Systemic immunosuppression remains essential for preventing allogeneic transplant rejection, but its chronic use causes substantial toxicity. Conceptually, local, site-specific immunomodulation offers a promising alternative, yet comparative mechanistic insight into how immunosuppressants behave when delivered directly to the graft is lacking. Here, we leveraged the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device, a subcutaneous, vascularized cell-encapsulation platform, as a spatially defined and reproducible model to study local immunomodulation in allogeneic islet transplantation. We systematically profiled the safety, local and systemic immunomodulatory effects, pharmacokinetics, and longitudinal biodistribution of five clinically relevant agents delivered locally at the graft site: CTLA4-Ig, anti-lymphocyte serum, anti-CD40L, anti-CD2, and anti-IL6. Sustained in situ exposure did not impair islet viability or function, and immunosuppressants were confined within the graft, with up to 100-fold lower systemic concentrations. Individual agents produced distinct immune signatures, spanning lymphocyte depletion and shifts in T-cell activation that can guide rational, mechanism-informed combinations for allogeneic cell transplantation. These findings provide a comparative framework for evaluating localized immunosuppression with the potential to transform immunoprotection in cell therapy.

Background: The long-term clinical efficacy of intraportal islet transplantation is hampered by islet loss due to inflammation, oxidative stress, and insufficient vascularization. This study explores the venous sac as an alternative implantation site for islet transplantation in large animal models. Methods: An immunosuppressed, diabetic cynomolgus monkey received allogeneic islet implants in its mesenteric venous sac, with metabolic assessments over 112 days. Dogs underwent islet autotransplantation into various venous sacs, with their glycemic control and other metabolic parameters monitored for 1 month. Results: In a nonhuman primate, the mesenteric venous sac site improved glycemic control over a 3-month period, followed by destabilization of graft function. Histological studies revealed healthy islets. The lack of mononuclear cell infiltrate suggested no signs of graft rejection. Saphenous venous sacs in dogs showed superior glycemic control, reduced insulin requirements, and maintained C-peptide levels, comparable to intraportal transplantation. Histological analyses confirmed islet preservation and graft vascularization in saphenous venous sacs. Conclusion: This study provides preclinical evidence in support of the venous sac as a valuable extrahepatic location for pancreatic islet implantation. We found that the saphenous vein is a more effective site for islet engraftment than the mesenteric vein. This study offers potential benefits for improving the success rates of clinical islet transplantation.

Prior studies of anti-CD40 ligand (CD40L)–based immunosuppression demonstrated effective prevention of islet and kidney allograft rejection in nonhuman primate models; however, clinical development was halted because of thromboembolic complications. An anti-CD40L-specific monoclonal antibody, AT-1501 (Tegoprubart), was engineered to minimize risk of thromboembolic complications by reducing binding to Fcγ receptors expressed on platelets while preserving binding to CD40L. AT-1501 was tested in both a cynomolgus macaque model of intrahepatic islet allotransplantation and a rhesus macaque model of kidney allotransplantation. AT-1501 monotherapy led to long-term graft survival in both islet and kidney transplant models, confirming its immunosuppressive potential. Furthermore, AT-1501–based regimens after islet transplant resulted in higher C-peptide, greater appetite leading to weight gain, and reduced occurrence of cytomegalovirus reactivation compared with conventional immunosuppression. These data support AT-1501 as a safe and effective agent to promote both islet and kidney allograft survival and function in nonhuman primate models, warranting further testing in clinical trials.

Pancreatic islet transplantation efficacy for type 1 diabetes (T1D) management is limited by hypoxia-related graft attrition and need for systemic immunosuppression. To overcome these challenges, we developed the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device, which integrates direct vascularization for facile mass transfer and localized immunosuppressant delivery for islet rejection prophylaxis. Here, we investigated NICHE efficacy for allogeneic islet transplantation and long-term diabetes reversal in an immunocompetent, male rat model. We demonstrated that allogeneic islets transplanted within pre-vascularized NICHE were engrafted, revascularized, and functional, reverting diabetes in rats for over 150 days. Notably, we confirmed that localized immunosuppression prevented islet rejection without inducing toxicity or systemic immunosuppression. Moreover, for translatability efforts, we showed NICHE biocompatibility and feasibility of deployment as well as short-term allogeneic islet engraftment in an MHC-mismatched nonhuman primate model. In sum, the NICHE holds promise as a viable approach for safe and effective islet transplantation and long-term T1D management.

