Printing@Clinic: From Medical Models to Organ Implants - ACS

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Printing@clinic: from medical models to organ implants Haiming Zhao, Feifei Yang, Jianzhong Fu, Qing Gao, An Liu, Miao Sun, and Yong He ACS Biomater. Sci. Eng., Just Accepted Manuscript • DOI: 10.1021/ acsbiomaterials.7b00542 • Publication Date (Web): 27 Sep 2017 Downloaded from http://pubs.acs.org on September 28, 2017

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ACS Biomaterials Science & Engineering

Printing@clinic: from medical models to organ implants HaiMing Zhao1,2, FeiFei Yang1,2, JianZhong Fu1,2*, Qing Gao1,2, An Liu4 , Miao Sun5, Yong He1,2,3* ( Key Laboratory of Fluid Power and Mechatronic Systems, School of Mechanical Engineering, Zhejiang University, Hangzhou 310027, China 2Key Laboratory of 3D Printing Process and Equipment of Zhejiang Province , School of Mechanical Engineering, Zhejiang University, Hangzhou 310027, China 3State Key Laboratory for Manufacturing Systems Engineering, Xi’an Jiaotong University, 710054, Xi’an China 4Department of Vascular Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China 5Department of Oral and Maxillofacial Surgery, The Affiliated Stomatology Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China *Correspondence to: Yong He; e-mail: [email protected], JianZhong Fu; e-mail: [email protected])

1State

Abstract: Since 1989, three-dimensional (3D) printing has developed rapidly in biomedical engineering because it is individually customizable. By printing medical products at clinics, this powerful tool can be used by doctors, which will enhance the response to surgery and increase the creative freedom of surgeons. In this article, we reviewed the progress of 3D printing in biomedicine with particular emphasis on the types of 3D printing methods that are most suitable for the clinical application, and proposed the concept of Printing@clinic. The four levels of Printing@clinic are discussed, from surgical implants to direct printing during surgery. Three major applications of Printing@clinic, which could be rapidly implemented in the clinical setting, are prosthesis fabrication to assist with surgeries, printing 3D implantable scaffolds, and bioprinting for tissue repair. We believe that Printing@clinic will be an attractive service in the decades to come.

Keywords: 3D printing; Clinic; Surgical implants; Directly printing; Prosthesis; Scaffold; Tissue repair; 1 Introduction In the last century, repair of human tissue defects was based on implantation of parallel/serial prostheses or autograft tissue transplants. For example, titanium alloy prostheses are used to repair bone defects, and healthy skin grafts are transplanted to repair skin wounds. In cosmetic surgery, the demand for prostheses and implants increases yearly. However, with tissue repair, surgical time is often too lengthy because companies that produce prosthetics can take too much time producing custom prostheses. As a result, patients will endure pain and discomfort while waiting prostheses, which may also exceed the optimal time for repair. In traditional surgeries, surgical risk is increased since before surgeries; doctors must evaluate and simulate the surgical process without the help of direct feedback.1 Three-dimensional (3D) printing technology currently offers new approaches to solve these medical and surgical issues. 3D printing evolved from a rapid prototyping technique in the late 1980’s,2-3 which has now developed into the present 3D printing technique. This technique creates actual objects using a computer-aided layered manufacturing technique, which generates sliced data of the model. Typical 3D printing technology includes, but is not limited to stereolithography (SLA), inkjet-based 3D printing (3DP), fused deposition modeling (FDM), laminated object manufacturing (LOM), and selective laser sintering (SLS). To date, due to its low cost, FDM4 technology has been used by most 3D printers for private and commercial use. ReaRap 3D printers were the first of a series of low-cost 3D printers, which also started an open-sources 3D printer revolution. In addition, Makerbot’s 3D printers (Stratasys, America), Ultimaker’s 3D printers (Ultimaker, Netherlands) and many other desktop 3D printers (D3DP) have moved 3D printing technology from laboratories, to companies, to hospitals, and even into our homes, making it a popular technology. Professor Thomas Boland of Clemson university introduced and patented 3D printing of cells by inkjet printing in 2003,5 an achievement that came about quickly. There are also many newer 3D printing applications in biotechnology launched, such as 3D printed bionic ears,6 silicone prosthesi,7 organ and tissue scaffolds,8 knee meniscus,9 and 3D printed skins.10 Novel biocompatible and implantable materials combined with other growth factors and cell sources will certainly emerge to meet the increasing demand for medical innovations.11 Direct fabricating at a clinic (Fab@clinic) can help doctors and specialists rapidly understand new concepts, which will set off a positive chain of innovation, application, and commercialization in clinical practice.12 Fab@clinic features rapid response and customization, which is an excellent method to appreciate the benefits of 3D printing. With this technology, prosthetics and tools can be custom-made for hospitals, which is a suitable method for “printing at the clinic” (Printing@clinic). ACS Paragon Plus Environment


