Hypothyroidism is a common condition of hormone deficiency, and oral administration of thyroid hormones is currently the only available treatment option. However, there are some disadvantages with this treatment modality including compliance challenges to patients. Therefore, a physiologically based alternative therapy for hypothyroidism with little or no side-effects is needed. In this study, we have developed a method for microencapsulating porcine thyroid cells as a thyroid hormone replacement approach. The hybrid wall of the polymer microcapsules permits thyroid hormone release while preventing immunoglobulin antibodies from entry. This strategy could potentially enable implantation of the microcapsule organoids containing allogeneic or xenogeneic thyroid cells to secret hormones over time without the need for immunosuppression of recipients. Porcine thyroid cells were isolated and encapsulated in alginate-poly-L-ornithine-alginate microcapsules using a microfluidic device. The porcine thyroid cells formed three-dimensional follicular spheres in the microcapsules with decent cell viability and proliferation. Thyroxine release from the encapsulated cells was higher than from unencapsulated cells (P < 0.05) and was maintained during the entire duration of experiment (>28 days). These results suggest that the microencapsulated thyroid cell organoids may have the potential to be used for therapy and/or drug screening.
HollowellJGStaehlingNWFlandersWDHannonWHGunterEWSpencerCABravermanLE. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab2002; 87: 489–99.
2.
McLachlanSMRapoportB. Why measure thyroglobulin autoantibodies rather than thyroid peroxidase autoantibodies?Thyroid2004; 14: 510–20.
3.
SantiniFMarzulloPRotondiMCeccariniGPaganoLIppolitoSChiovatoLBiondiB. Mechanisms in endocrinology: the crosstalk between thyroid gland and adipose tissue: signal integration in health and disease. Eur J Endocrinol2014; 171: R137–52.
4.
LimonardEJBisschopPHFliersENieveenVDE. Thyroid function after subtotal thyroidectomy in patients with Graves' hyperthyroidism. Sci World J2012; 2012: 548796–548796.
5.
LilleyJSLomenickJP. Delayed diagnosis of hypothyroidism following excision of a thyroglossal duct cyst. J Pediatr2013; 162: 427–28.
6.
BonatoCSeverinoRFElnecaveRH. Reduced thyroid volume and hypothyroidism in survivors of childhood cancer treated with radiotherapy. J Pediatr Endocrinol Metab2008; 21: 943–49.
7.
ClarkeNKabadiUM. Optimizing treatment of hypothyroidism. Treat Endocrinol2004; 3: 217–21.
8.
KangAParkJJuJJeongGSLeeSH. Cell encapsulation via microtechnologies. Biomaterials2014; 35: 2651–63.
9.
OlabisiRM. Cell microencapsulation with synthetic polymers. J Biomed Mater Res A2015; 103: 846–59.
10.
FortAFortNRicordiCStablerCL. Biohybrid devices and encapsulation technologies for engineering a bioartificial pancreas. Cell Transplant2008; 17: 997–1003.
11.
VaithilingamVKollarikovaGQiMLacikIOberholzerJGuilleminGJTuchBE. Effect of prolonged gelling time on the intrinsic properties of barium alginate microcapsules and its biocompatibility. J Microencapsul2011; 28: 499–507.
12.
ParetaRMcQuillingJPSittadjodySJenkinsRBowdenSOrlandoGFarneyACBreyEMOparaEC. Long-term function of islets encapsulated in a redesigned alginate microcapsule construct in omentum pouches of immune-competent diabetic rats. Pancreas2014; 43: 605–13.
13.
MoskalenkoVUlrichsKKerscherABlindEOttoCHamelmannWDemidchikYTimmS. Preoperative evaluation of microencapsulated human parathyroid tissue aids selection of the optimal bioartificial graft for human parathyroid allotransplantation. Transpl Int2007; 20: 688–96.
14.
PicarielloLBenvenutiSRecentiRFormigliLFalchettiAMorelliAMasiLTonelliFCicchiPBrandiML. Microencapsulation of human parathyroid cells: an “in vitro” study. J Surg Res2001; 96: 81–89.
15.
MeiJSgroiAMaiGBaertschigerRGonelle-GispertCSerre-BeinierVMorelPBuhlerLH. Improved survival of fulminant liver failure by transplantation of microencapsulated cryopreserved porcine hepatocytes in mice. Cell Transplant2009; 18: 101–10.
16.
MachlufMOrsolaABoorjianSKershenRAtalaA. Microencapsulation of Leydig cells: a system for testosterone supplementation. Endocrinology2003; 144: 4975–79.
17.
SittadjodySSaulJMJooSYooJJAtalaAOparaEC. Engineered multilayer ovarian tissue that secretes sex steroids and peptide hormones in response to gonadotropins. Biomaterials2013; 34: 2412–20.
18.
de VosPBuckoMGemeinerPNavratilMSvitelJFaasMStrandBLSkjak-BraekGMorchYAVikartovskaALacikIKollarikovaGOriveGPonceletDPedrazJLAnsorge-SchumacherMB. Multiscale requirements for bioencapsulation in medicine and biotechnology. Biomaterials2009; 30: 2559–70.
19.
TendulkarSMirmalek-SaniSHChildersCSaulJOparaECRamasubramanianMK. A three-dimensional microfluidic approach to scaling up microencapsulation of cells. Biomed Microdevices2012; 14: 461–69.
20.