Polyethylene glycol (PEG)–based conformal coating (CC) encapsulation of transplanted islets is a promising β cell replacement therapy for the treatment of type 1 diabetes without chronic immunosuppression because it minimizes capsule thickness, graft volume, and insulin secretion delay. However, we show here that our original CC method, the direct method, requiring exposure of islets to low pH levels and inclusion of viscosity enhancers during coating, severely affected the viability, scalability, and biocompatibility of CC islets in nonhuman primate preclinical models of type 1 diabetes. We therefore developed and validated in vitro and in vivo, in several small- and large-animal models of type 1 diabetes, an augmented CC method—emulsion method—that achieves hydrogel CCs around islets at physiological pH for improved cytocompatibility, with PEG hydrogels for increased biocompatibility and with fivefold increase in encapsulation throughput for enhanced scalability.

Mesenchymal stem cells (MSC) have been shown to be immunomodulatory, tissue regenerative, and graft promoting; however, several questions remain with regard to ideal MSC source and timing of administration. In this study, we utilized a rigorous preclinical model of allogeneic islet cell transplantation, incorporating reduced immune suppression and near to complete mismatch of major histocompatibility antigens between the diabetic cynomolgus monkey recipient and the islet donor, to evaluate both the graft promoting impact of MSC source, that is, derived from the islet recipient, the islet donor or an unrelated third party as well as the impact of timing. Co-transplant of MSC and islets on post-operative day 0, followed by additional IV MSC infusions in the first posttransplant month, resulted in prolongation of rejection free and overall islet survival and superior metabolic control for animals treated with recipient as compared to donor or third-party MSC. Immunological analyses demonstrated that infusion of MSC from either source did not prevent alloantibody formation to the islet or MSC donor; however, treatment with recipient MSC resulted in significant downregulation of memory T cells, decreased anti-donor T cell proliferation, and a trend toward increased Tregulatory:Tconventional ratios.

Islet transplantation (ITx) is a cellular therapy that has demonstrated efficacy in improving glycemic control and abolishing hypoglycemia in patients affected by type 1 diabetes complicated by hypoglycemia unawareness and episodes of severe hypoglycemia. Although the intrahepatic site is the only clinical site that has shown long-term islet allograft engraftment with achievement of insulin independence, it remains far from being an ideal transplantation site. In this chapter, we have described our clinical experience with ITx within a biodegradable scaffold transplanted onto an extravascular site, the omentum, through laparoscopic surgery. We have provided metabolic data showing efficacy and described the challenges associated with this approach. These encouraging initial results and the unique advantages offered by an extravascular site prompt the need for further evaluation of this transplantation technique. The development of strategies to improve local oxygen delivery, to promote graft neovascularization, and to minimize immunosuppression are required to improve long-term outcomes at this novel transplant site.

OBJECTIVE:Our goal was to assess the efficacy of encapsulated allogeneic islets transplanted in diabetic NOD mice and streptozotocin (STZ)-diabetic nonhuman primates (NHPs).MATERIALS AND METHODS:Murine or NHP islets were microencapsulated and transplanted in non-immunosuppressed mice or NHPs given clinically-acceptable immunosuppressive regimens, respectively. Two NHPs were treated with autologous mesenchymal stem cells (MSCs) and peri-transplant oxygen therapy. Different transplant sites (intraperitoneal [i.p.], omental pouch, omental surface, and bursa omentalis) were tested in separate NHPs. Graft function was monitored by exogenous insulin requirements, fasting blood glucose levels, glucose tolerance tests, percent hemoglobin A1c (% HbA1c), and C-peptide levels. In vitro assessment of grafts included histology, immunohistochemistry, and viability staining; host immune responses were characterized by flow cytometry and cytokine/chemokine multiplex ELISAS.RESULTS:Microencapsulated islet allografts functioned long-term i.p. in diabetic NOD mice without immunosuppression, but for a relatively short time in immunosuppressed NHPs. In the NHPs, encapsulated allo-islets initially reduced hyperglycemia, decreased exogenous insulin requirements, elevated C-peptide levels, and lowered % HbA1c in plasma, but graft function diminished with time, regardless of transplant site. At necropsy, microcapsules were intact and non-fibrotic, but many islets exhibited volume loss, central necrosis and endogenous markers of hypoxia. Animals receiving supplemental oxygen and autologous MSCs showed improved graft function for a longer post-transplant period. In diabetic NHPs and mice, cell-free microcapsules did not elicit a fibrotic response.CONCLUSIONS:The evidence suggested that hypoxia was a major factor for damage to encapsulated islets in vivo. To achieve long-term function, new approaches must be developed to increase the oxygen supply to microencapsulated islets and/or identify donor insulin-secreting cells which can tolerate hypoxia.

