Skip to main content

Advertisement

Log in

A Review of Decellularized Extracellular Matrix Biomaterials for Regenerative Engineering Applications

  • Published:
Regenerative Engineering and Translational Medicine Aims and scope Submit manuscript

Abstract

Biomaterials are a cornerstone technology of the biomedical device, tissue engineering, and regenerative medicine industries. While traditional biomaterials are fully defined synthetics, growing evidence supports the use of extracellular matrix-based biomaterials produced through the decellularization of organs, tissues, or cell cultures. These materials are particularly advantageous as they largely retain the structure and the biochemical nature of the original tissue, properties that are often difficult to reproduce with synthetics. Indeed, there are many FDA-approved and clinically used extracellular matrix-based materials that are generated through decellularization processes. In this review, we first describe methods of decellularization used to produce these materials and their associated advantages and limitations, discuss the current use of extracellular matrix-based materials in regenerative engineering applications, describe the areas where current research is occurring, and forecast areas where impactful research may appear.

Lay Summary

The regeneration of tissues often requires a scaffold material to support and guide the cells that are performing the repair. Often, these materials are manmade and lack many of the key features present in native tissue. However, a tissue can be processed to remove its cells (a process called decellularization), leaving behind a scaffold of proteins and polysaccharides known as the extracellular matrix. These decellularized matrices are attractive scaffolds for use in regenerative medicine applications, and they are the subject of this review.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Heath DE, Cooper SL. The development of polymeric biomaterials inspired by the extracellular matrix. J Biomater Sci Polym Ed. 2017;28:1051–69. https://doi.org/10.1080/09205063.2017.1297285.

    Google Scholar 

  2. Letocha CE, Pavlin CJ. Follow-up of 3 patients with Ridley intraocular lens implantation. J Cataract Refract Surg. 1999;25:587–91. https://doi.org/10.1016/S0886-3350(99)80061-3.

    Google Scholar 

  3. Voorhees AB, Jaretzki A, Blakemore AH. The use of tubes constructed from Vinyon “N” cloth in bridging arterial defects: a preliminary report*. Ann Surg. 1952;135:332–6. https://doi.org/10.1097/00000658-195409000-00008.

    Google Scholar 

  4. Benson DR. John Charnley: the man and the hip. Med Hist. 1991;35:377–8. https://doi.org/10.1136/ard.49.9.660-b.

    Google Scholar 

  5. Hench LL. Biomaterials. Science. 1980;208(80):826–31.

    Google Scholar 

  6. Heath DE, Sharif ARM, Ng CP, Rhoads MG, Griffith LG, Hammond PT, et al. Regenerating the cell resistance of micromolded PEG hydrogels. Lab Chip. 2015;15:2073–89. https://doi.org/10.1039/c4lc01416b.

    Google Scholar 

  7. Veleva AN, Heath DE, Cooper SL, Patterson C. Selective endothelial cell attachment to peptide-modified terpolymers. Biomaterials. 2008;29:3656–61. https://doi.org/10.1016/j.biomaterials.2008.05.022.

    Google Scholar 

  8. Wang X, Heath DE, Cooper SL. Endothelial cell adhesion and proliferation to PEGylated polymers with covalently linked RGD peptides. J Biomed Mater Res A. 2012;100:794–801. https://doi.org/10.1002/jbm.a.34026.

    Google Scholar 

  9. Massia SP, Hubbell JA. Vascular endothelial cell adhesion and spreading promoted by the peptide REDV of the IIICS region of plasma fibronectin is mediated by integrin alpha 4 beta 1. J Biol Chem. 1992;267:14019–26.

    Google Scholar 

  10. Reyes CD, García AJ. Engineering integrin-specific surfaces with a triple-helical collagen-mimetic peptide. J Biomed Mater Res A. 2003;65:511–23. https://doi.org/10.1002/jbm.a.10550.

    Google Scholar 

  11. Lin X, Takahashi K, Liu Y, Zamora PO. Enhancement of cell attachment and tissue integration by a IKVAV containing multi-domain peptide. Biochim Biophys Acta Gen Subj. 1760;2006:1403–10. https://doi.org/10.1016/j.bbagen.2006.05.010.

    Google Scholar 

  12. Mizuno K, Yamamura K, Yano K, Osada T, Saeki S, Takimoto N, et al. Effect of chitosan film containing basic fibroblast growth factor on wound healing in genetically diabetic mice. J Biomed Mater Res A. 2003;64:177–81. https://doi.org/10.1002/jbm.a.10396.

    Google Scholar 

  13. Lee JY, Nam SH, Im SY, Park YJ, Lee YM, Seol YJ, et al. Enhanced bone formation by controlled growth factor delivery from chitosan-based biomaterials. J Control Release. 2002;78:187–97. https://doi.org/10.1016/S0168-3659(01)00498-9.

    Google Scholar 

  14. Frith JE, Cameron AR, Menzies DJ, Ghosh P, Whitehead DL, Gronthos S, et al. An injectable hydrogel incorporating mesenchymal precursor cells and pentosan polysulphate for intervertebral disc regeneration. Biomaterials. 2013;34:9430–40. https://doi.org/10.1016/j.biomaterials.2013.08.072.

    Google Scholar 

  15. Lutolf MP, Lauer-Fields JL, Schmoekel HG, Metters AT, Weber FE, Fields GB, et al. Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: engineering cell-invasion characteristics. Proc Natl Acad Sci U S A. 2003;100:5413–8. https://doi.org/10.1073/pnas.0737381100.

    Google Scholar 

  16. Fonseca KB, Bidarra SJ, Oliveira MJ, Granja PL, Barrias CC. Molecularly designed alginate hydrogels susceptible to local proteolysis as three-dimensional cellular microenvironments. Acta Biomater. 2011;7:1674–82. https://doi.org/10.1016/j.actbio.2010.12.029.

