© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheimwww.advhealthmat.dewww.MaterialsViews.comwileyonlinelibrary.com667COMMUNICATION Core–Shell Hydrogel Microcapsules for Improved Islets Encapsulation DOI: 10.1002/adhm.201200341 Hydrogel microcapsules have been extensively investigated for encapsulation of living cells or cell aggregates for tissue engi-neering and regenerative medicine. [ 1 − 3 ] In general, capsules are designed to allow facile diffusion of oxygen and nutrients to the encapsulated cells, while releasing the therapeutic proteins secreted by the cells, and to protect the cells from attack by the immune system. These have been developed as potential thera-peutics for a range of diseases including type I diabetes, cancer, and neurodegenerative disorders such as Parkinson’s. [ 4 − 6 ] One of the most common capsule formulations is based on alginate hydrogels, which can be formed through ionic crosslinking. In a typical process, the cells are fi rst blended with a viscous algi-nate solution. The cell suspension is then processed into micro-droplets using different methods such as air shear, acoustic vibration or electrostatic droplet formation. [ 7 ] ( Figure 1 a) The alginate droplet is gelled upon contact with a solution of divalent ions, such as Ca 2 + or Ba 2 + . One challenge associated with alginate microcapsules for cell encapsulation, however, is the lack of control of the relative positions of the cells within the capsules. The cells can become trapped and exposed on the cap-sule surface, leading to inadequate immune-protection. [ 8 ] It has been recognized that incomplete coverage would not only cause the rejection of exposed cells but may also allow the infi ltration of macrophages and fi broblasts into the capsules through the exposed areas. [ 9 ] Alginate hydrogel microcapsules have been broadly investi-gated for their utility with pancreatic islets to treat Type I dia-betes. [ 10 ] Numerous promising results have been reported in several animal models including rodents, [ 11 , 13 ] dogs [ 14 ] and non-human primates. [ 15 , 16 ] Clinical trials have also been performed by Soon-Shiong et al., [ 17 ] Elliott et al., [ 18 ] Calafi ore et al., [ 19 , 20 ] and Tuch et al. [ 21 ] In general, these clinical trials have reported insulin secretion, but without long term correction of blood sugar con-trol, and additional challenges remain to advance these sys-tems. [ 22 , 24 ] One challenge is the biocompatibility of the capsules. Upon transplantation, the foreign body responses cause fi brotic cellular overgrowth on the capsules that cut off the diffusion of oxygen and nutrients, and lead to necrosis of encapsulated islets. To this end, research groups have developed polymers to reduce the fi brotic reactions. [ 25 ] Another challenge is the incomplete coverage of the islets within the capsules. [ 26 , 27 ] Islets protruding outside the capsules are more frequently observed when the islet number density in alginate solution increases or the capsule size decreases, both of which are desirable to minimize the transplan-tation volume. [ 28 ] It has been hypothesized that if even a small fragment of islet is exposed, immune effector cells may destroy the entire islet. [ 29 , 30 ] Furthermore, exposure of a small number of islets may start a cascade of events that leads to enhanced antigen-specifi c cellular immunity and transplant failure. A double-encapsulation process [ 18,31 ] has been used to improve the encapsulation and xenograft survival where very small cap-sules containing cells were fi rst formed and then several small capsules were enclosed in each larger capsule. This approach required two process steps and the large size of the fi nal cap-sules inevitably limited the mass transport that was essential to cell viability and functionality. Thin conformal coating of islets reduces the diffusion distance and total transplantation volume. [ 32 , 33 ] However, the process often involves multiple steps which cause damage to islets and it is not clear whether the coat-ings are suffi ciently robust for clinical use. [ 10 , 34 ] Previous data [ 35 ] has suggested conformal coatings may have reduced immune-protective capacity compared with the hydrogel capsules. Minglin Ma , Alan Chiu , Gaurav Sahay , Joshua C. Doloff , Nimit Dholakia , Raj Thakrar , Joshua Cohen , Arturo Vegas , Delai Chen , Kaitlin M. Bratlie , Tram Dang , Roger L. York , Jennifer Hollister-Lock , Gordon C. Weir , and Daniel G. Anderson * Dr. M. Ma, A. Chiu, Dr. G. Sahay, Dr. J. C. Doloff, N. Dholakia, R. Thakrar, Dr. A. Vegas, Dr. D. Chen, Dr. T. Dang, Dr. R. L. York, Prof. D. G. Anderson David H Koch Institute for Integrative Cancer ResearchMassachusetts Institute of Technology77 Massachusetts Avenue, Cambridge, MA, 02139, USA E-mail: [email protected] Prof. D. G. AndersonDepartment of Chemical EngineeringMassachusetts Institute of Technology77 Massachusetts Avenue, Cambridge, MA, 02139, USA Prof. D. G. AndersonDivision of Health Science TechnologyMassachusetts Institute of Technology77 Massachusetts Avenue, Cambridge, MA, 02139, USA Dr. M. Ma, A. Chiu, Dr. J. C. Doloff, N. Dholakia, R. Thakrar, Dr. A. Vegas, Dr. D. Chen, Dr. T. Dang, Dr. R. L. York, Prof. D. G. AndersonDepartment of AnesthesiologyChildren Hospital Boston300 Longwood Ave, Boston, MA 02115, USA J. Cohen, J. Hollister-Lock, Prof. G. C. Weir, Prof. D. G. AndersonSection on Islet Cell and Regenerative BiologyResearch DivisionJoslin Diabetes CenterOne Joslin Place, Boston, MA 02215, USA Prof. K. M. BratlieDepartments of Materials Science & Engineering and Chemical & Biological EngineeringIowa State University, Ames, IA, 50011 Adv. Healthcare Mater. 2013, 2, 667–672www.MaterialsViews.com© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheimwileyonlinelibrary.com668COMMUNICATIONwww.advhealthmat.de We report here a new type of alginate-based hydrogel micro-capsules with core–shell structures using a two-fl uid co-axial electro-jetting that is compatible with the current alginate-based cell encapsulation protocols. Improved immune-protection was achieved in a single step by simply confi ning the cells or cell aggregates in the core region of the capsules. Both the core–shell structure and better encapsulation were confi rmed by confocal
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