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Printing@clinic not only reduces fabrication time and cost, but also improves the success rate of retreatment; this technology represents a new method of precision medicine.13 In this review, different printing methods used in clinics are compared according to, material performance, cost of application, and size, of the products. Choosing the appropriate method to print scaffolds or prostheses for the doctors is a challenge faced by many 3D printing methods. Hence, this article presents an exhaustive review of the application of Printing@clinic and provides the readers with the latest advances, and future perspectives and directions, of 3D printing. The primary objective of this paper is: (1) to review the development of 3D printed implant and prosthesis fabrication; (2) to help researchers, especially doctors to better use 3D printing in the clinics; (3) to present future trends about Printing@clinic.

2 3D printing technology and 3D printing technology in biomedicine 2.1 A brief review of 3D printing technology 3D printing technology has made significant advances since Charles Hull created stereo lithography in 1984. It is a printing process that creates a solid 3D object from a digital model, and allows designers to evaluate products rapidly before subsequent manufacturing and investment. 3D printing technology is developed from inkjet printing. The first process involves discretizing digital models into a series of layers and then adds each new layer on top of the prior layer in line with the sliced pattern.14 Accordingly, the obtained 3D object is composed of these layers. Compared with the traditional two-dimensional manufacturing techniques, 3D printing is superior in creating models with complex geometries and fine structures. A brief description of the different 3D printing methods is presented in Fig. 1. 3D printing is the generic term for many addictive manufacturing methods, the main differences among these processes are the printing materials they use, including normal materials and biomaterials, which are listed in Table. 1. 3D printing technology is making a big impact in a variety of industries, with its low cost, high accuracy, and personalized customization. It has been widely used in industrial modelling design, machine manufacturing, vehicle manufacturing, biomedical sciences designs and manufacturing, archaeology, the food industry, and the building industry. On July 24, 2013, the United States National Aeronautics and Space Administration (NASA) space agency announced hot-fire test results from its two 3-Dprinted subscale injectors. These injectors withstood heat of 6,000 degrees Fahrenheit without melting. And, while traditional injectors typically take six months to make at a cost of $10,000, the NASA printed injectors only needed three weeks to manufacture and less than $5,000.15 This technology could have as profound an impact on the world similar to the arrival of big factories

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Type

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Technologies

Materials

Accuracy

Fused deposition modeling (FDM)

Thermoplastics, eutectic metal, edible materials, Rubbers, modeling clay, hydrogels Thermoplastics, eutectic metal, edible materials, Rubbers, modeling clay, hydrogels Ceramic materials, metal alloy, cermet, ceramic matrix composite, hydrogels

Medium

Stereolithography (SLA)

Photopolymer, novel synthetic polymer (PEGDMA, PPF-DEF, GelMA, etc)

High

Digital Light Processing (DLP)

Photopolymer, novel synthetic polymer (PEGDMA, PPF-DEF, GelMA, etc)

High

Powder bed and inkjet head 3D printing (3DP)

Almost any metal alloy, powdered polymers, plaster, cytocompatible ploymers

Low

Electron-beam melting (EBM)

