Oral delivery of stem-cell-loaded hydrogel microcapsules restores gut inflammation and microbiota

• Published in: Journal of controlled release 2022-07, Vol.347, p.508-520
• Main Authors: Kim, Do-Wan, Jeong, Hye-Seon, Kim, Eunseo, Lee, Hyomin, Choi, Chang-Hyung, Lee, Sei-Jung
• Format: Article
• Language: English
• Subjects: Colonic inflammation; Gut microbiota; Hydrogel microcapsule with a thin oil layer; Microfluidics; Stem cell oral delivery
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2022.05.028

Mesenchymal stem cells (MSCs) are an attractive candidate for the treatment of inflammatory bowel disease (IBD), but their poor delivery rate to an inflamed colon is a major factor hampering the clinical potential of stem cell therapies. Moreover, there remains a formidable hurdle to overcome with regard to survival and homing in to injured sites. Here, we develop a strategy utilizing monodisperse hydrogel microcapsules with a thin intermediate oil layer prepared by a triple-emulsion drop-based microfluidic approach as an in-situ oral delivering carrier. The oral delivery of stem-cell-loaded hydrogel microcapsules (SC-HM) enhances MSC survival and retention in the hostile stomach environment due to the intermediate oil layer and low value of the overall stiffness, facilitating programmable cell release during gastrointestinal peristalsis. SC-HM is shown to induce tissue repair, reduce the colonic macrophage infiltration responsible for the secretion of the pro-inflammatory factors, and significantly mitigate the severity of IBD in a mouse model, where MSCs released by SC-HM successfully accumulate at the colonic crypt. Moreover, a metagenomics analysis reveals that SC-HM ameliorates the dysbiosis of specific bacterial genera, including Bacteroides acidifaciens, Lactobacillus (L.) gasseri, Lactobacillus reuteri, and L. intestinalis, implying optimization of the microorganism's composition and abundance. These findings demonstrate that SC-HM is a potential IBD treatment candidate. Stem-cell-loaded hydrogel microcapsules (SC-HM) with a thin oil layer has the potential to rupture and release the encapsulated stem cells by the segmenting during the moment and peristalsis in the gut. Stem cells released from SC-HM induce the tissue repair, reduce the colonic macrophage infiltration responsible for the secretion of the pro-inflammatory factors, and significantly mitigate the severity of IBD in a mouse model. Moreover, SC-HM can restore gut microbiome dysbiosis and reestablish the composition of the gut microbiota in acute colitis. [Display omitted] •We develop the SC-HM prepared by a triple-emulsion drop-based microfluidic approach.•The delivery of SC-HM augments the local retention of the cell at colonic sites.•Stem cells released from the SC-HM ameliorate gut inflammation in a mouse IBD model.•SC-HM restores gut microbiome dysbiosis in active colitis.