We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Decellularized human-sized pulmonary scaffolds for lung tissue engineering: a comprehensive review

    Seyed Hossein Mahfouzi

    Department of Biomedical Engineering, The Research Center for New Technologies in Life Science Engineering, University of Tehran, No. 4, Orouji all., 16 Azar St., 11155-4563, Tehran, Iran

    ,
    Seyed Hamid Safiabadi Tali

    Department of Biomedical Engineering, The Research Center for New Technologies in Life Science Engineering, University of Tehran, No. 4, Orouji all., 16 Azar St., 11155-4563, Tehran, Iran

    &
    Ghassem Amoabediny

    *Author for correspondence:

    E-mail Address: amoabediny@ut.ac.ir

    Department of Biomedical Engineering, The Research Center for New Technologies in Life Science Engineering, University of Tehran, No. 4, Orouji all., 16 Azar St., 11155-4563, Tehran, Iran

    Department of Biotechnology & Pharmaceutical Engineering, School of Chemical Engineering, College of Engineering, University of Tehran, No. 4, Orouji all., 16 Azar St., 11155-4563, Tehran, Iran

    Published Online:https://doi.org/10.2217/rme-2020-0152

    The ultimate goal of lung bioengineering is to produce transplantable lungs for human beings. Therefore, large-scale studies are of high importance. In this paper, we review the investigations on decellularization and recellularization of human-sized lung scaffolds. First, studies that introduce new ways to enhance the decellularization of large-scale lungs are reviewed, followed by the investigations on the xenogeneic sources of lung scaffolds. Then, decellularization and recellularization of diseased lung scaffolds are discussed to assess their usefulness for tissue engineering applications. Next, the use of stem cells in recellularizing acellular lung scaffolds is reviewed, followed by the case studies on the transplantation of bioengineered lungs. Finally, the remaining challenges are discussed, and future directions are highlighted.

