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Review Article

Biological and Biomaterial Approaches for Improved Islet Transplantation

Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee

Abstract

I. Introduction

II. Obstacles to the Success of Islet Transplantation

A. Loss of Islet Viability during Isolation and Culture

B. Inadequate Revascularization of Transplanted Islets

C. Autoimmune Recurrence and Immune Rejection

D. Islet Mass and Site of Transplantation

III. Biological Strategies for Improving the Success of Islet Transplantation

A. Prevention of Immune Destruction of Transplanted Islets

1. Immunosuppression.

2. Immune Modulation and Tolerance.

a. Antibody pretreatment for xenografts.

b. Removal of passenger leukocytes for allografts.

c. Cytokine modulation.

d. Intrathymic islet or alloantigen injection.

e. Peripheral tolerance by T-cell inactivation or depletion.

f. Coactivation and costimulation blockade.

g. Dendritic cell infusion.

B. Counteracting Insufficient Tissue Supply

1. Xenotransplantation.

2. Regeneration Therapy.

a. Replication of pre-existing beta-cells.

b. Ectopic expression of beta-cell phenotype.

c. Using embryonic stem cells.

d. Using adult stem cells.

3. Insulin-Producing Cell Lines.

IV. Biomaterial-Based Strategies for Improving the Success of Islet Transplantation

A. Immunoisolation of Transplanted Islets

1. Types of Devices for Immunoisolation.

a. Intravascular macrocapsules.

b. Extravascular macrocapsules.

c. Extravascular microcapsules.

2. Biocompatibility Considerations.

3. Methods for Microencapsulation of Islets.

4. Enhancing the Performance of Microencapsulated Islets.

B. Surface Modification of Islets

V. Nucleic Acid-Based Therapeutics for Improving the Success of Islet Transplantation

A. Nonviral Gene Delivery

B. Viral Gene Delivery

1. Vector Backbone Modification.

2. Surface Modification of Viral Vectors.

C. Antisense Oligonucleotides and RNA Interference for Gene Silencing

VI. Concluding Remarks

Islet transplantation may be used to treat type I diabetes. Despite tremendous progress in islet isolation, culture, and preservation, the clinical use of this modality of treatment is limited due to post-transplantation challenges to the islets such as the failure to revascularize and immune destruction of the islet graft. In addition, the need for lifelong strong immunosuppressing agents restricts the use of this option to a limited subset of patients, which is further restricted by the unmet need for large numbers of islets. Inadequate islet supply issues are being addressed by regeneration therapy and xenotransplantation. Various strategies are being tried to prevent -cell death, including immunoisolation using semipermeable biocompatible polymeric capsules and induction of immune tolerance. Genetic modification of islets promises to complement all these strategies toward the success of islet transplantation. Furthermore, synergistic application of more than one strategy is required for improving the success of islet transplantation. This review will critically address various insights developed in each individual strategy and for multipronged approaches, which will be helpful in achieving better outcomes.