ABSTRACT
Inadequate oxygenation is a major challenge in cell encapsulation, a therapy which holds potential to treat many diseases including type I diabetes. In such systems, cellular oxygen (O2) delivery is limited to slow passive diffusion from transplantation sites through the poorly O2-soluble encapsulating matrix, usually a hydrogel. This constrains the maximum permitted distance between the encapsulated cells and host site to within a few hundred micrometers to ensure cellular function. Inspired by the natural gas-phase tracheal O2 delivery system of insects, we present herein the design of a biomimetic scaffold featuring internal continuous air channels endowed with 10,000-fold higher O2 diffusivity than hydrogels. We incorporate the scaffold into a bulk hydrogel containing cells, which facilitates rapid O2 transport through the whole system to cells several millimeters away from the device-host boundary. A computational model, validated by in vitro analysis, predicts that cells and islets maintain high viability even in a thick (6.6 mm) device. Finally, the therapeutic potential of the device is demonstrated through the correction of diabetes in immunocompetent mice using rat islets for over 6 months.
Subject(s)
Oxygen/chemistry , Animals , Biomimetics , Cell Encapsulation , Cell Survival/genetics , Cell Survival/physiology , Cells, Cultured , Electron Spin Resonance Spectroscopy , Humans , Hydrogels/chemistry , Male , Mice , Mice, Inbred C57BL , Rats, Sprague-DawleyABSTRACT
Cell encapsulation represents a promising therapeutic strategy for many hormone-deficient diseases such as type 1 diabetes (T1D). However, adequate oxygenation of the encapsulated cells remains a challenge, especially in the poorly oxygenated subcutaneous site. Here, we present an encapsulation system that generates oxygen (O2) for the cells from their own waste product, carbon dioxide (CO2), in a self-regulated (i.e., "inverse breathing") way. We leveraged a gas-solid (CO2-lithium peroxide) reaction that was completely separated from the aqueous cellular environment by a gas permeable membrane. O2 measurements and imaging validated CO2-responsive O2 release, which improved cell survival in hypoxic conditions. Simulation-guided optimization yielded a device that restored normoglycemia of immunocompetent diabetic mice for over 3 months. Furthermore, functional islets were observed in scaled-up device implants in minipigs retrieved after 2 months. This inverse breathing device provides a potential system to support long-term cell function in the clinically attractive subcutaneous site.
ABSTRACT
Cell replacement therapy is emerging as a promising treatment platform for many endocrine disorders and hormone deficiency diseases. The survival of cells within delivery devices is, however, often limited due to low oxygen levels in common transplantation sites. Additionally, replacing implanted devices at the end of the graft lifetime is often unfeasible and, where possible, generally requires invasive surgical procedures. Here, the design and testing of a modular transcutaneous biphasic (BP) cell delivery device that provides enhanced and unlimited oxygen supply by direct contact with the atmosphere is presented. Critically, the cell delivery unit is demountable from the fixed components of the device, allowing for surgery-free refilling of the therapeutic cells. Mass transfer studies show significantly improved performance of the BP device in comparison to subcutaneous controls. The device is also tested for islet encapsulation in an immunocompetent diabetes rodent model. Robust cell survival and diabetes correction is observed following a rat-to-mouse xenograft. Lastly, nonsurgical cell refilling is demonstrated in dogs. These studies show the feasibility of this novel device for cell replacement therapies.
Subject(s)
Cell- and Tissue-Based Therapy/instrumentation , Membranes, Artificial , Animals , Cell Line , Cell- and Tissue-Based Therapy/methods , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/therapy , Hydrocarbons/chemistry , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/transplantation , Mice , Mice, Inbred C57BL , Nanostructures/chemistry , Oxygen/metabolism , Polymers/chemistry , Polytetrafluoroethylene/chemistry , Rats , Rats, Sprague-Dawley , Titanium/chemistryABSTRACT
This review focuses on recent engineering advances in islet encapsulation technologies. ß cell replacement therapy in the form of allogeneic naked islet transplantation has become an established treatment for type 1 diabetes mellitus (T1DM). However, some limitations still impact the broad applicability and long-term efficacy of the procedure, including shortage of donor islets, the need for lifelong immunosuppression, and restriction to the most vulnerable patients. Islet encapsulation promises to overcome these constraints by providing a selectively permeable barrier between host and therapeutic tissues. While tremendous progress has been made and the clearing of key translational hurdles appears to be near, many challenges need to be addressed before this technology platform can enter the clinic. Here, we summarize the research in this area and seek to identify the outstanding challenges in translating islet encapsulation technology to human patients.