    Graphical abstract

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Courtwright A, Cantu E. Evaluation and management of the potential lung donor. Clin. Chest Med. 38(4), 751–759 (2017).
    • 2. Yeung JC, Keshavjee S. Overview of clinical lung transplantation. Cold Spring Harb. Perspect. Med. 4(1), a015628–a015628 (2014).
    • 3. Ali A, Keshavjee S, Cypel M. Rising to the challenge of unmet need: expanding the lung donor pool. Curr. Pulmonol. Reports 7(3), 92–100 (2018).
    • 4. Ghanei M, Nezhad LH, Harandi AA, Alaeddini F, Shohrati M, Aslani J. Combination therapy for airflow limitation in COPD. DARU, J. Pharm. Sci. 20(1), 6 (2012).
    • 5. Sikma MA, Hunault CC, van de Graaf EA et al. High tacrolimus blood concentrations early after lung transplantation and the risk of kidney injury. Eur. J. Clin. Pharmacol. 73(5), 573–580 (2017).
    • 6. Levy L, Huszti E, Tikkanen J et al. The impact of first untreated subclinical minimal acute rejection on risk for chronic lung allograft dysfunction or death after lung transplantation. Am. J. Transplant. 20(1), 241–249 (2020).
    • 7. Mahfouzi SH, Safiabadi Tali SH, Amoabediny G. 3D bioprinting for lung and tracheal tissue engineering: criteria, advances, challenges, and future directions. Bioprinting 21(4), e00124 (2021).
    • 8. Murphy SV, De Coppi P, Atala A. Opportunities and challenges of translational 3D bioprinting. Nat. Biomed. Eng. 4(4), 370–380 (2020).
    • 9. Skolasinski SD, Panoskaltsis-Mortari A. Lung tissue bioengineering for chronic obstructive pulmonary disease: overcoming the need for lung transplantation from human donors. Expert Rev. Respir. Med. 13(7), 665–678 (2019).
    • 10. De Santis MM, Bölükbas DA, Lindstedt S, Wagner DE. How to build a lung: latest advances and emerging themes in lung bioengineering. Eur. Respir. J. 52(1), 1601355 (2018).
    • 11. Calle EA, Ghaedi M, Sundaram S, Sivarapatna A, Tseng MK, Niklason LE. Strategies for whole lung tissue engineering. IEEE Trans. Biomed. Eng. 61(5), 1482–1496 (2014).
    • 12. Nikolova MP, Chavali MS. Recent advances in biomaterials for 3D scaffolds: a review. Bioact. Mater. 4, 271–292 (2019).
    • 13. Williams DF. Challenges with the development of biomaterials for sustainable tissue engineering. Front. Bioeng. Biotechnol. 7(1), 127 (2019).
    • 14. Kuttan R, Spall RD, Duhamel RC, Sipes IG, Meezan E, Brendel K. Preparation and composition of alveolar extracellular matrix and incorporated basement membrane. Lung 159(1), 333–345 (1981).
    • 15. Lwebuga-Mukasa JS, Ingbar DH, Madri JA. Repopulation of a human alveolar matrix by adult rat type II pneumocytes in vitro. A novel system for type II pneumocyte culture. Exp. Cell Res. 162(2), 423–435 (1986).
    • 16. Price AP, England KA, Matson AM, Blazar BR, Panoskaltsis-Mortari A. Development of a decellularized lung bioreactor system for bioengineering the lung: the matrix reloaded. Tissue Eng. – Part A 16(8), 2581–2591 (2010).
    • 17. Petersen TH, Calle EA, Zhao L et al. Tissue-engineered lungs for in vivo implantation. Science 329(5991), 538–541 (2010). • It and the following one are the pioneer studies in lung tissue engineering, both of which transplanted the engineered lung into rats. This study also performed the first human lung decellularization.
    • 18. Ott HC, Clippinger B, Conrad C et al. Regeneration and orthotopic transplantation of a bioartificial lung. Nat. Med. 16(8), 927–933 (2010). • The bioengineered lungs of this study participated in gas exchange for up to 6 h when transplanted in rat models.
