(476g) Oxidized Alginate Microgels for Drug Delivery and Cell Encapsulation

Introduction: Microgels are a versatile class of biomaterials that have been used extensively in applications of drug delivery, tissue engineering, and cell therapy.¹ They have similar molecular properties as their bulk hydrogel counterparts in addition to being injectable and modular with decreased diffusion distances for drug release or nutrient exchange. Alginate is commonly used to form microgels for biomedical applications due to its inherent biocompatibility and natural availability. However, alginate is not readily degradable under physiological conditions. Here, we synthesize oxidized alginate, a biodegradable form of the polysaccharide and report its applications in glucose-responsive insulin delivery as well as islet transplantation therapy.

Methods: Oxidized alginate was synthesized as previously described,² with theoretical extents of oxidation of 2.5%, 5%, and 7.5% to represent a range of degradation rates for drug and cell delivery applications. Calcium-crosslinked alginate microgels were formed with a custom electro-spray system. In vitro and in vivo degradation studies were performed, and the efficacy of these approaches in treating diabetes was tested with a STZ-injected Type 1 diabetic C57BL/6 mouse model.

Results: We first synthesized 3 polymers with varying extents of oxidation and characterized them in terms of their aldehyde content as well as their molecular weight. The more oxidized polymers had higher concentrations of aldehydes (Fig 1a), lower starting molecular weights, and larger percentages of degradation post-incubation (Fig. 1b). All polymers were < 60 kDa post-incubation, suggesting that they may be able to undergo renal clearance.³ We then formed microgels with diameters of either 0.5 mm (for subcutaneous glucose-responsive insulin injection) or 1.5 mm (for intraperitoneal islet transplantation) and studied their stability through in vitro swelling tests. We found that the larger microgels exhibit larger degrees of swelling at earlier time points compared to smaller microgels and the 2.5% oxidized microgels are relatively stable over ~ 30 washes (Fig. 1c,d). All formulations are largely degraded after 4 wks in vivo, with degradation rate dependent on degree of oxidation and implantation site. The oxidized alginate microgels were then used to encapsulate 1) glucose-responsive insulin-releasing nanoparticles or 2) insulin-secreting pancreatic islet cells, and showed efficacy in curing diabetes on the order of weeks in both cases.

Conclusion: We have tuned the extent of oxidation of alginate to form biodegradable microgels for drug and cell delivery. As a model application of this approach, we encapsulate glucose-responsive insulin nanoparticles or insulin-secreting islet cells for the closed-loop treatment of diabetes.

References:

1. Facklam, A. L.; Volpatti, L. R.; Anderson, D. G., Biomaterials for Personalized Cell Therapy. Adv. Mater. 2019, 1902005.
2. Bouhadir, K. H.; Lee, K. Y.; Alsberg, E.; Damm, K. L.; Anderson, K. W.; Mooney, D. J., Degradation of partially oxidized alginate and its potential application for tissue engineering. Biotechnol. Prog. 2001, 17 (5), 945-950.
3. Arturson, G.; Wallenius, G., The renal clearance of dextran of different molecular sizes in normal humans. Scand. J. Clin. Lab. Invest. 1964, 16 (1), 81-86.