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Decellularized tissues and organs: an historical perspective and prospects for the future

The success in the use of many types of autogenous and fresh and devitalized allogeneic tissues and organs for the treatment of a wide variety of profound clinical problems naturally led to the investigation of xenogeneic tissues/organs to overcome the notable problem of limited availability. The development of methods to completely and reliably remove the cellular elements from xenogeneic material has been an enabling step in their implementation. The review article on the topic of decellularized tissues and organs (‘Clinical applications of decellularized extracellular matrices for tissue engineering and regenerative medicine’, by M Parmaksiz et al) in this issue [1] demonstrates the many and myriad clinical applications for which this technology is being used. In fact, this journal has been publishing work on this subject for over 10 years [2–10]. There is no denying, however, the rapid increase recently in the number of published articles in the field. The subject has now grown such that no one review article can any longer capture the whole story. The current paper in this issue provides an overview of the technology and we hope will be a handy reference for its application to a wide array of tissues and organ problems. The article adds to the many other reviews published elsewhere in recent years [11]. The decellularization of tissues (i.e. structures comprising a population of cells of the same type and their extracellular matrix product) is necessary if there is a performance-controlling feature of the chemical composition, nano-/micro-structure, or mechanical properties of the matrix that cannot be duplicated through de novo synthesis. Decellularization of organs (i.e. structures comprising 2 or more tissues) is often necessary because of the difficulty of synthesizing such a complex structure de novo, whether ex vivo or in vivo. (Although, for some time 3D printing has also been addressing the production of complex organs ex vivo [12].) One of main goals of decellularization is the safe implementation of xenogeneic tissues and organs, and cell culture-produced matrices, with the retention of resident regulatory molecules (e.g. growth factors) as well as matrix molecules. To this end decellularization (the complete removal of cellular elements) versus the devitalization of tissues (i.e. the destruction of cells without removal of the cell debris) is compelling. At the outset it is important to distinguish applications for which the eventual absorption of the decellularized tissue/organ, for replacement with newly formed tissue, is the goal (e.g. treatment of defects in bone) versus applications for which the graft needs to function indefinitely and for which even a small amount of degradation of the matrix could result in failure (e.g. transplants for articular cartilage and heart). For the former, the decellularized matrix alone may be sufficient, but for the latter chemical treatment including cross-linking (e.g. glutaraldehyde fixation of porcine valves) or recellularization by exogenous or endogenous cells may be required. One objective of this editorial is to place decellularization of tissues and organs in an historical perspective that may serve to inform future applications. That perspective brings into clearer view the pathway that resulted in many decellularized tissue and organs: progression from autograft to devitalized allograft to decellularized xenograft. Understandably, in many applications the critically important and highly successful use of autogenous tissues was frustrated by the limited availability of donor sites. This naturally led to the attempts, often successful, to use allogeneic tissues and organs, with the limitations being: the necessity for immunosuppression for certain fresh allografts (viz., containing viable cells); concerns about residual immunogens in devitalized tissues; and availability. The potential for virtually unlimited numbers of grafts, and in some cases their availability as an off-the-shelf product, understandably directed attention to the investigation of decellularized xenogeneic tissues/organs. Toward the goal of assessing the prospects for the future, it is instructive herein to bring into focus the principles that determine which tissues and organs may perform satisfactorily when decellularized and which tissues/organs cannot function as such. Diverse examples of a tissue and an organ that can only function successfully when living, necessitating use as fresh allografts, are articular cartilage and heart. In the former, while the cells may generally appear to be rather dormant, in fact their vitality is required to maintain M Spector