In recent years, three-dimensional (3D)-printing of tissue-engineered cartilaginous scaffolds is intended to close the surgical gap and provide bio-printed tissue designed to fit the specific geometric and functional requirements of each cartilage defect, avoiding donor site morbidity and offering a personalizing therapy.
To investigate the role of 3D—bioprinting scaffolding for nasal cartilage defects repair a systematic review of the electronic databases for 3D-Bioprinting articles pertaining to nasal cartilage bio-modelling was performed. The primary focus was to investigate cellular source, type of scaffold utilization, biochemical evaluation, histological analysis, in-vitro study, in-vivo study, animal model used, length of research, and placement of experimental construct and translational investigation.
From 1011 publications, 16 studies were kept for analysis. About cellular sources described, most studies used primary chondrocyte cultures. The cartilage used for cell isolation was mostly nasal septum. The most common biomaterial used for scaffold creation was polycaprolactone alone or in combination. About mechanical evaluation, we found a high heterogeneity, making it difficult to extract any solid conclusion. Regarding biological and histological characteristics of each scaffold, we found that the expression of collagen type I, collagen Type II and other ECM components were the most common patterns evaluated through immunohistochemistry on in-vitro and in-vivo studies. Only two studies made an orthotopic placement of the scaffolds. However, in none of the studies analyzed, the scaffold was placed in a subperichondrial pocket to rigorously simulate the cartilage environment. In contrast, scaffolds were implanted in a subcutaneous plane in almost all of the studies included.
The role of 3D—bioprinting scaffolding for nasal cartilage defects repair is growing field. Despite the amount of information collected in the last years and the first surgical applications described recently in humans. Further investigations are needed due to the heterogeneity on mechanical evaluation parameters, the high level of heterotopic scaffold implantation and the need for quantitative histological data.
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Hull CW. Inventor; Uvp Inc., original assignee. Apparatus for production of three-dimensional objects by stereolithography. US Patent US4575330A (1986). https://www.google.com/patents/US4575330. Accessed 11 Oct 2020.
Kruth JP, Leu MC, Nakagawa T. Progress in additive manufacturing and rapid prototyping. CIRP Ann Manuf Technol. 1998;47:525–40.
Melchels FP, Domingos MA, Klein TJ, Malda J, Bartolo PJ, Hutmacher DW. Additive manufacturing of tissues and organs. Prog Polym Sci. 2012;37:1079–104.
Bak D. Rapid prototyping or rapid production? 3D printing processes move industry towards the latter. Assem Autom. 2003;23:340–5.
Setton LA, Elliott DM, Mow VC. Altered mechanics of cartilage with osteoarthritis: human osteoarthritis and an experimental model of joint degeneration. Osteoarthritis Cartilage. 1999;7:2–14.
Jackson DW, Scheer MJ, Simon TM. Cartilage substitutes: overview of basic science and treatment options. J Am Acad Orthop Surg. 2001;9:37–52.
Rengier F, Mehndiratta A, von Tengg-Kobligk H, Zechmann CM, Unterhinninghofen R, Kauczor HU, et al. 3D printing based on imaging data: review of medical applications. Int J Comput Assist Radiol Surg. 2010;5:335–41.
Kushnaryov A, Yamaguchi T, Briggs K, Reuther MS, Watson D, Masuda K, et al. Evaluation of autogenous engineered septal cartilage grafts in rabbits: a minimally invasive preclinical model. Otolaryngol Head Neck Surg. 2013;149:37–8.
Fulco I, Miot S, Haug MD, Barbero A, Wixmerten A, Feliciano S, et al. Engineered autologous cartilage tissue for nasal reconstruction after tumour resection: an observational first-in-human trial. Lancet. 2014;384:337–46.
Niermeyer WL, Rodman C, Li MM, Chiang T. Tissue engineering applications in otolaryngology-the state of translation. Laryngoscope Investig Otolaryngol. 2020;5:630–48.
Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA group. preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.
OCEBM Levels of Evidence Working Group. “The Oxford 2011 levels of evidence.” Oxford centre for evidence-based medicine. 2011. http://www.cebm.net/index.aspx?o=5653.
Wei D, Tang K, Wang Q, Estill J, Yao L, Wang X, et al. The use of GRADE approach in systematic reviews of animal studies. J Evid Based Med. 2016;9:98–104.
Shafiee A, Seyedjafari E, Sadat Taherzadeh E, Dinarvand P, Soleimani M, Ai J. Enhanced chondrogenesis of human nasal septum derived progenitors on nanofibrous scaffolds. Mater Sci Eng C Mater Biol Appl. 2014;40:445–54.