    • 19. Cortiella J, Niles J, Cantu A et al. Influence of acellular natural lung matrix on murine embryonic stem cell differentiation and tissue formation. Tissue Eng. - Part A 16(8), 2565–2580 (2010).
    • 20. Bonvillain RW, Scarritt ME, Pashos NC et al. Nonhuman primate lung decellularization and recellularization using a specialized large-organ bioreactor. J. Vis. Exp. (82), 1–11 (2013).
    • 21. Gilpin SE, Charest JM, Ren X et al. Regenerative potential of human airway stem cells in lung epithelial engineering. Biomaterials 108, 111–119 (2016).
    • 22. Scarritt ME, Pashos NC, Motherwell JM et al. Re-endothelialization of rat lung scaffolds through passive, gravity-driven seeding of segment-specific pulmonary endothelial cells. J. Tissue Eng. Regen. Med. 12(2), e786–e806 (2018).
    • 23. Mahfouzi SH, Amoabediny G, Safiabadi Tali SH. Advances in bioreactors for lung bioengineering: from scalable cell culture to tissue growth monitoring. Biotechnol. Bioeng. 118(6), 2142–2167 (2021).
    • 24. Doryab A, Heydarian M, Amoabediny G, Sadroddiny E, Mahfouzi S. Recellularization on acellular lung tissue scaffold using perfusion-based bioreactor: an online monitoring strategy. J. Med. Biol. Eng. 37(1), 53–62 (2017).
    • 25. Price AP, Godin LM, Domek A et al. Automated decellularization of intact, human-sized lungs for tissue engineering. 21(1), 94–103 (2015).
    • 26. Raredon MSB, Rocco KA, Gheorghe CP et al. Biomimetic culture reactor for whole-lung engineering. Biores. Open Access 5(1), 72–83 (2016).
    • 27. Engler AJ, Le AV, Baevova P, Niklason LE. Controlled gas exchange in whole lung bioreactors. J. Tissue Eng. Regen. Med. 12(1), e119–e129 (2018).
    • 28. Khalpey Z, Qu N, Hemphill C et al. Rapid porcine lung decellularization using a novel organ regenerative control acquisition bioreactor. ASAIO J. 61(1), 71–77 (2015).
    • 29. Mahfouzi SH, Amoabediny G, Doryab A, Safiabadi-Tali SH, Ghanei M. Noninvasive real-time assessment of cell viability in a three-dimensional tissue. Tissue Eng. – Part C Methods 24(4), 197–204 (2018). • Introduced an online, real-time and noninvasive monitoring bioreactor for assessment of recellularized lung tissue growth.
    • 30. Petersen TH, Calle EA, Colehour MB, Niklason LE. Bioreactor for the long-term culture of lung tissue. Cell Transplant. 20(7), 1117–1126 (2011).
    • 31. Raredon MSB, Ghaedi M, Calle EA, Niklason LE. A rotating bioreactor for scalable culture and differentiation of respiratory epithelium. Cell Med. 7(3), 109–121 (2015).
    • 32. Bonvillain RW, Danchuk S, Sullivan DE et al. A nonhuman primate model of lung regeneration: detergent-mediated decellularization and initial in vitro recellularization with mesenchymal stem cells. Tissue Eng. - Part A 18(23–24), 2437–2452 (2012).
    • 33. Nichols JE, Niles J, Riddle M et al. Production and assessment of decellularized pig and human lung scaffolds. Tissue Eng. - Part A 19(17–18), 2045–2062 (2013).
    • 34. Gilpin SE, Ren X, Okamoto T et al. Enhanced lung epithelial specification of human induced pluripotent stem cells on decellularized lung matrix. Ann. Thorac. Surg. 98(5), 1721–1729 (2014).
    • 35. Pouliot RA, Link PA, Mikhaiel NS et al. Development and characterization of a naturally derived lung extracellular matrix hydrogel. J. Biomed. Mater. Res. - Part A 104(8), 1922–1935 (2016).
    • 36. Balestrini JL, Gard AL, Gerhold KA et al. Comparative biology of decellularized lung matrix: implications of species mismatch in regenerative medicine. Biomaterials 102, 220–230 (2016).
    • 37. Nichols JE, La Francesca S, Vega SP et al. Giving new life to old lungs: methods to produce and assess whole human paediatric bioengineered lungs. J. Tissue Eng. Regen. Med. 11(7), 2136–2152 (2017).
