Six-Month Survival of Microencapsulated Pig Islets and Alginate Biocompatibility in Primates: Proof of Concept

Dufrane, Denis; Goebbels, Rose-Marie; Saliez, Alain; Guiot, Yves; Gianello, Pierre

doi:10.1097/01.tp.0000208610.75997.20

Cited by 205 publications

(150 citation statements)

References 26 publications

Supporting

Mentioning

144

Contrasting

Unclassified

Order By: Relevance

“…In this technology, donor islets are coated with a semipermeable membrane that blocks cells and large molecules of the host immune system but is permeable to essential nutrients, glucose, and insulin. Microencapsulation has been shown to be feasible in various experimental systems (14)(15)(16)(17)(18)(19) and in pilot clinical trials (20). However, the limited lifetime of microencapsulated islets and the large islet tissue volume required are obstacles that must be overcome to make this approach clinically viable.…”

mentioning

confidence: 99%

Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist

Ludwig

Rotem

Schmid

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

164

134

View full text Add to dashboard Cite

Islet transplantation is a feasible therapeutic alternative for metabolically labile patients with type 1 diabetes. The primary therapeutic target is stable glycemic control and prevention of complications associated with diabetes by reconstitution of endogenous insulin secretion. However, critical shortage of donor organs, gradual loss in graft function over time, and chronic need for immunosuppression limit the indication for islet transplantation to a small group of patients. Here we present a promising approach to address these limitations by utilization of a macrochamber specially engineered for islet transplantation. The s.c. implantable device allows for controlled and adequate oxygen supply and provides immunological protection of donor islets against the host immune system. The minimally invasive implantable chamber normalized blood glucose in streptozotocin-induced diabetic rodents for up to 3 mo. Sufficient graft function depended on oxygen supply. Pretreatment with the growth hormone-releasing hormone (GHRH) agonist, JI-36, significantly enhanced graft function by improving glucose tolerance and increasing β-cell insulin reserve in rats thereby allowing for a reduction of the islet mass required for metabolic control. As a result of hypervascularization of the tissue surrounding the device, no relevant delay in insulin response to glucose changes has been observed. Consequently, this system opens up a fundamental strategy for therapy of diabetes and may provide a promising avenue for future approaches to xenotransplantation. treatment of diabetes | immune isolation | beta cells

show abstract

mentioning

confidence: 99%

Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist

Ludwig

Rotem

Schmid

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

164

134

View full text Add to dashboard Cite

show abstract

“…The absence of solid consistent data on glucose metabolism renders these experimental studies difficult to consider as evidence for going to clinical trials. More recently, Gianello and colleagues (16) presented data showing that in nondiabetic primates some of the microencapsulated pig islets survived for up to 6 months and were able to respond in vitro to glucose challenge 135 and 180 days after implantation under the kidney capsula. In addition, the microcapsules were intact under the kidney capsule.…”

Section: Pig-to-primate Preclinical Datamentioning

confidence: 99%

“…Although several chemical formulations of alginate (e.g., high-mannuronic/guluronic and high/low viscosity, with or without additional peptide sequences) have been proposed for islet immunoisolation, high-mannuronic alginate was the most suitable to obtain selective impermeability for molecules over 150 kDa and optimal biocompatibility associated with surrounding angiogenesis and sufficient oxygen tension (up to 40 mmHg) (32). This type of alginate was biocompatible not only in rodents but also into a pig-to-primate model of xenotransplantation for up to 8 months (16,33,34).…”

Section: Biomaterials For Islet Encapsulation Technologymentioning

confidence: 99%

Cell Replacement Strategies Aimed at Reconstitution of the β-Cell Compartment in Type 1 Diabetes