Almost any metal alloy including titanium alloys

High

Selective laser melting (SLM)

Titanium alloys, cobalt chrome alloys, stainless steel, aluminum

High

Selective heat sintering (SHS)

Thermoplastic powder

Medium

Selective laser sintering (SLS)

Thermoplastics, metal powders, ceramic powders

High

Direct metal laser sintering (DMLS)

Almost any metal alloy

High

Inkjet

Inkjet printing

Almost any liquid materials, waxes, ceramics, cell suspension

High

Laminated

Laminated object manufacturing (LOM)

Paper, metal foil, plastic film

Medium

Powder Fed

Directed Energy Deposition (DED)


High

Wire

Electron beam freeform fabrication


High

Extrusion

Fused Filament Fabrication (FFF) Direct Ink Writing (DIW)

Light polymerized

Powder Bed

Medium Medium

Table 1. The different materials used in each 3D printing process

2.2 3D printing technology in biomedicine 3D printing technology has realized significant development and broad prospects in the biomedical industry since Professor John Hunt created a 3D printed bladder using real cells in 1999.16 With the rapid evolution of 3D printing, enormous progress has been make for applications in biomedicine. As evident, the rate of 3D printing articles published grew from 11.35% in 2006 to 14.93% in 2015, as shown in Fig. 2. In particular, it exhibited a dramatic development during the period of 2009-2011, as indicated by the elevated publication rate. Moreover, the growth in the 3D desktop printer market gave rise to extensive biomedical research; medical applications may include surgical planning, prostheses, implanted structures, medical education, and other applications.17


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Figure.2. Number of publications on 3D printing and 3D printing in biomedicine (“3D bio-printing” or “tissue scaffold 3D printing” or “cell 3D printing”) in the last ten years according to ISI Web of Science (Data obtained in May 2016, Rmeans the rate of the publications about 3D printing to the publications about 3D printing in medicine).



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Figure.3. Key developments in 3D printing and 3D printing in biomedicine.

Medical applications for 3D printing are rapidly expanding and are expected to revolutionize the healthcare industry.18 In Fig. 3, we present some key developments in 3D printing in biomedicine. For the past 35 years, an increasing number of 3D printing methods and applications in the life sciences have been introduced. In our opinion, the history of the development of 3D printing in biology and medicine can be divided into four progressive stages, as shown in Fig.4. The first stage involves printing 3D medical objects and medical devices in vitro, and the materials used have no biocompatibility requirements. The second stage involves printing good biocompatible implants using non-biodegradable materials for permanently in vivo use, such as in the fields of orthotics, arthroplasty and auxiliary supporting. The third stage involves printing degradable replacement implants using materials with good biocompatibility that can promote tissue regeneration, in vivo. Finally, the fourth stage involves printing custom tissues or organs using cells, proteins, and extracellular matrix as materials. ACS Paragon Plus Environment

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Figure.4.The four levels of 3D printing and the developmental history in biomedicine.

Although it is still too early to print an organ for direct implant, to satisfy the numerous biomedical demands, the first three stages of 3D printing have already been successfully applied in various practical applications. One important success is in the greatly improved surgical success rates. Since the use of both cadavers and the surgical training facilities are increasingly cost prohibitive.19-20 3D-printed prosthesis provides a new cost-effective approach to solve this problem.21-22 When doctors ACS Paragon Plus Environment


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use 3D printing technology during planning and preparation, they can perform surgery with high proficiency and with improved success rates. Also, 3D bioprinting is being investigated as a potential solution for the global shortage of donor organs.23 In 2014, The United Network for Organ Sharing (UNOS) reported that in the United States of America, one patient dies every 1.5 hours while waiting for a suitable organ, and over 8 million surgical procedures to repair tissue are performed every year. Accordingly, now is an appropriate time to promote 3D printing research for medical application. Instead of having to go through specialized companies, it is more efficient to make prosthetics and print implants directly on the surgical table. Artificial organs are often produced with the recipient's cells before transplantation to avoid severe immune rejection. To date, most 3D bioprinting studies have achieved initial success. And, as such, this exciting and interesting technology can radically change future health care and revolutionize modern surgery.24-25

