Encapsulation of Islets in Rough Surface, Hydroxymethylated Polysulfone Capillaries Stimulates VEGF Release and Promotes Vascularization after Transplantation

Abstract

The transplantation of encapsulated islets of Langerhans is one approach to treat type 1 diabetes without the need of lifelong immunosuppression. Capillaries have been used for macroencapsulation because they have a favorable surface-to-volume ratio and because they can be refilled. It is unclear at present whether the outer surface of such capillaries should be smooth to prevent, or rough to promote, cell adhesions. In this study we tested a new capillary made of modified polysulfone (MWCO: 50 kDa) with a rough, open-porous outer surface for islet transplantation. Compared with free-floating islets, encapsulation of freshly isolated rat islets affected neither the kinetics nor the efficiency of glucose-induced insulin release in perifusion experiments. Free-floating islets maintained insulin secretion during cell culture but encapsulated islets gradually lost their glucose responsiveness and released VEGF. This indicated hypoxia in the capillary lumen. Transplantation of encapsulated rat islets into diabetic rats significantly reduced blood glucose concentrations from the first week of implantation. This hypoglycaemic effect persisted until explantation 4 weeks later. Transplantation of encapsulated porcine islets into diabetic rats reduced blood glucose concentrations depending on the islet purity. With semipurified islets a transient reduction of blood glucose concentrations was observed (2, 8, 18, 18 days) whereas with highly purified islets a sustained normoglycaemia was achieved (more than 28 days). Explanted capillaries containing rat islets were covered with blood vessels. Vascularization was also observed on capillaries containing porcine islets that were explanted from normoglycaemic rats. In contrast, on capillaries containing porcine islets that were explanted from hyperglycemic rats a fibrous capsule and lymphocyte accumulations were observed. No vascularization on the surface of transplanted capillaries was observed in the absence of islets. In conclusion, encapsulated islets can release VEGF, which appears to be an important signal for the vascularization of the capillary material. The rough, open-porous outer surface of the polysulfone capillary provides a site well suited for vascular tissue formation and may allow a prolonged islet function after transplantation.

Regenerative Endodontics: A Review of Current Status and a Call for Action

“…Second, enlargement of the apical foramen is necessary to promote vascularizaton and to maintain initial cell viability via nutrient diffusion. Related to this point, cells must have an available supply of oxygen; therefore, it is likely that cells in the (122)(123)(124)(125)(126).…”

Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist

“…This effect was even more pronounced when islets are encapsulated (21)(22)(23)(24). Experimental approaches to overcome this problem include the generation of very small capsules (25), use of hypoxia-resistant islet cells (26), stimulation of blood vessel growth around implanted devices (27,28), increased oxygen permeability of the encapsulating material (29,30), use of To whom correspondence should be addressed. E-mail: andrew.schally@va.gov.…”

Encapsulated islets transplantation: Past, present and future

“…Lembert et al [39,40] developed hydroxy-methylated PSU "macroencapsulated" islets which showed good insulin releasing function similar to naked islets while blocking endogenous retrovirus infection. Transplantation of their device also achieved normoglycemia in diabetic rats for over 1 mo [41] . Polyvinyl alcohol (PVA) also has been used as a material for encapsulated islets.…”

“…Alginate [36] Microcapsule Porcine and bovine to rat Achieving normoglycemia for 9 mo Polysulphone [41] Macrocapsule Porcine to rat Normoglycemia over 1 mo Polyvinyl alcoho [8] Macrocapsule Rat to mouse Normoglycemia for 30 d Low molecular weight dextran sulfate [47] Microcapsule In vitro assay Inhibition of complement Figure 1 Scheme of the mechanism for encapsulated islets. Immune isolation can be achieved by covering islets with semi-permeable membranes consisting of high polymer.…”