The decellularized extracellular matrix in regenerative medicine.

Abstract

Regenerative MedicineVol. 12, No. 5 EditorialFree AccessThe decellularized extracellular matrix in regenerative medicineGirdhari RijalGirdhari Rijal*Author for correspondence: E-mail Address: girdhari.rijal@wsu.edu Department of Biomedical Science, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99210, USASearch for more papers by this authorPublished Online:13 Jul 2017https://doi.org/10.2217/rme-2017-0046AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: 3D scaffoldcellular behaviourscross-linkersdecellularized ECM (DECM)extracellular matrix (ECM)hydrogel native microenvironmentregenerative medicineFirst draft submitted: 30 March 2017; Accepted for publication: 19 May 2017; Published online: 13 July 2017The extracellular matrix (ECM) is a complex nonliving biomaterial, secreted by cells, which acts as a specific, functional and protective bed for cells. It is composed of many types of protein, which form a complex together with water-soluble and -insoluble molecules. The physical nature of ECM may be semifluid or solid depending on the protein types and their complexes.The ECM's components, its stiffness and the presence of ECM-bound inducers are key factors, which are necessary for the attachment, proliferation, migration and function of cells. The major components, such as collagen, fibronectin, laminin, elastin and various complexes (e.g., glycosaminoglycans) play vital roles in maintaining the native-like environment of the cells growing in in vitro or in vivo systems. The ECM has the viscoelasticity and mechanoconduction abilities to regulate dynamic cellular behaviors, such as proliferation and migration, and to influence rapid growth of the cells [1]. Besides the fundamental role of the ECM, the cells growing on the ECM bed generate forces spatiotemporally on the ECM that trigger signaling pathways to regulate the biological processes of proliferation and expansion [2].Removal of cellular components from the ECM leaves the water-insoluble matrix, generally known as decellularized ECM (DECM). Usually mild detergents like sodium dodecyl sulfate and Triton X-100 are used to decellularize the tissue, along with physical and enzymatic treatment. The DECM has physiological cues to mimic the native microenvironment and is, therefore, more appropriate for refunctionalization and better recovery of a tissue as a replaceable model compared with commonly used biomaterials. DECM is therefore in high demand in both basic research and clinics. The biocompatibility, biodegradability and bioinductivity of DECM are important factors to be considered in surgical practice and research. The DECM tissue/organ, DECM hydrogel and DECM microparticles are all used in regenerative medicine.DECM can be prepared from any organ or tissue according to the purpose of the research or a clinical application [3]. DECM from bone, breast, skin and bladder is most commonly used in clinical practice. Whole organ decellularization and its use as a scaffold to regenerate functional organs after loading of scaffold-specific cells have been practiced significantly in recent years. Whole tissues or organs can now be recellularized with the desired stem cells for functional tissue/organ development [4].The use of DECM as a hydrogel or scaffold has significantly increased in the fields of regenerative medicine, cancer research, and drug and cell delivery [5]. Once a DECM hydrogel is prepared, it can be coated onto coverslips/culture plates or onto a solid scaffold (usually porous) prepared through fabrication techniques such as 3D prototype printing, conventional mould method and stereolithographic methods. Coating the porous scaffold prepared from the synthetic biomaterials (e.g., polycaprolactone [PCL]) provides a hydrophilic surface for the cells, with the environment required for the initial cell-matrix interactions, which are of foremost importance for successful cell attachment and growth [6]. The DECM hydrogel coating in 3D porous PCL scaffold has been successfully studied. The preparation of a bioink, a mixture of hydrogel with the cells, is nowadays a hot