For patients with Type I diabetes mellitus, islet transplantation provides a moment-to-moment fine regulation of insulin that is unachievable by exogenous insulin injection. Islet cell death, caused either by transplant rejection, the presence of toxic immunosuppressive drugs, and/or the lack of blood and nutrient supply remains an important obstacle for successful therapy. For some time, advances have been made by encapsulating islets with alginate to achieve immunoprotection, but the overall success rate has been limited, with poor long-term survival of islets once transplanted into patients. From biopsies it is known that the currently used alginate capsule compositions are far from optimal, as they can elicit a foreign body host immune response culminating in fibrotic overgrowth of capsules and subsequent islet cell death. Unfortunately, there is currently no means to probe the mechanical stability and biocompatibility of engrafted microcapsules non-invasively over time, delaying further development and improvements of encapsulated islet cell therapy. Our goal is to develop a dual-mode magnetic resonance imaging (MRI) approach that can report on the mechanical stability of implanted capsules over time while simultaneously interrogating the absence or presence of a major host immune response. To this end, we will employ fluorine (19F) and magnetization transfer (MT) MRI, respectively, both of which are clinically available. Mixed Alginate Gradient (MAG) fluorocapsules will be developed as a new capsule formulation without the need for using potentially toxic polycations to achieve selectivity of capsule permeability. We hypothesize that these MAG fluorocapsules have improved biocompatibility profiles over conventional alginate encapsulants. We will first develop MAG fluorocapsules with different mechanical strengths, and test their stability, perm-selectivity, and islet- encapsulated functionality in vitro. We will then transplant empty capsules s.c. and i.p. in non-diabetic, immunocompetent Balb/c mice which will be followed for 180 days. The outcome of the MRI studies and immunohistopathology will be used to select the most promising formulation to encapsulate mouse (allogeneic) and porcine and human (xenogeneic) islets, which will be transplanted i.p. and s.c. in immunocompetent NOD Shi/Ltj and streptozotocin (STZ)-induced immunodeficient NOD scid/scid mice. 19F MRI (mechanical stability) and MT MRI (host immune response) signals will be collected over 180 days and compared to immunohistological and blood (c-peptide, glucose) parameters. The relative islet cell survival will be quantified with bioluminescent imaging (BLI) and correlated to the fluorine and MTR signals. By following a step-wise approach of allografting and xenografting islets from different sources, with increasing demand on immunoprotection, biocompatibility, and preservation of mechanical stability, we hope to demonstrate the usefulness of dual-mode MRI in developing novel encapsulating materials with potential for clinical translation.

Public Health Relevance

We will use two types of MRI scans to develop new single layer alginate capsule formulations that can be used to protect transplanted pancreatic islet cells from immunorejection by the host. To this end, fluorine MRI will be used to assess the stability and sturdiness of the new capsule formulations, and MT MRI will be used to interrogate the host immune response.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical Molecular Imaging and Probe Development (CMIP)
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Arreaza-Rubin, Guillermo
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Johns Hopkins University
Schools of Medicine
United States
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Bulte, Jeff W M; Daldrup-Link, Heike E (2018) Clinical Tracking of Cell Transfer and Cell Transplantation: Trials and Tribulations. Radiology 289:604-615
Paredes-Juarez, Genaro A; Barnett, Brad P; Bulte, Jeff W M (2017) Noninvasive Tracking of Alginate-Microencapsulated Cells. Methods Mol Biol 1479:143-155
Paredes-Juarez, Genaro A; de Vos, Paul; Bulte, Jeff W M (2017) Recent progress in the use and tracking of transplanted islets as a personalized treatment for type 1 diabetes. Expert Rev Precis Med Drug Dev 2:57-67
Arifin, Dian R; Valdeig, Steffi; Anders, Robert A et al. (2016) Magnetoencapsulated human islets xenotransplanted into swine: a comparison of different transplantation sites. Xenotransplantation 23:211-21