Oxygen Supply by Photosynthesis to an Implantable Islet Cell Device

Abstract

Transplantation of islet cells is an effective treatment for type 1 diabetes with critically labile metabolic control. However, during islet isolation, blood supply is disrupted, and the transport of nutrients/metabolites to and from the islet cells occurs entirely by diffusion. Adequate oxygen supply is essential for function/survival of islet cells and is the limiting factor for graft integrity. Recently, we developed an immunoisolated chamber system for transplantation of human islets without immunosuppression. This system depended on daily oxygen supply. To provide independence from this external source, we incorporated a novel approach based on photosynthetically-generated oxygen. The chamber system was packed sandwich-like with a slab of immobilized photosynthetically active microorganisms (Synechococcus lividus) on top of a flat light source (LEDs, red light at 660 nm, intensity of 8 μE/m(2)/s). Islet cells immobilized in an alginate slab (500-1,000 islet equivalents/cm(2)) were mounted on the photosynthetic slab separated by a gas permeable silicone rubber-Teflon membrane, and the complete module was sealed with a microporous polytetrafluorethylene (Teflon) membrane (pore size: 0.4 μm) to protect the contents from the host immune cells. Upon illumination, oxygen produced by photosynthesis diffused via the silicone Teflon membrane into the islet compartment. Oxygen production from implanted encapsulated microorganisms was stable for 1 month. After implantation of the device into diabetic rats, normoglycemia was achieved for 1 week. Upon retrieval of the device, blood glucose levels returned to the diabetic state. Our results demonstrate that an implanted photosynthetic bioreactor can supply oxygen to transplanted islets and thus maintain islet viability/functionality.

Survival of encapsulated islets: More than a membrane story

“…A simple solution to this apparent oxygen deficiency is active delivery of oxygen by generating it in situ or using stored reservoirs. Some solutions were ex perimentally tested including a direct supply of oxygen to cultured cells using decomposition of solid calcium peroxide [148] , electrochemical generator [149] (USP 8368592), or local photosynthesis [150,151] . Unfortunately, none of these systems generated enough oxygen to maintain clinical doses of islet graft viable and functional for long periods of time.…”

Development and Validation of Noninvasive Magnetic Resonance Relaxometry for the In Vivo Assessment of Tissue-Engineered Graft Oxygenation

“…2,7,8,[11][12][13] Lack of oxygen is the most critical issue preventing widespread utilization of macroencapsulated islet transplantation, and delivery of exogenous oxygen has been shown to enhance TEG survival and function in vivo. 2,14,15 Noninvasive monitoring of pO 2 can improve TEG development and allow the evaluation of TEG viability 16 and local changes in pO 2 with the delivery of supplemental oxygen (DSO). Oxygen measurements are especially important in TEGs that have not revascularized due to either lack of time or the presence of an immunoisolating membrane.…”

MECHANISMS IN ENDOCRINOLOGY: Towards the clinical translation of stem cell therapy for type 1 diabetes

“…This has been shown to be overcome by using devices that are oxygenised e.g. by external refilling of oxygen or internal oxygen production through photosynthesis (39,40,41). Based on a pilot study (42), we are currently evaluating an oxygenised macrocapsule (Beta-Air) approved for clinical use in an investigator-driven clinical trial with human islets (Clinicaltrials.gov NCT02064309).…”

“…By using the macroencapsulation approach, it will however be possible to gain valuable knowledge about how the cells respond to the in vivo environment in humans without great risks regarding the health and safety of the recipient. Due to the size of macroencapsulation devices, few implantation sites are eligible, and the devices are commonly placed in subcutaneous tissue (37,38,39,40,41). Also, the preperitoneal space has been used (42), whereas intraperioneal placement is difficult in the clinical perspective.…”