topic in the field of bioengineering and regenerative medicine. DECM is considered as the ideal biomaterial to use as a bioink. DECM has also been used comprehensively to study stem cell differentiation in in vitro models, for example differentiation to osteogenic, neural and renal progenitor cells [7,8].Despite in vitro results from these scaffolds showing promise for better tissue growth and drug release, their actual contributions in the hosts for the better recovery, replacement and normalization of cellular/tissue functions are minimal [9]. The utilization and naturalization of delivered factors, and natural growth of delivered cells without any host immune response are the main concerns for successful tissue engineering [10].Injectable DECM gel from full native ECM to regenerate the tissue as demonstrated in the in vivo study has been implemented using pericardial matrix gel [11] and tendon hydrogel [12] to address a few of the concerns mentioned above. Recently, a functional porous scaffold prepared by coating a PCL scaffold with a mixture of DECM and sodium alginate, containing the active catalase, has been tested for successful in vivo tissue regeneration [13]. The catalase within the scaffold helps to detoxify the hydrogen peroxide released by cells during the metabolic process and protects the cells and tissues to better support tissue growth and angiogenesis [13]. This indicates progress toward successful regenerative medicine.The concept of using a region-specific ECM is a focus for regenerating specific tissue types. For example, inner meniscus ECM has shown enhancement of differentiation of human bone marrow mesenchymal stem cells to fibrocartilaginous cells, whereas an outer meniscus ECM differentiated human bone marrow mesenchymal stem cells to fibroblast cell types [14]. Meanwhile, decellularized brain ECM improved behavior through the increased expression of neurotrophic proteins. Liver DECM for liver tissue engineering and cardiac DECM for cardiac repair are some additional examples of using specific DECM in bioengineering. Nonspecific, but relevant, types of DECM also show promise in differentiating stem cells and augmenting tissue, similar to those already used DECM [15,16]. Nonspecific ECM has been used to repair organs, but postgraft consequences may ultimately lead to graft rejection [17,18]. Overall, stem cells have the tendency to differentiate into cell types suited for DECM used in bioengineering. The matrix and its compliance are, therefore, very important in signaling pathways, via cell–matrix interactions, in the development of particular tissue types.The use of naturally derived cross-linkers, for example heparin and photosensitive vitamin B2, to cross-link the ECM and trap a growth factor is a great advancement in tissue engineering models. It helps to reduce the use of non-native cross-linkers and synthetic polymers, which have more cons than pros in tissue regeneration and a high possibility for graft rejections. Heparin also improves endothelialization and minimizes thrombogenization, allowing for a successful supply of oxygen and nutrients to a growing tissue [19]. However, the ECM microparticles have more binding sites compared with hydrogel and cross-linked ECM and are useful for cell and drug delivery, yet are not considered as a good graft model because of the technical difficulties in adhering them on a deeply localized defect tissue, as well as their dispersion after grafting. The antioxidant properties of DECM itself and the use of antibiotic drugs in the preparation of DECM grafts are some of the indicators that support successful in vivo tissue engineering.Currently, DECM is used in various formats and studied extensively to reveal its potential role in regenerating functional tissue. A whole organ/tissue DECM with mechanical supports, recellularization with stem cells, along with supplements of growth and inducing factors indicate future success for functional organ formation in vitro. The implantation of an in vitro functional organ to a particular system and the restoration of physiological function by a grafted organ may be achievable thereafter. However, the