printing of Bioactive Devices for Clinical Medicine Applications 15

across three main categories: instrumentation, implants, and external prostheses.This surge can be explained as many regulatory agencies have embraced 3D printingtechnology and are receptive to working with companies to create better productsfor patients. In 2016, the growing number of approved 3D-printed devices encour-aged the FDA to issue preliminary guidance to 3D printing manufacturers (Johnson2016). These guidelines focus on design and manufacturing considerations, as wellas device testing concerns (Lauer et al. 2017).

An additional explanation for these successful applications to the FDA is the verynature of 3D printing. This technology employs the use of automation equipmentresulting in high reproducibility, reliability, and strength to the fabricated medicaldevices. These features also facilitate scalability and high-throughput screening offabricated constructs, thus assisting in obtaining clearance by government oversightbodies such as the US Food and Drug Administration (FDA) and the EuropeanMedicines Agency (EMA) (Gatling 2009; Johnson 2016).

Current Regulation Regarding 3D-Printed Medical Devices

In order to gain FDA approval, strenuous testing including cytotoxicity,hemocompatibility, genotoxicity, sensitization, as well as sub-chronic and systemictoxicity is required (Gatling 2009; Johnson 2016; Lauer et al. 2017). The FDA hastwo significant classes of 3D-printed medical devices. The first group includesproducts that can be created using any manufacturing processes, including 3Dprinting. For the approval of these devices, manufacturers only have to prove thatthe final medical device product is substantially equivalent to a predicate product thatis already on the market. The critical consideration is demonstrating that the com-pany has proper manufacturing controls, processes, and standards. The majority ofthe 3D-printed medical devices currently on the market in the USA are in this firstclass, and companies have shown that their 3D-printed device is substantially similarto a product currently being marketed. The most complicated devices to regulatewithin the first class are patient-specific devices, such as prostheses, and are consid-ered as the biggest challenge in regulating 3D-printed medical devices (Gatling2009; Johnson 2016; Lauer et al. 2017).

The second class of FDA medical devices carries a higher risk and must gothrough a pre-market approval process as there is no similar predicate device on themarket. With a product that is customizable or designed to be patient specific, therecan be issues with testing every single device that is made, because the regulationstypically are not designed to address individually printed medical devices. Onesolution regulators are researching is the requirement that companies set a minimumand maximum size (features) for the customizable aspect of the device-testing andvalidation as well as requiring the testing of the “worst case” within a specific set ofdesign constraints (Crawford 2016).

The European Union (EU) has been following the FDA’s example. Relevantauthorities have approved 3D-printed medical devices and have published advicefor companies and others using 3D printing manufacturing techniques to create

16 A. W. McFarland JR et al.

medical devices. The EU’s governance is contained in Medical Devices Regulation2017/745, where it establishes that quality management systems are central toproduction, like with other manufacturing techniques.

After approving the country’s first 3D-printed medical device in 2015, theChinese FDA (CFDA) recently released an advisory document in March 2018(Embargo Group 2018). The focus of the guidance was on the required data neededin the approval process, such as validation testing of materials, equipment, andsoftware, as well as the final product. It also discussed the role of healthcareprofessionals in design input and output for 3D-printed medical devices.

Guidelines written by national regulators have been accompanied by internationalorganizations, such as the ISO and ASTM, starting to create consistent, globalstandards for 3D printing of medical devices. The advantage in following Iso andASTM standards is you can use one set of standards enabling complying mostcountry’s regulations.

Further Regulatory Challenges

Another challenge in the regulation of 3D-printed medical devices is that there aremany intersecting and conflicting governmental regulations from national and inter-national agencies (Gatling 2009). This issue can create a significant regulatoryred tape mess for companies seeking to use the technology to manufacture medicaldevices. The reason is simple; the burden is on the manufacturer to prove that thedevice is safe and effective. As such, companies have to demonstrate that theyunderstand and abide by industry standards. It becomes essential that 3D printingdevice manufacturers understand that this regulatory quagmire may slow downinnovation (Johnson 2016; Lauer et al. 2017). Even if a company has an outstandingand impactful device, the governmental regulatory process can make product devel-opment extremely difficult (Core-Ballais et al. 2018). For researchers contemplatingcommercialization of their 3D-printed devices, it is essential that they fully under-stand the FDA process and good laboratory practices and how to get a productlegally on the market.