3 Prosthesis fabricated for surgical assist Printing@Clinic aims to create surgical training aids based on computed tomography (CT) and magnetic resonance imaging (MRI) data for surgery education and planning, and for in vitro medical devices creation. Preoperative 3D printing modelling enables a better understanding of anatomy and pathologic changes and can assist in planning surgical procedure.2630 Human organ models used only for teaching are expensive, involve multi-step processes and are time-consuming. The emergence of 3D printing technology makes individualized fabrication of organ replicas. Accordingly, doctors can instantly make prostheses for didactic purposes.31 The number of surgical patients is ever increasing due to the advancements in medicine, in surgical techniques, and most importantly, in cancer survival rates.32 Surgeries carry a heightened risk for uncertain consequences. A comprehensive understanding of patient condition and application of correct surgical knowledge is needed.33 Computer-aided simulations of the operations do not reflect the surgical approach; however, 3D printing can solve this problem, as reported by Zheng et al.34 3D printing of models for surgical aids is often successful and is now more affordable and widely accessible. A 3D model of a bone reduction clamp for finger fractures has been manufactured, using online software.35 Jake Evill designed an exoskeletal cortex cast, which provides a highly technical and a localized trauma zone support system that is fully ventilated, ultra-light, water repellant, hygienic, recyclable and stylish. In 2013, Japanese doctors carved a 3D-printed replica of a patient’s liver before surgery that enabled accurate assessment of the liver volume and precise visualization of the liver anatomy. This method could be particularly useful in pediatric liver transplantation.36 A 70-year-old man with an extensive arteriosclerotic aneurysm extending from the ascending aorta to the descending aorta was referred for a complete aortic arch replacement, for which the medical procedure used a 3D-printed model as part of the perioperative planning.37 Additional cases are listed in Fig. 5.


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Figure.5. (i) 3D printed model of the “reverse image” and the appropriate filling of the soft tissue defect.38 (ii) 3D printed livers with clean-cut positional relationships of inner structures.39 (iii) 3D printed model showing a lesion (in blue) and functional MRI regions (in red) corresponding to right-hand activation.40 (iv) Transradial patient standing on socket created with three-dimensional printing technology and wrapped with carbon fiber-reinforced resin material.41 (v) A low-cost 3D-printed prosthetic hand for children.42 (vi) 3D printed cortex exoskeletal cast for better recovery. (vii) 3D-printed dogfish chondrocranium (Squalus acanthias) and cane toad skeleton (Rhinella marina) alongside the specimens that were scanned for 3D printing. Original specimens are shown along the top row and 3D prints are shown underneath. Dried connective tissue between the ribs of the cane toad skeleton is represented in the 3D print but not present in the photograph, as it was removed after 3D scanning. Images of 3D prints and original specimens are viewed at slightly different angles that results in different perceived proportions of some features (i.e. orbits in frog skeleton).43

In recent years, the fabrication of prosthetics by 3D printing provides a time saving and personalized solution for growing medical demands. More and more 3D printers have been exploited for business, and almost all commercial 3D printers can print a casting mold using a variety of materials.7 In this article, we discuss four common types of 3D printing methods used in prosthesis fabrication, which is shown in Fig. 6. A variety of materials are suitable for extrusion-based 3D printing by simply modifying the extruding nozzle. These include thermoplastic fibers, powder or liquid of thermoplastic, eutectic metal, ceramics44, and hydrogel.45 Biocompatible and degradable materials are frequently used in clinical applications to make prostheses and rehabilitation devices.46 All technologies are open-sourced, which results in fast dissemination worldwide. Thus far, these low cost 3D printing methods have been applied to multiple applications in prosthesis fabrication despite its relatively poor resolution and surface quality caused by the “staircase effect”. Photocuring for curing fine prostheses using liquid photosensitive resins is now affordable, and makes it possible to create transparent objects with high resolution and smooth surfaces. Two types of photocuring, namely the stereo lithography apparatus (SLA) and the digital light procession (DLP), are the most frequently adapted methods for surgical creation. However, only few application alternatives can be used clinically47 due to the mechanical property, which is limited by the types of liquid photosensitive resin used. Similar to photocuring, photomelting uses a powder-like material, which mainly includes metals, plastics, and waxes. Complex and hollow parts can be easily created since the unsintered powder can act as the support structure. However, the surface quality of the finished prosthesis relies on the size of the powder particles, which means a grainy surface cannot be avoided if the prosthesis is not polished. Besides the above three approaches, inkjet-based 3D printing also has a great number of practical applications, especially ACS Paragon Plus Environment