    Google Scholar 

  17. Shirbin SJ, Karimi F, Chan NJ-A, Heath DE, Qiao GG. Macroporous hydrogels composed entirely of synthetic polypeptides: biocompatible and enzyme biodegradable 3D cellular scaffolds. Biomacromolecules. 2016;17:2981–91. https://doi.org/10.1021/acs.biomac.6b00817.

    Google Scholar 

  18. Rayatpisheh S, Heath DE, Shakouri A, Rujitanaroj PO, Chew SY, Chan-Park MB. Combining cell sheet technology and electrospun scaffolding for engineered tubular, aligned, and contractile blood vessels. Biomaterials. 2014;35:2713–9. https://doi.org/10.1016/j.biomaterials.2013.12.035.

    Google Scholar 

  19. Heath DE, Lannutti JJ, Cooper SL. Electrospun scaffold topography affects endothelial cell proliferation, metabolic activity, and morphology. J Biomed Mater Res A. 2010;94:1195–204. https://doi.org/10.1002/jbm.a.32802.

    Google Scholar 

  20. Dalton BA, Walboomers XF, Dziegielewski M, Evans MD, Taylor S, Jansen JA, et al. Modulation of epithelial tissue and cell migration by microgrooves. J Biomed Mater Res. 2001;56:195–207. https://doi.org/10.1002/1097-4636(200108)56:2<195::AID-JBM1084>3.0.CO;2-7.

    Google Scholar 

  21. Rebollar E, Frischauf I, Olbrich M, Peterbauer T, Hering S, Preiner J, et al. Proliferation of aligned mammalian cells on laser-nanostructured polystyrene. Biomaterials. 2008;29:1796–806. https://doi.org/10.1016/j.biomaterials.2007.12.039.

    Google Scholar 

  22. Bettinger CJ, Zhang Z, Gerecht S, Borenstein JT, Langer R. Enhancement of in vitro capillary tube formation by substrate nanotopography. Adv Mater. 2008;20:99–103. https://doi.org/10.1002/adma.200702487.

    Google Scholar 

  23. Crapo PM, Gilbert TW, Badylak SF. An overview of tissue and whole organ decellularization processes. Biomaterials. 2011;32:3233–43. https://doi.org/10.1016/j.biomaterials.2011.01.057.

    Google Scholar 

  24. Keane TJ, Swinehart I, Badylak SF. Methods of tissue decellularization used for preparation of biologic scaffolds and in-vivo relevance. Methods. 2015;84:25–34. https://doi.org/10.1016/j.ymeth.2015.03.005.

    Google Scholar 

  25. Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI, et al. Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat Med. 2008;14:213–21. https://doi.org/10.1038/nm1684.

    Google Scholar 

  26. Jank BJ, Xiong L, Moser PT, Guyette JP, Ren X, Cetrulo CL, et al. Engineered composite tissue as a bioartificial limb graft. Biomaterials. 2015;61:246–56. https://doi.org/10.1016/j.biomaterials.2015.04.051.

    Google Scholar 

  27. Chen L, He Z, Chen B, Yang M, Zhao Y, Sun W, et al. Loading of VEGF to the heparin cross-linked demineralized bone matrix improves vascularization of the scaffold. J Mater Sci Mater Med. 2010;21:309–17. https://doi.org/10.1007/s10856-009-3827-9.

    Google Scholar 

  28. Singelyn JM, Sundaramurthy P, Johnson TD, Schup-Magoffin PJ, Hu DP, Faulk DM, et al. Catheter-deliverable hydrogel derived from decellularized ventricular extracellular matrix increases endogenous cardiomyocytes and preserves cardiac function post-myocardial infarction. J Am Coll Cardiol. 2012;59:751–63. https://doi.org/10.1016/j.jacc.2011.10.888.

    Google Scholar 

  29. Kusuma GD, Yang MC, Brennecke SP, O’Connor AJ, Kalionis B, Heath DE. Transferable matrixes produced from decellularized extracellular matrix promote proliferation and osteogenic differentiation of Mesenchymal stem cells and facilitate scale-up. ACS Biomater Sci Eng. 2018;4:1760–9. https://doi.org/10.1021/acsbiomaterials.7b00747.

    Google Scholar 

  30. Ungerleider JL, Johnson TD, Rao N, Christman KL. Fabrication and characterization of injectable hydrogels derived from decellularized skeletal and cardiac muscle. Methods. 2015;84:53–9. https://doi.org/10.1016/j.ymeth.2015.03.024.

    Google Scholar 

  31. Gubareva EA, Sjoqvist S, Sotnichenko AS, Lim ML, Torres NF, Danilenko KA, et al. Non-human primate oesophagus decellularization. Genes Cells. 2014;9:64–9.

    Google Scholar 

  32. Mendoza-Novelo B, Avila EE, Cauich-Rodríguez JV, Jorge-Herrero E, Rojo FJ, Guinea GV, et al. Decellularization of pericardial tissue and its impact on tensile viscoelasticity and glycosaminoglycan content. Acta Biomater. 2011;7:1241–12487. https://doi.org/10.1016/j.actbio.2010.11.017.

    Google Scholar 

  33. Pan MX, Hu PY, Cheng Y, Cai LQ, Rao XH, Wang Y, et al. An efficient method for decellularization of the rat liver. J Formos Med Assoc. 2014;113:680–7. https://doi.org/10.1016/j.jfma.2013.05.003.

    Google Scholar 

  34. Liao J, Joyce EM, Sacks MS. Effects of decellularization on the mechanical and structural properties of the porcine aortic valve leaflet. Biomaterials. 2008;29:1065–74. https://doi.org/10.1016/j.biomaterials.2007.11.007.

    Google Scholar 

  35. Poornejad N, Schaumann LB, Buckmiller EM, Momtahan N, Gassman JR, Ma HH, et al. The impact of decellularization agents on renal tissue extracellular matrix. J Biomater Appl. 2016;31:521–33. https://doi.org/10.1177/0885328216656099.

