Research review
Causes of limited survival of microencapsulated pancreatic islet grafts

https://doi.org/10.1016/j.jss.2004.02.018Get rights and content

Abstract

Successful transplantation of pancreatic tissue has been demonstrated to be an efficacious method of restoring glycemic control in type 1 diabetic patients. To establish graft acceptance patients require lifelong immunosuppression, which in turn is associated with severe deleterious side effects. Microencapsulation is a technique that enables the transplantation of pancreatic islets in the absence of immunosuppression by protecting the islet tissue through a mechanical barrier. This protection may even allow for the transplantation of animal tissue, which opens the perspective of using animal donors as a means to solve the problem of organ shortage. Microencapsulation is not yet applied in clinical practice, mainly because encapsulated islet graft survival is limited. In the present review we discuss the principal causes of microencapsulated islet graft failure, which are related to a lack of biocompatibility, limited immunoprotective properties, and hypoxia. Next to the causes of encapsulated islet graft failure we discuss possible improvements in the encapsulation technique and additional methods that could prolong encapsulated islet graft survival. Strategies that may well support encapsulated islet grafts include co-encapsulation of islets with Sertoli cells, the genetic modification of islet cells, the creation of an artificial implantation site, and the use of alternative donor sources. We conclude that encapsulation in combination with one or more of these additional strategies may well lead to a simple and safe transplantation therapy as a cure for diabetes.

Introduction

Diabetes mellitus type 1 accounts for approximately 10% of all diabetic cases worldwide and is characterized by an absolute insulin deficiency. Insulin injection therapy as a treatment for type 1 diabetic patients is lifesaving, but it cannot fully prevent the development of complications of the eyes, kidneys, nerves, and the cardiovascular system including the microvessels in the limbs. The only replacement therapy that currently improves metabolic control other than conventional and intensive insulin therapy is transplantation of insulin-producing tissue. Transplantation can be performed either by implantation of the pancreatic organ or by implantation of only the pancreatic islets of Langerhans. Results of pancreas transplantation have steadily improved with time from a 1-year pancreas graft survival of 75% at the end of the eighties to the current patient and graft survival rates of approximately 98 and 85%, respectively 1, 2. Results of islet transplantation were far less favorable during that period. The international Islet Transplant Registry reported that fewer than 12% of the islet allografts from 1990 to 2000 remained insulin-free for 1 year [3]. But at the beginning of this century Shapiro et al. demonstrated that islet transplantation can be as successful as pancreas transplantation [4]. The success of their Edmonton protocol has renewed a worldwide interest in pancreatic islet transplantation, which has two principal advantages when compared to pancreas transplantation. First, it does not require major surgery, but only a small implantation procedure with which an islet mass is delivered to the liver by intraportal infusion. Second, islet tissue has the advantage that it may be modulated prior to implantation to reduce the risk of rejection.

A major obstacle for both pancreas transplantation and pancreatic islet transplantation is the requirement of immunosuppressive drugs to establish graft acceptance. Immunosuppression is associated with deleterious side effects, such as increased susceptibility to viral, fungal, and bacterial infections, and increased risk (4- to up to 500-fold) for the development of malignancies 5, 6. For this reason, transplantation of either a pancreas or pancreatic islet tissue has been restricted to patients for whom the adverse effects of immunosuppression outweigh the risks associated with further development of diabetic complications. As a practical consequence, transplantation of pancreas or islets is mainly restricted to diabetic recipients of a renal transplant on the basis of severe diabetic nephropathy and end stage renal failure, since they already receive immunosuppression for their kidney graft [7]. Pancreas transplantation alone is being performed with an increasing frequency and with increasing success in type 1 diabetic patients without nephropathy, but with recurrent episodes of hypoglycemic unawareness, to restore normoglycemia [1].

