1.      Abbreviations

PCS        :               Pelvicalyceal System

PCNL     :               Percutaneous Nephrolithotomy

CT          :               Computerized Tomography

MRI       :               Magnetic Resonance Imaging

PN           :               Partial Nephrectomy

2.      Introduction

Charles W. Hull first described 3D printing in 1986. He named it ‘stereolithography’. Layers of a material that were treated with ultraviolet light were printed in sheets to form a solid 3D structure. This is transplanted after in vitro maturation [1]. 3D prints can demonstrate nephrotoxicity of medicines and its prevention [2]. Platforms can imitate in vivo conditions and tubular microenvironment [3]. Three-dimensional printing creates a kidney graft and pelvic cavity imitating the living kidney. This helps surgeons and residents to treat the given condition before surgery. It reduces operation time of kidney transplantation surgery [4]. 3D printing or additive manufacturing is used to create patient-specific models to help surgeons and trainees. Furthermore, it helps in further aspects including dose verification in radiation therapy and in forensic issues. 3D printing is efficient and cheaper than other tools [5]. Organ preservation would improve, thereby helping to relieve the organ shortage through increased availability and quality of donor organs [6]. 3D printed pelvicalyceal system was used before percutaneous nephrolithotripsy as Plasticine 3D models of pelvicalyceal systems were made. CT software, magnetic resonance images and ultra sound provides reconstructed 3D images of the PCS and used for PCNL [7]. This is a narrative review of the existing literature. In addition, we will summarize the present available uses of 3D printing and the potentials of future applications.

3.      Materials and Methods

3.1.  Sources

The review comprised a literature search of PubMed and Hinari for reports in English, using the keywords “Printing, Three-Dimensional”, “3D Printing”, “Three-Dimensional Printing”, “3DP”, and “urinary tract”. This review includes the 50 articles identified. All articles published up to June 2017 were included.

3.2.  Data Abstraction

Our literature searches yielded printing techniques to model native biology with preservation of cellular function. Issues as dose verification in radiation therapy and in forensic topics were looked for, in addition to other matters as nephrotoxicity and creating kidney grafts imitating the living kidney.

4.      Results

Our search identified 50 articles that were included in the final review. Study results were afterward entered into a table (Table 1).

All articles were in English. Of these articles, 10 were concerned with training and planning surgical procedures. Along with our selected articles, they were concerned with transplant surgery, tumor nephrectomy, PCNL training and needle (biopsy, and aspiration). With kidney (replacement and transplantation), there were 11 articles. Three-dimensional (3D) external geometry was used in tissue engineering and 3D printing. Plastic, metal, ceramics, powders, liquids, or even living cells are used in layers. Bio-ink to create implantable devices was developed. The final aim is to overcome finding kidney donors and to abolish immunosuppression problems. On the subjects of drug testing, therapeutics, toxicity, and cancer therapy, we included 10 articles. Printing applications include organ fabrication; creation of customized prosthetics, implants, anatomical models, and drug dosage. Models that review human responses are needed for drug screening. A 3D printer can build tissue structures for the use in testing pharmaceuticals. In the case of patients’ understanding and education, we included 5 articles. Tailored 3D models of pelvicalyceal systems were shown to patients before percutaneous nephrolithotripsy, partial adrenalectomy, and partial nephrectomy. It helped them understand their disease.

4.1.  Training and Planning Surgical Procedures

Three D models where obtained from MRI data [9]. Models as well were based on abdominal CT images, they were used in patients scheduled to undergo PCNL. Wax printing judged by CT reconstruction showed that the phantom imitates kidney’s anatomy [28]. This allowed staff and residents to train and later the operations were performed, and patients could be discharged after one day [19]. Models were used to plan surgical procedures for laparoscopic donor nephrectomy and recipient transplantation surgery [4]. In tumors, the operation was first carried out in a silicone model then laparoscopic removal of the tumor was performed with reduced ischemic time to only few minutes [8]. Applications for pre-surgical planning of partial adrenalectomy, partial nephrectomy in renal tumors, and for educating patients were used [11]. These models help learners to develop their skills [16]. Adult-to child kidney transplant became easier [20]. World first 3D printing used in kidney transplant was performed in 2016. A kidney was donated by a child’s father, then models of father’s kidney and child’s abdomen were produced using Guy’s and St Thomas’ 3D printer. Surgeons could plan the operations to reduce the risks [46]. Fine needle aspirations could also be taught ahead of the procedure [23].