    Google Scholar 

  36. Syed O, Walters NJ, Day RM, Kim HW, Knowles JC. Evaluation of decellularization protocols for production of tubular small intestine submucosa scaffolds for use in oesophageal tissue engineering. Acta Biomater. 2014;10:5043–54. https://doi.org/10.1016/j.actbio.2014.08.024.

    Google Scholar 

  37. Flynn LE. The use of decellularized adipose tissue to provide an inductive microenvironment for the adipogenic differentiation of human adipose-derived stem cells. Biomaterials. 2010;31:4715–24. https://doi.org/10.1016/j.biomaterials.2010.02.046.

    Google Scholar 

  38. Brown BN, Freund JM, Han L, Rubin JP, Reing JE, Jeffries EM, et al. Comparison of three methods for the derivation of a biologic scaffold composed of adipose tissue extracellular matrix. Tissue Eng Part C Methods. 2011;17:411–21. https://doi.org/10.1089/ten.tec.2010.0342.

    Google Scholar 

  39. Reing JE, Brown BN, Daly KA, Freund JM, Gilbert TW, Hsiong SX, et al. The effects of processing methods upon mechanical and biologic properties of porcine dermal extracellular matrix scaffolds. Biomaterials. 2010;31:8626–33. https://doi.org/10.1016/j.biomaterials.2010.07.083.

    Google Scholar 

  40. Prasertsung I, Kanokpanont S, Bunaprasert T, Thanakit V, Damrongsakkul S. Development of acellular dermis from porcine skin using periodic pressurized technique. J Biomed Mater Res - Part B Appl Biomater. 2008;85:210–9. https://doi.org/10.1002/jbm.b.30938.

    Google Scholar 

  41. Nakayama KH, Batchelder CA, Lee CI, Tarantal AF. Decellularized rhesus monkey kidney as a three-dimensional scaffold for renal tissue engineering. Tissue Eng Part A. 2010;16:2207–16. https://doi.org/10.1089/ten.tea.2009.0602.

    Google Scholar 

  42. Meyer SR, Chiu B, Churchill TA, Zhu L, Lakey JRT, Ross DB. Comparison of aortic valve allograft decellularization techniques in the rat. J Biomed Mater Res - Part A. 2006;79:254–62. https://doi.org/10.1002/jbm.a.30777.

    Google Scholar 

  43. Zhou J, Fritze O, Schleicher M, Wendel HP, Schenke-Layland K, Harasztosi C, et al. Impact of heart valve decellularization on 3-D ultrastructure, immunogenicity and thrombogenicity. Biomaterials. 2010;31:2549–54. https://doi.org/10.1016/j.biomaterials.2009.11.088.

    Google Scholar 

  44. Petersen TH, Calle EA, Colehour MB, Niklason LE. Matrix composition and mechanics of decellularized lung scaffolds. Cells Tissues Organs. 2012;195:222–31. https://doi.org/10.1159/000324896.

    Google Scholar 

  45. White LJ, Taylor AJ, Faulk DM, Keane TJ, Saldin LT, Reing JE, et al. The impact of detergents on the tissue decellularization process: a ToF-SIMS study. Acta Biomater. 2017;50:207–19. https://doi.org/10.1016/j.actbio.2016.12.033.

    Google Scholar 

  46. Yang B, Zhang Y, Zhou L, Sun Z, Zheng J, Chen Y, et al. Development of a porcine bladder Acellular matrix with well-preserved extracellular bioactive factors for tissue engineering. Tissue Eng Part C Methods. 2010;16:1201–11. https://doi.org/10.1089/ten.tec.2009.0311.

    Google Scholar 

  47. Keane TJ, Dziki J, Castelton A, Faulk DM, Messerschmidt V, Londono R, et al. Preparation and characterization of a biologic scaffold and hydrogel derived from colonic mucosa. J Biomed Mater Res - Part B Appl Biomater. 2017;105:291–306. https://doi.org/10.1002/jbm.b.33556.

    Google Scholar 

  48. Baiguera S, Jungebluth P, Burns A, Mavilia C, Haag J, De Coppi P, et al. Tissue engineered human tracheas for in vivo implantation. Biomaterials. 2010;31:8931–8. https://doi.org/10.1016/j.biomaterials.2010.08.005.

    Google Scholar 

  49. Cebotari S, Tudorache I, Jaekel T, Hilfiker A, Dorfman S, Ternes W, et al. Detergent decellularization of heart valves for tissue engineering: toxicological effects of residual detergents on human endothelial cells. Artif Organs. 2010;34:206–10. https://doi.org/10.1111/j.1525-1594.2009.00796.x.

    Google Scholar 

  50. Nonaka PN, Campillo N, Uriarte JJ, Garreta E, Melo E, De Oliveira LVF, et al. Effects of freezing/thawing on the mechanical properties of decellularized lungs. J Biomed Mater Res - Part A. 2014;102:413–9. https://doi.org/10.1002/jbm.a.34708.

    Google Scholar 

  51. Xu CC, Chan RW, Tirunagari N. A biodegradable, Acellular xenogeneic scaffold for regeneration of the vocal fold Lamina Propria. Tissue Eng. 2007;13:551–66. https://doi.org/10.1089/ten.2006.0169.

    Google Scholar 

  52. Montoya CV, McFetridge PS. Preparation of ex vivo-based biomaterials using convective flow decellularization. Tissue Eng Part C Methods. 2009;15:191–200. https://doi.org/10.1089/ten.tec.2008.0372.

    Google Scholar 

  53. Sawada K, Terada D, Yamaoka T, Kitamura S, Fujisato T. Cell removal with supercritical carbon dioxide for acellular artificial tissue. J Chem Technol Biotechnol. 2008;83:943–9. https://doi.org/10.1002/jctb.1899.

    Google Scholar 

  54. Zambon A, Vetralla M, Urbani L, Pantano MF, Ferrentino G, Pozzobon M, et al. Dry acellular oesophageal matrix prepared by supercritical carbon dioxide. J Supercrit Fluids. 2016;115:33–41. https://doi.org/10.1016/j.supflu.2016.04.003.