Zopf DA, Mitsak AG, Flanagan CL, Wheeler M, Green GE, Hollister SJ. Computer aided-designed, 3-dimensionally printed porous tissue bioscaffolds for craniofacial soft tissue reconstruction. Otolaryngol Head Neck Surg. 2015;152:57–62.
Xu Y, Fan F, Kang N, Wang S, You J, Wang H, et al. Tissue engineering of human nasal alar cartilage precisely by using three-dimensional printing. Plast Reconstr Surg. 2015;135:451–8.
Kim YS, Shin YS, Park DY, Choi JW, Park JK, Kim DH, et al. The application of three-dimensional printing in animal model of augmentation rhinoplasty. Ann Biomed Eng. 2015;43:2153–62.
Park SH, Yun BG, Won JY, Yun WS, Shim JH, Lim MH, et al. New application of three-dimensional printing biomaterial in nasal reconstruction. Laryngoscope. 2017;127:1036–43.
Möller T, Amoroso M, Hägg D, Brantsing C, Rotter N, Apelgren P, et al. In vivo chondrogenesis in 3D bioprinted human cell-laden hydrogel constructs. Plast Reconstr Surg Glob Open. 2017;5:e1227.
Apelgren P, Amoroso M, Lindahl A, Brantsing C, Rotter N, Gatenholm P, et al. Chondrocytes and stem cells in 3D-bioprinted structures create human cartilage in vivo. PLoS One. 2017;12:e0189428.
Rajzer I, Kurowska A, Jabłoński A, Jatteau S, Śliwka M, Ziąbka M, et al. Layered gelatin/PLLA scaffolds fabricated by electrospinning and 3D printing- for nasal cartilages and subchondral bone reconstruction. Mater Des. 2018;155:297–306.
Morrison RJ, Nasser HB, Kashlan KN, Zopf DA, Milner DJ, Flanangan CL, et al. Co-culture of adipose-derived stem cells and chondrocytes on three-dimensionally printed bioscaffolds for craniofacial cartilage engineering. Laryngoscope. 2018;128:E251–7.
Kim DH, Lim MH, Jeun JH, Park SH, Lee W, Park SH, et al. Evaluation of polycaprolactone-associated human nasal chondrocytes as a therapeutic agent for cartilage repair. Tissue Eng Regen Med. 2019;16:605–14.
Xia H, Zhao D, Zhu H, Hua Y, Xiao K, Xu Y, et al. Lyophilized scaffolds fabricated from 3D-printed photocurable natural hydrogel for cartilage regeneration. ACS Appl Mater Interfaces. 2018;10:31704–15.
Wiggenhauser PS, Schwarz S, Koerber L, Hoffmann TK, Rotter N. Addition of decellularized extracellular matrix of porcine nasal cartilage improves cartilage regenerative capacities of PCL-based scaffolds in vitro. J Mater Sci Mater Med. 2019;30:121.
Yi HG, Choi YJ, Jung JW, Jang J, Song TH, Chae S, et al. Three-dimensional printing of a patient-specific engineered nasal cartilage for augmentative rhinoplasty. J Tissue Eng. 2019;10:2041731418824797.
Kim DH, Yun WS, Shim JH, Park KH, Choi D, Park MI, et al. Clinical application of 3-dimensional printing technology for patients with nasal septal deformities: a multicenter study. JAMA Otolaryngol Head Neck Surg. 2018;144:1145–52.
Ruiz-Cantu L, Gleadall A, Faris C, Segal J, Shakesheff K, Yang J. Multi-material 3D bioprinting of porous constructs for cartilage regeneration. Mater Sci Eng C Mater Biol Appl. 2020;109:110578.
Rajzer I, Kurowska A, Jabłoński A, Kwiatkowski R, Piekarczyk W, Hajduga MB, et al. Scaffolds modified with graphene as future implants for nasal cartilage. J Mater Sci. 2020;55:4030–42.
Jodat YA, Kiaee K, Vela Jarquin D, De la Garza Hernández RL, Wang T, Joshi S, et al. A 3D-printed hybrid nasal cartilage with functional electronic olfaction. Adv Sci (Weinh). 2020;7:1901878.
Dhandayuthapani B, Yoshida Y, Maekawa T, Kumar DS. Polymeric scaffolds in tissue engineering application: a review. Int J Polym Sci. 2011;2011:290602.
Atala A. Tissue engineering of reproductive tissues and organs. Fertil Steril. 2012;98:21–9.
Forbes SJ, Rosenthal N. Preparing the ground for tissue regeneration: from mechanism to therapy. Nat Med. 2014;20:857–69.