4.2.  Kidney Replacement and Transplantation

3D-bioprinted tissues are used in transplantation, printing tissues, hollow tubes such as blood vessels, and solid organs such as the kidney [1]. Nano 3D printing has advantages over micro fabrication. Research is concentrating on 3D printed kidney-on-a-chip platforms [3]. Structured-light scanning techniques could shift the model for organ preservation. This relieves the organ shortage crisis by increased availability and quality of donor organs [6]. With the three-dimensional (3D) external geometry was used in tissue engineering and 3D printing, it is possible to regenerate organs and tissues with modified geometries to treat defects or injuries [13]. Materials such as plastic, metal, ceramics, powders, liquids, or even living cells are used in layers to produce a 3D object that is used in tissue and organ fabrication [14]. Artificial tissues and organs are printed by depositing cells, biomaterials, and molecules layer by layer. Attempts are made to print kidneys and other organs [21]. The development of (bio-ink) is one of the goals of 3D printing. It has enabled to create implantable devices such as biodegradable tissue engineering scaffolds [24]. 3D printing produces organ transplants that may overcome finding kidney donors. Furthermore, it would abolish immunosuppression problems and transplant rejection because it uses the patient’s own cells [27]. Organ printing allows fabrication of human organs with a ‘built in’ intra-organ branched vascular tree [30]. 3D human renal proximal tubules were created in vitro, they are embedded in an extracellular matrix and are perfusable. The epithelial morphology and functional properties are the same as the control. Bioprinting methods provide human kidney tissue models on demand [31]. Furthermore, 3D printing of plastic or collagen allows constructing scaffolds on which cells can grow [45].

4.3.  Drug Testing, Therapeutics, Toxicity, and Cancer Therapy

Tissues are printed for best possible protection of cellular function and transporter activity. This provides a perfect way to study nephrotoxicity [2]. Applications printing include organ fabrication; creation of customized prosthetics, implants, anatomical models, and drug dosage [14]. Models could simulate the microenvironment. Bio-printing of live human cells is used in oncology research in clinical cancer therapeutics [18]. Stem cells that are used as a controlled environment can be produced to affect cell growth and differentiation. Animal models could be partially replaced by biofabricated tissues [22]. Three-dimensional models of kidney tissue that review human responses are needed for drug screening, disease modeling, and, ultimately, kidney organ engineering [31]. Bioprinted 3D proximal tubule model can serve as a test of nephrotoxicity aided by the development of pathogenic states involving epithelial-interstitial interactions [33]. Investigators who model disease with 3D printing to define pathology, plan intervention, and treat patients [37]. Bioprinting is used in tissue structure fabrication based on the medical images, and is an efficient tool for drug discovery and preclinical testing [38]. Creating the complex vascular system to keep the tissue alive will help in therapeutic applications [44]. Printers has been developed to build 3D tissue structures that could be used to test pharmaceuticals [45].

4.4.  Patients’ Understanding and Education

Personalized Plasticine 3D models of pelvicalyceal systems were shown to patients before percutaneous nephrolithotripsy. It helped in their understanding of the disease and the surgical process [7]. Anatomic models were used for the planning of partial adrenalectomy, partial nephrectomy in the resection of renal tumors, and for educating patients [11]. Patients with renal cell carcinoma underwent clampless PN (partial nephrectomy). All patients answered that the 3D images had helped them understand their disease status and surgical risks [39]. Models of patients’ kidneys before surgery were made. Those patients had partial nephrectomy for their renal tumors and had the advantage of short ischemia time. Patients and trainees asserted that the models improved their understanding [41]. After inspecting their own 3D kidney model, patients had improved understanding of kidney physiology and anatomy [48].

