Sustained function of alginate-encapsulated human islet cell implants in the peritoneal cavity of mice leading to a pilot study in a type 1 diabetic patient

Abstract

Aims/hypothesis Alginate-encapsulated human islet cell grafts have not been able to correct diabetes in humans, whereas free grafts have. This study examined in immunodeficient mice whether alginate-encapsulated graft function was inferior to that of free grafts of the same size and composition. Methods Cultured human islet cells were equally distributed over free and alginate-encapsulated grafts before implantation in, respectively, the kidney capsule and the peritoneal cavity of non-obese diabetic mice with severe combined immunodeficiency and alloxan-induced diabetes. Implants were followed for in vivo function and retrieved for analysis of cellular composition (all) and insulin secretory responsiveness (capsules). Results Free implants with low beta cell purity (19±1%) were non-functional and underwent 90% beta cell loss. At medium purity (50±1%), they were functional at post-transplant week 1, evolving to normoglycaemia (4/8) or to C-peptide negativity (4/8) depending on the degree of beta cell-specific losses. Encapsulated implants immediately and sustainably corrected diabetes, irrespective of beta cell purity (16/16). Most capsules were retrievable as single units, enriched in endocrine cells that exhibited rapid secretory responses to glucose and glucagon. Single capsules with similar properties were also retrieved from a type 1 diabetic recipient at post-transplant month 3. However, the vast majority were clustered and contained debris, explaining the poor rise in plasma C-peptide. Conclusions/interpretation In immunodeficient mice, i.p. implanted alginate-encapsulated human islet cells exhibited a better outcome than free implants under the kidney capsule. They did not show primary non-function at low beta cell purity and avoided beta cell-specific losses by rapidly establishing normoglycaemia. Retrieved capsules presented secretory responses to glucose, which was also observed in a type 1 diabetic recipient.

Versatile click alginate hydrogels crosslinked via tetrazine–norbornene chemistry

“…Alternatively, click alginate polymers could be crosslinked using tetrazine or norbornene-modified matrix metalloproteinase-degradable peptide sequences to allow cell-mediated degradation [29,52]. The use of partially oxidized alginate polymers would also allow degradation of the hydrogel over controlled time scales for in vivo tissue engineering applications [20,53].The tissue compatibility and stability of click alginate hydrogels could make it particularly useful for applications where isolation from host immune cell infiltration is required [54,55].…”

Reward-based hypertension control by a synthetic brain–dopamine interface

“…Also, functional interconnection of recurrent behavioral activities with production and systemic delivery of protein therapeutics will likely foster gene-and cell-based treatment strategies that require seamless and self-sufficient drug dosing at regular intervals. With the advent of personalized medicine, it may now be foreseen that autologous designer cells that are implanted into humans inside vascularizing semipermeable microcontainers could be remote-controlled by brain activities to produce and systemically deliver protein therapeutics at the right time and dose (40)(41)(42)(43). Provided that such designer cell implants are scalable to the patients' needs and could be replaced by ambulant interventions at patient-compliant intervals when becoming fibrotic, such braininstructed peripheral designer cell implants could make the taking of pills in specified amounts and in precise doses a thing of the past (43)(44)(45)(46).…”

A Synthetic Mammalian Therapeutic Gene Circuit for Sensing and Suppressing Inflammation

“…Alginate microencapsulation has already been tested in clinical trials, 57,58 for example, microencapsulated human islets transplanted into a type 1 diabetic patient aided insulin independence for 9 months. 59 Besides alginate microencapsulation, there are alternative cell implantation technologies, such as biocompatible hollow fibers, which may enable an easy removal of the implanted device.…”