    Google Scholar 

  55. Stenn KS, Link R, Moellmann G, Madri J, Kuklinska E. Dispase, a neutral protease from Bacillus polymyxa, is a powerful fibronectinase and type IV collagenase. J Invest Dermatol. 1989;93:287–90. https://doi.org/10.1111/1523-1747.ep12277593.

    Google Scholar 

  56. Grauss RW, Hazekamp MG, Oppenhuizen F, Van Munsteren CJ, Gittenberger-De Groot AC, DeRuiter MC. Histological evaluation of decellularised porcine aortic valves: matrix changes due to different decellularisation methods. Eur J Cardio-Thoracic Surg. 2005;27:566–71. https://doi.org/10.1016/j.ejcts.2004.12.052.

    Google Scholar 

  57. Gilbert TW, Wognum S, Joyce EM, Freytes DO, Sacks MS, Badylak SF. Collagen fiber alignment and biaxial mechanical behavior of porcine urinary bladder derived extracellular matrix. Biomaterials. 2008;29:4775–82. https://doi.org/10.1016/j.biomaterials.2008.08.022.

    Google Scholar 

  58. Hodde J, Hiles M. Virus safety of a porcine-derived medical device: evaluation of a viral inactivation method. Biotechnol Bioeng. 2002;79:211–6. https://doi.org/10.1002/bit.10281.

    Google Scholar 

  59. Srinivasan M, Sedmak D, Jewell S. Effect of fixatives and tissue processing on the content and integrity of nucleic acids. Am J Pathol. 2002;161:1961–71. https://doi.org/10.1016/S0002-9440(10)64472-0.

    Google Scholar 

  60. Lumpkins SB, Pierre N, McFetridge PS. A mechanical evaluation of three decellularization methods in the design of a xenogeneic scaffold for tissue engineering the temporomandibular joint disc. Acta Biomater. 2008;4:808–16. https://doi.org/10.1016/j.actbio.2008.01.016.

    Google Scholar 

  61. Levy RJ, Vyavahare N, Ogle M, Ashworth P, Bianco R, Schoen FJ. Inhibition of cusp and aortic wall calcification in ethanol- and aluminum-treated bioprosthetic heart valves in sheep: background, mechanisms, and synergism. J Heart Valve Dis. 2003;12:209–16.

    Google Scholar 

  62. Gorschewsky O, Puetz A, Riechert K, Klakow A, Becker R. Quantitative analysis of biochemical characteristics of bone-patellar tendon-bone allografts. Biomed Mater Eng. 2005;15:403–11.

    Google Scholar 

  63. He M, Callanan A. Comparison of methods for whole-organ decellularization in tissue engineering of bioartificial organs. Tissue Eng Part B Rev. 2013;19:194–208. https://doi.org/10.1089/ten.teb.2012.0340.

    Google Scholar 

  64. Rieder E, Kasimir MT, Silberhumer G, Seebacher G, Wolner E, Simon P, et al. Decellularization protocols of porcine heart valves differ importantly in efficiency of cell removal and susceptibility of the matrix to recellularization with human vascular cells. J Thorac Cardiovasc Surg. 2004;127:399–405. https://doi.org/10.1016/j.jtcvs.2003.06.017.

    Google Scholar 

  65. Cartmell JS, Dunn MG. Effect of chemical treatments on tendon cellularity and mechanical properties. J Biomed Mater Res. 2000;49:134–40. https://doi.org/10.1002/(SICI)1097-4636(200001)49:1<134::AID-JBM17>3.0.CO;2-D.

    Google Scholar 

  66. Uygun BE, Soto-Gutierrez A, Yagi H, Izamis ML, Guzzardi MA, Shulman C, et al. Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat Med. 2010;16:814–20. https://doi.org/10.1038/nm.2170.

    Google Scholar 

  67. Choi JS, Williams JK, Greven M, Walter KA, Laber PW, Khang G, et al. Bioengineering endothelialized neo-corneas using donor-derived corneal endothelial cells and decellularized corneal stroma. Biomaterials. 2010;31:6738–45. https://doi.org/10.1016/j.biomaterials.2010.05.020.

    Google Scholar 

  68. Vavken P, Joshi S, Murray MM. TRITON-X is most effective among three decellularization agents for ACL tissue engineering. J Orthop Res. 2009;27:1612–8. https://doi.org/10.1002/jor.20932.

    Google Scholar 

  69. O’Neill JD, Anfang R, Anandappa A, Costa J, Javidfar J, Wobma HM, et al. Decellularization of human and porcine lung tissues for pulmonary tissue engineering. Ann Thorac Surg. 2013;96:1046–56. https://doi.org/10.1016/j.athoracsur.2013.04.022.

    Google Scholar 

  70. Petersen TH, Calle EA, Zhao L, Lee EJ, Gui L, Raredon MSB, et al. Tissue-engineered lungs for in vivo implantation. Science. 2010;329(80):538–41. https://doi.org/10.1126/science.1189345.

    Google Scholar 

  71. Keane TJ, Londono R, Carey RM, Carruthers CA, Reing JE, Dearth CL, et al. Preparation and characterization of a biologic scaffold from esophageal mucosa. Biomaterials. 2013;34:6729–37. https://doi.org/10.1016/j.biomaterials.2013.05.052.

    Google Scholar 

  72. Remlinger NT, Czajka CA, Juhas ME, Vorp DA, Stolz DB, Badylak SF, et al. Hydrated xenogeneic decellularized tracheal matrix as a scaffold for tracheal reconstruction. Biomaterials. 2010;31:3520–6. https://doi.org/10.1016/j.biomaterials.2010.01.067.

    Google Scholar 

  73. Stern MM, Myers RL, Hammam N, Stern KA, Eberli D, Kritchevsky SB, et al. The influence of extracellular matrix derived from skeletal muscle tissue on the proliferation and differentiation of myogenic progenitor cells ex vivo. Biomaterials. 2009;30:2393–9. https://doi.org/10.1016/j.biomaterials.2008.12.069.

