Regeneration – A New Therapeutic Dimension in Otorhinolaryngology

Summary

Regeneration as a therapeutic priniciple and regenerative medicine in general are promising new strategies to add new therapeutic dimensions to our current treatment options. Today, reconstructive surgery, drugs and implants such as the cochlear implant can replace the functions of damaged tissues. In contrast, regenerative therapies aim at the replacement of the damaged tissues themselves while at the same time replacing their lost tissue function. In this review article new technologies such as 3D-bioprinting and the application of decellularised tissues as biomaterials are introduced and explained. A summary of current preclinical and clinical regenerative studies in otorhinolaryngology is complementing these basic aspects.

Key words

Regeneration - Regenerative Medicine - Tissue Engineering - Otorhinolaryngology

• Literatur

• 1 Londono R, Badylak SF. Biologic scaffolds for regenerative medicine: mechanisms of in vivo remodeling. Ann Biomed Eng 2015; 43: 577-592
• 2 Kragl M, Knapp D, Nacu E. et al. Cells keep a memory of their tissue origin during axolotl limb regeneration. Nature 2009; 460: 60-65
• 3 Voss SR, Epperlein HH, Tanaka EM. Ambystoma mexicanum, the axolotl: a versatile amphibian model for regeneration, development, and evolution studies. Cold Spring Harb Protoc 2009; 2009: pdb emo128
• 4 Godwin JW, Pinto AR, Rosenthal NA. Macrophages are required for adult salamander limb regeneration. Proc Natl Acad Sci U S A 2013; 110: 9415-9420
• 5 Atala A, Irvine DJ, Moses M. et al. Wound Healing Versus Regeneration: Role of the Tissue Environment in Regenerative Medicine. MRS Bull 2010; 35: 8
• 6 Orlando G, Soker S, Stratta RJ et al. Will regenerative medicine replace transplantation? Cold Spring Harb Perspect Med 2013; 3:
• 7 Devauchelle B, Badet L, Lengele B. et al. First human face allograft: early report. Lancet 2006; 368: 203-209
• 8 Devauchelle BL, Testelin SR, Davrou J. et al. Face graft? Extrapolation of facial allotransplantation to children. J Craniomaxillofac Surg 2016; 44: 925-933
• 9 Duisit J, Maistriaux L, Taddeo A. et al. Bioengineering a Human Face Graft: The Matrix of Identity. Ann Surg 2017; 266: 754-764
• 10 Khademhosseini A, Langer R. A decade of progress in tissue engineering. Nat Protocols 2016; 11: 1775-1781
• 11 Murphy SV, Atala A. 3D bioprinting of tissues and organs. Nat Biotechnol 2014; 32: 773-785
• 12 Hölzl K, Lin S, Tytgat L. et al. Bioink properties before, during and after 3D bioprinting. Biofabrication 2016; 8: 032002
• 13 Chimene D, Lennox KK, Kaunas RR. et al. Advanced Bioinks for 3D Printing: A Materials Science Perspective. Annals of Biomedical Engineering 2016; 44: 2090-2102
• 14 Melchels FPW, Blokzijl MM, Levato R. et al. Hydrogel-based reinforcement of 3D bioprinted constructs. Biofabrication 2016; 8: 035004
• 15 Visser J, Melchels FP, Jeon JE. et al. Reinforcement of hydrogels using three-dimensionally printed microfibres. Nat Commun 2015; 6: 6933
• 16 Pati F, Jang J, Ha DH et al. Printing three-dimensional tissue analogues with decellularized extracellular matrix bioink. Nat Commun. 2014
• 17 Louvrier A, Marty P, Barrabe A. et al. How useful is 3D printing in maxillofacial surgery?. J Stomatol Oral Maxillofac Surg 2017; 118: 206-212
• 18 Visscher DO, Farre-Guasch E, Helder MN. et al. Advances in bioprinting technologies for craniofacial reconstruction. Trends Biotechnol 2016; 34: 700-710
