3D Printing Applied to Tissue Engineered Vascular Grafts
Round 1
Reviewer 1 Report
Overall. It is a stimulating review about 3D printing. Some suggestions have been proposed.
Abstract. Ok.
Introduction. Authors stated that “Vascular bypass is a common surgical procedure for limb salvage following critical limb ischemia and various peripheral vascular diseases associated with diabetes, atherosclerosis, or aging, and is a prevailing therapeutic option for coronary artery diseases”. Please add a Reference for this statement.
Introduction. Authors stated that “For applications such as peripheral and coronary bypasses that require small diameter grafts, the benchmark vascular grafts are autologous, including the internal mammary artery, the radial artery from the arm, and the saphenous vein from the leg”. Please add a Reference for this statement.
Introduction. Authors described the use of 3D printers for vascular disease. However, before introducing the use in vascular surgery, they could add some statements to the paragraph stressing on the importance of the recently introduced 3D technology, used in combination with other techniques in various fields. It could be added that “3D printed modules and frameworks are used in many medical fields, such as orthopedics, neurosurgery, cardiothoracic surgery, and dentistry (An Introduction to 3D Bioprinting: Possibilities, Challenges and Future Aspects. Kačarević ŽP, Rider PM, Alkildani S, Retnasingh S, Smeets R, Jung O, Ivanišević Z, Barbeck M. Materials (Basel). 2018 Nov 6;11(11).). Additionally, 3D printers can be used in combination with 3D radiologic (3D printing from microfocus computed tomography (micro-CT) in human specimens: education and future implications. Shelmerdine SC, Simcock IC, Hutchinson JC, Aughwane R, Melbourne A, Nikitichev DI, Ong JL, Borghi A, Cole G, Kingham E, Calder AD, Capelli C, Akhtar A, Cook AC, Schievano S, David A, Ourselin S, Sebire NJ, Arthurs OJ. Br J Radiol. 2018 Jul;91(1088):20180306.) or optical scansion devices (Computerized Casts for Orthodontic Purpose Using Powder-Free Intraoral Scanners: Accuracy, Execution Time, and Patient Feedback. Sfondrini MF, Gandini P, Malfatto M, Di Corato F, Trovati F, Scribante A. Biomed Res Int. 2018 Apr 23;2018:4103232) in order to allow a customized clinical treatment”. This enumeration of multiple applications of 3D printers could help the reader to understand the high potential of this relatively young technology.
2.1 Extrusion. Authors stated that “The coaxial extrusion has gained popularity for the bioprinting of hollow tubes.”. Please add some References related to this technique.
2.2 Inkjet. Authors stated that “The drawback of such a system is the drop size, which is larger than other inkjet methods.” Please add a reference.
3. Strategies. “This process offers multiple possibilities of controlling the spatial arrangement of the elements that compose the constructs and tuning the chemical and mechanical properties”. Please add some recent research results.
3.1 Scaffolds. “The molecular weight, crystallinity, internal organization, and degree of cross-linking are important tunable attributes that can be adjusted during the synthesis, or later, as a post-treatment.” Please complete the sentence with a reference.
3.2 Bioprinting. “Hydrogels are the most popular biomaterials found in bioinks”. Please add a reference for this statement.
Conclusions. Authors could add that “3D printing technology is a rapidly growing research field, and further studies are needed both in vitro and in vivo, in order to explore different application possibilities and interactions with other medical technologies”.
References. Some old references are reported (4:1988; 5:1999; 67:1998). I f possible, please change with recent research. Some studies have been suggested in the comments above.
Tables: ok
Figures. No figure has been presented. If possible, some explanation drawings could be added to describe different printing techniques or strategies, in order to have a graphical description of these processes.
Author Response
Reviewer 1:
We sincerely thank the reviewer for constructive suggestions and valuable comments, which are of great help.
Introduction. Authors stated that “Vascular bypass is a common surgical procedure for limb salvage following critical limb ischemia and various peripheral vascular diseases associated with diabetes, atherosclerosis, or aging, and is a prevailing therapeutic option for coronary artery diseases”. Please add a Reference for this statement.