    Google Scholar 

  74. Karabekmez FE, Duymaz A, Moran SL. Early clinical outcomes with the use of decellularized nerve allograft for repair of sensory defects within the hand. Hand. 2009;4:245–9. https://doi.org/10.1007/s11552-009-9195-6.

    Google Scholar 

  75. Huang H, Zhang J, Sun K, Zhang X, Tian S. Effects of repetitive multiple freeze-thaw cycles on the biomechanical properties of human flexor digitorum superficialis and flexor pollicis longus tendons. Clin Biomech. 2011;26:419–23. https://doi.org/10.1016/j.clinbiomech.2010.12.006.

    Google Scholar 

  76. Pulver SA, Leybovich B, Artyuhov I, Maleev Y, Peregudov A. Production of organ extracellular matrix using a freeze-thaw cycle employing extracellular cryoprotectants. Cryo-Letters. 2014;35:400–6.

    Google Scholar 

  77. Cox B, Emili A. Tissue subcellular fractionation and protein extraction for use in mass-spectrometry-based proteomics. Nat Protoc. 2006;1:1872–8. https://doi.org/10.1038/nprot.2006.273.

    Google Scholar 

  78. Funamoto S, Nam K, Kimura T, Murakoshi A, Hashimoto Y, Niwaya K, et al. The use of high-hydrostatic pressure treatment to decellularize blood vessels. Biomaterials. 2010;31:3590–5. https://doi.org/10.1016/j.biomaterials.2010.01.073.

    Google Scholar 

  79. Bolland F, Korossis S, Wilshaw SP, Ingham E, Fisher J, Kearney JN, et al. Development and characterisation of a full-thickness acellular porcine bladder matrix for tissue engineering. Biomaterials. 2007;28:1061–70. https://doi.org/10.1016/j.biomaterials.2006.10.005.

    Google Scholar 

  80. Guler S, Aslan B, Hosseinian P, Aydin HM. Supercritical carbon dioxide-assisted decellularization of aorta and cornea. Tissue Eng Part C Methods. 2017;23:540–7. https://doi.org/10.1089/ten.tec.2017.0090.

    Google Scholar 

  81. Casali DM, Handleton RM, Shazly T, Matthews MA. A novel supercritical CO2-based decellularization method for maintaining scaffold hydration and mechanical properties. J Supercrit Fluids. 2018;131:72–81. https://doi.org/10.1016/j.supflu.2017.07.021.

    Google Scholar 

  82. Waldrop FS, Puchtler H, Meloan SN, Younker TD. Histochemical investigations of different types of collagen. Acta Histochem Suppl. 1980;21:23–31.

    Google Scholar 

  83. Yang M, Chen CZ, Wang XN, Bin ZY, Gu YJ. Favorable effects of the detergent and enzyme extraction method for preparing decellularized bovine pericardium scaffold for tissue engineered heart valves. J Biomed Mater Res - Part B Appl Biomater. 2009;91:354–61. https://doi.org/10.1002/jbm.b.31409.

    Google Scholar 

  84. Dong X, Wei X, Yi W, Gu C, Kang X, Liu Y, et al. RGD-modified acellular bovine pericardium as a bioprosthetic scaffold for tissue engineering. J Mater Sci Mater Med. 2009;20:2327–36. https://doi.org/10.1007/s10856-009-3791-4.

    Google Scholar 

  85. Suthipintawong C, Leong ASY, Vinyuvat S. Immunostaining of cell preparations: a comparative evaluation of common fixatives and protocols. Diagn Cytopathol. 1996;15:167–74. https://doi.org/10.1002/(SICI)1097-0339(199608)15:2<167::AID-DC17>3.0.CO;2-F.

    Google Scholar 

  86. Moroni F, Mirabella T. Decellularized matrices for cardiovascular tissue engineering. Am J Stem Cells. 2014;3:1–20. https://doi.org/10.1517/14712598.2010.534079.

    Google Scholar 

  87. Di Meglio F, Nurzynska D, Romano V, Miraglia R, Belviso I, Sacco AM, et al. Optimization of human myocardium decellularization method for the construction of implantable patches. Tissue Eng Part C. 2017;23:525–39. https://doi.org/10.1089/ten.TEC.2017.0267.

    Google Scholar 

  88. Oberwallner B, Brodarac A, Choi YH, Saric T, Anic P, Morawietz L, et al. Preparation of cardiac extracellular matrix scaffolds by decellularization of human myocardium. J Biomed Mater Res - Part A. 2014;102(9):3263–3272. https://doi.org/10.1002/jbm.a.35000.

  89. Ye X, Wang H, Gong W, Li S, Li H, Wang Z, et al. Impact of decellularization on porcine myocardium as scaffold for tissue engineered heart tissue. J Mater Sci Mater Med. 2016;27. https://doi.org/10.1007/s10856-016-5683-8.

  90. Parmaksiz M, Dogan A, Odabas S, Elçin AE, Elçin YM. Clinical applications of decellularized extracellular matrices for tissue engineering and regenerative medicine. Biomed Mater. 2016;11. https://doi.org/10.1088/1748-6041/11/2/022003.

  91. Shakouri-Motlagh A, Khanabdali R, Heath DE, Kalionis B. The application of decellularized human term fetal membranes in tissue engineering and regenerative medicine (TERM). Placenta. 2017;59:124–30. https://doi.org/10.1016/j.placenta.2017.07.002.

    Google Scholar 

  92. Sabetkish S, Kajbafzadeh AM, Sabetkish N, Khorramirouz R, Akbarzadeh A, Seyedian SL, et al. Whole-organ tissue engineering: Decellularization and recellularization of three-dimensional matrix liver scaffolds. J Biomed Mater Res - Part A. 2015;103:1498–508. https://doi.org/10.1002/jbm.a.35291.

    Google Scholar 

  93. Price AP, Godin LM, Domek A, Cotter T, D’Cunha J, Taylor DA, et al. Automated decellularization of intact, human-sized lungs for tissue engineering. Tissue Eng Part C Methods. 2015;21:94–103. https://doi.org/10.1089/ten.tec.2013.0756.