We have shown safety and efficacy of islet transplantation (ITx) in the omentum using a biological scaffold in 3 subjects with type 1 diabetes (T1D). Two subjects (#1 and #3) achieved primary outcome at 1 year (A1c ≤6.5%; No severe hypoglycemia). Subject 1 developed progressive decline in C-peptide after 15 months likely attributed to change in immunosuppression. Subject 3 has had stable graft function for over 2 years. We report on 18 month follow-up data for subject 3. A 46 y/o woman with T1D of 26 years duration underwent single ITx on the omentum (12,648 IEQ/Kg) using a biologic scaffold under ATG induction and combination mycophenolate sodium and tacrolimus maintenance. Pre-ITx insulin dose was 0.45 units/Kg/day and A1c 6.3%. At 18 months, 90 min C-peptide was 1.49 ng/mL, A1c 5.7%, and insulin dose 0.18 units/Kg/day; 14-day continuous glucose monitoring (Guardian Sensor 3, Medtronic) showed glucose 109±28mg/dL (mean±SD), 92% time in glucose range 70-180 mg/dL, 6% time in <70mg/dL, and 0% time in <54 mg/dL. Mixed meal tolerance test data is shown in Table 1. Decline in BETA-2 score was observed by 1 year followed by stabilization. ITx resulted in stable graft function, excellent glycemic control, minimal glycemic variability, and reduction in hypoglycemia over 2 years. Strategies to improve oxygen delivery and neo-vascularization and minimize immunosuppression are needed to improve long-term outcomes at this site. Disclosure D. Baidal: None. D.M. Berman: None. C. Ricordi: Advisory Panel; Self; Zone Labs. A.M. Alvarez Gil: None. N. Padilla: None. G. Ciancio: None. E. Linetsky: None. R. Alejandro: None. Funding JDRF; The Leona M. and Harry B. Helmsley Charitable Trust; Diabetes Research Institute Foundation, State of Florida; University of Miami Clinical and Translational Science Institute; Sanofi Genzyme

Patients with autoimmune type 1 diabetes transplanted with pancreatic islets to their liver experience significant improvement in quality of life through better control of blood sugar and enhanced awareness of hypoglycaemia. However, long-term survival and efficacy of the intrahepatic islet transplant are limited owing to liver-specific complications, such as immediate blood-mediated immune reaction, hypoxia, a highly enzymatic and inflammatory environment and locally elevated levels of drugs including immunosuppressive agents, all of which are injurious to islets. This has spurred a search for new islet transplant sites and for innovative ways to achieve long-term graft survival and efficacy without life-long systemic immunosuppression and its complications.

Islet cell transplantation can lead to insulin independence, reduced hypoglycemia, and amelioration of diabetes complications in patients with type 1 diabetes. The systemic delivery of anti-inflammatory agents, while considered crucial to limit the early loss of islets associated with intrahepatic infusion, increases the burden of immunosuppression. In an effort to decrease the pharmaceutical load to the patient, we modified the pancreatic islet surface with long-chain poly(ethylene glycol) (PEG) to mitigate detrimental host-implant interactions. The effect of PEGylation on islet engraftment and long-term survival was examined in a robust nonhuman primate model via three paired transplants of dosages 4300, 8300, and 10 000 islet equivalents per kg body weight. A reduced immunosuppressive regimen of anti-thymocyte globulin induction plus tacrolimus in the first posttransplant month followed by maintenance with sirolimus monotherapy was employed. To limit transplant variability, two of the three pairs were closely MHC-matched recipients and received MHC-disparate PEGylated or untreated islets isolated from the same donors. Recipients of PEGylated islets exhibited significantly improved early c-peptide levels, reduced exogenous insulin requirements, and superior glycemic control, as compared to recipients of untreated islets. These results indicate that this simple islet modification procedure may improve islet engraftment and survival in the setting of reduced immunosuppression.

