An Injectable Cell Delivery System that Maintains Cell in a Discrete Area for Enhanced Function

Presented by: Lisa Stehno-Bittel

 

Authors: Lisa Stehno-Bittel, Stephen Harrington, Lindsey Ott, Karthik Ramachandran

Affiliations: University of Kansas, Kansas City, KS and Likarda LLC, Kansas City, MO

Introduction: Cells as medicine to repair or replace tissue is a rapidly expanding field with broad potential utility in the treatment of diseases such as diabetes, cancer, heart disease, arthritis and immune disorders. However, the delivery of the cells has been a challenge with IV administration leading to thrombosis and first-pass effects of the lungs. Localized delivery of cells can be best accomplished by first encapsulating the cells in hydrogels. While traditional alginate microspheres suffer from poor biocompatibility, microencapsulation of more advanced hydrogels is challenging due to their slower gelation rates.

Hypothesis / Objectives: A hydrogel manufacturing process using a shell to increase the time for gelation will result in firm microbeads that are not cytotoxic and can release cells into localized regions of the body.

Materials and Methods: We have developed a new method for microencapsulating cells so that they can be injected into localized areas where they remain. The method is call Core Shell Spherification (CSS) and it provides a method in which the biocompatible hydrogel is covered in an alginate shell prior to hardening. The shell give core structure time to harden, vastly expanding the options of precursors that can be formed into microparticles. Fabrication of microspheres via CSS derived from two slow-hardening hydrogels: hyaluronic acid (HA) and polyethylene glycol diacrylate (PEGDA) result in either degradable or durable microbeads.

Results: HA Microspheres had the greatest swelling ratio, largest average diameter, lowest diffusion barrier and degraded more quickly in vivo. In contrast, PEGDA microspheres had the smallest diameters, lowest swelling ratio, highest diffusion barrier and stability. Intraperitoneal injections of PEGDA microencapsulated canine islets into diabetic NOD mice reversed diabetes for the length of the study. In contrast, transplants using degradable MeHA microspheres restored normoglycemia, but only transiently (3-4 weeks). Non-encapsulated canine islet transplants did not restore normoglycemia for any length of time. Microbeads, with or without cells, were transplanted into immune-competent C57 mice and showed good biocompatibility.

Conclusions: Core Shell Spherification appears to offer several advantages as a novel, injectable cell therapy delivery system. Its applications include durable cell transplants as well as designed degradable delivery systems for localized release.

Acknowledgements, Funding, and Conflicts of Interest: The project was funded by Likarda, LLC. All Authors are employed by Likarda, LLC. Drs. Stehno-Bittel and Ramachandran are partial owners of Likarda, LLC