    Google Scholar 

  94. Scarrit ME. A review of cellularization strategies for tissue engineering of whole organs. Front Bioeng Biotechnol. 2015;3. https://doi.org/10.3389/fbioe.2015.00043.

  95. Brown B, Lindberg K, Reing J, Stolz DB, Badylak SF. The basement membrane component of biologic scaffolds derived from extracellular matrix. Tissue Eng. 2006;12:519–26. https://doi.org/10.1089/ten.2006.12.519.

    Google Scholar 

  96. Sacks MS, Claire GD. Quantification of the fiber architecture and biaxial mechanical behavior of porcine intestinal submucosa. J Biomed Mater Res. 1999;46:1–10. https://doi.org/10.1002/(SICI)1097-4636(199907)46:1<1::AID-JBM1>3.0.CO;2-7.

    Google Scholar 

  97. Saldin LT, Cramer MC, Velankar SS, White LJ, Badylak SF. Extracellular matrix hydrogels from decellularized tissues: structure and function. Acta Biomater. 2017;49:1–15. https://doi.org/10.1016/j.actbio.2016.11.068.

    Google Scholar 

  98. Czaja WK, Young DJ, Kawecki M, Brown RM. The future prospects of microbial cellulose in biomedical applications. Biomacromolecules. 2007;8:1–12. https://doi.org/10.1021/bm060620d.

    Google Scholar 

  99. Modulevsky DJ, Cuerrier CM, Pelling AE. Biocompatibility of subcutaneously implanted plant-derived cellulose biomaterials. PLoS One. 2016;11. https://doi.org/10.1371/journal.pone.0157894.

  100. Gershlak JR, Hernandez S, Fontana G, Perreault LR, Hansen KJ, Larson SA, et al. Crossing kingdoms: using decellularized plants as perfusable tissue engineering scaffolds. Biomaterials. 2017;125:13–22. https://doi.org/10.1016/j.biomaterials.2017.02.011.

    Google Scholar 

  101. Gruskin E, Doll BA, Futrell FW, Schmitz JP, Hollinger JO. Demineralized bone matrix in bone repair: history and use. Adv Drug Deliv Rev. 2012;64:1063–77. https://doi.org/10.1016/j.addr.2012.06.008.

    Google Scholar 

  102. Benders KEM, van Weeren PR, Badylak SF, Saris DBF, Dhert WJA, Malda J. Extracellular matrix scaffolds for cartilage and bone regeneration. Trends Biotechnol. 2013;31:169–76. https://doi.org/10.1016/j.tibtech.2012.12.004.

    Google Scholar 

  103. Yoo G, Lim JS. Tissue engineering of injectable soft tissue filler: using adipose stem cells and micronized acellular dermal matrix. J Korean Med Sci. 2009;24:104–9. https://doi.org/10.3346/jkms.2009.24.1.104.

    Google Scholar 

  104. Kimmel H, Rahn M, Gilbert TW. The clinical effectiveness in wound healing with extracellular matrix derived from porcine urinary bladder matrix: a case series on severe chronic wounds. J Am Col Certif Wound Spec. 2010;2:55–9. https://doi.org/10.1016/j.jcws.2010.11.002.

    Google Scholar 

  105. Spang MT, Christman KL. Extracellular matrix hydrogel therapies: in vivo applications and development. Acta Biomater. 2018;68:1–14. https://doi.org/10.1016/j.actbio.2017.12.019.

    Google Scholar 

  106. Kusuma GD, Yang MC, Brennecke SP, O’Connor AJ, Kalionis B, Heath DE. Transferable matrixes produced from decellularized extracellular matrix promote proliferation and osteogenic differentiation of Mesenchymal stem cells and facilitate scale-up. ACS Biomater Sci Eng. 2018;4:1760–9. https://doi.org/10.1021/acsbiomaterials.7b00747.

    Google Scholar 

  107. Pati F, Jang J, Ha D-H, Won Kim S, Rhie J-W, Shim J-H, et al. Printing three-dimensional tissue analogues with decellularized extracellular matrix bioink. Nat Commun. 2014;5:3935. https://doi.org/10.1038/ncomms4935.

    Google Scholar 

  108. Singelyn JM, Christman KL. Modulation of material properties of a decellularized myocardial matrix scaffold. Macromol Biosci. 2011;11:731–8. https://doi.org/10.1002/mabi.201000423.

    Google Scholar 

  109. Kayabolen A, Keskin D, Aykan A, Karslioglu Y, Zor F, Tezcaner A. Native extracellular matrix/fibroin hydrogels for adipose tissue engineering with enhanced vascularization. Biomed Mater. 2017;12:035007. https://doi.org/10.1088/1748-605X/aa6a63.

    Google Scholar 

  110. Young DA, Ibrahim DO, Hu D, Christman KL. Injectable hydrogel scaffold from decellularized human lipoaspirate. Acta Biomater. 2011;7:1040–9. https://doi.org/10.1016/j.actbio.2010.09.035.

    Google Scholar 

  111. Farnebo S, Woon CYL, Schmitt T, Joubert L-M, Kim M, Pham H, et al. Design and characterization of an injectable tendon hydrogel: a novel scaffold for guided tissue regeneration in the musculoskeletal system. Tissue Eng Part A. 2014;20:1550–61. https://doi.org/10.1089/ten.tea.2013.0207.

    Google Scholar 

  112. Crowe CS, Chiou G, McGoldrick R, Hui K, Pham H, Hollenbeck E, et al. In vitro characteristics of porcine tendon hydrogel for tendon regeneration. Ann Plast Surg. 2016;77:47–53. https://doi.org/10.1097/SAP.0000000000000361.

    Google Scholar 

  113. JA DQ, Lin JE, Cam C, Hu D, Salvatore MA, Sheikh F, et al. Injectable skeletal muscle matrix hydrogel promotes neovascularization and muscle cell infiltration in a hindlimb ischemia model. Eur Cells Mater. 2012;23:400–12. https://doi.org/10.22203/eCM.v023a31.

