[en] Application of alginate-microencapsulated therapeutic cells is a promising approach for diseases that require a local and constant supply of therapeutic molecules. However most conventional alginate microencapsulation systems are associated with low mechanical stability and protrusion of cells which is associated with higher surface roughness and limits their clinical application. Here we have developed a novel multilayer encapsulation system that prevents cells from protruding from capsules. The system was tested using a therapeutic protein with anti-tumor activity overexpressed in mammalian cells. The cell containing core of the multilayer capsule was formed by flexible alginate, creating a cell sustaining environment. Surrounded by a poly-L-lysine layer the flexible core was enveloped in a high-G alginate matrix that is less flexible and has higher mechanical stability, which does not support cell survival. The cells in the core of the multilayer capsule did not show growth impairment and protein production was normal for periods up to 70 days in vitro. The additional alginate layer also lowered the surface roughness compared to conventional cell containing alginate-PLL capsules. Our system provides a solution for two important, often overlooked phenomena in cell encapsulation: preventing cell protrusion and improving surface roughness.
Disciplines :
Oncology
Author, co-author :
Bhujbal, Swapnil V; 1] Department of Pathology and Medical Biology, Immunoendocrinology, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands [2] NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg.
de Haan, Bart; Department of Pathology and Medical Biology, Immunoendocrinology, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands.
NICLOU, Simone P. ; NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg.
de Vos, Paul; Department of Pathology and Medical Biology, Immunoendocrinology, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands.
External co-authors :
yes
Language :
English
Title :
A novel multilayer immunoisolating encapsulation system overcoming protrusion of cells.
De Vos, P., Faas, M. M., Strand, B. & Calafiore, R. Alginate-based microcapsules for immunoisolation of pancreatic islets. Biomaterials 27, 5603-5617 (2006).
Kulseng, B., Thu, B., Espevik, T., Skjak-Braek, G. & Skjåk-Braek, G. Alginate polylysine microcapsules as immune barrier: permeability of cytokines and immunoglobulins over the capsule membrane. Cell Transplant. 6, 387-394 (1997).
Jacobs-Tulleneers-Thevissen, D. et al. Sustained function of alginate-encapsulated human islet cell implants in the peritoneal cavity of mice leading to a pilot study in a type 1 diabetic patient. Diabetologia 56, 1605-14 (2013).
Jo K. Utvik & Simone, P. Niclou. in Bioartifical Pancreas other Biohybrid Ther. (Hallé, J.-P., Vos, P. De & Rosenberg, L.) 607-613 (Transworld Research Network, 2009).
Garcia, P. et al. Ciliary neurotrophic factor cell-based delivery prevents synaptic impairment and improves memory in mouse models of Alzheimer's disease. J. Neurosci. 30, 7516-7527 (2010).
Emerich, D. F. & Salzberg, H. C. Update on immunoisolation cell therapy for CNS diseases. Cell Transplant. 10, 3-24 (2001).
Emerich, D. F. et al. Protective effect of encapsulated cells producing neurotrophic factor CNTF in a monkey model of Huntington's disease. Nature 386, 395-399 (1997).
Read, T. A. et al. Local endostatin treatment of gliomas administered by microencapsulated producer cells. Nat. Biotechnol. 19, 29-34 (2001).
Johansson, M. et al. The soluble form of the tumor suppressor Lrig1 potently inhibits in vivo glioma growth irrespective of EGF receptor status. Neuro. Oncol. 15, 1200-11 (2013).
Lohr, M. et al. Microencapsulated cell-mediated treatment of inoperable pancreatic carcinoma. Lancet 357, 1591-1592 (2001).
Zimmermann, U. C., Jork, H., Thürmer, A., Zimmermann, F., Fuhr, H., Hasse, G. & Rothmund, C. M. in Biotechnol. Spec. Process. (H.J. Rehm, G. R.) 547-571 (Wiley-VCH Verlag GmbH, 2008).
Prüsse, U. et al. Comparison of different technologies for alginate beads production. Chem. Pap. 62, 364-374 (2008).
Bhujbal, S. V., de Vos, P. & Niclou, S. P. Drug and Cell Encapsulation: Alternative Delivery Options for the Treatment of Malignant Brain Tumors. Adv. Drug Deliv. Rev. 67-68, 142-53 (2014).
Terzis, A. J. A., Niclou, S. P., Rajcevic, U., Danzeisen, C. & Bjerkvig, R. Cell therapies for glioblastoma. Expert Opin. Biol. Ther. 6, 739-49 (2006).
