“Never has there been a more exciting time to be involved in surgical science.”
—Hollander et al. Regen Med 2009; 4: 147.
The objectives of this overview are threefold: to trace the history of regenerative medicine pertinent to solid organ transplantation; to summarize the clinical applications reported to date of regenerative medicine-based technologies implemented to manufacture organs; and to describe the progress achieved in the field towards the engineering of complex modular organs (CMO) (1). We will emphasize the historical and clinical perspectives and will touch only briefly on the related essential basic scientific aspects. Ultimately, this review will demonstrate that: (a) Regenerative medicine and organ transplantation pursue the same goal, namely to replace diseased organs with newly functioning ones (2, 3). (b) Despite significant progress that has been achieved in the field of regenerative medicine to date, current knowledge remains inadequate and whole organ engineering and regeneration of diseased organs remain unattainable goals. For space constraints, it is not our intention to present the entire history of regenerative medicine tout court—which instead can be reviewed elsewhere (4, 5).
Regenerative Medicine, Tissue Engineering, and Organ Transplantation Share the Same Parenthood
Alexis Carrel is considered the father of modern cardiovascular and transplant surgery (6). However, his visionary studies on cell culture and ex vivo organ preservation and growth anticipated concepts regarding tissue engineering and regenerative medicine that were not developed until decades later (6, 7). Carrel's seminal investigations provided the foundation for the development of modern regenerative medicine. In collaboration with engineer and legendary aviator Charles Lindbergh, Carrel created the perfusion pump, which allowed living organs to exist outside of the body during surgery. Their invention was a crucial step in the development of perfusion systems for cardiac and transplant surgery, and for bioreactors currently used in regenerative medicine and tissue engineering investigations. These pioneering developments occurred decades before organ transplantation, tissue engineering, and regenerative medicine became clinical realities (8–17), and almost a century before the implantation of a bioengineered trachea—namely, the first organ fully manufactured outside the body from human components and stem cells (19)—the production of heart (19), liver (20, 21), and lung (22, 23) organoids, and the implementation of the first embryonic stem cell (ESC)-based therapy to treat severe spinal cord injury (http://www.geron.com/media/pressview.aspx?id=1235) (Table 1). The collaboration between Carrel and Lindbergh, which may have appeared unusual to their contemporaries, represents one of the first paradigms of successful crossover between disciplines which, when harnessed, may complement each other and have the potential to open immense horizons.
From Tissue Engineering to Regenerative Medicine
After Carrel's death in 1944, tissue engineering and regenerative medicine remained quiescent for the next 30 years. During this time, formidable progress was made in the translation of findings from the bench to the bedside in the field of organ transplantation, which may be considered as one of the first forms of cell therapy in the history of medicine (4). The cradle of the new awakening in tissue engineering and regenerative medicine occurred in Massachusetts (4, 5). Skin substitutes represented one of the earliest attempts to engineering tissues (15, 16), and by the 1990s, commercialization of these products had begun (24). The term “tissue engineering” is mentioned for one of the first times in a case report of a successful keratoprosthesis (25). One of the first tissue engineering experimental studies pertaining to the field of transplantation was published by Vacanti et al. (26) in 1988. In this study, investigators seeded fetal and adult rat and mouse hepatocytes, pancreatic islet cells, and cells from the small intestine onto synthetic scaffolds. These scaffolds consisted of synthetic polymers organized into fiber networks that reproduced the intertwined branching networks present in all organs that allows cells to remain viable by diffusion, promotes vascular ingrowth, and permits cellular proliferation (27). After 4 days of culture, constructs were implanted in different locations in animals from diverse species. Six cases of successful engraftment were recorded, showing viable cells, mitotic figures, and vascularization of the cell mass. For the first time, scientists were able to manufacture ex vivo and implant living constructs made of a cellular component seeded on a supporting artificial scaffold.
Over the next few years, variations of this principle were implemented and numerous tissues were constructed and implanted (28). In 1997, Vacanti's group described an innovative technology for ear bioengineering (29). A synthetic scaffold shaped like the external ear was seeded with bovine chondrocytes and implanted under the dorsal skin of athymic mice. After 12 weeks, histology showed viable and functioning chondrocytes, formation of cartilage, and new extracellular matrix (ECM) that eventually replaced the totally degraded initial synthetic scaffold. The most striking finding was that the chondrocytes actually survived the implantation, which provided evidence that the combination of isolated parenchymal cells with custom-shaped biocompatible, biodegradable polymer scaffolds could reproduce relatively simple body parts.