    Google Scholar 

  114. Wassenaar JW, Boss GR, Christman KL. Decellularized skeletal muscle as an in vitro model for studying drug-extracellular matrix interactions. Biomaterials. 2015;64:108–14. https://doi.org/10.1016/j.biomaterials.2015.06.033.

    Google Scholar 

  115. Gothard D, Smith EL, Kanczler JM, Black CR, Wells JA, Roberts CA, et al. In vivo assessment of bone regeneration in alginate/bone ECM hydrogels with incorporated skeletal stem cells and single growth factors. PLoS One. 2015;10:e0145080. https://doi.org/10.1371/journal.pone.0145080.

    Google Scholar 

  116. Smith EL, Kanczler JM, Gothard D, Roberts CA, Wells JA, White LJ, et al. Evaluation of skeletal tissue repair, part 2: enhancement of skeletal tissue repair through dual-growth-factor-releasing hydrogels within an ex vivo chick femur defect model. Acta Biomater. 2014;10:4197–205. https://doi.org/10.1016/j.actbio.2014.05.025.

    Google Scholar 

  117. Visser J, Levett PA, te Moller NCR, Besems J, Boere KWM, van Rijen MHP, et al. Crosslinkable hydrogels derived from cartilage, meniscus, and tendon tissue. Tissue Eng Part A. 2015;27:1195–206. https://doi.org/10.1089/ten.tea.2014.0362.

    Google Scholar 

  118. Rothrauff BB, Yang G, Tuan RS. Tissue-specific bioactivity of soluble tendon-derived and cartilage-derived extracellular matrices on adult mesenchymal stem cells. Stem Cell Res Ther. 2017;8. https://doi.org/10.1186/s13287-017-0580-8.

  119. Yuan X, Wei Y, Villasante A, Ng JJD, Arkonac DE, Chao P, et al. Stem cell delivery in tissue-specific hydrogel enabled meniscal repair in an orthotopic rat model. Biomaterials. 2017;132:59–71. https://doi.org/10.1016/j.biomaterials.2017.04.004.

    Google Scholar 

  120. Shimomura K, Rothrauff BB, Tuan RS. Region-specific effect of the decellularized meniscus extracellular matrix on mesenchymal stem cell-based meniscus tissue engineering. Am J Sports Med. 2017;45:604–11. https://doi.org/10.1177/0363546516674184.

    Google Scholar 

  121. Pilipchuk SP, Vaicik MK, Larson JC, Gazyakan E, Cheng MH, Brey EM. Influence of crosslinking on the stiffness and degradation of dermis-derived hydrogels. J Biomed Mater Res - Part A. 2013;101:2883–95. https://doi.org/10.1002/jbm.a.34602.

    Google Scholar 

  122. Engel H, Kao S-W, Larson J, Uriel S, Jiang B, Brey EM, et al. Investigation of dermis-derived hydrogels for wound healing applications. Biom J. 2014;38:58–64. https://doi.org/10.4103/2319-4170.132899.

    Google Scholar 

  123. Crapo PM, Medberry CJ, Reing JE, Tottey S, van der Merwe Y, Jones KE, et al. Biologic scaffolds composed of central nervous system extracellular matrix. Biomaterials. 2012;33:3539–47. https://doi.org/10.1016/j.biomaterials.2012.01.044.

    Google Scholar 

  124. Viswanath A, Vanacker J, Germain L, Leprince JG, Diogenes A, Shakesheff KM, et al. Extracellular matrix-derived hydrogels for dental stem cell delivery. J Biomed Mater Res - Part A. 2017;105:319–28. https://doi.org/10.1002/jbm.a.35901.

    Google Scholar 

  125. Bible E, Dell’Acqua F, Solanky B, Balducci A, Crapo PM, Badylak SF, et al. Non-invasive imaging of transplanted human neural stem cells and ECM scaffold remodeling in the stroke-damaged rat brain by 19F- and diffusion-MRI. Biomaterials. 2012;33:2858–71. https://doi.org/10.1016/j.biomaterials.2011.12.033.

    Google Scholar 

  126. DeQuach JA, Yuan SH, Goldstein LSB, Christman KL. Decellularized porcine brain matrix for cell culture and tissue engineering scaffolds. Tissue Eng Part A. 2011;17:2583–92. https://doi.org/10.1089/ten.tea.2010.0724.

    Google Scholar 

  127. Chaimov D, Baruch L, Krishtul S, Meivar-levy I, Ferber S, Machluf M. Innovative encapsulation platform based on pancreatic extracellular matrix achieve substantial insulin delivery. J Control Release. 2017;257:91–101. https://doi.org/10.1016/j.jconrel.2016.07.045.

    Google Scholar 

  128. Pouliot RA, Link PA, Mikhaiel NS, Schneck MB, Valentine MS, Kamga Gninzeko FJ, et al. Development and characterization of a naturally derived lung extracellular matrix hydrogel. J Biomed Mater Res - Part A. 2016;104:1922–35. https://doi.org/10.1002/jbm.a.35726.

    Google Scholar 

  129. Merna NJ, Fung KM, Wang JJ, King CR, Hansen KC, Christman KL, et al. Differential β3 integrin expression regulates the response of human lung and cardiac fibroblasts to extracellular matrix and its components. Tissue Eng Part A. 2015;21:2195–205. https://doi.org/10.1089/ten.TEA.2014.0337.

    Google Scholar 

  130. Lee JS, Shin J, Park HM, Kim YG, Kim BG, Oh JW, et al. Liver extracellular matrix providing dual functions of two-dimensional substrate coating and three-dimensional injectable hydrogel platform for liver tissue engineering. Biomacromolecules. 2014;15:206–18. https://doi.org/10.1021/bm4015039.