5.      Discussion

3D printing in medicine has been rising dramatically and quickly [50]. Objects that have been printed in this field show the capability of this know-how in healthcare prospects. So far, twelve Items have been printed; they are:

• Tissues with blood vessels
• Prosthetic Parts
• Drugs
• Heart attached sensors to detect oxygenation
• CT and MRI models to orientate doctors
• Bone
• Heart Valve
• Ear cartilage
• Medical equipment
• Cranium Replacement
• Synthetic skin
• Organs

Training and surgical planning is one of the main successes of 3D printing. Structured-light scanning techniques enabled the 3D topographical matching of microfluidic device geometry to porcine kidney anatomy [6]. Materials used include acrylonitrile butadiene styrene (ABS) that has impact resistance, toughness, high radiodensity, and low cost. Printers use a polymer filament (that is heated to a liquid state in a printer head) and deposited in predefined locations corresponding to the model shape [7]. 3D printed models are useful in planning PCNL access. They provide a model for training in PCNL access [32]. Furthermore, it is used in the presurgical set up for laparoscopic and robotic partial nephrectomy [34] in renal cell carcinoma. Kidney models of T1N0M0 tumors were shown to urologists for planning and training. Operations were completed without clamping, with negative surgical margins and minimum or no blood transfusions. The surgeons confirmed the accuracy of the reconstructed 3D images and surgical simulations in all cases. In patients undergoing laparoscopic kidney tumorectomy due to renal cell cancer, average time of preparation is about 16 hours and 30 minutes. The average costs of casting mold, printing and casting of silicon replica were about 22 $ [40]. Renal tumor excision after practicing on a 3D replica can take only 90 minutes. It would have taken much longer time [47].

In kidney replacement and transplantation issue, the failure of organs and tissues is a difficult problem. 3D bioprinting was started by Dr. Anthony Attala from Wake Forest Institute for Regenerative Medicine, who applied 3DP to manufacture organ tissues of heart and kidney. Chinese investigators reported the 3D bioprinting of tissues of kidney replacement. Organovo is a company in the 3D bioprinting field. They have printed liver and kidney tissues [20]. The inadequate supply of organs has induced research on the design of a cell-scaffold microenvironment to help the regeneration of various types of tissues. Bioprinting is used in tissue engineering for the fabrication of scaffolds, cells, tissues, and organs. It is divided into three groups, inkjet-based bioprinting, pressure-assisted bioprinting and laser-assisted bioprinting. Bioprinting uses biomaterials, cells, or cell factors as a “bioink” to make tissue structures [21]. Artificial tissues and organs are printed by depositing cells, biomaterials, and molecules layer by layer. Bioprinting has good resolution of the input cells. Kidneys and blood vessels are on the list [21] World first 3D printing was used in kidney transplant in 2016. Surgeons at Guy’s and St Thomas’ have lead the way to the world’s first use of 3D printing to help in a successful transplantation of an adult kidney into a two-year-old child using a kidney donated by her father. Models of donor and recipient abdomen based on measurements obtained through CT and MRI scans were produced using Guy’s and St Thomas’ 3D printer so that the surgeons could accurately plan the operation to minimize the risks. It is the first time in the world that 3D printing has been used to help kidney transplant surgery involving an adult donor and a child recipient [46].

