Abstract
Cell microencapsulation is a rapidly expanding field with broad potential for stem cell therapies and tissue engineering research. Traditional alginate microspheres suffer from poor biocompatibility, and microencapsulation of more advanced hydrogels is challenging due to their slower gelation rates. We have developed a novel, noncytotoxic, nonemulsion-based method to produce hydrogel microspheres compatible with a wide variety of materials, called core-shell spherification (CSS). Fabrication of microspheres by CSS derived from two slow-hardening hydrogels, hyaluronic acid (HA) and polyethylene glycol diacrylate (PEGDA), was characterized. HA microspheres were manufactured with two different crosslinking methods: thiolation and methacrylation. Microspheres of methacrylated HA (MeHA) had the greatest swelling ratio, the largest average diameter, and the lowest diffusion barrier. In contrast, PEGDA microspheres had the smallest diameters, the lowest swelling ratio, and the highest diffusion barrier, while microspheres of thiolated HA had characteristics that were in between the other two groups. To test the ability of the hydrogels to protect cells, while promoting function, diabetic NOD mice received intraperitoneal injections of PEGDA or MeHA microencapsulated canine islets. PEGDA microspheres reversed diabetes for the length of the study (up to 16 weeks). In contrast, islets encapsulated in MeHA microspheres at the same dose restored normoglycemia, but only transiently (3–4 weeks). Nonencapsulated canine islet transplanted at the same dose did not restore normoglycemia for any length of time. In conclusion, CSS provides a nontoxic microencapsulation procedure compatible with various hydrogel types.Impact statementCore-shell spherification, described here for the first time, is a versatile method of coating cells to protect them following transplantation. Before the invention of this technique, only instantaneously hardening hydrogels, like alginate, could be used to encapsulate cells. With this new technology, biocompatible hydrogels can now be used for encapsulation without harsh emulsion chemicals. The technique involves a temporary shell of alginate around the slow-hardening gel that provides time for crosslinking to occur. Subsequently, the alginate shell is easily removed, leaving the cells in a protective microsphere with a higher surface area for diffusion than large encapsulating devices.
Highlights
The concept of cell encapsulation was introduced in 1980 by Lim and Sun, who showed that islets embedded in alginate microspheres could reverse diabetes in rats without the need for immunosuppression, for only a few weeks.[1]
The process starts with the slow-hardening hydrogel material (PEGDA, methacrylated HA (MeHA), or thiolated HA (ThHA)) that is entrapped in a shell as it hits the alginate bath (Fig. 1A), providing time for the core hydrogel to harden by either photo or chemical crosslinking (Fig. 1B)
The hyaluronic acid (HA) production was further divided into ThHA and MeHA to evaluate both chemically crosslinked and photo-crosslinked hydrogels, respectively, using the core-shell spherification (CSS)
Summary
The concept of cell encapsulation was introduced in 1980 by Lim and Sun, who showed that islets embedded in alginate microspheres could reverse diabetes in rats without the need for immunosuppression, for only a few weeks.[1] Encapsulation with alginate has persisted as the clear material of choice for cell therapies due to alginate’s unique, nearly instantaneous, crosslinking kinetics, enabling straightforward fabrication by dropping aqueous sodium alginate into a bath of crosslinking calcium.[2]. Alginate does present some challenges that researchers have attempted to resolve with numerous variations in the alginate fabrication process. The weakness of the alginate microspheres led researchers to alter the formulation for improved mechanical resistance required during
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