However, 3D printing as a technology has also created issues for regulatingbodies as theoretically anyone with a 3D printer and a blueprint could print theirown devices, not just registered companies (Core-Ballais et al. 2018). 3D-printedmedical devices pose a huge challenge for regulatory bodies because, unlike tradi-tional manufacturing techniques, 3D printers can be owned and used by anyone, notjust manufacturing companies.

How 3D Printing will Shape our Future

3D printing is most well-known for creating plastic prototypes, objects, andstructures, rapidly, cheaply, and with an incredible degree of accuracy. Recentdevelopments have shown that 3D printing has found its place in medicine,

3D Printing of Bioactive Devices for Clinical Medicine Applications 17

biotechnology, and nanotechnology, thus paving the way for the rapid printingof drugs, artificial devices, and prosthetics and even human tissue and organs.Currently, there is an intense research effort focused on the application of 3Dprinting for the development of blood vessels, bioengineered tissues, and the pro-duction of functional biomedical materials and devices for dental and orthopedicapplications. 3D printing will soon provide clinicians with the capability of provid-ing individualized treatments that meet specific patient needs.

3D printing continues to expand in popularity in both the medical and commercialfields. Schubert et al. (2014) speculated that industry will see a large expansion froma $700 million industry to upward of nearly $9 billion in the next decade. Of that,he concluded that an astounding 21% will come from the medical industry. Froma commercial standpoint, the key to keeping cost down and value high is tied to theability to mass produce a uniformed product (Schubert et al. 2014). Skilled com-puter-aided design (CAD) technicians can create a model that can be reproduced bythe 3D printer with few flaws. An experienced CAD designer is far more importantin the medical field, as some 3D-printed medical devices are custom designed for aspecific recipient. Scaffolds for tissues such as the bone and skin are currently able tobe 3D printed and seeded with cells in regenerative medical practices (Berman2012). With multiple print heads and printing materials, the complex structures,such as organs, that were thought to be impossible to manufacture are now feasible(Ventola 2014).

Compared to traditional techniques, the single biggest advantage of 3D printingis the ability to digitally define the construct of interest and reproduce the physical3D construct through automated techniques and at resolutions not possible throughconventional methods (Berman 2012; Derby 2012). Digitally aided processesallow fabrication of quality products with low variability, thus lending themselveseasily toward clinical translation and approval by regulatory agencies. Furthermore,3D printing allows control over process parameters designed to achieve the requiredconstruct characteristics, reducing patient posttreatment complications, losttime from work, and healthcare costs while improving the overall quality of life(Mills 2015).

Accordingly, we are rapidly creating a future where medical treatment willbecome on-demand and highly personalized, with treatment modalities that arepatient specific, not “one size fits all.” While this technology has yet to be fullyrealized, recent advances in biofabrication and bioprinting may soon bring uscloser to achieving this future with devices that possess customized capabilitiesand are tailored toward a specific patient (Diaz et al. 2012; Ventola 2014; Jijotiya andVerma 2013).

We expect in the next 5–10 years that major innovations in 3D-printed orthopedicand dental products, biological scaffolding materials, bioprinter, and bioprintedcells and tissues will witness a growing acceptance and use in biomedicine andsignificantly increase in commercialization.

Across the globe there is a massive research effort in the areas of tissue engineer-ing, innovative pharmaceuticals, and microfluidic chips, and diagnostics willboost the market for 3D-printed biomedical products over the long term (Borovjaginet al. 2017). Medical professionals may soon have an option to switch to 3D-printed

18 A. W. McFarland JR et al.

devices because a strong consumer value proposition will result in quickly increas-ing patient demand, which will support high sales volumes. This indicates thatdisruptive 3D printing methodologies and novel products will push growth in themarket rather than only 3D printing equipment.

Cross-References

▶Applications of Advanced Polymer and Ceramics Nanocomposites▶Biocompatible Nanopolymers▶ Polymeric and Ceramic Nanocomposites for Biomedical Applications▶ Progresses on Polymer Nanocomposites: Drug Delivery Systems and SensitiveDetections

Acknowledgments The authors wish to acknowledge the funding assistance provided by theCenter for Dental, Oral and Craniofacial Tissue and Organ Regeneration (C-DOCTOR) with thesupport of NIH NIDCR (U24DE026914) and the Louisiana Biomedical Research Network.