Another obstacle to the widespread application of pancreas or islet transplantation is the worldwide shortage of organ donors. Even without deleterious immunosuppressive protocols, only 0.1% of the type 1 diabetic population could be transplanted with the currently limited supply of donor organs [8]. The use of donor organs is especially inefficient with islet transplantation, since successful islet transplantation requires multiple (two to four) donors per recipient [9]. It can therefore be argued that islet transplantation cannot become a standard treatment modality for people with type 1 diabetes until graft acceptance can be established without deleterious side effects for the recipient and until a plentiful source of islets can be identified.

One strategy that may provide a solution both to the problems associated with immunosuppression and to the problem of organ shortage is immunoprotection by encapsulation. This technique aims to protect tissue or cells against immune cell- and antibody-mediated rejection by separation of the transplanted tissue from the host by enveloping the graft in a semipermeable capsule as a mechanical barrier. Immunoprotection by encapsulation enables transplantation without immunosuppressive drugs and opens up the perspective of using animal donor sources. Despite some promising results in animal studies, graft survival of immunoprotected grafts is still too short to introduce this technology into clinical practice.

In this review we discuss the principal causes that limit the success of immunoprotection by encapsulation of pancreatic islets, with specific focus on microencapsulation.

Section snippets

Immunoprotection by encapsulation

With immunoprotection by encapsulation, islets are enclosed in a matrix surrounded by a semipermeable membrane, which allows for the passage of small molecules like insulin and glucose, but not for the entry of the much larger cells and antibodies of the immune system (Fig. 1). Such a physical barrier can thus prevent allograft rejection, which depends on recognition of the MHC by host lymphocytes. Furthermore it can prevent antibody-mediated cytotoxicity, which plays a role in the autoimmune

Alginate—poly-l-lysine microencapsulation

Microencapsulation is a subject of study for a variety of endocrine diseases, which may be treated by substitution with the appropriate cells 26, 27. Successful function of encapsulated hepatocytes after transplantation in animals has been documented 28, 29. Microencapsulated parathyroid tissue has been transplanted with success in animals and recently even in humans 30, 31. Possibly, encapsulation can also be used for the treatment of neurodegenerative diseases, such as Parkinson’s and

Causes of microencapsulated islet graft failure

A better insight into the causes of microencapsulated islet graft failure may help in finding a way to improve graft survival. One important observation is that microencapsulated autograft and allograft survival rates are similar, which implies that graft failure is not caused by rejection due to allograft recognition [43]. If graft failure cannot be explained by allograft rejection, other factors must be involved. In search of these factors encapsulated islet graft failure was analyzed in our

Biocompatibility

Pericapsular overgrowth of microcapsules due to lack of biocompatibility is responsible for the loss of part of a graft. Overgrowth on microcapsules is established within the first few weeks after transplantation and does not increase thereafter 36, 44, 45. Only a small portion of approximately 10% of a retrieved encapsulated islet graft is affected by overgrowth with fibroblasts and macrophages 36, 46. However, a much higher percentage of approximately 40% of the number of initially implanted

Immunoprotective properties

A second factor that contributes to encapsulated islet graft failure is the limited immunoprotection of microcapsules. The semipermeable PLL layer effectively prevents the passage of large cells and antibodies of the immune system. However, small molecules such as cytokines or radicals may still enter microcapsules (Fig. 3) 68, 69. Nitric oxide (NO) and cytokines such as Il-1β (17.5 kDa), TNF-α (51 kDa), and IFN-γ (81 kDa) are examples of factors that have been shown to exert deleterious

Hypoxia

A third factor that contributes to encapsulated islet graft failure is hypoxia. Islets within the pancreas are provided with a glomerular-like network of capillaries, which is destroyed by islet isolation. The presence of microcapsules prevents revascularization of islets, which normally occurs within the first few weeks after non-encapsulated islet transplantation into the portal vein. Encapsulated islets suffer from irreversible and chronic hypoxic stress, because revascularization cannot

Final remarks

Islet transplantation is a cure for diabetes with limitations caused by risks associated with immunosuppression and donor organ shortage. Microencapsulation provides a means to transplant islets without immunosuppressive agents and may enable the performance of xenotransplantation. We have presented our view of the principal causes of microencapsulated islet graft failure, which are related to a lack of biocompatibility, limited immunoprotection, and hypoxia. A variety of strategies, such as

References (97)

  • P. Soon-Shiong et al.

