Dixit et al. Journal of Biological Engineering (2017) 11:49 DOI 10.1186/s13036-017-0089-9 REVIEW Open Access Immunological challenges associated with artificial skin grafts: available solutions and stem cells in future design of synthetic skin Saurabh Dixit1,2†, Dieudonné R. Baganizi1†, Rajnish Sahu1†, Ejowke Dosunmu1, Atul Chaudhari1, Komal Vig1, Shreekumar R. Pillai1, Shree R. Singh1 and Vida A. Dennis1* Abstract The repair or replacement of damaged skins is still an important, challenging public health problem. Immune acceptance and long-term survival of skin grafts represent the major problem to overcome in grafting given that in most situations autografts cannot be used. The emergence of artificial skin substitutes provides alternative treatment with the capacity to reduce the dependency on the increasing demand of cadaver skin grafts. Over the years, considerable research efforts have focused on strategies for skin repair or permanent skin graft transplantations. Available skin substitutes include pre- or post-transplantation treatments of donor cells, stem cell-based therapies, and skin equivalents composed of bio-engineered acellular or cellular skin substitutes. However, skin substitutes are still prone to immunological rejection, and as such, there is currently no skin substitute available to overcome this phenomenon. This review focuses on the mechanisms of skin rejection and tolerance induction and outlines in detail current available strategies and alternatives that may allow achieving full-thickness skin replacement and repair. Keywords: Skin allograft, Immune rejection, Biomaterial, Scaffolds, Stem cells, Skin tissue engineering, Skin substitutes Background severe skin injuries to protect the exposed layers of skin The skin, a subcomponent of the integumentary system, and allow the damaged portion to reform. Transplanting is a substantial fast-growing organ comprised of the epi- autologous skin grafts [4, 5] is the therapeutic approach dermis, dermis and hypodermis layers, which in adults of choice that successively reform the skin, but extensive weighs about 7–8 pounds, covering 21–22 square feet of injuries and chronic skin wounds could result in an in- surface area (2-m square). The skin is a protective bar- sufficient number of autografts, especially in severe burn rier for toxins, micro-organisms, radiation, and mechan- cases [6] and skin morbidities [7, 8]. When required, in ical impacts along with regulating several physiological such cases, either allogeneic or xenogeneic, skin grafts functions including temperature control, preventing de- are used for transplantation. Despite allogeneic trans- hydration and providing sensory detection and immune plantations becoming more tolerant with immunosup- surveillance [1, 2]. Human skin frequently is damaged/ pressive treatment, there are still some issues with early injured resulting in the loss of its integrity and physio- rejection. Skin allograft rejection is the recipient’s im- logical balance, which may result in significant disability mune response following the recognition of alloantigens and infections. The skin’s natural restorative capacity leading to the cellular destruction. Allogeneic or xeno- usually is sufficient to repair and heal itself when dam- geneic skin grafts may be employed but their short-term aged/injured [3]. However, skin grafts are required for graft survival time limits their clinical use [9]. Skin allo- grafts transplantation is employed for severe clinical cases to protect the damaged skin areas, but considering * Correspondence: [email protected] † the conundrum of the rejection mechanism, the recipi- Equal contributors 1Center for Nanobiotechnology Research and Department of Biological ent may require additional transplantation from a differ- Sciences, Alabama State University, 1627 Harris Way, Montgomery, AL 36104, ent donor [10]. Alternative strategies are now being USA developed to overcome skin allograft rejections and Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Dixit et al. Journal of Biological Engineering (2017) 11:49 Page 2 of 23 allowing adequate skin repair [11, 12]. Novel treatment this functionality with adoptive transfer of normal T cells approaches include the use of stem cell-based therapies, initiates rejection of the skin graft [25, 26]. Therefore, a specific immunosuppressive therapies targeting T cells hurdle in allogeneic skin grafting is the triggering of or donor immune cells and skin tissue engineering. Sev- CD4+ and CD8+ T cells immune responses, sometimes eral tissue-engineered skin substitutes are commercially involving both for first set rejection, although second set available and used in clinical settings with negligible risk rejection could be facilitated by antibodies [26]. of immunogenic responses such as the Integra dermal The mechanism of skin graft rejection (Fig. 1) starts regeneration template [13]. Available engineered skin with responses from dendritic cells (DCs), macrophages, substitutes are composed of either a cellular or acellular polymorphonuclear cells, angiogenic mediators, and cy- component and a biological (autologous, allogeneic, and tokines to promote rejection [22, 23], followed subse- xenogeneic) or synthetic (polymer) scaffold [14]. quently by the activation of T cells (CD4+ and CD8+). However, available skin alternatives engineered to Further, accumulation of inflammatory cytokines and ef- mimic natural skin still do not provide a permanent so- fector T cells permeate the skin graft to commence re- lution [5, 14, 15]. This review gives an insight into jection [22, 26, 27]. The event/stimulus that triggers skin different approaches and innovative advances to allow graft rejection arises from a mismatch in donor MHC overcoming skin allografts rejection. and recipient T cells receptors (TCRs) [28]. Even though matching the MHC type is critical in avoiding skin grafts Immunological rejection rejection, a single genetic difference at the loci of MHC Mechanisms of skin graft rejection molecules can still commence the rejection process by Allografts have been used for many years in transplant- stimulating alloreactive T cells [10]. Additionally, even if ation; however, donor tissue availability remains a critical the rejection rate is not very high in genetically related issue. Cadaver tissues, especially organs, are in high de- donor and recipient [29], it can be controlled by im- mand and harvesting of skin has to be completed rapidly munosuppressive drugs. The only scenario where allo- [16] post-death and preserved [17]. Critical issues associ- graft transplantation without immunosuppressive drugs ated with allografts are availability and rejection. is successful when the donor and recipient are identical Laboratory-grown artificial tissues are now in develop- twins, with true human leukocyte antigen (HLA) match ment to help overcome the immunological rejection is- [30], which shows the immunological importance of sues [18, 19]. Over the years, synthetic skins comprised MHC molecules in rejection of transplants. Thus match- mostly of human cell lines with biodegradable materials ing the HLA types [31] between non-identical twins have been used for transplantation onto burned and wounded skin patients [20, 21]. Even though the artifi- cial skin products are in development and available com- mercially, they are still prone to rejections [7]. Skin autografts transplantation is a well-known med- ical procedure. Grafting between genetically identical in- dividuals (syngeneic graft) can be successful without a prolonged immunosuppressive treatment. Even though immunosuppressive treatments for organ transplantation are effective in preventing early rejection, skin tissues whether from both donor or engineered are continu- ously failing [22]. Skin graft successfully placed at the donor site but rejected within 1–2 weeks is consistent and is termed first set rejection. The second set of rejec- tion is even faster if grafted from the same donor. Graft rejection is an intricate mechanism, which involves an array of processes and ultimately potent inflammatory responses initiated by innate immune responses and de- struction of the donor tissue [23]. The rate of rejection ’ of donor tissue at the recipient s graft site is dependent Fig. 1 Allorecognition pathways: Direct pathway is the process on the graft volume and antigens incompatibilities be- whereby the donor’s MHC molecules on APCs is recognized by the tween both. The role of T lymphocytes in graft rejection TCRs of recipient’s T cells. Indirect pathway recognizes the processed is vital as evidenced from studies in nude mice, which peptide presented by recipient’s MHC on APCs. Semi-direct pathway is ’ do not reject allogeneic skin grafts because they lack where T cell activation occurs by transfer of the donorsMHContothe recipient’sAPCs CD4+ and CD8+ functionality [24]; however restoring Dixit et al. Journal