et al. 2014

Self Cite

View full text Add to dashboard Cite

Emerging technologies in regenerative medicine have the potential to restore the b-cell compartment in diabetic patients, thereby overcoming the inadequacies of current treatment strategies and organ supply. Novel approaches include: 1) Encapsulation technology that protects islet transplants from host immune surveillance; 2) stem cell therapies and cellular reprogramming, which seek to regenerate the depleted b-cell compartment; and 3) whole-organ bioengineering, which capitalizes on the innate properties of the pancreas extracellular matrix to drive cellular repopulation. Collaborative efforts across these subfields of regenerative medicine seek to ultimately produce a bioengineered pancreas capable of restoring endocrine function in patients with insulin-dependent diabetes.Regenerative medicine promises to contribute to the advancement of b-cell replacement strategies through the development and implementation of microencapsulation technology, the production of insulin-producing cells either by regeneration from endogenous cells or reprogramming from nonendocrine adult cell sources, and, more recently, the exploitation of bioengineered microenvironments (1). Considering the shortage of available pancreata, the search for alternative cell sources has recently been categorized within one of the following three "Rs" of pancreatic b-cell replenishment: replacement (from stem cells or xenoislets), regeneration (from endogenous progenitor cells), and reprogramming (from nonendocrine adult cell sources) (2).The purpose of this article is to comprehensively and critically review the main regenerative medicine2based strategies that are currently being developed to treat type 1 diabetes. The first part of the article will illustrate and discuss islet encapsulation technology, which has been extensively investigated over the past 40 years (3) and represents one of the most promising regenerative medicine2based approaches to achieve immunoisolation of transplantable organs. The second part will focus on cell bioengineering, where different types of progenitor and differentiated cell sources are manipulated to ultimately yield insulin-producing cells. The last part of the article will summarize the most recent advancements in the study of the pancreatic extracellular matrix (ECM) as a platform for endocrine pancreas bioengineering. ISLET ENCAPSULATION TECHNOLOGYEncapsulation technology has been used to protect islets from the host immune system. This strategy holds the promise to allow implantation of islets without immunosuppression not only across genetically different individuals from the same species, but also across species barriers. MicroencapsulationThe first approach to immunoisolate cells consists of the microencapsulation of one to three islets per semipermeable immunoprotective capsule. The spherical configuration of these microcapsules results in a higher surface-tovolume ratio and a higher diffusion rate (4). Furthermore, microcapsules can be injected in large numbers, are durable, and are difficult to disrup...

show abstract

“…In conjunction with this outcome, the same research group discovered that the same graft implanted into diabetic cynomolgus primates resulted in a steady decrease in exogenous insulin requirements for up to 24 weeks post transplantation [ 40 ]. A separate study examined microencapsulated adult porcine islet viability in nondiabetic cynomolgus monkeys and concluded that despite a marked increase in circulating IgM and IgG following implantation as compared with the control group [blank microcapsules], a majority of the grafts were intact, responsive to stimulation by glucose, and free of PFO for up to 6 months post-transplant [ 52 ]. Since anti-porcine antibody levels were higher in the treatment group, it was concluded that some islets were inadequately encapsulated and/or antigenic secretion was occurring.…”

Section: Understanding Xenograft Rejection In Nonhuman Primate Recipimentioning

confidence: 99%

“…The hypothesis of soluble antigen secretion has emerged to explain why intact alginate microcapsules, verifi ably providing complete coverage of the islets via histological/microscopic examination [ 52 ], often failed to fully protect the xenografts from recognition by the adaptive immune system.…”

Section: Porcine Neonatal Pancreatic Cell Clusters [Npccs]mentioning

confidence: 99%

Immunological Challenges Facing Translation of Alginate Encapsulated Porcine Islet Xenotransplantation to Human Clinical Trials

Krishnan

Foster

et al. 2016

Methods in Molecular Biology

View full text Add to dashboard Cite

Transplantation of alginate-encapsulated islets has the potential to treat patients suffering from type I diabetes, a condition characterized by an autoimmune attack against insulin-secreting beta cells. However, there are multiple immunological challenges associated with this procedure, all of which must be adequately addressed prior to translation from trials in small animal and nonhuman primate models to human clinical trials. Principal threats to graft viability include immune-mediated destruction triggered by immunogenic alginate impurities, unfavorable polymer composition and surface characteristics, and release of membrane-permeable antigens, as well as damage associated molecular patterns (DAMPs) by the encapsulated islets themselves. The lack of standardization of signifi cant parameters of bioencapsulation device design and manufacture (i.e., purifi cation protocols, surface-modifi cation grafting techniques, alginate composition modifi cations) between labs is yet another obstacle that must be overcome before a clinically effective and applicable protocol for encapsulating islets can be implemented. Nonetheless, substantial progress is being made, as is evident from prolonged graft survival times and improved protection from immune-mediated graft destruction reported by various research groups, but also with regard to discoveries of specifi c pathways involved in explaining observed outcomes. Progress in the latter is essential for a comprehensive understanding of the mechanisms responsible for the varying levels of immunogenicity of certain alginate devices. Successful translation of encapsulated islet transplantation from in vitro and animal model testing to human clinical trials hinges on application of this knowledge of the pathways and interactions which comprise immune-mediated rejection. Thus, this review not only focuses on the different factors contributing to provocation of the immune reaction by encapsulated islets, but also on the defi ning characteristics of the response itself.

show abstract

Six-Month Survival of Microencapsulated Pig Islets and Alginate Biocompatibility in Primates: Proof of Concept

Abstract: Optimal alginate encapsulation significantly prolonged adult pig islet survival into primates for up to 6 months, even in the presence of antibody response.

Cited by 205 publications

References 26 publications

Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist

Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist

Cell Replacement Strategies Aimed at Reconstitution of the β-Cell Compartment in Type 1 Diabetes

Immunological Challenges Facing Translation of Alginate Encapsulated Porcine Islet Xenotransplantation to Human Clinical Trials

Contact Info

Product

Resources

About