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with the 3DP-LiquidResin (3DP-LR). The 3DP-LR can make multicolored objects of various shapes by loading different materials onto the printer head while it moves along the axis. The finished prostheses can be used for surgical aids and demonstrations with a high surface quality and a vivid inner structure detail. However, lots of material and equipment maintenance and management are required. Our group fabricated a low-cost soft prosthesis utilizing the SPPC (Scanning Printing Polishing Casting) method to address the use of indirect 3D printing for clinical issues,7 as shown in Fig.7. The anatomy of the prosthesis was scanned with a 3D scanner, and a tissue-casting mold was printed with a 3D printer. The casting mold was polished to remove the staircase effect and to acquire a smooth surface. Finally, a medical grade silicone cast was removed from the mold after it was cured. After the mold is fabricated, mass customization can be implemented. The greatest strengths of this method are low cost and convenience.

Figure.6. Advantages and disadvantages of different 3D printing methods used in prosthesis fabrication. A patient-specific anatomical replica of a 3D printed mandible with complex external bone geometry.46 Biomodels of clubfeet for preoperative planning helps in club foot corrections.48 Stereolithgraphical model of an auricle applied for reconstructive surgery.49 A stereolithographic model of a heart used for surgical planning and intraoperative orientation for surgical treatment in patients with primary cardiac tumors.50 A skull model fabricated by the SLS technique affords the surgeon a chance to lean complex anatomical relationships and to practice surgical skills.51 Three kinds to teeth made by SLS and used for dental glass-ceramic restoration;52 The 3D printed frontal sinus region can be used intra-operatively as an on-lay guide to frontal sinus mapping.53 An application of a 3D-printed liver during a hepatectomy;54


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Figure.7. (i) Typical SPPC process. (ii) Silicone ear. (iii) Part fabricating of a hand prosthesis.7

4 3D printed implants Many different research groups have examined various 3D printed implants for reliability and validity. These implants are printed in 3D from CT or MRI scanned images of abnormal tissues, which then serves as a scaffold, bridge, or internal splint to assist the healing process.55 There are three kinds of the biomaterial implants, namely, implantable medical devices,56-58 surgical fillers,59-61 and degradable bioactive implants.62-65 3D printed implants in clinical applications serve as great prospects or tissue injury treatments, and are particularly useful in plastic surgery.66 Deformity and partial loss normal appearance in humans may be caused by congenital, traumatic, or surgical means.67 Patient rehabilitation using prostheses to ameliorate defects has a simple application and gives patients a healthy revitalization. Tremendous progress in 3D-printed implants has been achieved in the past few years. Implantable medical devices can be used as physical tools.56, 68 In the field of plastic surgery, nondegradable surgical fillers are extremely valuable for reshaping faces.69-70 More attention is being given to the physical and biological properties of degradable bioactive implants.71-73 In Fig. 8, we list a few of the typical medical applications using biomaterial implants. Since the D3DP is so popular and can be easily performed by doctors, this approach will be more helpful for Printing@clinic. In summary, this type of 3D printer is considered as a new alternative to print biodegradable surgical implants.12