LinRYKuboAKellerGMDaviesTF. Committing embryonic stem cells to differentiate into thyrocyte-like cells in vitro. Endocrinology2003; 144: 2644–49.
21.
KhannaOMoyaMLOparaECBreyEM. Synthesis of multilayered alginate microcapsules for the sustained release of fibroblast growth factor-1. J Biomed Mater Res A2010; 95: 632–40.
22.
DarrabieMDKendallWJOparaEC. Characteristics of Poly-L-Ornithine-coated alginate microcapsules. Biomaterials2005; 26: 6846–52.
23.
ArufeMCLuMKuboAKellerGDaviesTFLinRY. Directed differentiation of mouse embryonic stem cells into thyroid follicular cells. Endocrinology2006; 147: 3007–15.
24.
ArufeMCLuMLinRY. Differentiation of murine embryonic stem cells to thyrocytes requires insulin and insulin-like growth factor-1. Biochem Biophys Res Commun2009; 381: 264–70.
25.
AntonicaFKasprzykDFOpitzRIacovinoMLiaoXHDumitrescuAMRefetoffSPeremansKMantoMKybaMCostagliolaS. Generation of functional thyroid from embryonic stem cells. Nature2012; 491: 66–71.
26.
BellEMooreHMitchieCSherSCoonH. Reconstruction of a thyroid gland equivalent from cells and matrix materials. J Exp Zool1984; 232: 277–85.
27.
TodaSSugiharaH. Reconstruction of thyroid follicles from isolated porcine follicle cells in three-dimensional collagen gel culture. Endocrinology1990; 126: 2027–34.
28.
TodaSKoikeNSugiharaH. Thyrocyte integration, and thyroid folliculogenesis and tissue regeneration: perspective for thyroid tissue engineering. Pathol Int2001; 51: 403–17.
29.
ArauchiAShimizuTYamatoMObaraTOkanoT. Tissue-engineered thyroid cell sheet rescued hypothyroidism in rat models after receiving total thyroidectomy comparing with nontransplantation models. Tissue Eng Part A2009; 15: 3943–49.
30.
WhitesidesGM. The origins and the future of microfluidics. Nature2006; 442: 368–73.
31.
BeebeDJMensingGAWalkerGM. Physics and applications of microfluidics in biology. Annu Rev Biomed Eng2002; 4: 261–86.
32.
de JongJLammertinkRGWesslingM. Membranes and microfluidics: a review. Lab Chip2006; 6: 1125–39.
33.
LimFSunAM. Microencapsulated islets as bioartificial endocrine pancreas. Science1980; 210: 908–10.
WuTJHuangHHHsuYMLyuSRWangYJ. A novel method of encapsulating and cultivating adherent mammalian cells within collagen microcarriers. Biotechnol Bioeng2007; 98: 578–85.
SakaiSHashimotoITanakaSSalmonsBKawakamiK. Small agarose microcapsules with cell-enclosing hollow core for cell therapy: transplantation of ifosfamide-activating cells to the mice with preestablished subcutaneous tumor. Cell Transplant2009; 18: 933–39.
38.
SakaiSItoSKawakamiK. Calcium alginate microcapsules with spherical liquid cores templated by gelatin microparticles for mass production of multicellular spheroids. Acta Biomater2010; 6: 3132–37.
39.
OhMJRyuTKChoiSW. Hollow polydimethylsiloxane beads with a porous structure for cell encapsulation. Macromol Rapid Commun2013; 34: 1728–33.
40.
SakaiSKawakamiK. Both ionically and enzymatically crosslinkable alginate-tyramine conjugate as materials for cell encapsulation. J Biomed Mater Res A2008; 85: 345–51.
41.
SantosEZarateJOriveGHernandezRMPedrazJL. Biomaterials in cell microencapsulation. Adv Exp Med Biol2010; 670: 5–21.
LeeKYMooneyDJ. Hydrogels for tissue engineering. Chem Rev2001; 101: 1869–79.
44.
WestERXuMWoodruffTKSheaLD. Physical properties of alginate hydrogels and their effects on in vitro follicle development. Biomaterials2007; 28: 4439–48.
45.
StablerCLSambanisAConstantinidisI. Effects of alginate composition on the growth and overall metabolic activity of betaTC3 cells. Ann N Y Acad Sci2002; 961: 130–33.
46.
YeZMahatoRI. Emerging trends in cell-based therapies. Preface. Adv Drug Deliv Rev2008; 60: 89–90.
47.
OriveGTamSKPedrazJLHalleJP. Biocompatibility of alginate-poly-L-lysine microcapsules for cell therapy. Biomaterials2006; 27: 3691–700.
48.
CoatesEERigginCNFisherJP. Matrix molecule influence on chondrocyte phenotype and proteoglycan 4 expression by alginate-embedded zonal chondrocytes and mesenchymal stem cells. J Orthop Res2012; 30: 1886–97.
49.
TamSKBilodeauSDusseaultJLangloisGHalleJPYahiaLH. Biocompatibility and physicochemical characteristics of alginate-polycation microcapsules. Acta Biomater2011; 7: 1683–92.
50.
LissitzkySFayetGGiraudAVerrierBTorresaniJ. Thyrotrophin-induced aggregation and reorganization into follicles of isolated porcine-thyroid cells. 1. Mechanism of action of thyrotrophin and metabolic properties. Eur J Biochem1971; 24: 88–99.
51.
WilliamsDWWynford-ThomasD. Human thyroid epithelial cells. Methods Mol Biol1997; 75: 163–72.