    • 38. Zhou H, Kitano K, Ren X et al. Bioengineering human lung grafts on porcine matrix. Ann. Surg. 267(3), 590–598 (2018). •• Proved the feasibility of engineering and transplantation of viable lung grafts based on decellularized porcine lung scaffolds and human endothelial and epithelial cells.
    • 39. Nichols JE, La Francesca S, Niles JA et al. Production and transplantation of bioengineered lung into a large-animal model. Sci. Transl. Med. 10(452), eaao3926 (2018). •• Long-term survival of recellularized porcine lungs following transplantation.
    • 40. Gorman DE, Wu T, Gilpin SE, Ott HC. A fully automated high-throughput bioreactor system for lung regeneration. Tissue Eng. – Part C Methods 24(11), 671–678 (2018). • Designed an automated multichannel bioreactor able to monitor and optimize many parameters of the culture media for rodent-scale isolated lung culture to promote lung bioengineering.
    • 41. Zvarova B, Uhl FE, Uriarte JJ et al. Residual detergent detection method for nondestructive cytocompatibility evaluation of decellularized whole lung scaffolds. Tissue Eng. – Part C Methods 22(5), 418–428 (2016).
    • 42. O’Neill JD, Anfang R, Anandappa A et al. Decellularization of human and porcine lung tissues for pulmonary tissue engineering. Ann. Thorac. Surg. 96(3), 1046–1056 (2013).
    • 43. Gilpin SE, Li Q, Evangelista-Leite D et al. Fibrillin-2 and Tenascin-C bridge the age gap in lung epithelial regeneration. Biomaterials 140, 212–219 (2017).
    • 44. Butler CR, Hynds RE, Crowley C et al. Vacuum-assisted decellularization: an accelerated protocol to generate tissue-engineered human tracheal scaffolds. Biomaterials 124, 95–105 (2017).
    • 45. Wagner DE, Bonenfant NR, Sokocevic D et al. Three-dimensional scaffolds of acellular human and porcine lungs for high throughput studies of lung disease and regeneration. Biomaterials 35(9), 2664–2679 (2014).
    • 46. Kim BS, Kim H, Gao G, Jang J, Cho DW. Decellularized extracellular matrix: a step towards the next generation source for bioink manufacturing. Biofabrication 9(3), 034104 (2017).
    • 47. Crapo PM, Gilbert TW, Badylak SF. An overview of tissue and whole organ decellularization processes. Biomaterials 32(12), 3233–3243 (2011).
    • 48. Ota T, Taketani S, Iwai S et al. Novel method of decellularization of porcine valves using polyethylene glycol and gamma irradiation. Ann. Thorac. Surg. 83(4), 1501–1507 (2007).
    • 49. Shafiq MA, Gemeinhart RA, Yue BYJT, Djalilian AR. Decellularized human cornea for reconstructing the corneal epithelium and anterior stroma. Tissue Eng. – Part C Methods 18(5), 340–348 (2012).
    • 50. Guyette JP, Gilpin SE, Charest JM, Tapias LF, Ren X, Ott HC. Perfusion decellularization of whole organs. Nat. Protoc. 9(6), 1451–1468 (2014).
    • 51. Khan AA, Vishwakarma SK, Bardia A, Venkateshwarulu J. Repopulation of decellularized whole organ scaffold using stem cells: an emerging technology for the development of neo-organ. J. Artif. Organs 17(4), 291–300 (2014).
    • 52. Gilbert TW, Sellaro TL, Badylak SF. Decellularization of tissues and organs. Biomaterials 27(19), 3675–3683 (2006).
    • 53. Nelson K, Bobba C, Eren E et al. Method of isolated ex vivo lung perfusion in a rat model: lessons learned from developing a rat EVLP program. J. Vis. Exp. 96(1), e52309 (2015).
    • 54. Epstein SE, Luger D, Lipinski MJ. Large animal model efficacy testing is needed prior to launch of a stem cell clinical trial: an evidence-lacking conclusion based on conjecture. Circ. Res. 121(5), 496–498 (2017).