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Figure.8. (i) Hip resurfacing anthroplasty and a guide for determining the optimal stem angle in HRA surgery.74 (ii) Design process of the implantable tracheobronchial splint.75 (iii) Three-dimensional printed mold and the silicone prosthesis.76 (iv) The screw-like scaffold was designed and fabricated using the D3DP.12 (v) Photograph of the bellows graft fabricated by ISFF based on pMSTL and bronchoscopic views of the bellows graft at the implanted site at (a) one, (b) two, and (c) four weeks after implantation. 77

The methods used to print biomaterial implants in 3D are basically the same as those used to fabricate prosthetic devices, but the printing process is different. When printing biomaterial implants, a specific biocompatible material should be chosen carefully considering its biodegradability and its degradative properties. Implants should be able to be sterilized to ensure that they are free of contamination. After implantation, the geometric size should be monitored continuously using real-time CT or MRI to evaluate operation methods and clinical outcomes, especially for implantable medical devices.76, 78-83

Figure.9. Comparison of three kinds of biomaterial implants. The materials and printing methods are both common.


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5 Organ printing for tissue repair Organ printing (a.k.a. cell printing) is an attractive emerging area in 3D printing, namely tissue engineering in the medical sciences.84 Tissue or organ failure due to aging, diseases, accidents, and birth defects is a serious medical problem.85 In 2009, more than 150,000 patients in the United States were on the waiting list for organ transplantation. However, only 27,996 patients received a transplant, which comprised only 18% of the original patients on the waiting list.33 Organ transplant surgery and follow-up visitation is also expensive, costing more than $300 billion in 2012.85 Additionally, 3D bioprinting has attracted much attention owing to its potential ability to produce 3D structures that support the proliferation, migration, and differentiation of cells.86 An important advantage of this technology is its ability to simultaneously deposit living cells, growth factors along with biomaterial scaffolds at precisely controlled locations that mimics native tissue architecture.87 Organ printing could minimize the risk of tissue rejection, and the need for patients to take lifelong immunosuppressants.88 Numerous materials to build the scaffolds are available, depending on the desired strength, porosity, and type of tissue, and hydrogels are usually considered to be most suitable for producing soft tissue,89-92 whereas calcium phosphate is considered most suitable for producing bone.71, 93-95 In 2013, scientists began to print ears, livers, and kidneys with living cells. Researchers reported successful printing of human organs using specialized 3D bioprinters using live cells instead of plastic. Researchers have worked on 3D organ printing for many years and explored several printing methods.96-100 Blood vessels play a unique role in the exchange of substances in whole organs. Thus, the fabrication of vascular structures has become the most concerning issue for many scholars.101-103 Our group proposed a potential solution that could be used in printing structures and nutrient delivery channels simultaneously.104 Different bioprinting methods for in vivo bioprinting,105 scaffolds with complex shapes106, scaffolds with different regions107, 3D cell-laden constructs with patterned vascular networks96 and three-dimensional bioprinting of thick vascularized tissues108 are shown in Fig. 10.

Figure.10. (i) In vivo laser printing in mouse calvaria defects.105 (ii) FRESH printed scaffolds with complex internal and external architectures based on 3D imaging data from whole organs.106 (iii) Acellular printed structure using 3D bioprinting technology with the sacrificial layer process, auricular cartilage region (red color), and lobe fat region (blue color).107 (iv) “Vascular unit cell” fabricated by sacrificing 3D printed rigid filament networks of cytocompatible carbohydrate glass.96 (v). Three-dimensional fabricated vascularized tissue remains stable during long-term



