3D printing in the research and development of medical devices

3D printing in the research and development of medical devices

12

Huan Zhou1 and Sarit B. Bhaduri2 1 School of Mechanical Engineering, Jiangsu University of Technology, Changzhou, P.R. China, 2 Department of Mechanical, Industrial and Manufacturing Engineering, The University of Toledo, Toledo, OH, United States

12.1

Introduction

The term “3D printing,” also referred to as additive manufacturing (AM), is a family of processes that produces 3D objects by adding selected materials together where necessary following digital 3D model guidance. This technology is highlighted with the ability to make one-off parts and create complex geometries efficiently and precisely with the aid of computers. With decades of development, 3D printing has pervaded into aspects of manufacturing, art, education, food, etc. It is not only a powerful tool to convert designs into real objects, but also is leading a revolution in how we design. Meanwhile, this revolution also advances the fast development of 3D printers and relevant materials to match the rapidly emerging applications. One rising market for 3D printing is medical devices—3D printing is ideal for quick and economical construction of patient-specific medical devices for lowvolume runs without design and cost restraints. The great ease in fabricating complex geometric structures in 3D printing allows the creation of engineered porous structures, tortuous internal channels, and internal support structures [1]. Until now, successful attempts using 3D printing in medicine have been validated from surgical planning tools to clinical implants. As 3D printing has made its way into the medical arena, it has opened up new opportunities and challenges in the creation of patient-specific products and services. Unfortunately its manufacturing advantages are not enough to promote its significance in the medical arena. First, the flexibility, maneuverability, and practicability of 3D printing process in medical applications are limited. Usually, 3D printers necessary for medical applications are specialized or industrial equipment that require unique materials, for example, which drives up production costs and creates a high-level technical demand for skilled operators and specific operational conditions, and the inconvenience of communicating at length between hospitals and factories during the production process delays the length of time between fabrication and application [2]. The solution to this issue is slowly evolving with the further development of 3D printing technologies and the communicating systems. Biomaterials in Translational Medicine. DOI: https://doi.org/10.1016/B978-0-12-813477-1.00012-8 © 2019 Elsevier Inc. All rights reserved.

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In addition, the wide application of 3D printing in medical devices is still controversial due to the fact that 3D printing is not 100% covered by the standards developed for medical devices validation and quality control. After years of appeals from industry and the medical community and continuous clinical trials in prosthetics, dental applications, and anatomical models, a breakthrough occurred in December 2017 when the Food and Drug Administration (FDA) issued a long-awaited draft guidance on 3D printed medical devices titled “Technical Considerations for Additive Manufactured Medical Devices,” to advance 3D printing innovation and application in health care. This draft includes information regarding both design and manufacturing considerations and device testing considerations. Although it is basic and not applicable to complex 3D printing processes, point-of-care devices, or bioprinting involving cells or human tissues, it is still great progress for 3D printing in medical devices with specifications on design, manufacturing, and testing. Indeed, it has changed the ecosystem of 3D printed medical devices. A few months after the FDA’s guide, the China Food and Drug Administration (CFDA) also released a draft guidance on the regulatory requirements for approval of 3D printed devices titled “Guidelines for the Technical Review of Custom Additive Manufacturing Medical Device Registration.” This guide mainly covers implantable devices for orthopedic and dental applications, the most common 3D printed product series in the medical device market. Encouraged by these documents and years of 3D printed medical devices launches, this chapter is devoted to the overview of 3D printing in medical devices in the past years.

12.2

Brief overview of 3D printing

The first 3D printing technology, known as stereolithography (SLA), was developed by Charles Hull in 1986, and was followed by numerous novel technologies evolved over the decades [3]. Customized functional products in 3D printing will be the mainstream of industry as predicted by Wohlers Associates, who has envisioned that about 50% of 3D printing will revolve around the manufacturing of commercial products in 2020 [4]. Currently, American Society for Testing Materials(ASTM) and ISO standards recognizes seven 3D printing technologies adapted for medical use to a certain extent: powder bed fusion, material extrusion, material jetting, binder jetting, sheet lamination, direct energy deposition, and vat photopolymerization [5]. Powder bed fusion (PBF) uses either a laser or electron beam to melt and fuse a bed of material powder layer by layer together (Fig. 12.1). Depending on the energy source applied, whether a vacuum environment is acquired, and the path to repeat spreading the powder material over previous layers, PBF can be further classified into direct metal laser sintering, electron beam melting, selective laser melting, and selective laser sintering [6]. Material extrusion is mainly referred to as fuse deposition modeling or fused filament fabrication in medical device fabrication. In the process material can be extruded through a horizontally moving nozzle where it is heated and is then

