Curr Diab Rep (2011) 11:434–444 It was subsequently shown that VEGF-A could be attached to heparinized islets without affecting insulin secretion and that in vitro the VEGF-A acted as an endothelial cell attractant [53••]. Self-assembling amphiphile peptides bound to heparin [54] have also been used as a growth factor delivery system for islet transplantation [55]. Using a diabetic mouse model, islets were transplanted into the omentum pouch alone, with local administration of VEGF-A and basic fibroblast growth factor (FGF) or together with heparin-coated poly (L-lactic acid/lactide) (PLA) matrices with or without VEGF-A and FGF. A higher proportion of mice trans- planted with biofunctionalized heparin-PLA scaffolds achieved normoglycemia and an increase in vessel density at the transplantation site, when compared to islets with or without administration of growth factors or heparin-PLA scaffolds [55]. Furthermore, this group recently showed that the biofunctionalized heparin-binding peptides could attach to isolated murine islets and increase islet viability, insulin secretion, and endothelial cell sprouting from within the islet [56]. These encouraging results with heparin suggest that synthetic materials with the ability to incorporate heparin and mimic the natural environment without elicit- ing an immune response (e.g., poly(ethylene glycol) [PEG] hydrogels) may improve islet transplantation outcome [57]. A variety of synthetic biomaterials has been used for islet culture and transplantation (Table 1) and is discussed below. Based on the small organic molecule, lactic acid polymers (PLA) can be easily manipulated during production or post- polymerization to produce a material with varying proper- ties [58]. We have already discussed its use in combination with heparin-binding nanostructures. One copolymer that has been used in animal models of islet transplantation derives from a mixture of lactide and glycolide, poly(lactic- co-glycolic acid) (PLGA). One notable feature of PLGA is the ability to decrease degradation time by increasing the ratio of glycolide to lactide [58]. The use of these polymers with islets was published in 2005. PLGA scaffolds with a ratio of 90% glycolide to 10% lactide (Vicryl®; Ethicon Inc., Somerville, NJ) were coated with varying numbers of islets in a matrigel suspension and transplanted into the epididymal fat pad of diabetic mice. More mice were able to achieve normoglycemia when transplanted with the islet-matrigel–coated scaffold when compared with free islets or islets in matrigel suspension, and insulin content in transplanted islet-matrigel–coated scaffolds was similar to that of islets transplanted under the kidney capsule [59]. Modifications to this approach have included PLGA scaffolds with interconnected pores from 250 to 400 μm so as to house a marginal islet mass for Lactic Acid–Based Polymers Hydrogels 437 transplantation. Mice receiving such grafts into the folds of intraperitoneal fat achieved normoglycemia at a faster rate than mice receiving islets alone in the same location [60]. Another study used the commercially available Ethisorb® (Codman, Raynham, MA), comprised of Vicryl® with a poly-p-dioxanone (PDS) backing, to determine islet graft survival into the omentum pouch of pancreatectomized dogs. Four animals received autologous islets seeded into the polymer scaffold and two received free islets into the omentum pouch. All four animals transplanted with the scaffold and none of the control animals achieved normo- glycemia without the administration of exogenous insulin secretion for a maximum of 5 months [61•]. Other Polyesters Polyhydroxyalkanoates (PHA) are polyesters produced by microorganisms in unfavorable growth conditions and have been commonly used in many medical devices. Copolymers of 3-hydroxybutyrate and 3-hydroxyhexanoate (PHBHHx) were used in a pilot study to determine the effect of PHBHHx on cluster formation and insulin secretion of the murine islet β-cell line NIT-1. After overnight culture, cell clustering and later islet-like aggregates were seen in wells containing PHBHHx. Cells cultured on PHBHHx had increased insulin secretion and viability compared to islets with tissue culture alone, PLA, and another PHA copolymer derivative [62]. Hydrogels, as the name implies, consist of highly absorbent polymers. By varying the amount of crosslinking of synthetic hydrogels, mechanical properties of the hydrogels can be attuned. A class of covalently linked hydrogel is based on the synthetic polymer PEG. The characteristics of PEG hydrogels include low immunogenicity, protein absorption, and cell adhesion. In a cell transplantation setting, these bio-inert properties can be modified by binding growth factors and incorporating cell attachment and enzyme-sensitive peptide sequences to allow the cells of interest to attach, proliferate, and function [63]. Further- more, copolymers of PEG can be formed to create an amphiphilic polymer that has both hydrophobic and hydrophilic properties. Ito and Taguchi [64] used such a modification by incorporating oleyl hydrophobic tails to crosslink rat insulinoma cells to form spheroids and found that oleyl-O-PEG crosslinked cells were more glucose responsive than non-crosslinked cells. Another synthetic polymer with similar properties to that of PEG hydrogels is the poly(vinyl alcohol) (PVA) hydro- gel. In a recent report, PVA was modified with thiol-alkyl side chains to allow attachment to the lipid bilayer of endocrine islet cells and further conjugation of protein-