• 19 Kesti M, Eberhardt C, Pagliccia G. et al. Bioprinting complex cartilaginous structures with clinically compliant biomaterials. Advanced Functional Materials 2015; 25: 7406-7417
• 20 Daly A, Critchley S, Rencsok E. et al. A comparison of different bioinks for 3D bioprinting of fibrocartilage and hyaline cartilage. Biofabrication 2016; 8: 045002
• 21 Nguyen D, Hägg DA, Forsman A. et al. Cartilage tissue engineering by the 3D Bioprinting of iPS cells in a nanocellulose/alginate bioink. Scientific Reports 2017; 7: 658
• 22 Müller M, Öztürk E, Arlov Ø. et al. Alginate sulfate–nanocellulose bioinks for cartilage bioprinting applications. Annals of Biomedical Engineering 2016; 10.1007/s10439-016-1704-5 1-14
• 23 Markstedt K, Mantas A, Tournier I. et al. 3D bioprinting human chondrocytes with Nanocellulose-Alginate bioink for cartilage tissue engineering applications. Biomacromolecules 2015; 16: 1489-1496
• 24 Hourd P, Medcalf N, Segal J. et al. A 3D bioprinting exemplar of the consequences of the regulatory requirements on customized processes. Regenerative Medicine 2015; 10: 863-883
• 25 Kiyotake EA, Beck EC, Detamore MS. Cartilage extracellular matrix as a biomaterial for cartilage regeneration. Ann N Y Acad Sci 2016; 1383: 139-159
• 26 Smith BD, Grande DA. The current state of scaffolds for musculoskeletal regenerative applications. Nat Rev Rheumatol 2015; 11: 213-222
• 27 Hiew VV, Simat SFB, Teoh PL. The Advancement of Biomaterials in Regulating Stem Cell Fate. Stem Cell Rev 2017;
• 28 Sampath U, Ching YC, Chuah CH. et al. Fabrication of porous materials from natural/synthetic Biopolymers and Their Composites. Materials (Basel) 2016; 9: 12
• 29 Edgar L, McNamara K, Wong T. et al. Heterogeneity of scaffold biomaterials in tissue engineering. Materials (Basel) 2016; 9: 5
• 30 Swinehart IT, Badylak SF. Extracellular matrix bioscaffolds in tissue remodeling and morphogenesis. Dev Dyn 2016; 245: 351-360
• 31 Sadtler K, Estrellas K, Allen BW. et al. Developing a pro-regenerative biomaterial scaffold microenvironment requires T helper 2 cells. Science 2016; 352: 366-370
• 32 Badylak SF. TISSUE REGENERATION. A scaffold immune microenvironment. Science 2016; 352: 298
• 33 Bissell MJ, Aggeler J. Dynamic reciprocity: how do extracellular matrix and hormones direct gene expression?. Prog Clin Biol Res 1987; 249: 251-262
• 34 Rozario T, DeSimone DW. The extracellular matrix in development and morphogenesis: a dynamic view. Dev Biol 2010; 341: 126-140
• 35 Gattazzo F, Urciuolo A, Bonaldo P. Extracellular matrix: a dynamic microenvironment for stem cell niche. Biochim Biophys Acta 2014; 1840: 2506-2519
• 36 Cravedi P, Farouk S, Angeletti A. et al. Regenerative immunology: the immunological reaction to biomaterials. Transpl Int 2017;
• 37 Badylak SF, Brown BN, Gilbert TW. et al. Biologic scaffolds for constructive tissue remodeling. Biomaterials 2011; 32: 316-319
• 38 Petrie TA, Strand NS, Yang CT. et al. Macrophages modulate adult zebrafish tail fin regeneration. Development 2014; 141: 2581-2591
• 39 Brown BN, Sicari BM, Badylak SF. Rethinking regenerative medicine: a macrophage-centered approach. Front Immunol 2014; 5: 510
• 40 Pettitt D, Arshad Z, Davies B. et al. An assessment of the factors affecting the commercialization of cell-based therapeutics: a systematic review protocol. Syst Rev 2017; 6: 120