De Haan, B. J., Faas, M. M. & de Vos, P. Factors influencing insulin secretion from encapsulated islets. Cell Transplant. 12, 617-25 (2003).
Uludag, H., De Vos, P. & Tresco, P. A. Technology of mammalian cell encapsulation. Adv. Drug Deliv. Rev. 42, 29-64 (2000).
De Vos, P., Lazarjani, H. A., Poncelet, D. & Faas, M. M. Polymers in cell encapsulation from an enveloped cell perspective. Adv. Drug Deliv. Rev. (2013).
Stabler, C., Wilks, K., Sambanis, A. & Constantinidis, I. The effects of alginate composition on encapsulated betaTC3 cells. Biomaterials 22, 1301-10 (2001).
Bhujbal, S. V., Paredes-Juarez, G. A., Niclou, S. P. & de Vos, P. Factors influencing the mechanical stability of alginate beads applicable for immunoisolation of mammalian cells. J. Mech. Behav. Biomed. Mater. 37C, 196-208 (2014).
Joki, T. et al. Continuous release of endostatin from microencapsulated engineered cells for tumor therapy. Nat. Biotechnol. 19, 35-9 (2001).
Bunger, C. M. et al. Biocompatibility and surface structure of chemically modified immunoisolating alginate-PLL capsules. J. Biomed. Mater. Res. A 67, 1219-1227 (2003).
Orr, A. W., Helmke, B. P., Blackman, B. R. & Schwartz, M. A. Mechanisms of mechanotransduction. Dev. Cell 10, 11-20 (2006).
García, J. R. & García, A. J. Cellular mechanotransduction: Sensing rigidity. Nat. Mater. 13, 539-40 (2014).
Huselstein, C. et al. Influence of mechanical stress on cell viability. Biorheology 43, 371-5 (2006).
Constantinidis, I., Rask, I., Long, R. C. & Sambanis, A. Effects of alginate composition on the metabolic, secretory, and growth characteristics of entrapped beta TC3 mouse insulinoma cells. Biomaterials 20, 2019-27 (1999).
Haug, A. & Smidsrød, O. Selectivity of Some Anionic Polymers for Divalent Metal Ions. Acta Chem. Scand 3, 843-854 (1970).
Mørch, Y. A., Donati, I., Strand, B. L. & Skjak-Braek, G. Effect of Ca2+, Ba2+, and Sr2+ on alginate microbeads. Biomacromolecules 7, 1471-1480 (2006).
Chan, E.-S. et al. Effect of formulation of alginate beads on their mechanical behavior and stiffness. Particuology 9, 228-234 (2011).
Goldmann, W. H. Mechanotransduction in cells. Cell Biol. Int. 36, 567-70 (2012).
Ross, T. D. et al. Integrins in mechanotransduction. Curr. Opin. Cell Biol. 25, 613-8 (2013).
Puklin-Faucher, E. & Sheetz, M. P. The mechanical integrin cycle. J. Cell Sci. 122, 179-86 (2009).
Matthews, B. D., Overby, D. R., Mannix, R. & Ingber, D. E. Cellular adaptation to mechanical stress: role of integrins, Rho, cytoskeletal tension and mechanosensitive ion channels. J. Cell Sci. 119, 508-18 (2006).
Huang, X. et al. Matrix stiffness in three-dimensional systems effects on the behavior of C3A cells. Artif. Organs 37, 166-74 (2013).
Tam, S. K. et al. Biocompatibility and physicochemical characteristics of alginatepolycation microcapsules. Acta Biomater. 7, 1683-92 (2011).
Vos, P. De. et al Effect of the alginate composition on the biocompatibility of alginate-polylysine microcapsules. Biomaterials 18, 273-278 (1997).
Tam, S. K. et al. Factors influencing alginate gel biocompatibility. J. Biomed. Mater. Res. A 98, 40-52 (2011).
De Vos, P. et al. Multiscale requirements for bioencapsulation in medicine and biotechnology. Biomaterials 30, 2559-70 (2009).
De Vos, P., de Haan, B. J., Kamps, J. A. A. M., Faas, M. M. & Kitano, T. Zetapotentials of alginate-PLL capsules: a predictive measure for biocompatibility? J. Biomed. Mater. Res. A 80, 813-9 (2007).
