Renal Bioengineering with Scaffolds Generated from Human Kidneys

Abstract

Background: In 2012, about 16,487 people received kidney transplants in the USA whereas 95,022 candidates were on the waiting list at the end of the year. Moreover, more than 2,600 kidneys procured annually for transplantation are discarded for a variety of reasons. We hypothesize that this pool of discarded kidneys could in part meet the growing, urgent need for transplantable kidneys using current methods for organ bioengineering and regeneration and surgical transplantation. The recellularization of extracellular matrix (ECM) scaffolds has the potential to meet the uniquely ambitious engineering challenges posed by complex solid organs such as the kidney. Summary: Attempts to manufacture and implant simpler, hollow structures such as bladders, vessels, urethras, and segments of the upper airways have been successful in the short and mid terms. However, the bioengineering of complex solid organs such as the kidney is a more challenging task that requires a different approach. In previous studies, we showed that decellularized porcine kidneys yield renal ECM scaffolds that preserve their basic architecture and structural components, support cell growth in vivo and in vitro, and maintain a patent vasculature capable of sustaining physiological blood pressure. In a subsequent report, using the same methods, we found that detergent-based decellularization of discarded human renal kidneys preserved their innate ECM framework, biochemical properties, and angiogenic capacity and - importantly - a patent vascular network. Furthermore, the process resulted in the clearance of immunogenic antigens, which has monumental implications for clinical outcomes in the long term in terms of graft rejection. Consequently, these kidneys show promise in bioengineering and transplantation. We refer to this avenue of research and development as ‘cell-scaffold technology'. Key Messages: In 2011, more than 4,700 patients died while on the waiting list for a kidney transplant. In this context, we believe that cell-scaffold technology has the potential to form a bridge between regenerative medicine and transplantation surgery. These methods, in theory, could provide a potentially inexhaustible source of transplantable organs. Unfortunately, current investigations are still in their very early stages and clinical translation is not immediately available in the short term. Thus, identifying the most important obstacles confronting cell-scaffold technology and focusing research efforts in this direction will be important for advancing the state of the art and meeting the clinical needs. We believe that cell-scaffold technology research and development would benefit greatly from a deeper understanding of the physiological mechanisms underlying the natural organogenesis, regeneration, and repair that characterize embryonic humans and simpler organisms. Furthermore, the importance of vascularization - the fundamental caveat of modern surgery - cannot be overstated, especially when discussing the implantation of de novo organs.

Avoiding Detrimental Human Immune Response Against Mammalian Extracellular Matrix Implants

“…This is since rapid ingrowth of blood vessels is a major prerequisite for successful implantation of biomaterials in reconstructive surgery and has to be effectively induced following implantation of ECM scaffolds that were seeded in vitro with cells. 86 In vivo quantitative realtime polymerase chain reaction studies with a-gal nanoparticles-injected skin of GT-KO mice further demonstrated elevation in the activity of a number of cytokine genes including FGF, IL1, PDGF, and CSF, suggesting that macrophages recruited into the skin by a-gal nanoparticles are activated to produce a wide range of pro-healing cytokines/ growth factors. 73 The pro-healing effects of cytokines/ growth factors produced by the activated macrophages could be demonstrated in vivo by the marked acceleration in healing of skin injuries treated with a-gal nanoparticles.…”

Re-epithelialization of whole porcine kidneys with renal epithelial cells

“…A promising approach for creating artificial organs is decellularization of allogeneic or xenogeneic organs to clear away all potential immunogens followed by recellularization with patient-specific cells to regenerate whole healthy organs. 5–7 …”

Recellularization via the bile duct supports functional allogenic and xenogenic cell growth on a decellularized rat liver scaffold

“…Furthermore, preservation of vasculature channels can permit rapid exchange of nutrients and oxygen to growing and functioning cells. 2 Following the success of perfusion decellularization in the cardiac model, the principle has been applied to other whole organs such as the kidney, [3][4][5][6] lungs, [7][8][9] and liver. 6,[10][11][12][13][14][15][16][17][18] A number of effective strategies for the decellularization of rat livers have been described by Uygun et al, 10 Bao et al 19 and Baptista et al…”