The need for chronic immune suppression (IS) is one of the hurdles precluding widespread use of islet cell transplantation to restore glycemic control in patients with type 1 diabetes. We report the case of a healthy nonhuman primate (NHP) treated on and off for over 2.5 years with steroid-free IS, consisting of daclizumab induction and maintenance therapy with rapamycin and low dose tacrolimus. Treatment for 1 year resulted in a striking destabilization of glycemic control, with concomitant decreases in fasting c-peptide and insulin levels. Although these changes gradually reversed during a wash out period of 7 months, retreatment with the same therapy led to accelerated deterioration in glycemic control. Intravenous glucose tolerance and percentage of glycosylated hemoglobin testing further supported a dramatic effect on metabolic control. IS also led to decreases in weight during treatment. Histological evaluation of the pancreas revealed islet hyperplasia, with varying sizes and endocrine cell ratios that differed from normal islet composition, and parenchymal infiltration with adipose tissue. These deleterious effects of IS on glucose control and endocrine components in the native pancreas of a healthy NHP suggest that IS agents commonly utilized for islet transplantation may contribute to failure in islet allograft function in long-term transplant patients.

Background Xenogeneic donors would provide an unlimited source of islets for the treatment of type 1 diabetes (T1D). The goal of this study was to assess the function of microencapsulated adult porcine islets (APIs) transplanted ip in streptozotocin (STZ)-diabetic non-human primates (NHPs) given targeted immunosuppression. Methods APIs were encapsulated in: (a) single barium-gelled alginate capsules or (b) double alginate capsules with an inner, islet-containing compartment and a durable, biocompatible outer alginate layer. Immunosuppressed, streptozotocin-diabetic NHPs were transplanted ip with encapsulated APIs, and graft function was monitored by measuring blood glucose, %HbA1c, and porcine C-peptide. At graft failure, explanted capsules were assessed for biocompatibility and durability plus islet viability and functionality. Host immune responses were evaluated by phenotyping peritoneal cell populations, quantitation of peritoneal cytokines and chemokines, and measurement of anti-porcine IgG and IgM plus anti-Gal IgG. Results NHP recipients had reduced hyperglycemia, decreased exogenous insulin requirements, and lower percent hemoglobin A1c (%HbA1c) levels. Porcine C-peptide was detected in plasma of all recipients, but these levels diminished with time. However, relatively high levels of porcine C-peptide were detected locally in the peritoneal graft site of some recipients at sacrifice. IV glucose tolerance tests demonstrated metabolic function, but the grafts eventually failed in all diabetic NHPs regardless of the type of encapsulation or the host immunosuppression regimen. Explanted microcapsules were intact, "clean," and free-floating without evidence of fibrosis at graft failure, and some reversed diabetes when re-implanted ip in diabetic immunoincompetent mice. Histology of explanted capsules showed scant evidence of a host cellular response, and viable islets could be found. Flow cytometric analyses of peritoneal cells and peripheral blood showed similarly minimal evidence of a host immune response. Preformed anti-porcine IgG and IgM antibodies were present in recipient plasma, but these levels did not rise post-transplant. Peritoneal graft site cytokine or chemokine levels were equivalent to normal controls, with the exception of minimal elevation observed for IL-6 or IL-1 beta, GRO-alpha, I-309, IP-10, and MCP-1. However, we found central necrosis in many of the encapsulated islets after graft failure, and explanted islets expressed endogenous markers of hypoxia (HIF-1 alpha, osteopontin, and GLUT-1), suggesting a role for non-immunologic factors, likely hypoxia, in graft failure. Conclusions With donor xenoislet microencapsulation and host immunosuppression, APIs corrected hyperglycemia after ip transplantation in STZ-diabetic NHPs in the short term. The islet xenografts lost efficacy gradually, but at graft failure, some viable islets remained, substantial porcine C-peptide was detected in the peritoneal graft site, and there was very little evidence of a host immune response. We postulate that chronic effects of non-immunologic factors, such as in vivo hypoxic and hyperglycemic conditions, damaged the encapsulated islet xenografts. To achieve long-term function, new approaches must be developed to prevent this damage, for example, by increasing the oxygen supply to microencapsulated islets in the ip space.