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Figure 12.1 Typical schematic of PBF, in which powders are fused layer by layer with new powders continuously delivered from powder feed bed. PBF, Powder bed fusion

deposited layer by layer to a vertically moving platform to solidify into a 3D object (Fig. 12.2). Not only thermoplastic materials but also paste-like materials, such as bioceramics, can be fabricated into 3D objects via this technology [7,8]. Material jetting produces 3D objects of the highest dimensional accuracy with a very smooth surface finish, used for both visual prototypes and tools manufacturing. In the layer by layer printing process, wax-like melted materials are jetted through inkjet print heads, which then cure and solidify (Fig. 12.3). Material jetting allows for different materials to be printed in the same object, making it one of the only types of 3D printing technology to offer objects to be made from multiple materials and in full color. Besides, it should be noted that support material may be required and jetted, which is usually built from a different material and removed in postprocessing. Indeed, technologies such as photopolymer jetting or polyjetting, drop on demand (DoD), thermojet printing, inkjet printing, and multijet modeling/printing all belong to the family of material jetting [9]. Binder jetting, also referred to as binder jet printing (BJP), is a 3D printing method in which powder is deposited layer by layer and selectively joined in each layer with a liquid binder [10]. Different from material jetting, the binder jetting printed object is self-supported within the removable powder bed (Fig. 12.4). However, printed objects have limited mechanical characteristics, requiring further infiltration, sintering, or casting to strengthen if necessary [11].

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Figure 12.2 Typical schematic of FDM, in which material is fed from a coil through a moving, heated head; molten material is drawn out of the nozzle and is deposited on the growing 3D object. FDA, fuse deposition modeling

Figure 12.3 Typical schematic of material jetting, in which printer jets both build and support material on a platform using either a continuous or droplet approach.

In sheet lamination layers of paper, plastic, or metal laminates are successively bonded together using ultrasonic welding or adhesive, followed by modeling using a blade or laser cutter (Fig. 12.5). Depending on the materials and binding method used, sheet lamination can be subdivided into ultrasonic AM focusing on metals and laminated object manufacturing based on adhesive and paper [12]. The process

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Figure 12.4 Typical schematic of binder jetting, in which powders are adhered layer by layer with liquid binder.

Figure 12.5 Typical schematic of sheet lamination, in which the feeding roller heats in order to melt the adhesive to bind the materials together, with a laser used to draw the geometry of the object.

is highlighted for making display models rapidly and economically, but is not recommended for fabricating functional or structural objects. In direct energy deposition a moving heat source with high-intensity melts and fuses metal powders/wire together to print parts (Fig. 12.6) [13]. Although this basic approach can work for polymers, ceramics, and metal matrix composites, it is predominantly used for metal powders; thus, this technology is often referred to as “metal deposition” technology [14]. Briefly, a typical direct energy deposition machine consists of a nozzle mounted on a multiaxis arm to deposit melted material in multiple directions onto the specified surface, where it solidifies.

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Figure 12.6 Typical schematic of direct energy deposition, in which material is deposited from the nozzle layer by layer onto existing surfaces of the object and melted using a laser, electron beam, or plasma arc upon deposition.

Figure 12.7 In photopolymerization, light cures photopolymers layer by layer with the platform moving downwards and additional layers fabricated on top of the previous one.

Vat polymerization is a 3D printing technology based on photopolymerization, which is the irradiation process of exposing radiation-curable resins, or photopolymers to ultraviolet (UV) light/visible light to turn liquids into solids [15]. The 3D printer projects the input 3D digital design with light onto a vat of liquid polymers layer by layer with continuing draining and light irradiation (Fig. 12.7).