By the early 1990s, tissue engineering had become an established field of investigation (30). Concurrently, adult stem cells and ESC were isolated in animals (31, 32) and humans (33), and the advent of nuclear transfer technology made animal cloning possible (7, 34–36). These apparently distinct fields of science had one unifying concept, namely the regeneration of living and functioning body parts destined to replace diseased or damaged cells, tissues, or organs (7). In 1999, the term “regenerative medicine” was coined to describe the use of natural human substances, such as genes, proteins, cells, and biomaterials to regenerate diseased or damaged human tissue (4, 7). It is important to note that the terms tissue engineering and regenerative medicine are not synonymous. The term regenerative medicine is used to define a field in the health sciences that aims to replace or regenerate human cells, tissues, or organs to restore or establish normal function (37). The process of regenerating body parts can occur in vivo or ex vivo and may require cells, natural or artificial scaffolding materials, growth factors, or combinations of all three elements. In contrast, the term tissue engineering is narrower in scope and strictly defined as manufacturing body parts ex vivo, by seeding cells on or into a supporting scaffold.
Clinical Applications of Regenerative Medicine Technologies
Tokyo: Shinoka et al. (11) reported the first implantation of a bioengineered vessel destined to replace the right intermediate pulmonary artery in a child who was suffering from single right ventricle and pulmonary atresia. The principle adopted to engineer the new vessel was identical to the one used by Vacanti's laboratory. Cells harvested from all layers of the wall of a 2-cm segment of a peripheral vein were seeded on a biodegradable polymer made of polycaprolactone and polylactic acid, reinforced with polyglycolic acid. The conduit was successfully implanted after 10-day maturation in a bioreactor. Nine years from the implantation, the patient is doing well, growth is normal, and imaging shows a patent graft (Shinoka T, unpublished data).
The main advantage of using a bioengineered vessel versus prosthetic material is the potential for growth in the former. In fact, as children grow, a prosthetic construct may need to be replaced at some point, whereas tissue-engineered constructs have the potential to grow and remodel because they contain living cells.
Novato: McAllister et al. (12) and L'Heureux et al. (13) and bioengineered vessel grafts which were implanted in nine hemodialysis patients. All had previous hemodialysis access failure, had no suitable vein for a new arteriovenous fistula, and would therefore be candidates for implantation of a synthetic vascular graft. Autologous fibroblasts and endothelial cells (ECs) were collected from patient's skin and superficial vein biopsies. Fibroblasts were cultured in conditions that promote ECM deposition to produce a cohesive sheet that can be detached intact from the culture dishes. Neovessels were produced by wrapping these sheets around a stainless steel mandrel and allow them to fuse. After 10-week maturation, mandrel was removed and autologous ECs were seeded within the lumen to reconstitute the endothelial layer. Mean total time to manufacture the new vessel was 7.5 months and vessel length ranged between 14 and 40 cm. Grafts were implanted in the upper arm between the brachial artery and axillary vein.
At 3-year follow up, results are encouraging (12, 13 and McAllister T, L'Heureux N, unpublished data). Three grafts failed. One patient died of causes unrelated to the study treatment and with a functioning graft. The remaining five patients had functioning grafts for 6 to 20 months after implantation. Cumulatively, primary patency rate was maintained in 7 of 9 (78%) and 5 of 9 cases (60%), at 1 and 6 months from surgery, respectively. These results are consistent with data from the Dialysis Outcomes Quality Initiative (76% primary patency at 3 months after placement of an arteriovenous fistula) (12). Updated results which are currently under review demonstrate a significant reduction in the overall event rate relative to preoperative care (McAllister T, L'Heureux N, unpublished data).
Although time consuming, this technology is peculiar for having produced autologous vessels. No synthetic or exogenous materials were used based on the rationale that vascular graft biomaterials such as synthetic or chemically modified scaffolds would interfere with, rather than guide, the natural assembly of key structural proteins (38). The same authors have recently implanted the first allogeneic tissue-engineered vessel graft. At 4-month follow-up, the outcome is excellent (McAllister T, L'Heureux N, unpublished data).