• 41 Brittberg M, Lindahl A, Nilsson A. et al. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 1994; 331: 889-895
• 42 Peterson L, Minas T, Brittberg M. et al. Two- to 9-year outcome after autologous chondrocyte transplantation of the knee. Clin Orthop Relat Res 2000;
• 43 Lindahl A, Brittberg M, Peterson L. Health economics benefits following autologous chondrocyte transplantation for patients with focal chondral lesions of the knee. Knee Surg Sports Traumatol Arthrosc 2001; 9: 358-363
• 44 Schuette HB, Kraeutler MJ, McCarty EC. Matrix-Assisted Autologous Chondrocyte Transplantation in the Knee: A Systematic Review of Mid- to Long-Term Clinical Outcomes. Orthop J Sports Med 2017; 5: 2325967117709250
• 45 Mumme M, Barbero A, Miot S. et al. Nasal chondrocyte-based engineered autologous cartilage tissue for repair of articular cartilage defects: an observational first-in-human trial. Lancet 2016; 388: 1985-1994
• 46 Pelttari K, Pippenger B, Mumme M. et al. Adult human neural crest-derived cells for articular cartilage repair. Sci Transl Med 2014; 6: 251ra119
• 47 Pelttari K, Mumme M, Barbero A. et al. Nasal chondrocytes as a neural crest-derived cell source for regenerative medicine. Curr Opin Biotechnol 2017; 47: 1-6
• 48 Fulco I, Miot S, Haug MD. et al. Engineered autologous cartilage tissue for nasal reconstruction after tumour resection: an observational first-in-human trial. Lancet 2014; 384: 337-346
• 49 Dodson BP, Levine AD. Challenges in the translation and commercialization of cell therapies. BMC Biotechnol 2015; 15: 70
• 50 Stace ET, Dakin SG, Mouthuy PA. et al. Translating Regenerative Biomaterials Into Clinical Practice. J Cell Physiol 2016; 231: 36-49
• 51 McLaren A. Ethical and social considerations of stem cell research. Nature 2001; 414: 129-131
• 52 Leeper NJ, Hunter AL, Cooke JP. Stem cell therapy for vascular regeneration: adult, embryonic, and induced pluripotent stem cells. Circulation 2010; 122: 517-526
• 53 Frantz S. Embryonic stem cell pioneer Geron exits field, cuts losses. Nat Biotechnol 2012; 30: 12-13
• 54 Kirouac DC, Zandstra PW. The systematic production of cells for cell therapies. Cell Stem Cell 2008; 3: 369-381
• 55 Badylak S. Perspective: Work with, not against, biology. Nature 2016; 540: S55
• 56 Yanaga H, Koga M, Imai K. et al. Clinical application of biotechnically cultured autologous chondrocytes as novel graft material for nasal augmentation. Aesthetic Plast Surg 2004; 28: 212-221
• 57 Yanaga H, Yanaga K, Imai K. et al. Clinical application of cultured autologous human auricular chondrocytes with autologous serum for craniofacial or nasal augmentation and repair. Plast Reconstr Surg 2006; 117: 2019-2030 discussion 2031-2012
• 58 Yanaga H, Imai K, Tanaka Y. et al. Two-stage transplantation of cell-engineered autologous auricular chondrocytes to regenerate chondrofat composite tissue: clinical application in regenerative surgery. Plast Reconstr Surg 2013; 132: 1467-1477
• 59 Ceccarelli G, Gentile P, Marcarelli M et al. In Vitro and In Vivo Studies of Alar-Nasal Cartilage Using Autologous Micro-Grafts: The Use of the Rigenera(R) Protocol in the Treatment of an Osteochondral Lesion of the Nose. Pharmaceuticals (Basel) 2017; 10:
• 60 Purpura V, Bondioli E, Graziano A et al. Tissue Characterization after a New Disaggregation Method for Skin Micro-Grafts Generation. J Vis Exp 2016; doi:10.3791/53579 e53579
