www advhealthmat de www MaterialsViews com COMMUNICATION Core Shell Hydrogel Microcapsules for Improved Islets Encapsulation 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 Hydrogel microcapsules have been extensively investigated for encapsulation of living cells or cell aggregates for tissue engineering 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 therapeutics 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 first blended with a viscous alginate solution The cell suspension is then processed into microdroplets using different methods such as air shear acoustic vibration or electrostatic droplet formation 7 Figure 1a The alginate droplet is gelled upon contact with a solution of 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 Research Massachusetts Institute of Technology 77 Massachusetts Avenue Cambridge MA 02139 USA E mail dgander mit edu Prof D G Anderson Department of Chemical Engineering Massachusetts Institute of Technology 77 Massachusetts Avenue Cambridge MA 02139 USA Prof D G Anderson Division of Health Science Technology Massachusetts Institute of Technology 77 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 Anderson Department of Anesthesiology Children Hospital Boston 300 Longwood Ave Boston MA 02115 USA J Cohen J Hollister Lock Prof G C Weir Prof D G Anderson Section on Islet Cell and Regenerative Biology Research Division Joslin Diabetes Center One Joslin Place Boston MA 02215 USA Prof K M Bratlie Departments of Materials Science Engineering and Chemical Biological Engineering Iowa State University Ames IA 50011 DOI 10 1002 adhm 201200341 Adv Healthcare Mater 2013 2 667 672 divalent ions such as Ca2 or Ba2 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 capsule 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 infiltration of macrophages and fibroblasts into the capsules through the exposed areas 9 Alginate hydrogel microcapsules have been broadly investigated for their utility with pancreatic islets to treat Type I diabetes 10 Numerous promising results have been reported in several animal models including rodents 11 13 dogs 14 and nonhuman primates 15 16 Clinical trials have also been performed by Soon Shiong et al 17 Elliott et al 18 Calafiore 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 control and additional challenges remain to advance these systems 22 24 One challenge is the biocompatibility of the capsules Upon transplantation the foreign body responses cause fibrotic 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 fibrotic 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 transplantation 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 specific cellular immunity and transplant failure A double encapsulation process 18 31 has been used to improve the encapsulation and xenograft survival where very small capsules containing cells were first formed and then several small capsules were enclosed in each larger capsule This approach required two process steps and the large size of the final capsules 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 coatings are sufficiently robust for clinical use 10 34 Previous data 35 has suggested conformal coatings may have reduced immuneprotective capacity compared with the hydrogel capsules 2013 WILEY VCH Verlag GmbH Co KGaA Weinheim wileyonlinelibrary com 667 www advhealthmat de COMMUNICATION www MaterialsViews com Figure 1 Schematic depictions of a a conventional cell encapsulation approach and b the two fluid co axial electro jetting for core shell capsules and cell encapsulation We report here a new type of alginate based hydrogel microcapsules with core shell structures using a two fluid 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 confining the cells or cell aggregates in the core region of the capsules Both the core shell structure and better encapsulation were confirmed by confocal microscopy Using a type I diabetic mouse model we also showed that the core shell capsules encapsulating rat islets provided a significantly better treatment than the currently used regular capsules The composition and thickness of the core and shell can be independently designed and controlled for many types of biomedical applications Figure 1b shows a schematic of the two fluid co axial electro jetting for the fabrication of core shell
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