RESUMEN
Encapsulation of cells in biocompatible polymer matrices represents a powerful tool for cell-based therapies and therapeutic delivery systems. This technology has successfully been used to deliver pancreatic islets to humans for the treatment of Type 1 diabetes. However, the clinical impact of this technology may be improved by reducing the inflammatory response brought on after implantation of capsules in vivo. Within this study a biocompatible polymeric delivery system combining alginate and photo-crosslinked methacrylated glycol chitosan (MGC) was developed. This approach involved encapsulating cells in calcium-alginate beads, coating with MGC and photo-polymerizing using UVA in the presence of photo-initiator (VA-086), resulting in the formation of capsules â¼600 µm in size. Crosslinking of the MGC outer wall allowed control over capsule swelling and improved the capsules overall properties. Capsule characterization demonstrated the stabilizing influence of polymerization and fluorescence imaging showed that the distribution of glycol chitosan is dependent on molecular weight. Good islet viability and insulin release was demonstrated in vitro over the course of a month, and in vivo transplantation of the capsules demonstrated good biocompatibility, particularly when compared with standard alginate/poly-l-ornithine/alginate capsules.
Asunto(s)
Alginatos/química , Materiales Biocompatibles/química , Quitosano/análogos & derivados , Composición de Medicamentos/métodos , Rechazo de Injerto/prevención & control , Trasplante de Islotes Pancreáticos/métodos , Islotes Pancreáticos , Metacrilatos/química , Alginatos/aislamiento & purificación , Animales , Cápsulas , Conformación de Carbohidratos , Células Cultivadas , Quitosano/química , Quitosano/inmunología , Quitosano/aislamiento & purificación , Quitosano/efectos de la radiación , Femenino , Reacción a Cuerpo Extraño/prevención & control , Ácido Glucurónico/química , Ácido Glucurónico/inmunología , Ácido Glucurónico/aislamiento & purificación , Ácidos Hexurónicos/química , Ácidos Hexurónicos/inmunología , Ácidos Hexurónicos/aislamiento & purificación , Hidrogeles , Interacciones Hidrofóbicas e Hidrofílicas , Islotes Pancreáticos/metabolismo , Prueba de Limulus , Masculino , Ensayo de Materiales , Metacrilatos/aislamiento & purificación , Metacrilatos/efectos de la radiación , Ratones , Microesferas , Estructura Molecular , Péptidos , Cavidad Peritoneal , Permeabilidad , Polimerizacion/efectos de la radiación , Sus scrofa , Porcinos , Trasplante Heterólogo , Rayos UltravioletaRESUMEN
DIABECELL® capsules comprise an inner core of alginate (Alg) coated with a polycationic polymer, poly-L-ornithine (PLO), designed as a stabilizing agent for strengthening the capsule wall, which is masked by an outer layer of biocompatible Alg. These polymeric microcapsules have demonstrated excellent mechanical properties and a reduction in hypoglycemia after tranplantation in human clinical trials; however, degradation of the outer Alg layer leaves the underlying layers of PLO exposed, which ultimately leads to reduced biocompatibility in vivo. Here we aim to improve capsule biocompatibility and to increase the hydrophilic properties of the capsule surface through chemical crosslinking/modification of the PLO layer using genipin. Fluorescence microscopy established crosslinking was limited to the layers of PLO. In vitro experiments confirmed islet viability and insulin release within chemically modified capsules over the course of a month and in vivo investigations demonstrated improved biocompatibility when comparing standard Alg/PLO/Alg capsules with genipin modified capsules.
