Effect of alginate matrix engineered to mimic the pancreatic microenvironment on encapsulated islet function

Abstract

Islet transplantation is emerging as a therapeutic option for type 1 diabetes, albeit, only a small number of patients meeting very stringent criteria are eligible for the treatment because of the side effects of the necessary immunosuppressive therapy and the relatively short time frame of normoglycemia that most patients achieve. The challenge of the immune‐suppressive regimen can be overcome through microencapsulation of the islets in a perm‐selective coating of alginate microbeads with poly‐l‐lysine or poly‐ l‐ornithine. In addition to other issues including the nutrient supply challenge of encapsulated islets a critical requirement for these cells has emerged as the need to engineer the microenvironment of the encapsulation matrix to mimic that of the native pancreatic scaffold that houses islet cells. That microenvironment includes biological and mechanical cues that support the viability and function of the cells. In this study, the alginate hydrogel was modified to mimic the pancreatic microenvironment by incorporation of extracellular matrix (ECM). Mechanical and biological changes in the encapsulating alginate matrix were made through stiffness modulation and incorporation of decellularized ECM, respectively. Islets were then encapsulated in this new biomimetic hydrogel and their insulin production was measured after 7 days in vitro. We found that manipulation of the alginate hydrogel matrix to simulate both physical and biological cues for the encapsulated islets enhances the mechanical strength of the encapsulated islet constructs as well as their function. Our data suggest that these modifications have the potential to improve the success rate of encapsulated islet transplantation.

An Overview of Engineered Hydrogel-Based Biomaterials for Improved β-Cell Survival and Insulin Secretion

“… Zhu et al, 2020 ). Incorporation of decellularized ECM into inert hydrogel substrate (e.g., alginate) not only may mimic the native pancreas ECM and enhance encapsulated islets function but also can improve the mechanical stability of hydrogels ( Enck et al, 2021 ).…”

Islet cell encapsulation – Application in diabetes treatment

“…43 The main proteins in the extracellular matrix are laminin, collagen, elastin, fibronectin as well as many other peptides entwined with glycosaminoglycans (like heparan sulfate, chondroitin sulfate, dermatan sulfate, or keratan sulfate), 43 which provide cell-to-cell signaling, stimulation of growth factors release, structural support, and stability important for islet viability and function. 44,45 Hence, designing an encapsulating hydrogel matrix that is similar to the microenvironment of the native pancreas is desirable. The matrix is reengineered to provide: (a) structural support for the islet, (b) biological cues for cell-to-cell interaction, and (c) immunoprotection/isolation for the islet.…”

“…Increased glucosestimulated release of insulin and islet viability was observed in porcine islets encapsulated in RGD-bound alginate when compared to islets encapsulated in alginate non adhered to RGD and alginate adhered with other peptide sequences LRE, YIGSR, PDGEA, and PDSGR. 46 Enck et al 45 modified alginate hydrogel microcapsule matrix by addition of decellularized ECM (dECM) components from human pancreas and observed improved stability of the morphology and mechanical strength of alginate microcapsules with significant increase in matrix stiffness of Sr 2þ relative to Ca 2þ crosslinked hydrogels (Figure 2), as well as improved function of encapsulated human islets (Figure 3).…”

“…Initial count of 100 beads were made with or without ECM and crosslinked with either 25 mM or 50 mM SrCl 2 . Student's t-test (mean AE SD, n ¼ 5, *P < 0.05, **P < 0.01, ****P < 0.0001).Reprinted with kind permission from Enck et al45…”

“…Effects of alginate crosslinking cation and the incorporation of ECM into the encapsulation matrix on encapsulated islets glucose-stimulated insulin secretion (GSIS) results on day 7 post-encapsulation one-way ANOVA (mean AE SD, *P < 0.05, **P < 0.01, ***P < 0.001, n ¼ 3). Reprinted with kind permission from Enck et al45…”