The liver is the preferred site for islet transplantation (ITx) but not ideal due to limitations affecting engraftment. We evaluated the safety and efficacy of ITx in the omentum using a resorbable biological scaffold in 3 subjects with type 1 diabetes and negative C-peptide. Islets were combined with autologous plasma and thrombin to generate a biologic scaffold and layered laparoscopically on the omentum. Induction was with anti-thymocyte globulin and etanercept. Maintenance was with mycophenolate sodium and tacrolimus. Demographics, islet dose and metabolic data are shown in the Table.Subject #Age (years)Duration T1DM (years)BMI (Kg/m2)IEQ†/KgMMTT‡ Stimulated Glucose (mg/dl)/C-peptide (ng/ml)Insulin dose U/Kg/day (Units/day)HbA1c%6 months12 months24 monthsPre-ITxLatestPre-ITxLatest1432621.511,386181/3.32277/1.79317/0.490.62 (33)0.14 (7)6.85.32321625.39,635372/0.88374/0.65332/0.52*0.45 (31)0.45 (30)5.75.6346422412,648277/2.47--0.45 (20)0.2 (11)6.36.3* 18 months Post-ITx † IEQ= islet equivalents ‡ MMTT = mixed meal tolerance test Subject 1 was insulin independent for 15 months and maintains stable glycemic control. Subject 2 had marginal graft function with persistence of severe hypoglycemia (SH) and then underwent intrahepatic ITx resulting in insulin independence. Subject 3 had a 55% reduction in insulin dose and maintains excellent glycemic control. Our initial experience demonstrates feasibility and safety of ITx on the omentum. Graft function persisted throughout follow-up (6-24 months) resulting in improved glycemic control and absence of SH (subjects 1 and 3). Results suggest a significant loss of islets early post-ITx followed by gradual functional decline similar to intrahepatic ITx. Strategies to improve oxygen delivery and neo-vascularization and minimize immunosuppression are needed to improve long-term outcomes at this site. Disclosure D. Baidal: None. C. Ricordi: None. D.M. Berman: Stock/Shareholder; Self; Pfizer Inc. A. Pileggi: Stock/Shareholder; Self; Converge Biotech, Inc.. Stock/Shareholder; Spouse/Partner; Converge Biotech, Inc. A.M. Alvarez Gil: None. N. Padilla: None. G. Ciancio: None. E. Linetsky: None. R. Alejandro: None.

Every animal species has a signature blood glucose level or glycemic set point. These set points are different, and the normal glycemic levels (normoglycemia) of one species would be life threatening for other species. Mouse normoglycemia can be considered diabetic for humans. The biological determinants of the glycemic set point remain unclear. Here we show that the pancreatic islet imposes its glycemic set point on the organism, making it the bona fide glucostat in the body. Moreover, and in contrast to rodent islets, glucagon input from the alpha cell to the insulin-secreting beta cell is necessary to fine-tune the distinctive human set point. These findings affect transplantation and regenerative approaches to treat diabetes because restoring normoglycemia may require more than replacing only the beta cells. Furthermore, therapeutic strategies using glucagon receptor antagonists as hypoglycemic agents need to be reassessed, as they may reset the overall glucostat in the organism.

This letter describes islet transplantation onto the omentum with the use of a degradable scaffold in a patient with a 25-year history of type 1 diabetes mellitus. The patient remained insulin-independent for more than 1 year.

