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Understanding the fundamental cell−material interactions is essential to designing functional materials for biomedical applications. Although mesenchymal stromal cells (MSCs) are known to secrete cytokines and exosomes that are effective to treat degenerative diseases, the inherent property of biomaterials to modulate the therapeutic function of MSCs remains to be investigated. Here, a multivalent cell-membrane adhesive conjugate was generated through polyamindoamine (PAMAM) and an oligopeptide, IKVAV, and the conjugate was further complexed with hyaluronic acid (HA). The adhesive particulates were used to coat the surface of adipose-derived mesenchymal stromal cells (Ad-MSCs) and studied in the MSC spheroid culture. The analysis showed that the adhesive complexes formed via PAMAM conjugates and HA significantly promoted the proliferation and the gene expression of pro-angiogenesis cytokines in MSCs; the production of anti-inflammatory miRNAs in exosomes could also be elevated. The transplantation of the Ad-MSCs primed with PAMAM-IKVAV/HA composite particulates in a rat myocardial infarction model further demonstrated the beneficial effects of membrane-binding materials on improving the cell retention and tissue angiogenesis. The new function of membrane-binding adhesive materials potentially provides useful ways to improve cell-based therapy.

Immunoisolation is an important strategy to protect transplanted cells from rejection by the host immune system. Recently, microfabrication techniques have been used to create hydrogel membranes to encapsulate microtissue in an arrayed organization. The method illustrates a new macroencapsulation paradigm that may allow transplantation of a large number of cells with microscale spatial control, while maintaining an encapsulation device that is easily maneuverable and remaining integrated following transplantation. This study aims to investigate the design principles that relate to the translational application of micropatterned encapsulation membranes, namely, the control over the transplantation density/quantity of arrayed microtissues and the fidelity of pre-formed microtissues to micropatterns. Agarose hydrogel membranes with microwell patterns were used as a model encapsulation system to exemplify these principles. Our results show that high-density micropatterns can be generated in hydrogel membranes, which can potentially maximize the percentage volume of cellular content and thereby the transplantation efficiency of the encapsulation device. Direct seeding of microtissues demonstrates that microwell structures can efficiently position and organize pre-formed microtissues, suggesting the capability of micropatterned devices for manipulation of cellular transplants at multicellular or tissue levels. Detailed theoretical analysis was performed to provide insights into the relationship between micropatterns and the transplantation capacity of membrane-based encapsulation. Our study lays the ground for developing new macroencapsulation systems with microscale cellular/tissue patterns for regenerative transplantation.hydrogel, micropattern, array, multi-cellular spheroids, macroencapsulation Citation:Jiang LY, Liu JY, Wang K, Gu X, Luo Y. Investigating design principles of micropatterned encapsulation systems containing high-density microtissue arrays.