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12.3

275

Regulation guidance of 3D printing in medical devices

Briefly, no matter what 3D printing technology is applied, the major principles of 3D printing include 3D digital modeling and printing conduction accordingly. In the guide document of the FDA the overall process is extended to six sections with consideration of the strict regulation of medical devices production (Fig. 12.8) [1]. The first step is the design process, which can include a standard design with discrete prespecified sizes and models, or a patient-matched device designed using one or more anatomic references, or by using the full anatomic features from patient imaging. It is highly suggested to compare the desired feature sizes of the final finished device to the minimum possible feature size of 3D printing technology applied and the manufacturing tolerances of the individual machine. Meanwhile, for patient-matched device design, specific attentions should be paid to the accuracy of the imaged patient’s anatomy, identification of the iteration of the design, maintenance of data integrity throughout file conversions, and protection of personally identifiable information and protected health information. Once the device design is converted to a digital file, the software workflow phase begins to prepare to build a file for printing with the printing parameters optimized. Verification of the critical attributes and performance criteria of the final products as part of the software workflow validation as well as of the possibility to retrieve design information when necessary is recommended. Concurrently, material controls are established for materials used in the printing of the medical devices. To ensure the consistency of the raw material and the final product, information regarding each starting material used, as well as any processing aids, additives, and cross-linkers used, should be documented following specific regulations. In the building step, careful controls of build volume placement, support materials, layer thickness, build path, machine parameters, and environmental conditions should be conducted and documented. Postprocessing of the built device or component (e.g., cleaning, annealing, postprinting machining, sterilization, packing, and labeling) takes place after printing. All postprocessing steps should be documented and include a discussion of the effects of postprocessing on the materials used and the final device; it is important to make sure the postprocessing maintains device performance and residual manufacturing materials are sufficiently cleaned to a level that does not adversely

Figure 12.8 Flow chart of 3D printing.

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affect the device’s quality. Followed by postprocessing, the final finished device is delivered for testing and characterizations, which include but are not limited to feature geometry, overall dimensions, material characteristics, mechanical properties, biocompatibility, etc.

12.4

FDA approved applications of 3D printed medical devices

As shown by some FDA approved 3D printed medical devices in the last few years (Table 12.1), 3D printing has been mainly applied to medical device related fields of surgical planning, surgical guidance, and custom device manufacturing. The majority of 3D printed devices received FDA clearance via 510(k). Increasingly, 3D printed models are also used for educating physicians, trainees, and patients, but this application is out of the translation scope of the current work. Meanwhile, although 3D bioprinting of artificial organs is significantly popular in research, it is still far away from achieving FDA clearance to allow market entry [16,17]. Surgical planning is a process to integrate imaging information and the surgeon’s experience together to determine the optimum therapeutic options with reduced risk and improved outcomes. The printed models provide surgeons with an opportunity to fully understand the complex anatomy of the human body before surgery. In the process of model creation, first a stack of either computed tomography (CT) and magnetic resonance imaging images is acquired and put together to construct an anatomy in the computer. After that, it is processed to smooth out noise and improve quality using software. Further, the model that is made can again be overlaid onto the images that were initially acquired to verify that the built model corresponds to the patient’s anatomy before printing [18,19]. Precisely printed anatomical models have been proved to help surgeons make better informed decisions and plans in numerous cases. According to some systematic reviews of surgery, it is globally recognized that printed models can provide a better impression of the anatomic characteristics and then facilitate the preoperative planning by visualization of potential difficulties and/or anatomic variations [20,21]. For example, in neurosurgery a realistic 3D model reflecting the relationship between a lesion and normal brain structures can be helpful in determining the safest surgical corridor and can also be useful for the neurosurgeon to rehearse challenging cases; similarly, complex spinal deformities can be better appreciated with a 3D model [22]. In orthognathic surgery, 3D printed models have significantly improved preoperative assessment, orthognathic surgical planning, as well as intraoperative orientation and prebending of miniplates [23]. In the treatment of primary cardiac tumors, 3D printed models can be used to evaluate the best surgical strategy (total tumor resection, partial tumor resection, or heart transplant) for the individual patient by showing the exact position and infiltration of the cardiac tumor into cardiac tissue in patients [24]. 3D printed auricular models of the scapha, triangular fossa, and cymba were applied in autogenous auricular reconstruction to reduce the

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A list of medical device related products that have received FDA clearance in the last few years

Table 12.1

No.

