Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine

Abstract

Tissue-engineered decellularized extracellular matrix (ECM) scaffolds hold great potential to address the donor shortage as well as immunologic rejection attributed to cells in conventional tissue/organ transplantation. Decellularization, as the key process in manufacturing ECM scaffolds, removes immunogen cell materials and significantly alleviates the immunogenicity and biocompatibility of derived scaffolds. However, the application of these bioscaffolds still confronts major immunologic challenges. This review discusses the interplay between damage-associated molecular patterns (DAMPs) and antigens as the main inducers of innate and adaptive immunity to aid in manufacturing biocompatible grafts with desirable immunogenicity. It also appraises the impact of various decellularization methodologies (i.e., apoptosis-assisted techniques) on provoking immune responses that participate in rejecting allogenic and xenogeneic decellularized scaffolds. In addition, the key research findings regarding the contribution of ECM alterations, cytotoxicity issues, graft sourcing, and implantation site to the immunogenicity of decellularized tissues/organs are comprehensively considered. Finally, it discusses practical solutions to overcome immunogenicity, including antigen masking by crosslinking, sterilization optimization, and antigen removal techniques such as selective antigen removal and sequential antigen solubilization.

Papain-Based Solubilization of Decellularized Extracellular Matrix for the Preparation of Bioactive, Thermosensitive Pregels

“…There is currently no specific guidance from the FDA regarding remnant cellular content in commercially available decellularized tissues, while a number of yet inconclusive data has been reported on the immune (in)tolerance of dECMbased materials, largely varying with the tissue type, source, and processing. 38 Although α-amylase does not fall under the category of classical peptide proteases, it was included in this study based on recent research demonstrating its efficacy as a digestive enzyme for successfully generating dECM hydrogels. 12,13,15 Based on the enzyme manufacturers' recommendations for buffers, pH, and temperature, the digestion time, steps, and enzyme concentration were optimized for all tested enzymes via visual inspection of the digestion progress (Figure S1).…”

“…However, their specific safe use in terms of a potential adverse immune response in vivo particularly in the long term during and after cellular matrix remodeling needs to be assessed. There is currently no specific guidance from the FDA regarding remnant cellular content in commercially available decellularized tissues, while a number of yet inconclusive data has been reported on the immune (in)­tolerance of dECM-based materials, largely varying with the tissue type, source, and processing …”

Fabrication and Characterization of an Electro‐Compacted Collagen/Elastin/Hyaluronic Acid Sheet as a Potential Skin Scaffold

“…[ 8,9 ] However, the immunogenicity of dECM remains a significant challenge to clinical applications due to its componential complexity. [ 10 ] Therefore, as the main component of skin ECM, collagen and its degraded form‐gelatin, have received more interest in the fabrication of skin scaffolds through various methods such as freeze‐drying and 3D printing. [ 11–14 ] There are also commercial epidermal and full‐thickness skin models that are based on a collagen matrix.…”

Decellularized diseased tissues: current state‐of‐the‐art and future directions

“…Alternatives made from abandoned tissues/organs can serve as effective sources for decellularized biomaterials and can alleviate ethical concerns. 13 It is widely known that deserted tissues and organs, especially those from human sources, have varying degrees of pathological changes. Notwithstanding evolutionarily conserved properties of ECM proteins, there are significant differences in the physiochemical properties of the ECM among tissues and organs in different physiological and pathological states.…”

“…Despite significant research progresses and promising application prospects, the development of decellularized biomaterials is limited to some extent due to the restricted harvest of native tissues and organs. Alternatives made from abandoned tissues/organs can serve as effective sources for decellularized biomaterials and can alleviate ethical concerns 13 . It is widely known that deserted tissues and organs, especially those from human sources, have varying degrees of pathological changes.…”