• 61 Zhou L, Pomerantseva I, Bassett EK. et al. Engineering ear constructs with a composite scaffold to maintain dimensions. Tissue Eng Part A 2011; 17: 1573-1581
• 62 Pomerantseva I, Bichara DA, Tseng A. et al. Ear-Shaped Stable Auricular Cartilage Engineered from Extensively Expanded Chondrocytes in an Immunocompetent Experimental Animal Model. Tissue Eng Part A 2016; 22: 197-207
• 63 Cervantes TM, Bassett EK, Tseng A. et al. Design of composite scaffolds and three-dimensional shape analysis for tissue-engineered ear. J R Soc Interface 2013; 10: 20130413
• 64 Cao Y, Vacanti JP, Paige KT. et al. Transplantation of chondrocytes utilizing a polymer-cell construct to produce tissue-engineered cartilage in the shape of a human ear. Plast Reconstr Surg 1997; 100: 297-302 discussion 303-294
• 65 Lee SJ, Broda C, Atala A. et al. Engineered cartilage covered ear implants for auricular cartilage reconstruction. Biomacromolecules 2011; 12: 306-313
• 66 Yanaga H, Imai K, Fujimoto T. et al. Generating ears from cultured autologous auricular chondrocytes by using two-stage implantation in treatment of microtia. Plast Reconstr Surg 2009; 124: 817-825
• 67 Yanaga H, Imai K, Koga M. et al. Cell-engineered human elastic chondrocytes regenerate natural scaffold in vitro and neocartilage with neoperichondrium in the human body post-transplantation. Tissue Eng Part A 2012; 18: 2020-2029
• 68 Firmin F. Ear reconstruction in cases of typical microtia. Personal experience based on 352 microtic ear corrections. Scand J Plast Reconstr Surg Hand Surg 1998; 32: 35-47
• 69 Firmin F. State-of-the-art autogenous ear reconstruction in cases of microtia. Adv Otorhinolaryngol 2010; 68: 25-52
• 70 Utomo L, Pleumeekers MM, Nimeskern L. et al. Preparation and characterization of a decellularized cartilage scaffold for ear cartilage reconstruction. Biomed Mater 2015; 10: 015010
• 71 Ozmen OA, Falcioni M, Lauda L. et al. Outcomes of facial nerve grafting in 155 cases: predictive value of history and preoperative function. Otol Neurotol 2011; 32: 1341-1346
• 72 Ray WZ, Mackinnon SE. Management of nerve gaps: autografts, allografts, nerve transfers, and end-to-side neurorrhaphy. Exp Neurol 2010; 223: 77-85
• 73 Gaudin R, Knipfer C, Henningsen A. et al. Approaches to Peripheral Nerve Repair: Generations of Biomaterial Conduits Yielding to Replacing Autologous Nerve Grafts in Craniomaxillofacial Surgery. Biomed Res Int 2016; 2016: 3856262
• 74 Brunelli GA, Vigasio A, Brunelli GR. Different conduits in peripheral nerve surgery. Microsurgery 1994; 15: 176-178
• 75 Navissano M, Malan F, Carnino R. et al. Neurotube for facial nerve repair. Microsurgery 2005; 25: 268-271
• 76 Jiang X, Lim SH, Mao HQ. et al. Current applications and future perspectives of artificial nerve conduits. Exp Neurol 2010; 223: 86-101
• 77 Inada Y, Hosoi H, Yamashita A. et al. Regeneration of peripheral motor nerve gaps with a polyglycolic acid-collagen tube: technical case report. Neurosurgery 2007; 61: E1105-E1107 discussion E1107
• 78 Yamanaka T, Hosoi H, Murai T. et al. Regeneration of the nerves in the aerial cavity with an artificial nerve conduit – reconstruction of chorda tympani nerve gaps. PLoS One 2014; 9: e92258
• 79 Gunn S, Cosetti M, Roland Jr. JT. Processed allograft: novel use in facial nerve repair after resection of a rare racial nerve paraganglioma. Laryngoscope 2010; 120 (Suppl. 04) S206