The Artificial Bladder and Urethra
Atala et al. (9) engineered human bladders for patients with neurogenic bladder disease requiring cystoplasty. Urothelial and muscle cells obtained from bladder biopsies were grown and expanded in culture. Next, cells were seeded on a biodegradable bladder-shaped scaffold. Eight weeks after the initial bladder biopsy, the new organs were ready for implantation and the bladders were anastomosed to the stump of the native bladders. Fibrin glue was applied to the exterior surface of the scaffolds to prevent leak. An omental wrap was used to enhance angiogenesis and protect the bladder anastomosis.
After 46-month follow up, the new bladders showed improved function, compliance, and capacity. Renal function remained normal throughout the reported follow-up because no metabolic complications occurred and urinary calculi did not form. Protocol biopsies showed a tri-layered structure, consisting of an urothelial cell-lined lumen surrounded by submucosa and muscle, with all of the expected components of bladder tissue present.
The main advantage of this technology was the use of autologous cells without the need for immunosuppression. On the other hand, the major drawback was that the vascular supply of the new bladder was not reconstructed. It should be emphasized, however, that all bioengineered organs illustrated so far receive oxygen and nutrients by diffusion from neighboring tissues immediately after implantation. Neoangiogenesis begins during the inflammatory response that follows implantation, which might not be rapid or adequate enough to prevent ischemia and consequent stenoses at anastomoses. Notably, this technology has been exploited to bioengineer urethras which were successfully implanted in individuals suffering from severe urethral stenosis (10). The 6-year outcome is excellent.
Upper Airways Bioengineering
A bioengineered trachea was manufactured ex vivo and implanted in a 30-year-old woman with end-stage bronchomalacia (18). To do so, a deceased donor trachea was retrieved, decellularized, and seeded with autologous epithelial cells and chondrocytes. Epithelial cells were obtained from bronchoscopy samples of bronchial mucosa. Chondrocytes were differentiated from mesenchymal stem cells isolated from patient's bone marrow. After a 4-day maturation period, the construct was implanted to replace the diseased left main bronchus. The early postoperative course was uneventful and no immunosuppression was administered. Eight months later, imaging showed ventral collapse of the proximal end of the graft, possibly caused by compression from the aortic arch superiorly with consequent migration of stem cell-derived chondrocytes into the graft endoluminal surface (39) or ischemia as the vascular supply of the new windpipe was not reconstructed. Although the patient was asymptomatic, a temporary endoluminal stent was placed as a precaution. Eighteen months after the initial operation, the patient is doing well and imaging shows normal architecture.
This case is innovative for two reasons. First, stem cells were used for the first time to produce a specific tissue. Second, a human organ was used to generate the scaffolding material. A major advantage of using natural scaffolds is preservation of native tissue architecture and vascular tree (1). Additionally, growth factors will remain within the ECM despite decellularization (40). Moreover, use of human scaffolds avoids potential risks of transmission of zoonotic infections or of development of hyperacute rejection associated with the use of animal scaffolds.
In 2008, Taylor and coworkers (19) described the ex vivo production of a functioning heart. Complete decellularization of rat hearts was achieved through coronary perfusion with detergents. The so-obtained acellular heart scaffolds had preserved ECM components, intact and perfusable vascular tree, competent acellular valves, and maintained chamber architecture and geometry. Scaffolds were repopulated by intramural injection of neonatal cardiac cells and by perfusion of rat aortic ECs. After maturation, the recellularized constructs resumed macroscopic contractile function and were able to generate pump function.
For the first time, a CMO was manufactured ex vivo. Resumption of contractile function provided evidence that this technology—which represents the evolution of the initial seeding of cells on inert synthetic scaffolds lacking any vascular system—may effectively produce viable and functioning organs on a small scale, yet ex vivo. Such an approach has also been applied successfully to engineer small livers and lungs from rodents (1, 20–23, 41). Baptista et al. (21, 41) and Uygun et al. (20) have developed in parallel liver organoids by applying similar technologies. Rat (20) and ferret (21) livers were successfully decellularized and repopulated with ECs and hepatocytes from rats and humans by intravascular infusion, respectively. After maturation, histology revealed a high density of viable cells throughout the new organ with visible tissue formation. Immunohistochemical analysis showed extensive and intense albumin expression and urea secretion. The recellularized rodent liver grafts were successfully implanted into rats, supporting hepatocyte survival and function. In a similar fashion, functioning lung organoids were produced through the seeding of pulmonary epithelium and vascular endothelium on rat lung ECM (22, 23). The bioengineered lung constructs showed mechanical characteristics that were comparable with those of native lungs and which were effective at mediating gas exchange when implanted into rats.