protocol for preparation of a porous, flexible and spongy scaffold that could mimic the native tissue from pure DECM is still lacking for translation into regenerative medicine. Such a scaffold should have the capacity to maintain its own physiomechanical integrity and provide a native-like environment for the cells, while growing in an in vitro system to regenerate tissue types according to needs. A soft functional tissue regenerated on DECM scaffold could be subsequently grafted to restore tissue functions. In addition, for a regenerated hard functional tissue like bone, DECM scaffold should be hardened in a way that mimics native hard tissue that could provide minimum mechanical support. There is much hope that such an ideal 3D DECM scaffold will be invented for functional tissue regeneration and for the restoration of a functional organ after grafting in the near future.Financial & competing interests disclosureThe author has no relevant financial affiliations with any organization or entity with a financial interest in or financial conflicts with the subject matter or materials discussed in the manuscript. This includes grants or patents pending or received, employment, expert testimony, consultancies or stock ownership or options.No writing assistance was utilized in the production of this manuscript.References1 Chaudhuri O, Koshy ST, Branco Da Cunha C et al. Extracellular matrix stiffness and composition jointly regulate the induction of malignant phenotypes in mammary epithelium. Nat. Mater. 13(10), 970–978 (2014).Crossref, Medline, CAS, Google Scholar2 Nam S, Lee J, Brownfield DG, Chaudhuri O. Viscoplasticity enables mechanical remodeling of matrix by cells. Biophys. J. 111(10), 2296–2308 (2016).Crossref, Medline, CAS, Google Scholar3 Baptista PM, Siddiqui MM, Lozier G, Rodriguez SR, Atala A, Soker S. The use of whole organ decellularization for the generation of a vascularized liver organoid. Hepatology 53(2), 604–617 (2011).Crossref, Medline, CAS, Google Scholar4 Chani B, Puri V, Sobti RC, Jha V, Puri S. Decellularized scaffold of cryopreserved rat kidney retains its recellularization potential. PLoS ONE 12(3), e0173040 (2017).Crossref, Medline, Google Scholar5 Rijal G, Li W. 3D scaffolds in breast cancer research. Biomaterials 81, 135–156 (2016).Crossref, Medline, CAS, Google Scholar6 Lih E, Park KW, Chun SY et al. Biomimetic porous PLGA scaffolds incorporating decellularized extracellular matrix for kidney tissue regeneration. ACS Appl. Mater. Interfaces 8(33), 21145–21154 (2016).Crossref, Medline, CAS, Google Scholar7 Hoshiba T, Chen G, Endo C et al. Decellularized extracellular matrix as an in vitro model to study the comprehensive roles of the ECM in stem cell differentiation. Stem Cells Int. 2016(2), 1–10 (2016).Crossref, Google Scholar8 Murphy AR, Laslett A, O'brien CM, Cameron NR. Scaffolds for 3D in vitro culture of neural lineage cells. Acta Biomater. 54, 1–20 (2017).Crossref, Medline, CAS, Google Scholar9 Bonandrini B, Figliuzzi M, Papadimou E et al. Recellularization of well-preserved acellular kidney scaffold using embryonic stem cells. Tissue Eng. Part A 20(9–10), 1486–1498 (2014).Crossref, Medline, CAS, Google Scholar10 Allaire E, Bruneval P, Mandet C, Becquemin JP, Michel JB. The immunogenicity of the extracellular matrix in arterial xenografts. Surgery 122(1), 73–81 (1997).Crossref, Medline, CAS, Google Scholar11 Seif-Naraghi SB, Salvatore MA, Schup-Magoffin PJ, Hu DP, Christman KL. Design and characterization of an injectable pericardial matrix gel: a potentially autologous scaffold for cardiac tissue engineering. Tissue Eng. Part A 16(6), 2017–2027 (2010).Crossref, Medline, CAS, Google Scholar12 Farnebo S, Woon CY, Schmitt T 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 20(9–10), 1550–1561 (2014).Crossref, Medline, CAS, Google Scholar13 Rijal G, Kim BS, Pati F, Ha DH, Kim SW, Cho DW. Robust tissue growth and angiogenesis in large-sized scaffold by reducing H2O2-mediated oxidative stress. Biofabrication 9(1), 015013 (2017).Crossref, Medline, Google Scholar14 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. 