Transplantation of pancreatic islets is a therapeutic option to preserve or restore β-cell function. Our study was aimed at developing a clinically applicable protocol for extrahepatic transplantation of pancreatic islets. The potency of islets implanted onto the omentum, using an in situ–generated adherent, resorbable plasma-thrombin biologic scaffold, was evaluated in diabetic rat and nonhuman primate (NHP) models. Intraomental islet engraftment in the biologic scaffold was confirmed by achievement of improved metabolic function and preservation of islet cytoarchitecture, with reconstitution of rich intrainsular vascular networks in both species. Long-term nonfasting normoglycemia and adequate glucose clearance (tolerance tests) were achieved in both intrahepatic and intraomental sites in rats. Intraomental graft recipients displayed lower levels of serum biomarkers of islet distress (e.g., acute serum insulin) and inflammation (e.g., leptin and α2-macroglobulin). Importantly, low-purity (30:70% endocrine:exocrine) syngeneic rat islet preparations displayed function equivalent to that of pure (>95% endocrine) preparations after intraomental biologic scaffold implantation. Moreover, the biologic scaffold sustained allogeneic islet engraftment in immunosuppressed recipients. Collectively, our feasibility/efficacy data, along with the simplicity of the procedure and the safety of the biologic scaffold components, represented sufficient preclinical testing to proceed to a pilot phase I/II clinical trial.

Event Abstract Back to Event A novel biologic resorbable scaffold for tissue engineering of an intra-abdominal endocrine pancreas Camillo Ricordi1, David A. Baidal1, Dora Berman-Weinberg1, Antonello Pileggi1, Gaetano Ciancio2 and Rodolfo Alejandro1 1 University of Miami, Diabetes Research Institute, United States 2 UHealth and Jackson Health System, Miami Transplant Institute, United States Currently, islet transplantation has been generally performed in the liver, by intra-portal vein infusion. Islet transplants in this site, in a selected group of subjects with Type 1 diabetes, have shown excellent long-term function with stabilization of blood glucose levels and prevention of severe hypoglycemia. However, main limitations remain associated with the need for systemic immunosuppression to maintain function and with the observed loss of islet function over time. Additionally, several studies have demonstrated that the liver may not be the ideal site for islet transplantation due to several factors, including: (1) Instant Blood Mediated Inflammatory Reaction (IBMIR) following islet infusion responsible for the loss of over 50% of the transplanted islets; (2) potential procedure-related complications such as bleeding and thrombosis; (3) high levels of immunosuppressive drugs and GI toxins in the liver contributing to islet dysfunction; (4) the inability to retrieve islets after infusion. Based on these premises, we developed a novel transplant technology for the implantation of allogeneic human islets on the surface of the omentum, using a biodegradable biologic construct made of autologous plasma and human recombinant thrombin and minimizing any procedure-related “danger” signal that could activate pro-inflammatory reactions. The islets were re-suspended in autologous plasma and placed with “no-touch” technique on the surface of the omentum during a minimally invasive, laparoscopic surgical procedure. Pancreatic islet adherence to the omentum was achieved by addition of clinical-grade recombinant human thrombin to create a biocompatible, degradable gel containing the islet graft. The omentum was folded over the biologic scaffold and sealed by human recombinant thrombin. The first patient was transplanted on August 18, 2015 using this technology (Phase I/II trial; clinicaltrials.gov NCT02213003) and has been free from insulin injections with an excellent glucose profile, following implantation of pancreatic islets obtained from a single donor pancreas. This was the first successful tissue engineered clinical islet transplant using a ‘biodegradable scaffold’ implanted on the surface of the omentum. This work was supported in part by the DRIF, the JDRF, The Helmsley Trust and the NIH Keywords: Tissue Engineering, Clinical Trial, 3D scaffold, Biodegradable material Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016. Presentation Type: New Frontier Oral Topic: Biomaterials in constructing tissue substitutes Citation: Ricordi C, Baidal DA, Berman-Weinberg D, Pileggi A, Ciancio G and Alejandro R (2016). A novel biologic resorbable scaffold for tissue engineering of an intra-abdominal endocrine pancreas. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.00037 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Mar 2016; Published Online: 30 Mar 2016. Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Camillo Ricordi David A Baidal Dora Berman-Weinberg Antonello Pileggi Gaetano Ciancio Rodolfo Alejandro Google Camillo Ricordi David A Baidal Dora Berman-Weinberg Antonello Pileggi Gaetano Ciancio Rodolfo Alejandro Google Scholar Camillo Ricordi David A Baidal Dora Berman-Weinberg Antonello Pileggi Gaetano Ciancio Rodolfo Alejandro PubMed Camillo Ricordi David A Baidal Dora Berman-Weinberg Antonello Pileggi Gaetano Ciancio Rodolfo Alejandro Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.