Lindahl A. From gristle to chondrocyte transplantation: treatment of cartilage injuries. Philos Trans R Soc Lond B Biol Sci. 2015;370:20140369.
Brent B. The correction of mi-rotia with autogenous cartilage grafts: I. The classic deformity. Plast Reconstr Surg. 1980;66:1–12.
Firmin F. State-of-the-art autogenous ear reconstruction in cases of microtia. In: Staudenmaier R, editor. Aesthetics and functionality in ear reconstruction. Basel: Karger Publishers; 2010. p. 25–52.
Zopf DA, Iams W, Kim JC, Baker SR, Moyer JS. Full-thickness skin graft overlying a separately harvested auricular cartilage graft for nasal alar reconstruction. JAMA Facial Plast Surg. 2013;15:131–4.
Firmin F, Marchac A. A novel algorithm for autologous ear reconstruction. Semin Plast Surg. 2011;25:257–64.
Osorno G. Autogenous rib cartilage reconstruction of congenital ear defects: report of 110 cases with Brent’s technique. Plast Reconstr Surg. 1999;104:1951–62.
Romo T 3rd, Presti PM, Yalamanchili HR. Medpor alternative for microtia repair. Facial Plast Surg Clin North Am. 2006;14:129–36.
Zhao YY, Zhuang HX, Jiang HY, Jiang WJ, Hu XG, Hu SD, et al. Clinical application of three methods for total ear reconstruction. Zhonghua Zheng Xing Wai Ke Za Zhi. 2008;24:287–90.
Tian H, Tang Z, Zhuang X, Chen X, Jing X. Biodegradable synthetic polymers: preparation, functionalization and biomedical application. Prog Polym Sci. 2012;37:237–80.
O’Brien FJ. Biomaterials and scaffolds for tissue engineering. Mater Today (Kidlington). 2011;14:88–95.
Bose S, Vahabzadeh S, Bandyopadhyay A. Bone tissue engineering using 3D printing. Mater Today (Kidlington). 2013;16:496–504.
Gauvin R, Chen YC, Lee JW, Soman P, Zorlutuna P, Nichol JW, et al. Microfabrication of complex porous tissue engineering scaffolds using 3D projection stereolithography. Biomaterials. 2012;33:3824–34.
Martin JR, Gupta MK, Page JM, Yu F, Davidson JM, Guelcher SA, et al. A porous tissue engineering scaffold selectively degraded by cell-generated reactive oxygen species. Biomaterials. 2014;35:3766–76.
Teh TK, Toh SL, Goh JC. Aligned hybrid silk scaffold for enhanced differentiation of mesenchymal stem cells into ligament fibroblasts. Tissue Eng Part C Methods. 2011;17:687–703.
Unadkat HV, Hulsman M, Cornelissen K, Papenburg BJ, Truckenmüller RK, Carpenter AE, et al. An algorithm-based topographical biomaterials library to instruct cell fate. Proc Natl Acad Sci U S A. 2011;108:16565–70.
Thomas V, Jose MV, Chowdhury S, Sullivan JF, Dean DR, Vohra YK. Mechano-morphological studies of aligned nanofibrous scaffolds of polycaprolactone fabricated by electrospinning. J Biomater Sci Polym Ed. 2006;17:969–84.
Bedi A, Feeley BT, Williams RJ 3rd. Management of articular cartilage defects of the knee. J Bone Joint Surg Am. 2010;92:994–1009.
Discher DE, Janmey P, Wang YL. Tissue cells feel and respond to the stiffness of their substrate. Science. 2005;310:1139–43.
Homicz MR, McGowan KB, Lottman LM, Beh G, Sah RL, Watson D. A compositional analysis of human nasal septal cartilage. Arch Facial Plast Surg. 2003;5:53–8.
Bas O, De-Juan-Pardo EM, Meinert C, D’Angella D, Baldwin JG, Bray LJ, et al. Biofabricated soft network composites for cartilage tissue engineering. Biofabrication. 2017;9:025014.
Kafienah W, Jakob M, Démarteau O, Frazer A, Barker MD, Martin I, et al. Three-dimensional tissue engineering of hyaline cartilage: comparison of adult nasal and articular chondrocytes. Tissue Eng. 2002;8:817–26.
Rotter N, Bonassar LJ, Tobias G, Lebl M, Roy AK, Vacanti CA. Age dependence of biochemical and biomechanical properties of tissue-engineered human septal cartilage. Biomaterials. 2002;23:3087–94.