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perfusion.108

Figure.11. Human tissues and their corresponding bioprinting methods.109-125

Human tissues for organ printing can be divided into three kinds: (1) tissues with simple compositions, which can be easily printed (such as cartilage); (2) tissues with multiple cells that overlap or touch each other (such as liver and heart); and (3) tissues with complex structure and small sizes (such as capillaries and artery). Four main bioprinting methods are used in organ printing, as shown in Fig. 11. Each method has its specialty. Shape precision of the printed structure is limited in extrusion bioprinting, but it is widely used in cell-laden constructs because of its easy operation and low-cost. Inkjet bioprinting can accurately deposit biologics including cells, growth factors, genes, drugs and biomaterials using commercially available nozzles.126 Advantages of Laser direct bioprinting are excellent resolution and cell viability but a costly and timeconsuming method.127 Photocuring-based bioprinting has the fastest printing speed of the four methods; however, it can only be applied to photopolymers,128-131 and multiple biomaterials are hard to print. The study of organ printing is presently in the exploratory stage. Printed objects have the shape and biocompatibility of organs, but lack organ function, so at this point, cannot truly replace human organs or tissues. As an example, the structure of single cells or cells from multiple skin types can be printed, but skin with sweat glands and nerves is difficult to manufacture. For organ printing, there are even more challenges for recapitulating an organ’s functions compared to printing its 3D structure. It seems to be an impossible job to construct a bioreactor completely in vitro that will simulate the complex in vivo environments. More research is needed to recapitulate an organ’s functions. At this time, it is more practical to focus on assembly of different cells by organ printing, in vitro, while testing organ function with 3D printed organs will need more complex in vivo experiments.


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6 Merits and challenges of Printing@clinic 6.1 Merits of Printing@clinic Printing@clinic can produce prostheses and implantable materials that can be manufactured in clinic as part of the surgical repair. The technology is well positioned to the produce precise and personalized implants based on a patient’s anatomy, which provides a well-fitting and esthetically pleasing experience for the patients. Printing@clinic, which uses 3D printing, has the merits of convenience, efficiency and quick-response compared to traditional methods of tissue engineering, thus facilitating the design and manufacture processes. If Printing@clinic can be appreciated, it would stimulate the creativity in many doctors. 6.2 Challenges of Printing@clinic Although 3D printing in biomedicine has developed rapidly, it is far from 3D organ printing, as is the case for Printing@clinic. The challenges of Printing@clinic can be classified into three aspects: (1) the bioprinter must be highly efficient, accurate, and easily accessible; (2) the printing process must not affect cells negatively; and (3) multiple materials and cells are needed in organ printing. The 3D printer is an effective and convenient tool for fabricating various objects, but that does not mean the 3D printer can print everything. The hardest part of organ printing is not the shape of the organs, but the complex heterogeneous structures like blood vessel networks inside organs. This requires accurate deposition at any point that contains a variable number of cells. Even the laser-assisted printer, which has the highest accuracy, has difficulty building blood capillaries, not to mention other structures at a cellular level. In addition, as with all 3D printing processes, current 3D bioprinters take a long time printing organs, which places a high demand on printing speed that must consider cell viability and risk of contamination. Moreover, for the clinical uses, most of the bioprinters are still in experimental stages rather than in the commercialization stage, which creates an urgent need for easy accessibility at low cost and high performance. Since doctors are not engineers, bioprinter software and operation issues that arise at the clinic represent another challenge. Specific challenges in regards to the main bioprinting methods are listed: Extrusion-based bioprinting, concerning the dispensing volume, can fabricate tissues using relatively high viscosity biomaterials. And, since it is relatively inexpensive and has mechanically attainable features, it is widely used. However, to stack 3D structures, bio-ink should have a proper viscosity and formability. Precise dispensing with cell-laden bio-ink may result in a low cell viability due to high shear force. High resolution is also a challenge for extrusion-based bioprinting. Inkjet bioprinting, as well as laser direct bioprinting have the advantage of high throughput, resolution, and cell viability in organ printing. While these two droplet-based techniques are limited by the biomaterials they can apply, low-viscosity or liquid bio-ink cannot provide high mechanical stiffness in some surgical cases. Besides, these techniques often take too much time because the size of printing tissues increases and a prolonged printing time may cause adverse effects on the cell viability, and the functionality of printed analogs of clinically relevant size. Because of the expense of using a laser source and the complexity of the laser pulse control, laser direct bioprinting is hard to promote in clinics. Although Photocuring-based bioprinting is commonly used in organ printing by replacing the ink with biocompatible photopolymerizable materials, there are still some shortcomings before practical in organ fabrication can be realized. The scarcity of biocompatible water-soluble photopolymers may be cytotoxic, entrapment of unreacted. Monomer and residual photoinitiators are also not reactive. Photopolymerized bio-ink also has poor mechanical stiffness is needed for hard tissue engineering. Novel synthetic or hydrogel is required before clinical use. A series of strict disinfection used in printing biologics is needed, especially in Printing@clinic, where printing needs to be fast. Living cells are weak, but the viability, growth, variation, and neoplastic transformation of cells are all potential issues. Some studies have mainly focused on achieving >90% cell viability132-134 and on cell growth with a survival of as much as four months after printing. Future research should concentrate on 3D printers and their effects on cells. Human organs are comprised of many different cell types and extracellular matrix. There are 20 different cell types in a complicated kidney. Researchers induced stem cell differentiation to specific cell types in vitro after printing instead of focusing on printing an organ with all of its required cells. However, cell survival, directed differentiation, angiogenesis, and ACS Paragon Plus Environment