Introduction. Authors stated that “For applications such as peripheral and coronary bypasses that require small diameter grafts, the benchmark vascular grafts are autologous, including the internal mammary artery, the radial artery from the arm, and the saphenous vein from the leg”. Please add a Reference for this statement.
Accordingly, the revised manuscript has been systematically improved with a reference to the extremely interesting review from Tillman et al (2013) that covers in great details both of statements.
Introduction. Authors described the use of 3D printers for vascular disease. However, before introducing the use in vascular surgery, they could add some statements to the paragraph stressing on the importance of the recently introduced 3D technology, used in combination with other techniques in various fields.
Accordingly, a new paragraph has been added in the introduction and presents a broader aspect of 3D printing within the medical field (line 155-158)
3D printed modules and frameworks are already used in many medical fields, such as orthopedics, neurosurgery, cardiothoracic surgery, and dentistry (Kačarević et al, 2018)]. Additionally, 3D printers can be used in combination with 3D radiologic (Shelmerdine et al, 2018) or optical scansion devices (Sfondrini et al, 2018) in order to allow a customized clinical treatment.
2.1 Extrusion. Authors stated that “The coaxial extrusion has gained popularity for the bioprinting of hollow tubes.”. Please add some References related to this technique.
We have now added new references (line 139):
26. Jia, W.; Gungor-Ozkerim, P.S.; Zhang, Y.S.; Yue, K.; Zhu, K.; Liu, W.; Pi, Q.; Byambaa, B.; Dokmeci, M.R.; Shin, S.R.; et al. Direct 3D bioprinting of perfusable vascular constructs using a blend bioink. Biomaterials 2016, 106, 58–68.
27. Zhang, Y.; Yu, Y.; Akkouch, A.; Dababneh, A.; Dolati, F.; Ozbolat, I.T. In vitro study of directly bioprinted perfusable vasculature conduits. Biomaterials Science 2015, 3, 134–143.
28. Luo, Y.; Lode, A.; Gelinsky, M. Direct plotting of three-dimensional hollow fiber scaffolds based on concentrated alginate pastes for tissue engineering. Adv Healthc Mater 2013, 2, 777–783.
29. Liu, W.; Zhong, Z.; Hu, N.; Zhou, Y.; Maggio, L.; Miri, A.K.; Fragasso, A.; Jin, X.; Khademhosseini, A.; Zhang, Y.S. Coaxial extrusion bioprinting of 3D microfibrous constructs with cell-favorable gelatin methacryloyl microenvironments. Biofabrication 2018, 10, 024102.
30. Mistry, P.; Aied, A.; Alexander, M.; Shakesheff, K.; Bennett, A.; Yang, J. Bioprinting Using Mechanically Robust Core–Shell Cell-Laden Hydrogel Strands. Macromolecular Bioscience 2017, 17, 1600472.
2.2 Inkjet. Authors stated that “The drawback of such a system is the drop size, which is larger than other inkjet methods.” Please add a reference.
We have now added a new reference (line 152):
34. Long Ng, W.; Min Lee, J.; Yee Yeong, W.; Naing, M.W. Microvalve-based bioprinting – process, bio-inks and applications. Biomaterials Science 2017, 5, 632–647.
3. Strategies. “This process offers multiple possibilities of controlling the spatial arrangement of the elements that compose the constructs and tuning the chemical and mechanical properties”. Please add some recent research results.
We have now added recent references (line 173):
38. Schöneberg, J.; De Lorenzi, F.; Theek, B.; Blaeser, A.; Rommel, D.; Kuehne, A.J.C.; Kießling, F.; Fischer, H. Engineering biofunctional in vitro vessel models using a multilayer bioprinting technique. Scientific Reports 2018, 8.
39. Suri, S.; Han, L.-H.; Zhang, W.; Singh, A.; Chen, S.; Schmidt, C.E. Solid freeform fabrication of designer scaffolds of hyaluronic acid for nerve tissue engineering. Biomed Microdevices 2011, 13, 983–993.
