Transplantation of macroencapsulated human islets within the bioartificial pancreas βAir to patients with type 1 diabetes mellitus

Abstract

Macroencapsulation devices provide the dual possibility of immunoprotecting transplanted cells while also being retrievable, the latter bearing importance for safety in future trials with stem cell–derived cells. However, macroencapsulation entails a problem with oxygen supply to the encapsulated cells. The βAir device solves this with an incorporated refillable oxygen tank. This phase 1 study evaluated the safety and efficacy of implanting the βAir device containing allogeneic human pancreatic islets into patients with type 1 diabetes. Four patients were transplanted with 1‐2 βAir devices, each containing 155 000‐180 000 islet equivalents (ie, 1800‐4600 islet equivalents per kg body weight), and monitored for 3‐6 months, followed by the recovery of devices. Implantation of the βAir device was safe and successfully prevented immunization and rejection of the transplanted tissue. However, although beta cells survived in the device, only minute levels of circulating C‐peptide were observed with no impact on metabolic control. Fibrotic tissue with immune cells was formed in capsule surroundings. Recovered devices displayed a blunted glucose‐stimulated insulin response, and amyloid formation in the endocrine tissue. We conclude that the βAir device is safe and can support survival of allogeneic islets for several months, although the function of the transplanted cells was limited (Clinicaltrials.gov: NCT02064309).

Extracellular hemoglobin combined with an O2‐generating material overcomes O2 limitation in the bioartificial pancreas

“…The gas delivery is the most advanced technique but requires multiple daily O 2 ‐gas injections (Ludwig et al, ; Barkai et al, ). However, the efficiency of this system is limited by the low O 2 diffusivity in the large clinically relevant device (Carlsson et al, ). Chemical O 2 ‐generating biomaterials, such as solid calcium peroxide (CaO 2 ), are promising to store large quantities of O 2 in an aqueous medium.…”

“…The gas delivery is the most advanced technique but requires multiple daily O 2 -gas injections (Ludwig et al, 2013;Barkai et al, 2016). However, the efficiency of this system is limited by the low O 2 diffusivity in the large clinically relevant device (Carlsson et al, 2018).…”

Integration of nano‐ and biotechnology for beta‐cell and islet transplantation in type‐1 diabetes treatment

“…Using CRISPR/Cas9 targeting technology in hiPSCs, we created iRFP reporter cell lines with the same construct as iRFP transgenic animals were generated. This cell line will enable the non‐invasive, optoacoustic detection of viable iPSC‐derived human beta cells within a bioartificial pancreas, implanted into a pre‐clinical porcine model. Using directed differentiation methods, iPSCs were differentiated into pancreatic progenitor cells, which expressed the most relevant marker proteins of pancreatic progenitor cells (Figure ), suitable for transplantations and further in vivo or in vitro maturation.…”

Microencapsulated adult porcine islets transplanted intraperitoneally in streptozotocin‐diabetic non‐human primates

“…The issue of hypoxia as a limiting factor in islet graft survival is acknowledged as a major problem in the field of islet transplantation today (for both allografts and xenografts), and our laboratory, as well as others, will be actively seeking solutions to this potential roadblock. 80 We have begun to explore the possibility of administering oxygen to our NHP recipients by inhalation during the immediate post-transplant period, in order to substantially increase peritoneal oxygen levels and so improve the viability and function of encapsulated islets in the ip site. Recently, oxygen inhalation therapy has been tested successfully in Lewis rats with subcutaneous syngeneic islet transplants in a prevascularized site, 81 and we expect that this simple technique may prove useful in NHPs and possibly in human patients.…”