• 80 Kusaba H, Terada-Nakaishi M, Wang W. et al. Comparison of nerve regenerative efficacy between decellularized nerve graft and nonwoven chitosan conduit. Biomed Mater Eng 2016; 27: 75-85
• 81 Wang W, Itoh S, Takakuda K. Comparative study of the efficacy of decellularization treatment of allogenic and xenogeneic nerves as nerve conduits. J Biomed Mater Res A 2016; 104: 445-454
• 82 Wust S, Muller R, Hofmann S. 3D Bioprinting of complex channels-Effects of material, orientation, geometry, and cell embedding. J Biomed Mater Res A 2015; 103: 2558-2570
• 83 Roy N, Merrill RM, Gray SD. et al. Voice disorders in the general population: prevalence, risk factors, and occupational impact. Laryngoscope 2005; 115: 1988-1995
• 84 Benninger MS, Alessi D, Archer S. et al. Vocal fold scarring: current concepts and management. Otolaryngol Head Neck Surg 1996; 115: 474-482
• 85 Li L, Stiadle JM, Lau HK. et al. Tissue engineering-based therapeutic strategies for vocal fold repair and regeneration. Biomaterials 2016; 108: 91-110
• 86 Fishman JM, Wiles K, Lowdell MW. et al. Airway tissue engineering: an update. Expert Opin Biol Ther 2014; 14: 1477-1491
• 87 Fishman JM, Long J, Gugatschka M. et al. Stem cell approaches for vocal fold regeneration. Laryngoscope 2016; 126: 1865-1870
• 88 Bartlett RS, Thibeault SL, Prestwich GD. Therapeutic potential of gel-based injectables for vocal fold regeneration. Biomed Mater 2012; 7: 024103
• 89 Ling C, Li Q, Brown ME. et al. Bioengineered vocal fold mucosa for voice restoration. Sci Transl Med 2015; 7: 314ra187
• 90 Hung SH, Su CH, Lee FP. et al. Larynx decellularization: combining freeze-drying and sonication as an effective method. J Voice 2013; 27: 289-294
• 91 Baiguera S, Gonfiotti A, Jaus M. et al. Development of bioengineered human larynx. Biomaterials 2011; 32: 4433-4442
• 92 Hamilton NJI, Birchall MA. Tissue-Engineered Larynx: Future Applications in Laryngeal Cancer. Curr Otorhinolaryngol Rep 2017; 5: 42-48
• 93 Farwell DG, Birchall MA, Macchiarini P. et al. Laryngotracheal transplantation: technical modifications and functional outcomes. Laryngoscope 2013; 123: 2502-2508
• 94 Krishnan G, Du C, Fishman JM. et al. The current status of human laryngeal transplantation in 2017: A state of the field review. Laryngoscope 2017; 127: 1861-1868
• 95 Zopf DA, Hollister SJ, Nelson ME. et al. Bioresorbable airway splint created with a three-dimensional printer. N Engl J Med 2013; 368: 2043-2045
• 96 Delaere PR, Van Raemdonck D. The trachea: the first tissue-engineered organ?. J Thorac Cardiovasc Surg 2014; 147: 1128-1132
• 97 Delaere P, Van Raemdonck D. Tracheal replacement. J Thorac Dis 2016; 8: S186-S196
• 98 Macchiarini P, Jungebluth P, Go T. et al. Clinical transplantation of a tissue-engineered airway. Lancet 2008; 372: 2023-2030
• 99 Vogel G. Trachea transplants test the limits. Science 2013; 340: 266-268
• 100 Cyranoski D. Surgeon commits misconduct. Nature 2015; 521: 406-407
• 101 Hamilton NJ, Kanani M, Roebuck DJ. et al. Tissue-Engineered Tracheal Replacement in a Child: A 4-Year Follow-Up Study. Am J Transplant 2015; 15: 2750-2757
• 102 Elliott MJ, De Coppi P, Speggiorin S. et al. Stem-cell-based, tissue engineered tracheal replacement in a child: a 2-year follow-up study. Lancet 2012; 380: 994-1000
• 103 Villar-Fernandez MA, Lopez-Escamez JA. Outlook for Tissue Engineering of the Tympanic Membrane. Audiol Res 2015; 5: 117