The same technology has been implemented in the attempt to manufacture kidney (Fig. 1), pancreas, and intestine organoids from rats (1, 41–45) and pigs (41). Although kidneys, pancreata, and intestines can be decellularized successfully, the repopulation of the obtained scaffolds is challenging (41–45). The most promising results have been obtained with kidneys and pancreata. Preliminary results show that murine ESCs, injected through the renal artery and ureter of a decellularized rat kidney, express markers of differentiation to mature renal cells, in the absence of any differentiation factor (42). These results provide further proof that natural scaffolds maintain the microenvironment necessary for the determination of cell fate (40). In the case of the pancreas, when islets are seeded on pancreas ECM, they adhere to the matrix and show a constant glucose-induced insulin release during long-term in vitro incubation. In contrast, when islets are cultured in the absence of the pancreatic matrix or on a liver matrix, they show a progressive reduction in insulin release (45), which is consistent with the hypothesis that ECM is organ specific.
Taken together, these studies suggest that the perfusion method used to decellularize organs can also be used to deliver cells for repopulation. Human and animal ECM seem to provide all the information required to guide and drive cell fate, whereas maintaining an intact vascular network for an adequate support of oxygen and nutrients. However, many hurdles (Table 2) remain to be overcome in scaling these technologies to human organs.
In the case of use of animal-derived scaffolds, such an approach will validate what is referred to as “semi-xenotransplantation” (Fig. 2). Although in xenotransplantation the whole organ is animal-derived, in semi-xenotransplantation only the scaffold is animal-derived. Theoretically, this approach has the potential to overcome hyperacute rejection and the risk for transmission of zoonoses that to date have restricted widespread application of xenotransplantation. Interestingly, previous studies have ruled out the transmission to sheep of a porcine endogenous retrovirus genome in acellular porcine cardiovascular scaffolds (46, 47). When the potential risk for hyperacute rejection was investigated, the 1,3 Gal epitope—which may persist in porcine-derived ECM scaffold material—had been demonstrated to elicit a clinically irrelevant serum antibody response in primate models, but no adverse effect on tissue remodeling was observed (48).
The other important aspect of this technology is that these new organs will require vascular reconstruction. Mertsching et al. (49) implanted a 10-cm decellularized porcine small bowel segment seeded with autologous cells into the arm of a patient suffering from a major tracheoesophageal defect. Study endpoints were to investigate the following: (1) the technical feasibility of such an implantation; (2) the thrombogenicity of the vascular network; and (3) construct viability after 1 week. The treatment strategy was to ultimately repair the tracheoesophageal breach with a new organ engineered from porcine jejunum and recipient cells. The postoperative course in this patient was uneventful and on day 7, the organ was harvested and processed for histology. Strikingly, viable cells were present and the vasculature was patent.
Stem-Cell Technology and Developmental Biology
Although we are still a long way from understanding how stem cells may generate viable complex organs, it is reasonable to predict that stem cells may revolutionize regenerative medicine and organ transplantation in the future (1). The immunomodulatory properties of mesenchymal stem cells are well known (50–54); however, harnessing of these properties for tissue repair and regeneration should be the ultimate objective to pursue (55). Developmental biology and stem-cell research hold a great potential, and the focus of both is to identify and characterize cells with varying degrees of “stemness” that can be used for different applications in regenerative medicine (56). Researchers are using development biology approaches to reproduce, for example, kidneys from embryologic precursors of the urinary tract. In vitro, culture of such precursors in the presence of specific growth factors lead to the formation of a primordial kidney structure (57). In parallel, stem-cell research is aiming to exploit the intrinsic capability of the kidney for injury repair (58). Because this repair process seems to occur through the migration of new cells into the damaged region with eventual reconstitution of a functional epithelium, researchers are currently identifying niches within the kidney where cells with regenerative capacities may reside.
“[...] the scale and number of technical and commercial hurdles that must be overcome before we can deliver a full-sized, functional organ, [...] are considerable. In this context, the provision of ‘new’ organs to replace transplants is beyond the realms of the possible both now and for the foreseeable future.”
—Kemp P. Regen Med 2006; 1: 653–669.
The authors thank Drs. Shinoka, McAllister, and L'Heureux for providing updated outcome of their patients.
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