    • 55. Denayer T, Stöhrn T, Van Roy M. Animal models in translational medicine: validation and prediction. New Horizons Transl. Med. 2(1), 5–11 (2014).
    • 56. Weymann A, Patil NP, Sabashnikov A et al. Perfusion-decellularization of porcine lung and trachea for respiratory bioengineering. Artif. Organs 39(12), 1024–1032 (2015).
    • 57. Booth AJ, Hadley R, Cornett AM et al. Acellular normal and fibrotic human lung matrices as a culture system for in vitro investigation. Am. J. Respir. Crit. Care Med. 186(9), 866–876 (2012).
    • 58. Gilpin SE, Guyette JP, Gonzalez G et al. Perfusion decellularization of human and porcine lungs: bringing the matrix to clinical scale. J. Hear. Lung Transplant. 33(3), 298–308 (2014).
    • 59. Gilpin SE, Charest JM, Ren X, Ott HC. Bioengineering lungs for transplantation. Thorac. Surg. Clin. 26(2), 163–171 (2016).
    • 60. Servier Laboratories. Servier Medical Arts (2020). https://smart.servier.com/
    • 61. Wagner DE, Fenn SL, Bonenfant NR et al. Design and synthesis of an artificial pulmonary pleura for high throughput studies in acellular human lungs. Cell. Mol. Bioeng. 7(2), 184–195 (2014).
    • 62. Balestrini JL, Gard AL, Liu A et al. Production of decellularized porcine lung scaffolds for use in tissue engineering. Integr. Biol. (Camb) 7(12), 1598–1610 (2015).
    • 63. Platz J, Bonenfant NR, Uhl FE et al. Comparative decellularization and recellularization of wild-type and alpha 1,3 galactosyltransferase knockout pig lungs: a model for ex vivo xenogeneic lung bioengineering and transplantation. Tissue Eng. – Part C Methods 22(8), 725–739 (2016).
    • 64. Blackwell DL, Lucas JW, Clarke TC. Summary health statistics for U.S. adults: national health interview survey, 2012. Vital Health Stat. 10(260), 1–161 (2014).
    • 65. Hoeper MM, Humbert M, Souza R et al. A global view of pulmonary hypertension. Lancet Respir. Med. 4(4), 306–322 (2016).
    • 66. Huang X, Mu X, Deng L et al. The etiologic origins for chronic obstructive pulmonary disease. Int. J. COPD 14, 1139–1158 (2019).
    • 67. Wagner DE, Bonenfant NR, Parsons CS et al. Comparative decellularization and recellularization of normal versus emphysematous human lungs. Biomaterials 35(10), 3281–3297 (2014).
    • 68. Zhou Y, Peng H, Sun H et al. Chitinase 3-like 1 suppresses injury and promotes fibroproliferative responses in mammalian lung fibrosis. Sci. Transl. Med. 6(240), 240ra76–240ra76 (2014).
    • 69. Parker MW, Rossi D, Peterson M et al. Fibrotic extracellular matrix activates a profibrotic positive feedback loop. J. Clin. Invest. 124(4), 1622–1635 (2014).
    • 70. Sava P, Ramanathan A, Dobronyi A et al. Human pericytes adopt myofibroblast properties in the microenvironment of the IPF lung. JCI Insight 2(24), 1–13 (2017).
    • 71. Tjin G, White ES, Faiz A et al. Lysyl oxidases regulate fibrillar collagen remodelling in idiopathic pulmonary fibrosis. DMM Dis. Model. Mech. 10(11), 1301–1312 (2017).
    • 72. van der Velden JL, Wagner DE, Lahue KG et al. TGF-β1-induced deposition of provisional extracellular matrix by tracheal basal cells promotes epithelial-to-mesenchymal transition in a c-Jun NH2-terminal kinase-1-dependent manner. Am. J. Physiol. – Lung Cell. Mol. Physiol. 314(6), L984–L997 (2018).
    • 73. Hedström U, Hallgren O, Öberg L et al. Bronchial extracellular matrix from COPD patients induces altered gene expression in repopulated primary human bronchial epithelial cells. Sci. Rep. 8(1), 1–13 (2018).
    • 74. Sun H, Zhu Y, Pan H et al. Netrin-1 regulates fibrocyte accumulation in the decellularized fibrotic scleroderma lung microenvironment and in bleomycin induced pulmonary fibrosis. Arthritis Rheumatol. 68(5), 1251–1261 (2016).
