Abstract
Microfluidics-based alginate microgels have shown great potential to encapsulate cells in a high-throughput and controllable manner. However, cell viability and biological functions are substantially compromised due to the harsh conditions for gelation, which remains a major challenge for cell encapsulation. Herein, we presented an efficient and biocompatible method by on-chip triggered gelation to generate microfluidic alginate microgels for single-cell encapsulation. Two calcium complexes of calcium–ethylenediaminetetraacetic acid (Ca-EDTA) and calcium–nitrilotriacetic (Ca-NTA) as crosslinkers for triggered gelation of alginate were compared and investigated for feasible application. By triggered release of Ca2+ ions from the calcium complex via adding acetic acid in the oil phase, the alginate precursor in the aqueous droplets can be crosslinked to form alginate microgels. Although using Ca-EDTA and Ca-NTA both achieved on-chip gelation, Ca-NTA led to significantly higher cell viability since the dissociation of Ca2+ ions from Ca-NTA can be obtained using less concentration of acid compared to Ca-EDTA. We further demonstrated the functionality of encapsulated mesenchymal stem cells (MSCs) in alginate microgels prepared using Ca-NTA, as evidenced by the osteogenesis of encapsulated MSCs upon inductive culture. In summary, our study provided a biocompatible strategy to prepare alginate microgels for single-cell encapsulation which can be further used for applications in tissue engineering and cell therapies.
Highlights
IntroductionHydrogels containing hydrophilic polymeric networks are widely used as matrix materials to construct cell carriers because it resembles a natural extracellular matrix (ECM) and can be further functionalized to offer physiologically relevant environmental cues (Borenstein et al, 2007; Mao et al, 2017)
Constructing cell carriers has become a powerful way to address biomedical questions, such as screening and delivery of drugs (Holloway et al, 2014; Yeung et al, 2016; Kang et al, 2020), cell therapy (Lim and Sun, 1980; Burdick et al, 2016), and tissue regeneration (Caiazzo et al, 2016; An et al, 2020)
To trigger the gelation of alginate, we used calcium complexes, i.e., calcium– ethylenediaminetetraacetic acid (Ca-ethylenediaminetetraacetic acid (EDTA)) and Ca-NTA, as the crosslinker, which can chelate with calcium ions and remain soluble in the aqueous phase without reacting with alginate molecules
Summary
Hydrogels containing hydrophilic polymeric networks are widely used as matrix materials to construct cell carriers because it resembles a natural extracellular matrix (ECM) and can be further functionalized to offer physiologically relevant environmental cues (Borenstein et al, 2007; Mao et al, 2017). Calcium Complex for Cell-Laden Microgels communication and inaccurate control of cell behavior. With this aim, micrometer-sized hydrogels (microgels) were extensively studied as cell vehicles. Cell transplantation in uniform microgels can offer administration by injection in a minimally invasive manner, which enables the promotion of cell viability and leveraged therapeutic activities of encapsulated cells (Velasco et al, 2012; Wan, 2012). Due to the tight microenvironment control of cells, cells encapsulated in microgels can be served as a tissue engineering module for constructing large tissues and organs
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