Tay AG, Farhadi J, Suetterlin R, Pierer G, Heberer M, Martin I. Cell yield, proliferation, and postexpansion differentiation capacity of human ear, nasal, and rib chondrocytes. Tissue Eng. 2004;10:762–70.
Liu X, Sun H, Yan D, Zhang L, Lv X, Liu T, et al. In vivo ectopic chondrogenesis of BMSCs directed by mature chondrocytes. Biomaterials. 2010;31:9406–14.
Keller B, Yang T, Chen Y, Munivez E, Bertin T, Zabel B, et al. Interaction of TGFbeta and BMP signaling pathways during chondrogenesis. PLoS One. 2011;6:e316421.
Kim JS, Ryoo ZY, Chun JS. Cytokine-like 1 (Cytl1) regulates the chondrogenesis of mesenchymal cells. J Biol Chem. 2007;282:29359–67.
Choi YS, Lim SM, Shin HC, Lee CW, Kim SL, Kim DI. Chondrogenesis of human periostiumderived progenitor cells in atelocollagen. Biotechnol Lett. 2007;29:323–9.
Mo XT, Guo SC, Xie HQ, Deng L, Zhi W, Xiang Z, et al. Variations in the ratios of co-cultured mesenchymal stem cells and chondrocytes regulate the expression of cartilaginous and osseous phenotype in alginate constructs. Bone. 2009;45:42–51.
Shieh SJ, Terada S, Vacanti JP. Tissue engineering auricular reconstruction: in vitro and in vivo studies. Biomaterials. 2004;25:1545–57.
Zhou L, Pomerantseva I, Bassett EK, Bowley CM, Zhao X, Bichara DA, et al. Engineering ear constructs with a composite scaffold to maintain dimensions. Tissue Eng Part A. 2011;17:1573–81.
Xue J, Feng B, Zheng R, Lu Y, Zhou G, Liu W, et al. Engineering earshaped cartilage using electrospun fibrous membranes of gelatin/polycaprolactone. Biomaterials. 2013;34:2624–31.
Ruszymah BH, Chua KH, Mazlyzam AL, Aminuddin BS. Formation of tissue engineered composite construct of cartilage and skin using high density polyethylene as inner scaffold in the shape of human helix. Int J Pediatr Otorhinolaryngol. 2011;75:805–10.
Yanaga H, Imai K, Fujimoto T, Yanaga K. Generating ears from cultured autologous auricular chondrocytes by using two-stage implantation in treatment of microtia. Plast Reconstr Surg. 2009;124:817–25.
von der Mark K, Gauss V, von der Mark H, Müller P. Relationship between cell shape and type of collagen synthesised as chondrocytes lose their cartilage phenotype in culture. Nature. 1977;267:531–2.
Kusuhara H, Isogai N, Enjo M, Otani H, Ikada Y, Jacquet R, et al. Tissue engineering a model for the human ear: assessment of size, shape, morphology, and gene expression following seeding of different chondrocytes. Wound Repair Regen. 2009;17:136–46.
Tsutsumi S, Shimazu A, Miyazaki K, Pan H, Koike C, Yoshida E, et al. Retention of multilineage differentiation potential of mesenchymal cells during proliferation in response to FGF. Biochem Biophys Res Commun. 2001;288:413–9.
Martin I, Shastri VP, Padera RF, Yang J, Mackay AJ, Langer R, et al. Selective differentiation of mammalian bone marrow stromal cells cultured on three-dimensional polymer foams. J Biomed Mater Res. 2001;55:229–35.
Hwang NS, Elisseeff J. Application of stem cells for articular cartilage regeneration. J Knee Surg. 2009;22:60–71.
Hickok NJ, Haas AR, Tuan RS. Regulation of chondrocyte differentiation and maturation. Microsc Res Tech. 1998;43:174–90.
Merceron C, Vinatier C, Portron S, Masson M, Amiaud J, Guigand L, et al. Differential effects of hypoxia on osteochondrogenic potential of human adipose-derived stem cells. Am J Physiol Cell Physiol. 2010;298:C355–64.
Zhang L, Hu J, Athanasiou KA. The role of tissue engineering in articular cartilage repair and regeneration. Crit Rev Biomed Eng. 2009;37:1–57.
Ferril GR, Wudel JM, Winkler AA. Management of complications from alloplastic implants in rhinoplasty. Curr Opin Otolaryngol Head Neck Surg. 2013;21:372–8.
Glasgold MJ, Kato YP, Christiansen D, Hauge JA, Glasgold AI, Silver FH. Mechanical properties of septal cartilage homografts. Otolaryngol Head Neck Surg. 1988;99:374–9.