    Insulin independence in a type 1 diabetic patient after encapsulated islet transplantation

    Lancet

    (1994)
  • P. Soon-Shiong

    Treatment of type I diabetes using encapsulated islets

    Adv. Drug. Deliv. Rev.

    (1999)
  • P. de Vos et al.

    Effect of the alginate composition on the biocompatibility of alginate—polylysine microcapsules

    Biomaterials

    (1997)
  • M.F. Paule et al.

    Murine chemokine gene expression in rejecting pig proislet xenografts

    Transplant. Proc.

    (2000)
  • M. de Groot et al.

    Macrophage overgrowth affects neighbouring non-overgrown encapsulated islets

    J. Surg. Res.

    (2003)
  • B. Kulseng et al.

    Alginate polylysine microcapsules as immune barrierPermeability of cytokines and immunoglobulins over the capsule membrane

    Cell Transplant.

    (1997)
  • A. Rabinovitch et al.

    Cytokines and their roles in pancreatic islet beta-cell destruction and insulin-dependent diabetes mellitus

    Biochem. Pharmacol.

    (1998)
  • R. Salcedo et al.

    Human endothelial cells express CCR2 and respond to MCP-1Direct role of MCP-1 in angiogenesis and tumor progression

    Blood

    (2000)
  • J.C.J. Cleveland et al.

    Clinical applications of ischemic preconditioningFrom head to toe

    Surgery

    (2001)
  • J.R.J. Wright et al.

    Tilapia—A source of hypoxia-resistant islet cells for encapsulation

    Cell Transplant.

    (1998)
  • A.C. Gruessner et al.

    Pancreas transplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of October 2002

    Clin. Transplant.

    (2002)
  • N. Mamode et al.

    Transplantation for diabetes mellitus

    Br. J. Surg.

    (2003)
  • M. Brendel et al.

    International Islet Transplant Registry Report

    (1999)
  • A.M. Shapiro et al.

    Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen

    N. Engl. J. Med.

    (2000)
  • I. Penn

    Post-transplant malignancyThe role of immunosuppression

    Drug Safety

    (2000)
  • S. Hariharan et al.

    Pancreas after kidney transplantation

    J. Am. Soc. Nephrol.

    (2002)
  • J.R. Lakey et al.

    Technical aspects of islet preparation and transplantation

    Transplant. Int.

    (2003)
  • H.J. Medbury et al.

    The cytokine and histological response in islet xenograft rejection is dependent upon species combination

    Transplantation

    (1997)
  • C.J. Weber et al.

    Evaluation of graft-host response for various tissue sources and animal models

    Ann. N. Y. Acad. Sci.

    (1999)
  • R.T. Prehn et al.

    The diffusion-chamber technique applied to a study of the nature of homograft resistance

    J. Natl. Cancer Inst.

    (1954)
  • R.P. Lanza et al.

    Encapsulated cell therapy

    Sci. Am.

    (1995)
  • F. Lim et al.

    Microencapsulated islets as bioartificial endocrine pancreas

    Science

    (1980)
  • M.F. Goosen et al.

    Optimization of microencapsulation parametersSemipermeable microcapsules as a bioartificial pancreas

    Biotechnol. Bioeng.

    (1985)
  • A.M. Rokstad et al.

    Microencapsulation of cells producing therapeutic proteinsOptimizing cell growth and secretion

    Cell Transplant.

    (2002)
  • B.L. Strand et al.

    Poly-L-lysine induces fibrosis on alginate microcapsules via the induction of cytokines

    Cell Transplant.