As for drug testing, therapeutics, toxicity, and cancer therapy; The cellular and architectural structure of ExVive^™ Human Kidney Tissue provides an ideal means to study the many phenotypes of nephrotoxicity including tubular transport. An example is Cisplatin-mediated nephrotoxicity and its prevention by cimetidine. This was well shown in ExVive^™ Human Kidney Tissue [2]. 3D printing is being used in drugs development. This is achieved by 3D printing by personalized medications. Pharmacists could analyze a patient’s profile, such as age, race, or gender, to determine an optimal dose. They could then print and dispense the personalized medication via an automated 3D printing system. Patients who have multiple diseases could have their medications printed in one multi-dose form providing patients with an accurate single dose. Bone infections are another example where direct treatment with a drug implant is more desirable than systemic treatment [14]. 3D bio-printed tissues and organs are used in the preclinical testing and therapeutics of anticancer drugs [18]. 3D biofabrication will help in drug testing where animal testing may be replaced by use of 3D biofabricated tissue. Drugs-by either themselves or embedded in microspheres or nanospheres-could be deposited within the construct optimizing the tissue formation. Furthermore, it is possible to transfer genes into cells by inkjet printing in addition to the precise delivery of the modified cells to a given target [22]. In drug toxicity testing, Cyclosporine A, a drug given to prevent rejection, is a known nephrotoxin that damages proximal tubule cells. To study its effect a perfused 3D proximal tubule model, was exposed to various concentrations of Cyclosporine A (CysA) then alterations of cell morphology were monitored [31, 33].

Concerning Patients’ understanding, and education 3D information helps patients in choosing treatments [7]. Models have been used for educating patients about the anatomy of their kidney and tumor before resection [11]. Urosurgeons asked patients whether the 3D images had helped them understand their operations more clearly than 2D images would have. All patients answered that the 3D images had helped them understand their disease status and surgical risks [39]. Patients and trainees could use the individualized model before certain operations as partial nephrectomy [41]. Patient nicely understood the disease and procedure.

Our search identified 50 articles that were included in the final review. Study results were afterward entered into a table (Table 1).

1.       Sean V Murphy and Anthony Atala (2014) 3D bioprinting of tissues and organs. Nature Biotechnology 32.

2.       Modeling Human Kidney Biology.

3.       Ryan D. Sochol, Navin R. Gupta, Joseph V. Bonventre (2016) A Role for 3D Printing in Kidney-on-a-Chip Platforms. Curr Transplant Rep 3: 82-92.

4.       M. Kusakaa, M. Sugimotob, N. Fukamia, H. Sasakia, M. Takenakaa, et al. (2015) Initial Experience with a Tailor-made Simulation and Navigation Program Using a 3-D Printer Model of Kidney Transplantation Surgery. Transplantation Proceedings 47: 596-599.

5.       Shuai Len, Kiaran McGee, Jonathan Morris, Amy Alexander, Joel Kuhlmann, et al. (2017) McCollough and Jane Matsumoto. Anatomic modeling using 3D printing: quality assurance and optimization. 3D Printing in Medicine 3: 6.

6.       Singh M, Tong Y, Webster K, Cesewski E, Haring AP, et al. (2017) 3D printed conformal microfluidics for isolation and profiling of biomarkers from whole organs. Lab Chip 2017.

7.       Atalay HA, Canat HL, Ülker V, Alkan İ, Özkuvanci Ü, et al. (2017) Impact of personalized three-dimensional -3D- printed pelvicalyceal system models on patient information in percutaneous nephrolithotripsy surgery: a pilot study.Int Braz J Urol 43: 470-475.

8.       Golab A, Smektala T, Kaczmarek K, Stamirowski R, Hrab M, et al. (2017) Laparoscopic Partial Nephrectomy Supported by Training Involving Personalized Silicone Replica Poured in Three-Dimensional Printed Casting Mold. J Laparoendosc Adv Surg Tech A 27: 420-422.

9.       Wake N, Rude T, Kang SK, Stifelman, Borin JF, et al. (2017) 3D printed renal cancer models derived from MRI data: application in pre-surgical planning. Abdom Radiol (NY) 42: 1501-1509.

10.    Woliner-van der Weg W, Deden LN, Meeuwis AP, Koenrades M, Peeters LH, et al. (2016) A 3D-printed anatomical pancreas and kidney phantom for optimizing SPECT/CT reconstruction settings in beta cell imaging using 111In-exendin. EJNMMI Phys 3: 29.