References

Abdullah KA, Reed W (2018) 3D printing in medical imaging and healthcare services. J MedRadiat Sci 65(3):237–239. https://doi.org/10.1002/jmrs.292

Ahangar P, Cooke ME, Weber MH,Rosenzweig DH (2019) Current biomedical applications of 3Dprinting and additive manufacturing. Applied Sciences, 9(8), p.1713

Alhnan MA, Okwuosa TC, Sadia M, Wan KW, Ahmed W, Arafat B (2016) Emergence of 3Dprinted dosage forms: opportunities and challenges. Pharm Res 33(8):1817–1832

Ballard DH, Anthony PT, Sayed A, Taryn H, Matthew EZ, Carolynn MD, Stacy ES et al (2018)Clinical applications of 3D printing: primer for radiologists. Acad Radiol 25(1):52–65

Banerjee I, Pangule RC, Kane RS (2011) Antifouling coatings: recent developments in the designof surfaces that prevent fouling by proteins, bacteria, and marine organisms. Adv Mater23:690–718

Berman B (2012) 3-D printing: the new industrial revolution. Bus Horiz 55(2):155–162Borovjagin AV, Ogle BM, Berry JL, Zhang J (2017) From microscale devices to 3D printing:

advances in fabrication of 3D cardiovascular tissues. Circ Res 120(1):150–165. https://doi.org/10.1161/CIRCRESAHA.116.308538

Chen CS, Mrksich M, Huang S, Whitesides GM, Ingber DE (1998) Micropatterned surfaces forcontrol of cell shape, position, and function. Biotechnol Prog 14:356–363

Chen CS, Alons JL, Ostuni E, Whitesides GM, Ingber DE (2003) Cell shape provides global controlof focal adhesion assembly. Biochem Biophys Res Commun 307:355–361

Chung JH, Naficy S, Yue Z, Kapsa R, Quigley A, Moulton SE, Wallace GG (2013) Bio-inkproperties and printability for extrusion printing living cells. Biomat Sci 1(7):763–773

Columbus L (2017) The state of 3D printing 2017. https://www.forbes.com/sites/louiscolumbus/2017/05/23/the-state-of-3d-printing-2017/#4608d4bd57eb

Core-Ballais M, Bensoussan H, Richardot A, Kusnadi H (2018) The state of 3D printing 2018.Sculpteo https://www.forbes.com/sites/louiscolumbus/2018/05/30/the-state-of-3d-printing-2018/

Crawford C (2016) Validation and verification for medical devices. https://www.asme.org/engineering-topics/articles/manufacturing-design/validation-verification-for-medical-devices

Derby B (2012) Printing and prototyping of tissues and scaffolds. Science 338:921–925

3D Printing of Bioactive Devices for Clinical Medicine Applications 19

Dias AD, Kingsley DM, Corr DT (2014) Recent advances in bioprinting and applications forbiosensing. Biosensors 4:11–136

Domingos M, Intranuovo F, Russo T, Santis RD, Gloria A, Ambrosio L et al (2013) The firstsystematic analysis of 3D rapid prototyped poly(ε-caprolactone) scaffolds manufacturedthrough BioCell printing: the effect of pore size and geometry on compressive mechanicalbehaviour and in vitro hMSC viability. Biofabrication 5(4):45004

Embargo Group (2018) https://www.massdevice.com/china-cfda-proposes-regulatory-framework-for-3d-printed-medical-devices/

Fedorovich NE, Jacqueline A, Wim EH, Ör FC, JAD W (2011) Organ printing: the future of boneregeneration? Trends Biotechnol 29(12):601–606

Feygin M, Hsieh B (1991) Laminated object manufacturing (LOM): a simpler process. InternationalSolid Freeform Fabrication symposium, Austin

Flowers J, Moniz M (2002) Rapid prototyping in technology education. Proc SITE 62:7–11Garcia J, Yang Z, Mongrain R et al (2018) 3D printing materials and their use in medical education:

a review of current technology and trends for the future. BMJ Simul Technol Enhanc Learn24:27–40