Establishment

1 2 3

4WEB medical Joimax K2M

4

ChoiceSpine

5

ChoiceSpine

6 7 8

EIT Medicrea Camber Spine Technologies Renovis Surgical Technologies

9

10 11

Centinel Spine Stryker

12 13

Zimmer Biomet Additive Orthopedics

14 15

SI-BONE Materialise

16

Mighty oak medical

17 18 19

Zimmer biomet Onkos surgical BioArchitects

20

Oxford performance materials MedShape Oventus medical Candid Align technology DynaFlex

21 22 23 24 25

Product

Application

Lateral spine truss system EndoLIF on-cage CASCADIA lateral interbody system HAWKEYE vertebral body replacement system Tiger shark porous interbody system Cellular titanium cervical cage IB3D TLIF-banana SPIRA open matrix ALIF

Spine Spine Spine

Posterior lumbar tesera porous Titanium interbody fusion systems FLX devices Tritanium TL curved posterior lumbar cage Unite3D bridge fixation system 3D printed bone segments, bunion correction system, locking lattice plating system, osteotomy wedge system iFuse-3D implant 3D printed patient-specific radius and ulna osteotomy guides FIREFLY pedicle screw navigation guides Unite3D bridge fixation system ELEOS limb salvage system Titanium cranial/craniofacial implant OsteoFab patient-specific facial device FastForward bone tether plate O2Vent device Teeth aligners (candid) Teeth Aligners (invisalign) Teeth aligners (EZ-align)

Spine

Spine Spine Spine Spine Spine

Spine Spine Foot and ankle joint Fractures, osteotomies and arthrodesis of small bones Sacroiliac joint Surgical guides

Surgical guides Ankle and foot Oncology Cranium Cranium Hallux valgus Sleep apnea Orthodontics Orthodontics Orthodontics (Continued)

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Table 12.1 No.

(Continued)

Establishment

26

EnvisonTEC

27

Taulman3D

28 29 30 31

Lantos technologies 3D Systems Materialise Phonak

Product E-denture, E-guard, E-IDB, E-shell, E-guide, E-dent (materials for 3D printing) Guideline (material for 3D printing) 3D ear scanning system VSP system Mimics inPrint Virto B-titanium hearing aids

Application Dentistry

Surgical tools and implants Ear canal Software Software Hearing aid

degree of estimation required by surgeons [25]. In the cases of orthopedic trauma such as acetabular fractures and clavicular shaft fractures, patient-specific acetabular models improved understanding of complex acetabular anatomy and fracture pattern to plan the optimal positioning of a reduction clamp and the trajectory of screws [26]. Besides, 3D printed liver models can help facilitate complicated surgery planning in liver diseases treatment and living-donor liver transplantation [27]. Unfortunately, the accuracy of the 3D printed anatomical models, the time required to process 3D printing, as well as the cost still limit their widespread use in hospitals [20]. On the other hand, in 2018 Materialise became the first company in the world to receive FDA clearance for the software designed for 3D printing of anatomical models for diagnostic use, which is classified as a class II medical device according to FDA regulation [28]. In addition to its use in the manufacturing of anatomic models, 3D printing can also be used for producing surgical guides showing the variance and complexity of patients. Surgical guides in the field of dentistry were already established more than 10 years ago for oral surgery applications. By transferring radiographic digital information to surgical templates, dental implants can be positioned more precisely which can play a major role in difficult anatomical situations and allow a better prosthetic fit consequently [29]. Chen et al. prepared a novel bone-tooth-combinedsupported surgical guide template using 3D printing to improve the fit accuracy and reliability of an implant [30]. Bae et al. conducted miniscrews insertion in cadaver maxillae using patient-specific surgical guides, reporting no root damage from miniscrew placement, and 84% of the miniscrews were placed without contacting adjacent anatomic structures as compared to the control group of 50% of miniscrews placed between the roots [31]. Recently, 3D printed guides have also been successfully used in the autotransplantation of teeth and guided osteotomy and root resection [32,33]. It is also noted that most 3D printer resins used in dentistry today are exempt from the FDA 510(k) process, although the FDA requires that the source specifically list them as exempt before marketing them [34]. Apart from dentistry, 3D printed surgical guides were also used in neurosurgery, spinal surgery, orthopedic surgery and maxillofacial surgery to facilitate the

