Engineering a local microenvironment for pancreatic islet replacement

Abstract

Intraportal islet transplantation has emerged as a promising treatment for type 1 diabetes mellitus (T1DM). Nevertheless, long-term efficacy has been limited to a marginal number of patients. Outcomes have been restricted, in part, by challenges associated with the transplant site, poor vascularization, and disruption of the native islet architecture during the isolation process. Engineering a biomaterial platform that recapitulates critical components of the pancreatic environment can serve to address these hurdles. This review highlights the challenges and opportunities in engineering 3D niches for islets, specifically: the importance of site selection; the application of scaffold functionalization to present bioactive motifs; and the development of technologies for enhancing implant nutritional profiles. The potential of these novel approaches to improve islet engraftment and duration of function is discussed.

Figure 1

Various novel approaches implemented within islet transplants to improve overall function and efficacy include: (A) macroporous scaffold designed to provide mechanical protection and 3-D distribution of islet clusters; (B) co-encapsulation of islets with helper cells such as MSCs or ECs to promote revascularization and engraftment; (C) incorporation or tethering of growth factors to biomaterials to hasten and direct the revascularization process; (D) implementation of devices/materials to supplement oxygen; and (E) incorporation of ECM proteins to recapitulate native islet niche. (Illustration courtesy of Jessica A. Weaver)

Figure 2

Incorporation of native cell binding sites to material framework can minimize anoikis, induced by islet isolation procedures, islet dissociation, and/or β-cell culture. (A) Scheme employed to synthesize thiolated fusion protein EphA5 and ephrinA5. (B) Incorporation of thiolated proteins within PEG hydrogels via thiol-acrylate photopolymerization. (C) Representative live/dead (green=live; red=dead) z-stack confocal images of cultured β-cells, embedded within increasing concentrations (indicated by top panel) of functionalized PEG hydrogels, illustrate benefits of functionalization on β-cell clustering, particularly after extended culture periods. [32••]

Figure 3

In situ oxygen generation approaches to improve oxygen profiles within implants. (A) Schematic of immunoisolating macrochamber device, containing an embedded oxygen tank, implanted within a rodent model to evaluate islet engraftment, and immunohistochemical staining of immobilized islets for insulin (bottom left) and glucagon (bottom right). [43•] (B)Top: Schematic and photograph of an oxygen generating material based on CaO₂ encapsulation in PDMS. Bottom: Representative live/dead (green=live; red=dead) z-stack confocal images of rat islets co-cultured without (left) or with (right) a single CaO₂-PDMS disk and incubated for 24 hrs under 0.05 mM oxygen. [44•]