Evaluation of a Collagen-Chitosan Hydrogel for Potential Use as a Pro-Angiogenic Site for Islet Transplantation

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.

Functionalised type-I collagen as a hydrogel building block for bio-orthogonal tissue engineering applications

“…5, 15 Crosslinked collagen-chitosan hydrogels, which were mechanically stronger than collagen alone, promoted angiogenesis and has been used for islet transplantations in murine models. 16 Li et al…”

“…When tested in mini-pig eyes, these hybrid biomaterials promoted regeneration of corneal and neural tissues. 16 Another technique is the fabrication of interpenetrating networks of biomaterials using gold standard EDC-NHS coupling. Our team had developed a carbodiimide crosslinked recombinant human collagen network that was reinforced with a network of synthetic phosphorylcholinepoly(ethylene glycol) diacrylate to form an interpenetrating network that were subsequently moulded into corneal implants.…”

“…5, 15 Crosslinked collagen-chitosan hydrogels, which were mechanically stronger than collagen alone, promoted angiogenesis and has been used for islet transplantations in murine models. 16 Li et alco-polymerized collagen with laminin-peptide functionalized poly(N´-isopropylacrylamide) (PNIPAAm) to form a corneal implant. When tested in mini-pig eyes, these hybrid biomaterials promoted regeneration of corneal and neural tissues.…”

Alginate-Collagen Fibril Composite Hydrogel

“…Similar to alginate, collagen hydrogels have been used for various applications including investigation of adherence of bone marrow stromal cells, as scaffold for cartilage tissue engineering, in vascular grants, and for applications in wound healing and as a pro-angiogenic site for islet transplantation [37,38,39,40,41]. Native type I collagen fibrils have characteristic periodic patterns of 60–70 nm [42] (See Figure 2).…”

“…However, no mechanical properties were reported [53]. The mechanical properties of collagen-chitosan hydrogel were characterized using compression experiment [41]. For this hydrogel, soluble collagen molecules were used after pH adjustment, which resulted in fibril formation.…”