Abstract
Islet transplantation to treat type 1 diabetes (T1D) has shown varied long-term success, due in part to insufficient blood supply to maintain the islets. In the current study, collagen and collagen:chitosan (10:1) hydrogels, +/- circulating angiogenic cells (CACs), were compared for their ability to produce a pro-angiogenic environment in a streptozotocin-induced mouse model of T1D. Initial characterization showed that collagen-chitosan gels were mechanically stronger than the collagen gels (0.7kPa vs. 0.4kPa elastic modulus, respectively), had more cross-links (9.2 vs. 7.4/µm2), and were degraded more slowly by collagenase. After gelation with CACs, live/dead staining showed greater CAC viability in the collagen-chitosan gels after 18h compared to collagen (79% vs. 69%). In vivo, collagen-chitosan gels, subcutaneously implanted for up to 6 weeks in a T1D mouse, showed increased levels of pro-angiogenic cytokines over time. By 6 weeks, anti-islet cytokine levels were decreased in all matrix formulations ± CACs. The 6-week implants demonstrated increased expression of VCAM-1 in collagen-chitosan implants. Despite this, infiltrating vWF+ and CXCR4+ angiogenic cell numbers were not different between the implant types, which may be due to a delayed and reduced cytokine response in a T1D versus non-diabetic setting. The mechanical, degradation and cytokine data all suggest that the collagen-chitosan gel may be a suitable candidate for use as a pro-angiogenic ectopic islet transplant site.
Highlights
Islet transplantation has become an attractive therapy for type I diabetes (T1D)
Mass loss peaked after 4 weeks (Table 1); some of the collagen hydrogels were completely degraded at this time point, but not the collagen-chitosan hydrogels
The current study evaluated collagen-based hydrogels as pro-angiogenic environments suitable for islet transplantation in a chronic type 1 diabetes (T1D) model system
Summary
Islet transplantation has become an attractive therapy for type I diabetes (T1D). The Edmonton protocol has greatly increased the survival and initial function of transplanted islets in humans with T1D [1]. Long-term islet survival remains sub-optimal and these patients only yielded an ~10% rate of insulin independence after 5 years [2]. Portal vein injection of islets into the liver is the most common procedure for islet transplantation (and used in the Edmonton protocol), the need for a safer transplant site has been identified as an important issue to address [3,4,5,6]. An ideal transplant site should provide liberal access to oxygen and nutrients, as well as venous drainage for the control of blood glucose levels through insulin secretion. A strategy for promoting angiogenesis at the transplant site may be necessary for islet grafting and function
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