Li X, Cui R, Sun L, Aifantis KE, Fan Y, Feng Q, et al. 3D-printed biopolymers for tissue engineering application. Int J Polym Sci. 2014;2014:829145. https://doi.org/10.1155/2014/829145.
Dang JM, Leong KW. Natural polymers for gene delivery and tissue engineering. Adv Drug Deliv Rev. 2006;58:487–99.
Liu M, Zeng X, Ma C, Yi H, Ali Z, Mou X, et al. Injectable hydrogels for cartilage and bone tissue engineering. Bone Res. 2017;5:17014.
Wiggenhauser PS, Schantz JT, Rotter N. Cartilage engineering in reconstructive surgery: auricular, nasal and tracheal engineering from a surgical perspective. Regen Med. 2017;12:303–14.
Elsaesser AF, Bermueller C, Schwarz S, Koerber L, Breiter R, Rotter N. In vitro cytotoxicity and in vivo effects of a decellularized xenogeneic collagen scaffold in nasal cartilage repair. Tissue Eng Part A. 2014;20:1668–78.
Goldberg-Bockhorn E, Schwarz S, Elsässer A, Seitz A, Körber L, Dürselen L, et al. Physical characterization of decellularized cartilage matrix for reconstructive rhinosurgery. Laryngorhinootologie. 2014;93:756–63.
Schwarz S, Elsaesser AF, Koerber L, Goldberg-Bockhorn E, Seitz AM, Bermueller C, et al. Processed xenogenic cartilage as innovative biomatrix for cartilage tissue engineering: effects on chondrocyte differentiation and function. J Tissue Eng Regen Med. 2015;9:E239–51.
Schwarz S, Koerber L, Elsaesser AF, Goldberg-Bockhorn E, Seitz AM, Durselen L, et al. Decellularized cartilage matrix as a novel biomatrix for cartilage tissue-engineering applications. Tissue Eng Part A. 2012;18:2195–209.
Guillotin B, Guillemot F. Cell patterning technologies for organotypic tissue fabrication. Trends Biotechnol. 2011;29:183–90.
Frampton JP, Hynd MR, Shuler ML, Shain W. Fabrication and optimization of alginate hydrogel constructs for use in 3D neural cell culture. Biomed Mater. 2011;6:015002.
Martínez Ávila H, Feldmann EM, Pleumeekers MM, Nimeskern L, Kuo W, de Jong WC, et al. Novel bilayer bacterial nanocellulose scaffold supports neocartilage formation in vitro and in vivo. Biomaterials. 2015;44:122–33.
Wu L, Leijten JC, Georgi N, Post JN, van Blitterswijk CA, Karperien M. Trophic effects of mesenchymal stem cells increase chondrocyte proliferation and matrix formation. Tissue Eng Part A. 2011;17:1425–36.
Zuo Q, Cui W, Liu F, Wang Q, Chen Z, Fan W. Co-cultivated mesenchymal stem cells support chondrocytic differentiation of articular chondrocytes. Int Orthop. 2013;37:747–52.
Wu L, Prins HJ, Helder MN, van Blitterswijk CA, Karperien M. Trophic effects of mesenchymal stem cells in chondrocyte co-cultures are independent of culture conditions and cell sources. Tissue Eng Part A. 2012;18:1542–51.
de Windt TS, Hendriks JA, Zhao X, Vonk LA, Creemers LB, Dhert WJ, et al. Concise review: unraveling stem cell cocultures in regenerative medicine: which cell interactions steer cartilage regeneration and how? Stem Cells Transl Med. 2014;3:723–33.
Leijten JC, Georgi N, Wu L, van Blitterswijk CA, Karperien M. Cell sources for articular cartilage repair strategies: shifting from monocultures to cocultures. Tissue Eng Part B Rev. 2013;19:31–40.
Chiesa-Estomba C, González-Fernández I, Iglesias-Otero M. 3D printing for biomedical applications: where arewe now? Eur Med J. 2017;2:16–22.
Conceptualization, C.M.C.E. and A.A.; methodology, C.M.C.E.; validation, A.I., X.A. and I.G.; formal analysis, C.M.C.E. and R.H; investigation, C.R. and A.D.; data curation, J.P. and J.A; writing—original draft preparation, C.M.C.E.; writing—review and editing, C.M.C.E.; supervision. All authors have read and agreed to the published version of the manuscript.
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Chiesa-Estomba, C.M., Aiastui, A., González-Fernández, I. et al. Three-Dimensional Bioprinting Scaffolding for Nasal Cartilage Defects: A Systematic Review. Tissue Eng Regen Med (2021). https://doi.org/10.1007/s13770-021-00331-6