11.    Don Hoang, David Perrault, Milan Stevanovic, Alidad Ghiassi (2016) Surgical applications of three-dimensional printing: a review of the current literature & how to get started. Ann Transl Med 4: 456.

12.    Christopher M. O'Brien, Benjamin Holmes, Scott Faucett, Lijie Grace Zhang (2015) Three-Dimensional Printing of Nanomaterial Scaffolds for Complex Tissue Regeneration. Tissue Eng Part B Rev 21: 103-114.

13.    Jin Woo Jung, Jung-Seob Lee, Dong-Woo Choa (2016) Computer-aided multiple-head 3D printing system for printing of heterogeneous organ/tissue constructs Sci Rep 6: 21685.

14.    C. Lee Ventola (2014) Medical Applications for 3D Printing: Current and Projected Uses P T 39: 704-711.

15.    Jordan S. Miller (2014) The Billion Cell Construct: Will Three-Dimensional Printing Get Us There? PLoS Biol 12: e1001882.

16.    Guk Bae Kim, Sangwook Lee Haekang Kim, Dong Hyun Yang, Young-Hak Kim, et al. (2016) Three-Dimensional Printing: Basic Principles and Applications in Medicine and Radiology, Korean J Radiol 17: 182-197.

17.    Verma Walker (2017) Implementing a 3D printing service in a biomedical library J Med Libr Assoc 105: 55-60.

18.    Nitin Charbe, Paul A McCarron, Murtaza M Tambuwala (2017) Three-dimensional bio-printing: A new frontier in oncology research World J Clin Oncol 8: 21-36.

19.    Bruyère F, Leroux C, Brunereau L, Lermusiaux P (2008) Rapid prototyping model for percutaneous nephrolithotomy training. J Endourol 22: 91-96.

20.    Helena Dodziuk (2016) Applications of 3D printing in healthcare Kardiochir Torakochirurgia 13: 283-293.

21.    Jipeng Li, Mingjiao Chen, Xianqun Fan, Huifang Zhou (2016) Recent advances in bioprinting techniques: approaches, applications and future prospects J Transl Med 14: 271.

22.    Silke Wüst, Ralph Müller, Sandra Hofmann (2011) Controlled Positioning of Cells in Biomaterials-Approaches Towards 3D Tissue Printing. J Funct Biomater 2: 119-154.

23.    Thore M. Bücking, Emma R. Hill, James L. Robertson, Efthymios Maneas, et al. (2017) From medical imaging data to 3D printed anatomical models PLoS One 12: e0178540.

24.    Bon Kang Gu, Dong Jin Choi, Sang Jun Park, Min Sup Kim, et al. (2016) 3-dimensional bioprinting for tissue engineering applications, Biomater Res 20: 12.

25.    Mahmoud A. Hafez, Khaled Abdelghany, Hosamuddin Hamza (2015) Highlighting the medical applications of 3D printing in Egypt Ann Transl Med 3: 359.

26.    Jangwook P. Jung, Didarul B. Bhuiyan, Brenda M. Ogle (2016) Solid organ fabrication: comparison of decellularization to 3D bioprinting Biomater Res 20: 27.

27.    Youssef Soliman, Allison H Feibus, Neil Baum (2015) 3D Printing and Its Urologic Applications. Rev Urol 17: 20-24.

28.    Fabian Adams, Tian Qiu, Andrew Mark, Benjamin Fritz, et al. (2017) Soft 3D-Printed Phantom of the Human Kidney with Collecting System. Ann Biomed Eng 45: 963-972.

29.    Roland Partridge, Noel Conlisk, Jamie A. Davies (2012) In-lab three-dimensional printing an inexpensive tool for experimentation and visualization for the field of organogenesis 8: 22-27.

30.    Richard P Visconti, Vladimir Kasyanov, Carmine Gentile, Jing Zhang, et al. (2010) Towards organ printing: engineering an intra-organ branched vascular tree Expert Opin Biol Ther 10: 409-420.