Gatling R (2009) The regulation of medical devices. https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=3&cad=rja&uact=8&ved=2ahUKEwiOu575p8viAhUIQK0KHaerCbQQFjACegQIBBAC&url=https%3A%2F%2Fwww.fda.gov%2Fmedia%2F89070%2Fdownload&usg=AOvVaw3E4PsfgxhhUpPI19O6JqN5

Guo N, Leu MC (2013) Additive manufacturing: technology, applications and research needs. FrontMech Eng 8(3):215–243

Jensen J et al (2014) Surface-modified functionalized polycaprolactone scaffolds for bone repair: invitro and in vivo experiments. J Biomed Mater Res A 102:2993–3003

Jijotiya D, Prabhu LV (2013) A survey of performance based advanced rapid prototypingtechniques. Sch J Eng Tech 1.1: 4–12

Johnson J (2016) FDA regulation of medical devices. Congressional Research Service 7-5700,www.crs.gov

Karageorgiou V, Kaplan D (2005) Porosity of 3D biomaterial scaffolds and osteogenesis.Biomaterials 26:5474–5491

Katz J, Tayek JA (1998) Gluconeogenesis and the Cori cycle in 12-, 20-, and 40-h-fasted humans.Am J Physiol Endocrinol Metab 275(3):E537–E542

Kim BS, Jang J, Chae S, Gao G, Kong J-S, Ahn M, Cho D-W (2016) Three-dimensional bioprintingof cell-laden constructs with polycaprolactone protective layers for using various thermoplasticpolymers. Biofabrication 8(3):035013

Kruth JP, Mercelis P, Van Vaerenbergh J, Froyen L, Rombouts M (2005) Binding mechanisms inselective laser sintering and selective laser melting. Rapid Prototyp J 11(1):26–36

Lauer M, Barker JP, Solano M, Dubin J (2017) FDA device regulation. Mo Med 114(4):283–288Lee SJ et al (2016) Surface modification of 3D-printed porous scaffolds via mussel-inspired

polydopamine and effective immobilization of rhBMP-2 to promote osteogenic differentiationfor bone tissue engineering. Acta Biomater 40:182–191

Mahamood RM, Akinlabi ET, Shukla M, Pityana S (2014) Revolutionary additive manufacturing:an overview. Lasers Eng 27(3/4):161–178

Manavitehrani I, Fathi A, Badr H, Daly S, Ali Negahi Shirazi AN, Dehghani F (2016)Biomedical applications of biodegradable polyesters. Polymers 8:20. https://doi.org/10.3390/polym8010020

Mapili G, Lu Y, Chen S, Roy K (2005) Laser-layered microfabrication of spatially patternedfunctionalized tissue-engineering scaffolds. J Biomed Mater Res Part B Appl Biomater75:414–424

Mills DK (2015) Future medicine: the impact of 3D printing. J Nanomater Mol Nanotechnol4(3):1–3

Murgu SD, Colt HG (2007) Complications of silicone stent insertion in patients with expiratorycentral airway collapse. Ann Thorac Surg 84(6):1870–1877

20 A. W. McFarland JR et al.

Nair LS, Laurencin CT (2007) Biodegradable polymers as biomaterials. Prog Polym Sci32(8–9):762–798

Porter JR, Ruckh TT, Popat KC (2009) Bone tissue engineering: a review in bone biomimetics anddrug delivery strategies. Biotechnol Prog 25(6):1539–1560

Sachs EM, Haggerty JS, Cima MJ, Williams PA (1994) Three-dimensional printing techniques. USPatent 5,204,055

Schubert C, Van Langeveld MC, Donoso LA (2014) Innovations in 3D printing: a 3D overviewfrom optics to organs. Br J Ophthalmol 98(2):159–161

Spottiswoode BS, Van den Heever DJ, Chang Y, Engelhardt S, Du Plessis S, Nicolls F,Hartzenberg HB, Gretschel A (2013) Preoperative three-dimensional model creation of mag-netic resonance brain images as a tool to assist neurosurgical planning. Stereotact FunctNeurosurg 91(3):162–169