45(3), 604–611 (2017).Crossref, Medline, Google Scholar15 Paduano F, Marrelli M, White LJ, Shakesheff KM, Tatullo M. Odontogenic differentiation of human dental pulp stem cells on hydrogel scaffolds derived from decellularized bone extracellular matrix and collagen type I. PLoS ONE 11(2), e0148225 (2016).Crossref, Medline, Google Scholar16 Rijal G, Shin H-I. Human tooth-derived biomaterial as a graft substitute for hard tissue regeneration. Regen. Med. 12(3), 263–273 (2017).Link, CAS, Google Scholar17 Woo JS, Fishbein MC, Reemtsen B. Histologic examination of decellularized porcine intestinal submucosa extracellular matrix (CorMatrix) in pediatric congenital heart surgery. Cardiovasc. Pathol. 25(1), 12–17 (2016).Crossref, Medline, CAS, Google Scholar18 Pollot BE, Goldman SM, Wenke JC, Corona BT. Decellularized extracellular matrix repair of volumetric muscle loss injury impairs adjacent bone healing in a rat model of complex musculoskeletal trauma. J. Trauma Acute Care Surg. 81(5 Suppl. 2), S184–S190 (2016).Crossref, Medline, CAS, Google Scholar19 Jiang B, Suen R, Wertheim JA, Ameer GA. Targeting heparin to collagen within extracellular matrix significantly reduces thrombogenicity and improves endothelialization of decellularized tissues. Biomacromolecules 17(12), 3940–3948 (2016).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByAngiogenesis and Re-endothelialization in decellularized scaffolds: Recent advances and current challenges in tissue engineering16 February 2023 | Frontiers in Bioengineering and Biotechnology, Vol. 11The biomimetic extracellular matrix: a therapeutic tool for breast cancer researchTranslational Research, Vol. 247Chondrocytes In Vitro Systems Allowing Study of OA7 September 2022 | International Journal of Molecular Sciences, Vol. 23, No. 18Mimicking the Natural Basement Membrane for Advanced Tissue Engineering15 July 2022 | Biomacromolecules, Vol. 23, No. 8Engineering Vascularized Composite Allografts Using Natural Scaffolds: A Systematic ReviewTissue Engineering Part B: Reviews, Vol. 28, No. 3Engineering Vascularized Composite Allografts Using Natural Scaffolds: A Systematic Review9 July 2021 | Tissue Engineering Part B: Reviews, Vol. 142MRL/MpJ tendon matrix‐derived therapeutic promotes improved healing outcomes in scar‐mediated canonical tendon healing1 June 2020 | Journal of Orthopaedic Research, Vol. 39, No. 7Nanotechnology, and scaffold implantation for the effective repair of injured organs: An overview on hard tissue engineeringJournal of Controlled Release, Vol. 333Emerging biomaterials for reproductive medicineEngineered Regeneration, Vol. 2Comparison of Volume Retention and Biocompatibility of Acellular Dermal Matrix/Hyaluronic Acid Filler to Autologous Fat Grafts in a Mouse Model30 March 2020 | Aesthetic Plastic Surgery, Vol. 44, No. 3Efficient myotube formation in 3D bioprinted tissue construct by biochemical and topographical cuesBiomaterials, Vol. 230Evaluating two ovarian decellularization methods in three speciesMaterials Science and Engineering: C, Vol. 102Lymphatic endothelium contributes to colorectal cancer growth via the soluble matrisome component GDF119 April 2019 | International Journal of Cancer, Vol. 7Decellularization Concept in Regenerative Medicine2 February 2019Native-mimicking in vitro microenvironment: an elusive and seductive future for tumor modeling and tissue engineering12 September 2018 | Journal of Biological Engineering, Vol. 12, No. 1 Vol. 12, No. 5 Follow us on social media for the latest updates Metrics History Published online 13 July 2017 Published in print July 2017 Information© 2017 Future Medicine LtdKeywords3D scaffoldcellular behaviourscross-linkersdecellularized ECM (DECM)extracellular matrix (ECM)hydrogel native microenvironmentregenerative medicineFinancial & competing interests disclosureThe author has no relevant financial affiliations with any organization or entity with a financial interest in or financial conflicts with the subject matter or materials discussed in the manuscript. This includes grants or patents pending or received, employment, expert testimony, consultancies or stock ownership or options.No writing assistance was utilized in the production of this manuscript.PDF download