    (2001)
  • M.E. Pueyo et al.

    In vitro activation of human macrophages by alginate-polylysine microcapsules

    J. Biomater. Sci. Polym. Ed.

    (1993)
  • G.M. Cruise et al.

    In vitro and in vivo performance of porcine islets encapsulated in interfacially photopolymerized poly(ethylene glycol) diacrylate membranes

    Cell Transplant.

    (1999)
  • H. Iwata et al.

    Evaluation of microencapsulated islets in agarose gel as bioartificial pancreas by studies of hormone secretion in culture and by xenotransplantation

    Diabetes

    (1989)
  • B.A. Zielinski et al.

    Chitosan as a matrix for mammalian cell encapsulation

    Biomaterials

    (1994)
  • T. Wang et al.

    An encapsulation system for the immunoisolation of pancreatic islets

    Nat. Biotechnol.

    (1997)
  • R.P. Lanza et al.

    Encapsulated cell technology

    Nat. Biotechnol.

    (1996)
  • K. Hamazaki et al.

    Microencapsulated multicellular spheroid of rat hepatocytes transplanted intraperitoneally after 90% hepatectomy

    Hepatogastroenterology

    (2002)
  • C. Hasse et al.

    Parathyroid xenotransplantation without immunosuppression in experimental hypoparathyroidismLong-term in vivo function following microencapsulation with a clinically suitable alginate

    World J. Surg.

    (2000)
  • D.F. Emerich et al.

    Update on immunoisolation cell therapy for CNS diseases

    Cell Transplant.

    (2001)
  • N. Trivedi et al.

    Islets in alginate macrobeads reverse diabetes despite minimal acute insulin secretory responses

    Transplantation

    (2001)
  • P. de Vos et al.

    Why do microencapsulated islet grafts fail in the absence of fibrotic overgrowth?

    Diabetes

    (1999)
  • C. Weber et al.

    NOD mouse peritoneal cellular response to poly-L-lysine-alginate microencapsulated rat islets

    Transplant. Proc.

    (1994)
  • P. Soon-Shiong et al.

    Long-term reversal of diabetes by the injection of immunoprotected islets

    Proc. Natl. Acad. Sci. USA

    (1993)

    • Cited by (160)

    • Polymers for implantable bioartificial pancreas

      2023, Polymeric Materials for Biomedical Implants: Characterization, Properties, and Applications

    • Modulating the foreign body response of implants for diabetes treatment

      2021, Advanced Drug Delivery Reviews

    • Microencapsulated islet-like microtissues with toroid geometry for enhanced cellular viability

      2019, Acta Biomaterialia
      Citation Excerpt :

      Hence there was minimal difference in the thickness of the alginate layers surrounding each type of microtissue, and thus these layers were unlikely to affect metabolite diffusion and cell viability. Furthermore, despite their non-spheroidal geometry, toroid (Fig. 6A and D) and rod (Fig. 6B and E) microtissues did not result in alginate microcapsules with undesirable irregularities such as tails or deformed hydrogel surface, which might otherwise lead to increased recruitment of immune cells and subsequent fibrotic host response following in vivo transplantation [6]. For all three geometries, encapsulated microtissues were covered by the alginate hydrogel membranes without any visible irregular tissue protrusion (Fig. 6A–F), providing adequate immuno-protection for the encapsulated microtissues [47,48].

    • Oxygen generating biomaterial improves the function and efficacy of beta cells within a macroencapsulation device

      2019, Biomaterials

    • Type 1 Diabetes Mellitus reversal via implantation of magnetically purified microencapsulated pseudoislets

      2019, International Journal of Pharmaceutics

    • Co-encapsulation of mesenchymal stromal cells to enhance islet function

      2019, Transplantation, Bioengineering, and Regeneration of the Endocrine Pancreas: Volume 2
    View all citing articles on Scopus
    View full text
    Copyright © 2004 Elsevier Inc. All rights reserved.