    • 75. Ghaedi M, Calle EA, Mendez JJ et al. Human iPS cell-derived alveolar epithelium repopulates lung extracellular matrix. J. Clin. Invest. 123(11), 4950–4962 (2013).
    • 76. Huang SXL, Islam MN, O’Neill J et al. Efficient generation of lung and airway epithelial cells from human pluripotent stem cells. Nat. Biotechnol. 32(1), 84–91 (2014).
    • 77. Ghaedi M, Mendez JJ, Bove PF, Sivarapatna A, Raredon MSB, Niklason LE. Alveolar epithelial differentiation of human induced pluripotent stem cells in a rotating bioreactor. Biomaterials 35(2), 699–710 (2014).
    • 78. Mendez JJ, Ghaedi M, Steinbacher D, Niklason LE. Epithelial cell differentiation of human mesenchymal stromal cells in decellularized lung scaffolds. Tissue Eng. – Part A 20(11–12), 1735–1746 (2014).
    • 79. Ghaedi M, Le AV, Hatachi G et al. Bioengineered lungs generated from human iPSCs-derived epithelial cells on native extracellular matrix. J. Tissue Eng. Regen. Med. 12(3), e1623–e1635 (2018).
    • 80. Nakayama KH, Lee CCI, Batchelder CA, Tarantal AF. Tissue Specificity of decellularized rhesus monkey kidney and lung scaffolds. PLoS ONE 8(5), e64134 (2013).
    • 81. Minutti CM, Knipper JA, Allen JE, Zaiss DMW. Tissue-specific contribution of macrophages to wound healing. Semin. Cell Dev. Biol. 61, 3–11 (2017).
    • 82. Broekman W, Khedoe PPSJ, Schepers K, Roelofs H, Stolk J, Hiemstra PS. Mesenchymal stromal cells: a novel therapy for the treatment of chronic obstructive pulmonary disease? Thorax 73(6), 565–574 (2018).
    • 83. Cho DI, Kim MR, Jeong HY et al. Mesenchymal stem cells reciprocally regulate the M1/M2 balance in mouse bone marrow-derived macrophages. Exp. Mol. Med. 46(1), e70–e70 (2014).
    • 84. Badenes SM, Fernandes TG, Miranda CC et al. Long-term expansion of human induced pluripotent stem cells in a microcarrier-based dynamic system. J. Chem. Technol. Biotechnol. 92(3), 492–503 (2017).
    • 85. Derakhti S, Safiabadi-Tali SH, Amoabediny G, Sheikhpour M. Attachment and detachment strategies in microcarrier-based cell culture technology: a comprehensive review. Mater. Sci. Eng. C 103, 109782 (2019).
    • 86. Song JJ, Kim SS, Liu Z et al. Enhanced in vivo function of bioartificial lungs in rats. Ann. Thorac. Surg. 92(3), 998–1006 (2011).
    • 87. Ren X, Moser PT, Gilpin SE et al. Engineering pulmonary vasculature in decellularized rat and human lungs. Nat. Biotechnol. 33(10), 1097–1102 (2015).
    • 88. Doi R, Tsuchiya T, Mitsutake N et al. Transplantation of bioengineered rat lungs recellularized with endothelial and adipose-derived stromal cells. Sci. Rep. 7(1), 1–15 (2017).
    • 89. Obata T, Tsuchiya T, Akita S et al. Utilization of natural detergent potassium laurate for decellularization in lung bioengineering. Tissue Eng. – Part C Methods 25(8), 459–471 (2019).
    • 90. Jensen T, Roszell B, Zang F et al. A rapid lung de-cellularization protocol supports embryonic stem cell differentiation in vitro and following implantation. Tissue Eng. – Part C Methods 18(8), 632–646 (2012).
    • 91. Yuan Y, Engler AJ, Raredon MS et al. Epac agonist improves barrier function in iPSC-derived endothelial colony forming cells for whole organ tissue engineering. Biomaterials 200, 25–34 (2019).
    • 92. Tsuchiya T, Doi R, Obata T, Hatachi G, Nagayasu T. Lung microvascular niche, repair, and engineering. Front. Bioeng. Biotechnol. 8, 1–19 (2020).
    • 93. Stabler CT, Caires LC, Mondrinos MJ et al. Enhanced re-endothelialization of decellularized rat lungs. Tissue Eng. – Part C Methods 22(5), 439–450 (2016).