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orientation and execution of drillings, as well as to conduct an accurate implant placement [35]. Sieira et al. conducted mandibular reconstruction of 20 patients using 3D printed precontoured titanium plate for surgical guides [36]. The preoperative planning using 3D printed surgical guides can increase the accuracy of microvascular mandibular reconstruction and reduce the operating time for reconstruction. Similar results were also seen in the report of Hanasono et al. [37]. In the clinical cases of adult single developmental dysplasia of hip, Zhang et al. used patient customized 3D printed surgical guides to facilitate accurate placement of acetabular components in dysplasia of acetabulum, exhibiting significantly smaller differences from the predetermined angles than those in the control group after 1 year follow-up [38]. Boonen compared blood loss, operation time, and alignment of 40 total knee arthroplasty performed using a 3D printed templating alignment technique with values from a matched control group of patients who were operated on by conventional intramedullary alignment technique [39]. The cases that applied 3D printed surgical guides showed improved accuracy of alignment and a small reduction in blood loss and operating time. Liu et al. developed a method of pedicle screw placement in spinal deformity correction surgeries with multilevel 3D printing drill guides, and reported a reduction in the incidence of cortex perforation in severe and rigid scoliosis in comparison to free-hand surgery [40]. Similarly, Michael et al. designed 3D printed surgical guides differently for thoracic and lumbar segments according to the individual anatomy to achieve an optimal coupling to the surface of the patient’s spine, to maximize the stability of the device itself, and to increase user friendliness for the complete screw positioning process [41]. In addition, Ciocca et al. designed a 3D printed surgical guide system to control the insertion of craniofacial implants for nasal prosthesis retention [42]. The whole system was composed of a helmet to support the others, a starting guide to mark the skin before flap elevation, and a surgical guide for bone drilling. Though widely attempted in surgeries, the outcomes of application of 3D printed surgical guides are not 100% satisfactory. In a statistical analysis of 137 clinical cases, researchers concluded that 3D printed surgical guides reduced operation room time and increased cost in 46% and 33% of the studies, respectively; 76 % of the studies mentioned that the printed part had good accuracy, and 72% mentioned improved medical outcomes [35]. In the market, currently Materialise has been granted FDA clearance for 3D printed patient-specific surgical guides for ulna and radius pediatric osteotomies, to help orthopedic surgeons plan and execute complex cases for children as young as 7 years old [43]. Surgeons can combine the use of 3D printed guides with 3D preoperative planning, and increase their confidence in the outcome before and during these difficult surgical cases. The other vendor Mighty Oak Medical launched its FIREFLY Pedicle Screw Navigation Guides to mechanically constrain the drill and tap to follow the preselected trajectories, and to limit intraoperative radiation exposure [44]. Custom implant is one of the most promising applications of 3D printing in medical devices, particularly highlighted with the advantages of producing implants in complex clinical cases [45 47]. For hip or knee surgery, a series of general

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implants can be created to service the needs of a wide range of patients. In some applications treating a patient’s complex anatomy the use of general implants however is prevented and custom implants are required to achieve satisfactory results. Additionally, some of the commonly used materials include metals, bioceramics, synthetic and natural polymers, exhibiting specific mechanical properties, processing methods, chemical properties, and cell material interactions. For example, a 3D printed customized axial vertebral body fabricated according to a computer model using titanium alloy powder was implanted in the upper cervical spine of a patient after a complex C2 Ewing sarcoma resection [48]. The related CT studies revealed evidence of implant osseointegration and no subsidence or displacement of the construct. In the 3D fabrication of cranial implants, polyetheretherketone (PEEK) can be applied as raw materials for both clinical and commercial attempts [49]. Bernd et al. conducted a retrospective study comparing patients who underwent reconstruction with titanium and PEEK printed custom implants with control subjects who had their stored bone grafts reimplanted [50]. The results showed that for the tested group the complication rate, the rate of necessary reoperation, and hospital stay were significantly reduced. Saijo et al. fabricated custom-made artificial bones from α-tricalcium phosphate powder and implanted them in 10 patients with maxillofacial deformities, reporting reduction of operation time and partial union between the artificial bones and host bone tissues as expected [51]. More cases of custom implant and materials can be found in Table 12.2. Among 3D printed medical devices in the market, a custom implant for orthopedic application is the mainstream, as the 3D printing technology and implant macro/micro design continue to evolve. According to SmarTech Publishing the production of all 3D printed orthopedic and medical implants is estimated to grow by 29% compound annual growth rate (CAGR) through 2026, with the fastest growing segments being components of spinal fusion devices, knee reconstruction systems, and nonload-bearing extremity fracture devices greatly exceeding total average growth. From 2016 to 2018 numerous FDA approved 3D printed orthopedic implants entered the market. Apart from their patient-specific significance, these products have adopted distinguishing characteristics including design and materials to increase their advantages over others. For example, the SPIRA Open Matrix ALIF device manufactured by Camber Spine Technologies is a unique, interbody fusion implant consisting of spiral support arches and a deliberately designed roughened surface [65]. Here the spiral support arches can decrease subsidence by load sharing over the entire endplate, while also maximizing bone graft capacity; and the designed surface is estimated to facilitate bone growth through an optimized pore diameter, strut thickness, and trabecular pattern. Stryker released 3D printed Tritanium TL Curved Posterior Lumbar Cage for patients suffering from degenerative disc disease, grade I spondylolisthesis, and degenerative scoliosis to help with lumbar spinal fixation [66]: the term “Tritanium” refers to a new and highly porous titanium material used in Stryker’s orthopedic implants designed for bone in-growth, and biological fixation. Meanwhile the 3D printed cage features open central graft windows and lateral windows to help reduce stiffness of the cage, aid in visualization of fusion, and allow for bone graft containment. Shaped for