De Vos, P., Hoogmoed, C. G. & Busscher, H. J. Chemistry and biocompatibility of alginate-PLL capsules for immunoprotection of mammalian cells. J. Biomed. Mater. Res. 60, 252-9 (2002).
De Vos, P., van Hoogmoed, C. G., de Haan, B. J. & Busscher, H. J. Tissue responses against immunoisolating alginate-PLL capsules in the immediate posttransplant period. J. Biomed. Mater. Res. 62, 430-437 (2002).
Strand, B. L. et al. Alginate-polylysine-alginate microcapsules: effect of size reduction on capsule properties. J. Microencapsul. 19, 615-630 (2002).
Strand, B. L. et al. Poly-L-Lysine induces fibrosis on alginate microcapsules via the induction of cytokines. Cell Transplant. 10, 263-275 (2001).
Juste, S., Lessard, M., Henley, N., Ménard, M. & Hallé, J.-P. Effect of poly-L-lysine coating on macrophage activation by alginate-based microcapsules: assessment using a new in vitro method. J. Biomed. Mater. Res. A 72, 389-98 (2005).
Vandenbossche, G. M. et al. Host reaction against empty alginate-polylysine microcapsules. Influence of preparation procedure. J. Pharm. Pharmacol. 45, 115-120 (1993).
Zhao, W. et al. Oxygen diffusivity in alginate/chitosan microcapsules. J. Chem. Technol. Biotechnol. 88, 449-455 (2013).
Kuijlen, J. M. et al. The efficacy of alginate encapsulated CHO-K1 single chain-TRAIL producer cells in the treatment of brain tumors. J. Neurooncol. 78, 31-39 (2006).
De Vos, P., Spasojevic, M., de Haan, B. J. & Faas, M. M. The association between in vivo physicochemical changes and inflammatory responses against alginate based microcapsules. Biomaterials 33, 5552-9 (2012).
Thu, B. et al. Inhomogeneous alginate gel spheres: an assessment of the polymer gradients by synchrotron radiation-induced X-ray emission, magnetic resonance microimaging, and mathematical modeling. Biopolymers 53, 60-71 (2000).
Thu, B., Skjåk-Bræk, G., Micali, F., Vittur, F. & Rizzo, R. The spatial distribution of calcium in alginate gel beads analysed by synchrotron-radiation induced X-ray emission (SRIXE). Carbohydr. Res. 297, 101-105 (1997).
Machida-Sano, I. et al. Surface characteristics determining the cell compatibility of ionically cross-linked alginate gels. Biomed. Mater. 9, 025007 (2014).
Lekka, M., Sainz-Serp, D., Kulik, A. J. & Wandrey, C. Hydrogel microspheres: influence of chemical composition on surface morphology, local elastic properties, and bulk mechanical characteristics. Langmuir 20, 9968-77 (2004).
De Vos, P., De Haan, B., Pater, J. & Van Schilfgaarde, R. Association between capsule diameter, adequacy of encapsulation, and survival of microencapsulated rat islet allografts. Transplantation 62, 893-899 (1996).
De Vos, P., De Haan, B. J., Wolters, G. H., Strubbe, J. H. & Van Schilfgaarde, R. Improved biocompatibility but limited graft survival after purification of alginate for microencapsulation of pancreatic islets. Diabetologia 40, 262-270 (1997).
Zimmermann, H. et al. Physical and biological properties of barium cross-linked alginate membranes. Biomaterials 28, 1327-45 (2007).
Albrecht, K., Christian, S., Jörg, B., Birgit, K. & Jörg, K. in Acoust. Imaging (Maev, R. G.) 223-229 (Plenum Publishers, New York, 2002). doi:10.1007/978-1-4419-8606-1-29.
Wang, C. X., Cowen, C., Zhang, Z. & Thomas, C. R. High-speed compression of single alginate microspheres. Chem. Eng. Sci. 60, 6649-6657 (2005).
De Vos, P., De Haan, B. J. & Van Schilfgaarde, R. Upscaling the production of microencapsulated pancreatic islets. Biomaterials 18, 1085-90 (1997).
Van Schilfgaarde, R. & de Vos, P. Factors influencing the properties and performance of microcapsules for immunoprotection of pancreatic islets. J. Mol. Med. (Berl). 77, 199-205 (1999).
Siedlecki, C. A. & Marchant, R. E. Atomic force microscopy for characterization of the biomaterial interface. Biomaterials 19, 441-54 (1998).