Chelator Regulation of In Situ Calcium Availability to Enable Spray-Dry Microencapsulation in Cross-Linked Alginates

A recently patented one-step in situ cross-linked alginate microencapsulation (CLAM) by spray-drying (i.e., the UC Davis CLAMs technology) can overcome the high cost of scale-up that limits commercial applications. While increasing calcium loading in the CLAMs process can increase the extent of cross-linking and improve retention and protection of the encapsulated cargo, the potential for residual undissolved calcium salt crystals in the final product can be a concern for some applications. Here, we demonstrate an alternate one-step spray-dry CLAMs process using pH-responsive chelation of calcium. The "Chelate CLAMs" process is an improvement over the patented process that controls ion availability based on pH-responsive solubility of the calcium salt. Hyaluronic acid was encapsulated in CLAMs to minimize swelling and release in aqueous formulations. CLAMs with 61% (d.b.) hyaluronic acid (HA-CLAMs) demonstrated restricted plumping, limited water absorption capacity, and reduced leaching, retaining up to 49% hyaluronic acid after 2 h in water. Alternatively, "Chelate HA-CLAMs" formed by the improved process exhibited nearly full retention of hyaluronic acid over 2 h in water and remained visibly insoluble after 1 year of storage in water at 4 °C. Successful hyaluronic acid retention in CLAMs is likely due in part to its ability to cross-link with calcium.