Table 12.2

Custom implant for clinical trails

No.

Materials

Technology

Application summary

References

1 2

Ti6Al4V PMMA

Direct metal laser sintering Fused deposition modeling

[52] [53]

3 4

PMMA Hydroxyapatite

5

Titanium alloy

Selective laser sintering Photopolymerization of a mixture of resin and powder HA followed by sintering to remove resin N/A

Cranial implant Orbital implant that aids in volume augmentation as well as recenteration of the migrated orbital implant Cranial implant Cranial implant

[56]

6

Ti6Al4V

Electron beam melting

7 8

N/A Fused deposition modeling

9 10 11

Titanium alloy Polyhedral oligomeric silsesquioxane poly (carbonate-urea) urethane Ti6Al4V PEEK Polycaprolactone

Plate as a fixation system in maxillary movement Implant for reconstruction of orbital wall defects Cage for complex acetabular bone defects Lumbar cage

[60] [61] [62]

12

Silicone

Cervical cage Vertebral body replacement (VBR) cage Airway splint for infant with tracheobronchomalacia Airway stent

13

Ti6Al4V

Bone tether plate for correcting hallux valgus (bunion) deformities

[64]

Direct metal laser sintering N/A Laser-based 3D printing Indirect 3D printing (i.e., generate a digital airway related mold for casting) Selective laser melting

[54] [55]

[57] [58] [59]

[63]

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steerability, its multidirectional teeth are designed for multidirectional fixation as the cage can be steered and rotated to the surgeon’s desired placement. They are also designed to maximize surface area for endplate contact with the implant. On the other hand, Emerging Implant Technologies GmbH (EIT) introduced its Cellular Titanium Cervical Cage highlighted by its anatomical design to assist the surgical and biomechanical challenges of cervical multilevel fusion by being adapted to maximize vertebral endplate contact and sagittal balance restoration, and its postprinting etching procedures as well as porosity design to favor fusion [67]. Instead of an implant, the prosthetic limb is another promising field of 3D printing. Because prosthetics are such personal items, each one has to be custom-made or fit to the needs of the wearer. With the advantage of manufacturing convenience and cost-effectiveness, 3D printing enables patients to have prosthetics mimcking their limbs, making for a more natural fitting and appearance.

12.5

Bioprinting

Tissue engineering has been considered as a promising option for damaged tissues/ organs, in which scaffolds have found their place as templates for cell interaction, providing physical support to the afresh developed tissue. Also, they can function as carriers to incorporate essential growth factors to control and enhance tissue growth [68]. In this field, 3D printing (bioprinting) has been significantly studied recently with the purpose of depositing selected biomaterials-encapsulating cells (bio-ink) at the micrometer scale to form subtle structures comparable to tissue. Compared to traditional tissue engineering methods, the technologies utilized by bioprinting systems allow for greater precision in the spatial relationship between the individual elements of the desired tissue [69]. It is recognized that many concepts developed in the conventional tissue engineering studies and cell-free implants, such as the architecture, biomaterials phase combination, surface modification strategy, and cell induction, have already been adopted in the work of bioprinting to stimulate improved tissue regeneration. Indeed, there are numerous articles reviewing the progress of bioprinting every year (for more detail see Refs. [5,68 71]). With the ability to further mimic the cellular and extracellular structure and components of tissues and organs via the deposition of biomaterials and cells, bioprinting possesses significant potential in regenerative medicine theoretically. In comparison to regular 3D printing, bioprinting is more complicated and challenging. Although the architecture design of the target object is derived from the imaging data similarly, the followed processing is significantly different. The processing stage includes bio-ink preparation, clinical cell sorters, cell propagation bioreactors, and cell differentiators to construct the desired biological structures [17]. In particularly, the bio-ink must possess satisfactory biocompatibility allowing cell adhesion and proliferation, have proper viscosity, and exhibit homogenous and shear thinning properties in order to be dispensed from the printer nozzle without causing clotting, as well as providing sufficient strength and stiffness to maintain