• 104 Kanemaru S, Umeda H, Kitani Y. et al. Regenerative treatment for tympanic membrane perforation. Otol Neurotol 2011; 32: 1218-1223
• 105 Jackler RK. A regenerative method of tympanic membrane repair could be the greatest advance in otology since the cochlear implant. Otol Neurotol 2012; 33: 289
• 106 Omae K, Kanemaru SI, Nakatani E. et al. Regenerative treatment for tympanic membrane perforation using gelatin sponge with basic fibroblast growth factor. Auris Nasus Larynx 2017; 44: 664-671
• 107 Kanemaru S, Umeda H, Kanai R. et al. Regenerative treatment for soft tissue defects of the external auditory meatus. Otol Neurotol 2014; 35: 442-448
• 108 Kuo CY, Wilson E, Fuson A. et al. Repair of Tympanic Membrane Perforations with Customized Bioprinted Ear Grafts Using Chinchilla Models. Tissue Eng Part A 2017;
• 109 Vos JD, Latev MD, Labadie RF. et al. Use of AlloDerm in type I tympanoplasty: a comparison with native tissue grafts. Laryngoscope 2005; 115: 1599-1602
• 110 Haynes DS, Vos JD, Labadie RF. Acellular allograft dermal matrix for tympanoplasty. Curr Opin Otolaryngol Head Neck Surg 2005; 13: 283-286
• 111 Fishman AJ, Marrinan MS, Huang TC. et al. Total tympanic membrane reconstruction: AlloDerm versus temporalis fascia. Otolaryngol Head Neck Surg 2005; 132: 906-915
• 112 Kaftan H. [Tympanic membrane reconstruction with non-autogenous transplants and alloplastic materials]. Laryngorhinootologie 2010; 89: 562-568 quiz 569-570
• 113 Schwarz D, Pazen D, Gosz K. et al. Acoustic Properties of Collagenous Matrices of Xenogenic Origin for Tympanic Membrane Reconstruction. Otol Neurotol 2016; 37: 692-697
• 114 Kanemaru S, Nakamura T, Omori K. et al. Regeneration of mastoid air cells: clinical applications. Acta Otolaryngol Suppl 2004;
• 115 Kanemaru S, Nakamura T, Omori K. et al. Regeneration of mastoid air cells in clinical applications by in situ tissue engineering. Laryngoscope 2005; 115: 253-258
• 116 Sade J, Luntz M, Levy D. Middle ear gas composition and middle ear aeration. Ann Otol Rhinol Laryngol 1995; 104: 369-373
• 117 Kanemaru S, Umeda H, Yamashita M. et al. Improvement of eustachian tube function by tissue-engineered regeneration of mastoid air cells. Laryngoscope 2013; 123: 472-476
• 118 Gould TW, Birchall JP, Mallick AS. et al. Development of a porous poly(DL-lactic acid-co-glycolic acid)-based scaffold for mastoid air-cell regeneration. Laryngoscope 2013; 123: 3156-3161
• 119 Jang CH, Cho YB, Kim JS. et al. Regeneration of mastoid air cells using polycaprolactone/beta-tricalcium phosphate biocomposites: an experimental study. Laryngoscope 2012; 122: 660-664
• 120 Lyon J. Hearing Restoration: A Step Closer?. JAMA 2017; 318: 319-320
• 121 McLean WJ, Yin X, Lu L. et al. Clonal Expansion of Lgr5-Positive Cells from Mammalian Cochlea and High-Purity Generation of Sensory Hair Cells. Cell Rep 2017; 18: 1917-1929
• 122 Vergeer MR, Doornaert PA, Rietveld DH. et al. Intensity-modulated radiotherapy reduces radiation-induced morbidity and improves health-related quality of life: results of a nonrandomized prospective study using a standardized follow-up program. Int J Radiat Oncol Biol Phys 2009; 74: 1-8
• 123 Scott-Brown M, Miah A, Harrington K. et al. Evidence-based review: quality of life following head and neck intensity-modulated radiotherapy. Radiother Oncol 2010; 97: 249-257
• 124 Riley P, Glenny AM, Hua F. et al. Pharmacological interventions for preventing dry mouth and salivary gland dysfunction following radiotherapy. Cochrane Database Syst Rev 2017; 7: CD012744