    Google Scholar 

  131. Loneker AE, Faulk DM, Hussey GS, D’Amore A, Badylak SF. Solubilized liver extracellular matrix maintains primary rat hepatocyte phenotype in-vitro. J Biomed Mater Res - Part A. 2016;104:957–65. https://doi.org/10.1002/jbm.a.35636.

    Google Scholar 

  132. Dziki JL, Wang DS, Pineda C, Sicari BM, Rausch T, Badylak SF. Solubilized extracellular matrix bioscaffolds derived from diverse source tissues differentially influence macrophage phenotype. J Biomed Mater Res - Part A. 2017;105:138–47. https://doi.org/10.1002/jbm.a.35894.

    Google Scholar 

  133. Sicari BM, Dziki JL, Siu BF, Medberry CJ, Dearth CL, Badylak SF. The promotion of a constructive macrophage phenotype by solubilized extracellular matrix. Biomaterials. 2014;35:8605–12. https://doi.org/10.1016/j.biomaterials.2014.06.060.

    Google Scholar 

  134. Meng FW, Slivka PF, Dearth CL, Badylak SF. Solubilized extracellular matrix from brain and urinary bladder elicits distinct functional and phenotypic responses in macrophages. Biomaterials. 2015;46:131–40. https://doi.org/10.1016/j.biomaterials.2014.12.044.

    Google Scholar 

  135. Wang RM, Christman KL. Decellularized myocardial matrix hydrogels: in basic research and preclinical studies. Adv Drug Deliv Rev. 2016;96:77–82. https://doi.org/10.1016/j.addr.2015.06.002.

    Google Scholar 

  136. Hoch AI, Mittal V, Mitra D, Vollmer N, Zikry CA, Leach JK. Cell-secreted matrices perpetuate the bone-forming phenotype of differentiated mesenchymal stem cells. Biomaterials. 2016;74:178–87. https://doi.org/10.1016/j.biomaterials.2015.10.003.

    Google Scholar 

  137. Chen XD, Dusevich V, Feng JQ, Manolagas SC, Jilka RL. Extracellular matrix made by bone marrow cells facilitates expansion of marrow-derived mesenchymal progenitor cells and prevents their differentiation into osteoblasts. J Bone Miner Res. 2007;22:1943–56. https://doi.org/10.1359/jbmr.070725.

    Google Scholar 

  138. Prewitz MC, Seib FP, von Bonin M, Friedrichs J, Stißel A, Niehage C, et al. Tightly anchored tissue-mimetic matrices as instructive stem cell microenvironments. Nat Methods. 2013;10:788–94. https://doi.org/10.1038/nmeth.2523.

    Google Scholar 

  139. Rao Pattabhi S, Martinez JS, TCS K. Decellularized ECM effects on human mesenchymal stem cell stemness and differentiation. Differentiation. 2014;88:131–43. https://doi.org/10.1016/j.diff.2014.12.005.

    Google Scholar 

  140. Decaris ML, Leach JK. Design of experiments approach to engineer cell-secreted matrices for directing osteogenic differentiation. Ann Biomed Eng. 2011;39:1174–85. https://doi.org/10.1007/s10439-010-0217-x.

    Google Scholar 

  141. Decaris ML, Mojadedi A, Bhat A, Leach JK. Transferable cell-secreted extracellular matrices enhance osteogenic differentiation. Acta Biomater. 2012;8:744–52. https://doi.org/10.1016/j.actbio.2011.10.035.

    Google Scholar 

  142. Harvestine JN, Orbay H, Chen JY, Sahar DE, Leach K. Cell-secreted extracellular matrix, independent of cell source, promotes the osteogenic differentiation of human stromal vascular fraction. J Mater Chem B. 2018;6:4104–15. https://doi.org/10.1039/C7TB02787G.

    Google Scholar 

  143. Kusuma GD, Brennecke SP, O’Connor AJ, Kalionis B, Heath DE. Decellularized extracellular matrices produced from immortal cell lines derived from different parts of the placenta support primary mesenchymal stem cell expansion. PLoS One. 2017;12. https://doi.org/10.1371/journal.pone.0171488.

  144. Ng CP, Sharif ARM, Heath DE, Chow JW, Zhang CBY, Chan-Park MB, et al. Enhanced ex vivo expansion of adult mesenchymal stem cells by fetal mesenchymal stem cell ECM. Biomaterials. 2014;35:4046–57. https://doi.org/10.1016/j.biomaterials.2014.01.081.

    Google Scholar 

  145. Shakouri-Motlagh A, O’Connor AJ, Brennecke SP, Kalionis B, Heath DE. Native and solubilized decellularized extracellular matrix: a critical assessment of their potential for improving the expansion of mesenchymal stem cells. Acta Biomater. 2017;55:1–12. https://doi.org/10.1016/j.actbio.2017.04.014.

    Google Scholar 

  146. Guneta V, Loh QL, Choong C. Cell-secreted extracellular matrix formation and differentiation of adipose-derived stem cells in 3D alginate scaffolds with tunable properties. J Biomed Mater Res - Part A. 2016;104:1090–101. https://doi.org/10.1002/jbm.a.35644.

    Google Scholar 

  147. Lai Y, Sun Y, Skinner CM, Son EL, Lu Z, Tuan RS, et al. Reconstitution of marrow-derived extracellular matrix ex vivo: a robust culture system for expanding large-scale highly functional human mesenchymal stem cells. Stem Cells Dev. 2010;19:1095–107. https://doi.org/10.1089/scd.2009.0217.

    Google Scholar 

  148. Decaris ML, Binder BY, Soicher MA, Bhat A, Leach JK. Cell-derived matrix coatings for polymeric scaffolds. Tissue Eng Part A. 2012;18:2148–57. https://doi.org/10.1089/ten.tea.2011.0677.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Daniel E. Heath.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Heath, D.E. A Review of Decellularized Extracellular Matrix Biomaterials for Regenerative Engineering Applications. Regen. Eng. Transl. Med. 5, 155–166 (2019). https://doi.org/10.1007/s40883-018-0080-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40883-018-0080-0

Keywords

Navigation