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the integrity of the printed object. Unfortunately, most publications are repeatedly using several classical biomaterials for bioprinting without disruptive innovation [72]. Besides, with the advances of 3D printing technology, some engineering limitations, including printing resolution, cost, scale, and speed, can be properly solved via the application of scalable automated robotic technology and by building an integrated biofabrication line with emerging facilities including printer, cell sorter, bioreactor etc. [73]. Another issue is that bioprinted constructs for tissue engineering, being ultimately implanted in body, need also to support vascularization in vivo to provide the cells with sufficient nutrition, growth factors, oxygen, and to remove waste [68]. Without a functional circulatory system, tissue constructs are limited to diffusion for nutrition, which in itself is limited to a distance of just a few hundred microns [74]. Strategies such as the guided infiltration of host microvessels into the implanted construct, integration of autologous vascular grafts, or directly bioprinting vascular structures have been attempted at the laboratory level only, and are still currently far away from commercialization [75 77]. The postprocessing of bioprinting comprises the necessary procedures to transform the printed construct into a functional tissue engineered organ suitable for surgical implantations with the applications of perfusion bioreactors, cell encapsulators, and a set of biomonitoring systems [73]. Although some facilities are commercialized, there is a lack of standards in the regulation of these stages for quality control.

12.6

4D printing

The term 4D printing is defined as 3D printing of objects which can, immediately after printing, self-transform in form or function when exposed to a predetermined stimulus, including osmotic pressure, heat, current, UV light, or other energy sources [78]. For the 4D printed object, the configuration or function before and

Figure 12.9 The differences between 3D printing and 4D printing.

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after the stimulation should be structurally or functionally stable. In the printing design, mathematical modeling is always required for programing the smart materials in the structure (Fig. 12.9) [79]. Actually, the concept of using smart materials in a medical device is not completely new. In invasive medical devices, smart materials with shape memory properties have been widely attempted. For example, a shape memory stent can be deformed into its temporary shape, inserted in the body, and then self-expanded into its permanent shape after exposure to body temperature [80,81]. In contrast, if a shape memory 3D stent is fabricated based on anatomical data, it can be classified as a 4D printed object [82]. Apart from shape memory effect, 3D printed objects that exhibit a designed shape that changes under tissue growth and resorption conditions over time can also be claimed as a 4D printed one [83].

12.7

Conclusions

In summary, this chapter provides comprehensive information regarding 3D printing and its application in medical devices as well as FDA regulatory points. It can be seen that 3D printing has gained great success in the field of anatomic models, surgical guides, custom implants, and prosthetic limbs with impressive clinical outcomes. The global 3D printing medical devices market is projected to reach US $1.88 billion by 2022 from US$0.84 billion in 2017, at a CAGR of 17.5% [84]. Factors such as technological advancements, increasing public-private funding, easy development of customized medical products, and growing applications in the health care industry are expected to drive the growth of the 3D printing medical devices market. Besides, bioprinting and 4D printing are still at a stage of infancy in the laboratory, although they are exhibiting great application potential and continuing to generate research interest. To enhance the translation of these 3D printed prototypes from laboratory to real products, external efforts from engineers, material scientists, biologists, doctors, entrepreneurs, and regulatory supervisors are highly desired.

References [1] FDA, Technical considerations for additive manufactured medical devices, guidance for industry and food and drug Administration staff. 2017. [2] Liu A, Xue G-h, Sun M, Shao H-f, Ma C-y, Gao Q, et al. 3D printing surgical implants at the clinic: a experimental study on anterior cruciate ligament reconstruction. Sci Rep 2016;6 21704-21704. [3] C.W. Hull, Apparatus for production of three-dimensional objects by stereolithography, U.S. Patent 4575330. 1986. [4] Berman B. 3-D printing: the new industrial revolution. Bus Horiz 2012;55(2):155 62. [5] Nagarajan N, Dupret-Bories A, Karabulut E, Zorlutuna P, Vrana NE. Enabling personalized implant and controllable biosystem development through 3D printing. Biotechnol Adv 2018;36(2):521 33.

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