• 125 van Luijk P, Pringle S, Deasy JO. et al. Sparing the region of the salivary gland containing stem cells preserves saliva production after radiotherapy for head and neck cancer. Sci Transl Med 2015; 7: 305ra147
• 126 Lombaert I, Movahednia MM, Adine C. et al. Concise Review: Salivary Gland Regeneration: Therapeutic Approaches from. Stem Cells to Tissue Organoids. Stem Cells 2017; 35: 97-105
• 127 Nagler RM. The enigmatic mechanism of irradiation-induced damage to the major salivary glands. Oral Dis 2002; 8: 141-146
• 128 Nagler RM. Effects of head and neck radiotherapy on major salivary glands – animal studies and human implications. In Vivo 2003; 17: 369-375
• 129 Redman RS. On approaches to the functional restoration of salivary glands damaged by radiation therapy for head and neck cancer, with a review of related aspects of salivary gland morphology and development. Biotech Histochem 2008; 83: 103-130
• 130 Schwarz S, Huss R, Schulz-Siegmund M. et al. Bone marrow-derived mesenchymal stem cells migrate to healthy and damaged salivary glands following stem cell infusion. Int J Oral Sci 2014; 6: 154-161
• 131 Lim JY, Yi T, Choi JS. et al. Intraglandular transplantation of bone marrow-derived clonal mesenchymal stem cells for amelioration of post-irradiation salivary gland damage. Oral Oncol 2013; 49: 136-143
• 132 Lim JY, Ra JC, Shin IS. et al. Systemic transplantation of human adipose tissue-derived mesenchymal stem cells for the regeneration of irradiation-induced salivary gland damage. PLoS One 2013; 8: e71167
• 133 Sumita Y, Liu Y, Khalili S. et al. Bone marrow-derived cells rescue salivary gland function in mice with head and neck irradiation. Int J Biochem Cell Biol 2011; 43: 80-87
• 134 Pringle S, Nanduri LS, van der Zwaag M. et al. Isolation of mouse salivary gland stem cells. J Vis Exp 2011;
• 135 Pringle S, Maimets M, van der Zwaag M. et al. Human Salivary Gland Stem Cells Functionally Restore Radiation Damaged Salivary Glands. Stem Cells 2016; 34: 640-652
• 136 Nanduri LS, Maimets M, Pringle SA. et al. Regeneration of irradiated salivary glands with stem cell marker expressing cells. Radiother Oncol 2011; 99: 367-372
• 137 Lombaert IM, Brunsting JF, Wierenga PK. et al. Rescue of salivary gland function after stem cell transplantation in irradiated glands. PLoS One 2008; 3: e2063
• 138 Comella K, Bell W. First-in-man intraglandular implantation of stromal vascular fraction and adipose-derived stem cells plus platelet-rich plasma in irradiation-induced gland damage: a case study. Int Med Case Rep J 2017; 10: 295-299
• 139 Gronhoj C, Jensen DH, Glovinski PV. et al. First-in-man mesenchymal stem cells for radiation-induced xerostomia (MESRIX): study protocol for a randomized controlled trial. Trials 2017; 18: 108
• 140 Ferreira JN, Rungarunlert S, Urkasemsin G. et al. Three-Dimensional Bioprinting Nanotechnologies towards Clinical Application of Stem Cells and Their Secretome in Salivary Gland Regeneration. Stem Cells Int 2016; 2016: 7564689
• 141 Flores RL, Liss H, Raffaelli S. et al. The technique for 3D printing patient-specific models for auricular reconstruction. PlumX Metrics 2017; 6: 937-943
• 142 Otto IA, Melchels FPM, Randolph MA et al. Auricular reconstruction using biofabrication-based tissue engineering strategies. Biofabrication 2015; 7 (3)