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metabolic exchange are far from clinical trials and are processes whose technical feasibility needs to be addressed.135 Since bioprinting developed so rapidly, an increasing number of cell laden biomaterials have been reported. Accordingly, some materials are more suitable for Printing@clinic where high performance can be expected. Besides the technical challenges, there is also some issue of medical expenses could interface with commercialization of Printing@clinic. Nevertheless, once the printing costs of prostheses and implants are covered by medical insurance, a broader range of applications will be seen.

7 Future trends of Printing@clinic 7.1 From centimeter to the decimeter level Biomedical 3D printing has developed from the nanometer level to the decimeter level. 3D printing of protein and DNA belong to the nanometer level, the 3D printing of cells belongs to the micrometer level, and 3D printing of nerve, vessel, and tissue belong to the centimeter level. The ultimate goal, namely the decimeter level, is printing a heart, liver, or kidney. We predict that the focus in bioprinting will soon be cross-scale manufacturing. 7.2 Form industrialization to individualization Organovo developed the NovoGen bioprinting technology and partnered with Invetech (Invetch Pty Ltd, Australia) in May 2009 to help develop the 3D bioprinters. With an ever-increasing number of 3D bioprinters on the market, the method of Printing@Clinic will be spread from one printer in one hundred hospitals or clinics to one printer in every hospital or clinic in the future. 7.3 Lower cost and easier operation Although the cost of 3D-printed prosthesis or implants is lower than the cost of those made through traditional methods, the cost involved in the pre- and post-operation, and in other medical treatments for organ transplants of bioprinted organs is substantially higher than when using commercial bioprinters. Therefore, the economic feasibility of the techniques needs to be addressed before bioprinting becomes a standard and sustainable treatment intervention. Also, it will be risky to rely solely on the skills of a doctor when contemplating success of 3D printed prostheses produced by Printing@Clinic. However, we predict that 3D bioprinters will soon be easier to operate than the previous generation printers.

8 Conclusion Printing@Clinic is an evolving technology that appeals to biomedical demands due to its customization and flexibility. Rapid advances in surgical planning, prosthesis, and implant applications have also occurred. However, many types of 3D printers are not able to achieve clinical needs due to their defects, and the prospect of practical implementation will be realized as new materials are synthesized, and novel printing methods are discovered. Ultimately, Printing@Clinic may be the key to giving patients suffering from organ dysfunction and failure, a chance at an improved quality of life.

Acknowledgements This paper was sponsored by the National Nature Science Foundation of China (No. 51622510, U1609207), the Science Fund for Creative Research Groups of the National Natural Science Foundation of China (no. 51521064), the Nature Science Foundation of Zhejiang Province, China (No. LR17E050001).


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Printing@Clinic: From Medical Models to Organ Implants - ACS

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