31.    Kimberly A. Homan, David B. Kolesky, Mark A. Skylar-Scott, Jessica Herrmann, et al. (2016) Bioprinting of 3D Convoluted Renal Proximal Tubules on Perfusable Chips Sci Rep 6: 34845.

32.    Benjamin W. Turney (2014) A New Model with an Anatomically Accurate Human Renal Collecting System for Training in Fluoroscopy-Guided Percutaneous Nephrolithotomy Access. J Endourol 28: 360-363.

33.    Shelby M. King, J. William Higgins, Celina R. Nino, Timothy R. Smith, et al. (2017) 3D Proximal Tubule Tissues Recapitulate Key Aspects of Renal Physiology to Enable Nephrotoxicity Testing Front Physiol 8: 123.

34.    Luciano A. Favorito (2017) Kidney anatomy: three dimensional (3D) printed pelvicalyceal system models of the collector system improve the diagnosis and treatment of stone disease. Int Braz J Urol 43: 381-382.

35.    Leonid Chepelev, Andreas Giannopoulos, Anji Tang, Dimitrios Mitsouras et al. (2017) Medical 3D printing: methods tostandardize terminology and report trends 3D Printing in Medicine 3: 4.

36.    Andy Christensen and Frank J. Rybick (2017) Maintaining safety and efficacy for 3D printing in medicine. 3D Printing in Medicine 3:1.

37.    Frank J. Rybicki (2015) 3D Printing in Medicine: an introductory message from the Editor-in-Chief, 3D Printing in Medicine 1: 1.

38.    Huang Y, Zhang XF, Gao G, Yonezawa T, et al. (2017) 3D bioprinting and the current applications in tissue engineering. Biotechnol J 2017.

39.    Komai Y, Sakai Y, Gotohda N, Kobayashi T, Kawakami S, et al. (2014) A novel 3-dimensional image analysis system for casespecific kidney anatomy and surgical simulation to facilitate clampless partial nephrectomy. Urology 83: 500-506.

40.    Smektala T, Goląb A, Królikowski M, Slojewski M (2016) Low cost silicone renal replicas for surgical training - technical note. Arch Esp Urol 69: 434-436.

41.    Silberstein JL, Maddox MM, Dorsey P, Feibus A, Thomas R, et al. (2014) Physical models of renal malignancies using standard cross-sectional imaging and 3-dimensional printers: A pilot study. Urology 84: 268-272.

42.    Yi Zhang, Hong‑wei Ge, Ning‑chen Li, Cheng‑fan Yu, et al. (2015) Evaluation of three-dimensional printing for laparoscopic partial nephrectomy of renal tumors: a preliminary report. World J Urol 34: 533-537.

43.    Bieniosek MF, Lee BJ, Levin CS (2015) Technical note: characterization of custom 3D printed multimodality imaging phantoms. Med Phys 42: 5913-8.

44.    Bartlett S (2013) Printing organs on demand. Lancet Respir Med 1: 684.

45.    Jones N (2012) Science in three dimensions: the print revolution. Nature 487: 22-23.

46.    World first 3D printing used in life-changing kidney transplant.

47.    Hipolite W (2016) 3D Printing Saves a Woman’s Kidney: Surgeons perform impressive renal tumor surgery.

48.    Bernhard JC, Isotani S, Matsugasumi T, Duddalwar V, Hung AJ, et al. (2016) Personalized 3D printed model of kidney and tumor anatomy: a useful tool for patient education. World J Urol 34: 337-345.

49.    Song JJ, Guyette JP, Gilpin SE, Gonzalez G, Vacanti JP, et al. (2013) Regeneration and experimental orthotopic transplantation of a bioengineered kidney. Nat Med 19: 646-651.

50.    Desrochers, TM, Palma E. & Kaplan DL (2014) Tissue-engineered kidney disease models. Adv Drug Deliv Rev 2014: 69-70.