Tham CY, Hamid ZAA, Ahmad ZA, Ismail H 2014 Surface engineered poly (lactic acid)(PLA)microspheres by chemical treatment for drug delivery system, vol. 594. Trans Tech Publications

Uhrich KE, Cannizzaro SM, Langer RS, Shakesheff KM (1999) Polymeric systems for controlleddrug release. Chem Rev 99(11):3181–3198

Ventola, CL (2014) Medical applications for 3D printing: current and projected uses. Pharmacy andTherapeutics 39(10):704

Vert M, Li SM, Spenlehauer G, Guérin P (1992) Bioresorbability and biocompatibility of aliphaticpolyesters. J Mater Sci Mater Med 3(6):432–446

Vieira AC, Vieira JC, Guedes RM, Marques AT (2010) Degradation and viscoelastic properties ofPLA-PCL, PGA-PCL, PDO and PGA fibres. In: Materials science forum, vol 636. Trans TechPublications, Aedermannsdorf, pp 825–832

Weisman J, Nicholson C, Tappa K, Jammalamadaka U, Wilson C, Mills DK (2014) Antibioticand chemotherapeutic enhanced 3D printer filaments and constructs for biomedical applications.Int J Nanomed 10:357–370

Weisman JA, Jammalamadaka U, Tappa K, Nicholson JC, Ballard DH, Wilson CG, D’Agostino H,Mills DK (Feb. 2015) 3D printing antibiotic and chemotherapeutic eluting catheters andconstructs. J Vasc Interv Radiol 26(2):S12

Weisman JA, Ballard DH, Jammalamadaka U, Tappa K, Sumerel J, D’Agostino HB, Mills DK,Woodard PK (2019) 3D printed antibiotic and chemotherapeutic eluting catheters for potentialuse in interventional radiology: in vitro proof of concept study. Acad Radiol 26(2):270–274

Whitaker M (2014) The history of 3D printing in healthcare. Bull R Coll Surg Engl 96:228–229Wong KV, Hernandez A (2012) A review of additive manufacturing. ISRN Mechanical Engineer-

ing 2012. https://doi.org/10.5402/2012/208760Wu AM, Wang K, Wang JS et al (2018) The addition of 3D printed models to enhance the teaching

and learning of bone spatial anatomy and fractures for undergraduate students: a randomizedcontrolled study. Ann Transl Med 6(20):403. https://doi.org/10.21037/atm.2018.09.59

Wuisman PIJM, Smit TH (2006) Bioresorbable polymers: heading for a new generation of spinalcages. Eur Spine J 15(2):133–148

Yeh C-H, Chen Y-W, Shie M-Y, Fang H-Y (2015) Poly (dopamine)-assisted immobilization of XuDuan on 3D printed poly (lactic acid) scaffolds to up-regulate osteogenic and angiogenicmarkers of bone marrow stem cells. Materials (Basel) 8:4299–4315

Yu H, VandeVord PJ, Mao L, Matthew HW, Wooley PH, Yang SY (2009) Improved tissue-engineered bone regeneration by endothelial cell mediated vascularization. Biomaterials30(4):508–517

Zein DWH, Tan KC, Teoh SH (Feb. 2002) Fused deposition modeling of novel scaffold architec-tures for tissue engineering applications. Biomaterials 23(4):1169–1185

Zhang Y (2017) Post-printing surface modification and functionalization of 3D-printed biomedicaldevice. Int J Bioprint 3:93–99

Zhang AP, Qu X, Soman P, Hribar K, Lee JW et al (2012) Rapid fabrication of complex 3Dextracellular microenvironments by dynamic optical projection stereolithography. Adv Mater24:4266–4270

3D Printing of Bioactive Devices for Clinical Medicine Applications 21

Zhang B et al (2018) 3D bioprinting: an emerging technology full of opportunities and challengesBio-Design and Manufacturing 3D bioprinting: an emerging technology full of opportunitiesand challenges. Bio Design Manuf 1:2–13

Zhou X, Zhu W, Nowicki M, Miao S, Cui H, Holmes B, Glazer RI, Zhang LG (2016) 3Dbioprinting a cell-laden bone matrix for breast cancer metastasis study. ACS Appl MaterInterfaces 8(44):30017–30026

22 A. W. McFarland JR et al.