40. Cui, H.; Nowicki, M.; Fisher, J.P.; Zhang, L.G. 3D Bioprinting for Organ Regeneration. Adv Healthc Mater 2017, 6.
41. Park, J.Y.; Shim, J.-H.; Choi, S.-A.; Jang, J.; Kim, M.; Lee, S.H.; Cho, D.-W. 3D printing technology to control BMP-2 and VEGF delivery spatially and temporally to promote large-volume bone regeneration. J. Mater. Chem. B 2015, 3, 5415–5425.
3.1 Scaffolds. “The molecular weight, crystallinity, internal organization, and degree of cross-linking are important tunable attributes that can be adjusted during the synthesis, or later, as a post-treatment.” Please complete the sentence with a reference.
We have now added new references (line 184):
31. Hölzl, K.; Lin, S.; Tytgat, L.; Van Vlierberghe, S.; Gu, L.; Ovsianikov, A. Bioink properties before, during and after 3D bioprinting. Biofabrication 2016, 8, 032002.
43. Gopinathan, J.; Noh, I. Recent trends in bioinks for 3D printing. Biomaterials Research 2018, 22, 11.
44. Ouyang, L.; Yao, R.; Zhao, Y.; Sun, W. Effect of bioink properties on printability and cell viability for 3D bioplotting of embryonic stem cells. Biofabrication 2016, 8, 035020.
45. Chung, J.H.Y.; Naficy, S.; Yue, Z.; Kapsa, R.; Quigley, A.; Moulton, S.E.; Wallace, G.G. Bio-ink properties and printability for extrusion printing living cells. Biomaterials Science 2013, 1, 763.
46. Tabriz, A.G.; Hermida, M.A.; Leslie, N.R.; Shu, W. Three-dimensional bioprinting of complex cell laden alginate hydrogel structures. Biofabrication 2015, 7, 045012.
3.2 Bioprinting. “Hydrogels are the most popular biomaterials found in bioinks”. Please add a reference for this statement.
We have now added new references (line 349):
78. Ji, S.; Guvendiren, M. Recent Advances in Bioink Design for 3D Bioprinting of Tissues and Organs. Front Bioeng Biotechnol 2017, 5.
79. Gelinsky, M. 6 - Biopolymer hydrogel bioinks. In 3D Bioprinting for Reconstructive Surgery; Thomas, D.J., Jessop, Z.M., Whitaker, I.S., Eds.; Woodhead Publishing, 2018; pp. 125–136 ISBN 978-0-08-101103-4.
Conclusions. Authors could add that “3D printing technology is a rapidly growing research field, and further studies are needed both in vitro and in vivo, in order to explore different application possibilities and interactions with other medical technologies”.
We have implemented the reviewers' comment in the conclusion (lines 161-164)
References. Some old references are reported (4:1988; 5:1999; 67:1998). I f possible, please change with recent research. Some studies have been suggested in the comments above.
We have implemented numerous recent references and would rather leave these important ones as well.
Tables: ok
Figures. No figure has been presented. If possible, some explanation drawings could be added to describe different printing techniques or strategies, in order to have a graphical description of these processes.
We are thankful for the constructive suggestion. We would like to refer the reader to the cited references as all the techniques have been broadly described and graphical explanations are broadly available. It would be extremely difficult to provide an innovative, original or new way to draw the described methods.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
I found this review very interesting and nicely written.
Author Response
We would like to thank the reviewers for their thoughtful reading and reviews of our manuscript
Reviewer 3 Report
This manuscript reviewed 3D printing technology used for tissue-engineered blood grafts (TEBGs). The authors summarized processes, biomaterials, cell types, and spatial dimensions in the application of TEBGs. The authors also discussed bioprinting approaches, including agarose, alginate, fibrin, collagen, gelatin, PEG, NovoGel®, and scaffold-free vascular construct. The article was well-written and the content is within the field of this journal. I recommended it to be accepted.
Author Response
We would like to thank the reviewers for their thoughtful reading and reviews of our manuscript
Round 2
Reviewer 1 Report
good job.
