Islet cell replacement therapies represent an effective way to restore physiologic glycemic control in patients with type 1 diabetes (T1DM) and severe hypoglycemia. Despite being able to provide long-term insulin independence, patients still require lifelong immunosuppression, which has myriad detrimental effects including an increased risk for opportunistic infections and some types of cancer. This vital issue precludes widespread application of these therapies as a true cure for T1DM. Encapsulation of islets into immunoisolating/immunoprotective devices provides the potential of abrogating the requisite for lifelong immunosuppression. The field of cellular encapsulation lies at a complex intersection between the areas of chemistry, physics, bioengineering, cell biology, immunology, and clinical medicine. In diabetes, cellular encapsulation has existed for nearly 50 years, nevertheless, a resurgence of interest in the field has been motivated by promising results in small- and large-animal models. Recent studies have demonstrated that long-term diabetes reversal without immunosuppression is indeed routinely achievable. Future researchers interested in exploring cellular encapsulation strategies will require a clear understanding of the basic theoretical and practical principles, guiding this rapidly expanding field. This article will provide essential considerations concerning the physicochemical properties of the most commonly used biomaterials, relevant aspects of the immune response to bioencapsulation, current encapsulation strategies, potential implantation sites for encapsulated cell therapies and, finally, a comprehensive review on the current state of clinical translation. © 2020 American Physiological Society. Compr Physiol 10:839-878, 2020.
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