Pericapsular fibrotic overgrowth mitigated in immunocompetent mice through microbead formulations based on sulfated or intermediate G alginates
[Display omitted] Cell encapsulation in alginate microbeads is a promising approach to provide immune isolation in cell therapy without immunosuppression. However, the efficacy is hampered by pericapsular fibrotic overgrowth (PFO), causing encapsulated cells to lose function. Stability of the microb...
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| Veröffentlicht in: | Acta biomaterialia 2022-01, Vol.137, p.172-185 |
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| creator | Coron, Abba E. Kjesbu, Joachim S. Kjærnsmo, Fredrikke Oberholzer, José Rokstad, Anne Mari A. Strand, Berit L. |
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Cell encapsulation in alginate microbeads is a promising approach to provide immune isolation in cell therapy without immunosuppression. However, the efficacy is hampered by pericapsular fibrotic overgrowth (PFO), causing encapsulated cells to lose function. Stability of the microbeads is important to maintain immune isolation in the long-term. Here, we report alginate microbeads with minimal PFO in immunocompetent C57BL/6JRj mice. Microbead formulations included either alginate with an intermediate (47 %) guluronate (G) content (IntG) or sulfated alginate (SA), gelled in Ca2+/Ba2+ or Sr2+. A screening panel of eleven microbead formulations were evaluated for PFO, yielding multiple promising microbeads. Two candidate formulations were evaluated for 112 days in vivo, exhibiting maintained stability and minimal PFO. Microbeads investigated in a human whole blood assay revealed low cytokine and complement responses, while SA microbeads activated coagulation. Protein deposition on microbeads explanted from mice investigated by confocal laser scanning microscopy (CLSM) showed minimal deposition of complement C3. Fibrinogen was positively associated with PFO, with a high deposition on microbeads of high G (68 %) alginate compared to IntG and SA microbeads. Overall, stable microbeads containing IntG or SA may serve in long-term therapeutic applications of cell encapsulation.
Alginate-based hydrogels in the format of micrometer size beads is a promising approach for the immunoisolation of cells in cell therapy. Clinical trials in type 1 diabetes have so far had limited success due to fibrotic responses that hinder the diffusion of nutrients and oxygen to the encapsulated cells, resulting in graft failure. In this study, minimal fibrotic response towards micrometer size alginate beads was achieved by chemical modification of alginate with sulfate groups. Also, the use of alginate with intermediate guluronic acid content resulted in minimally fibrotic microbeads. Fibrinogen deposition was revealed to be a good indicator of fibrosis. This study points to both new microsphere developments and novel insight in the mechanisms behind the fibrotic responses. |
| doi_str_mv | 10.1016/j.actbio.2021.10.004 |
| format | Article |
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Cell encapsulation in alginate microbeads is a promising approach to provide immune isolation in cell therapy without immunosuppression. However, the efficacy is hampered by pericapsular fibrotic overgrowth (PFO), causing encapsulated cells to lose function. Stability of the microbeads is important to maintain immune isolation in the long-term. Here, we report alginate microbeads with minimal PFO in immunocompetent C57BL/6JRj mice. Microbead formulations included either alginate with an intermediate (47 %) guluronate (G) content (IntG) or sulfated alginate (SA), gelled in Ca2+/Ba2+ or Sr2+. A screening panel of eleven microbead formulations were evaluated for PFO, yielding multiple promising microbeads. Two candidate formulations were evaluated for 112 days in vivo, exhibiting maintained stability and minimal PFO. Microbeads investigated in a human whole blood assay revealed low cytokine and complement responses, while SA microbeads activated coagulation. Protein deposition on microbeads explanted from mice investigated by confocal laser scanning microscopy (CLSM) showed minimal deposition of complement C3. Fibrinogen was positively associated with PFO, with a high deposition on microbeads of high G (68 %) alginate compared to IntG and SA microbeads. Overall, stable microbeads containing IntG or SA may serve in long-term therapeutic applications of cell encapsulation.
Alginate-based hydrogels in the format of micrometer size beads is a promising approach for the immunoisolation of cells in cell therapy. Clinical trials in type 1 diabetes have so far had limited success due to fibrotic responses that hinder the diffusion of nutrients and oxygen to the encapsulated cells, resulting in graft failure. In this study, minimal fibrotic response towards micrometer size alginate beads was achieved by chemical modification of alginate with sulfate groups. Also, the use of alginate with intermediate guluronic acid content resulted in minimally fibrotic microbeads. Fibrinogen deposition was revealed to be a good indicator of fibrosis. This study points to both new microsphere developments and novel insight in the mechanisms behind the fibrotic responses.</description><identifier>ISSN: 1742-7061</identifier><identifier>EISSN: 1878-7568</identifier><identifier>DOI: 10.1016/j.actbio.2021.10.004</identifier><identifier>PMID: 34634509</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Alginate ; Alginates ; Alginates - pharmacology ; Alginic acid ; Animals ; Biocompatibility ; Calcium alginate ; Calcium ions ; Cell therapy ; Coagulation ; Complement component C3 ; Confocal microscopy ; Cytokines ; Deposition ; Encapsulation ; Fibrinogen ; Fibrosis ; Glucuronic Acid ; Hexuronic Acids ; Immunocompetence ; Immunosuppression ; In vivo methods and tests ; Mice ; Mice, Inbred C57BL ; Microbeads ; Microspheres ; Nanoparticles ; Scanning microscopy ; Stability analysis ; Sulfates ; Therapeutic applications</subject><ispartof>Acta biomaterialia, 2022-01, Vol.137, p.172-185</ispartof><rights>2021</rights><rights>Copyright © 2021. Published by Elsevier Ltd.</rights><rights>Copyright Elsevier BV Jan 1, 2022</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c305t-665c5f8aff18dfa3a9c1df8cf641f8e5778c82ebfd4891e2dc290048bf876ac33</citedby><cites>FETCH-LOGICAL-c305t-665c5f8aff18dfa3a9c1df8cf641f8e5778c82ebfd4891e2dc290048bf876ac33</cites><orcidid>0000-0002-9951-0355</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.actbio.2021.10.004$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34634509$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Coron, Abba E.</creatorcontrib><creatorcontrib>Kjesbu, Joachim S.</creatorcontrib><creatorcontrib>Kjærnsmo, Fredrikke</creatorcontrib><creatorcontrib>Oberholzer, José</creatorcontrib><creatorcontrib>Rokstad, Anne Mari A.</creatorcontrib><creatorcontrib>Strand, Berit L.</creatorcontrib><title>Pericapsular fibrotic overgrowth mitigated in immunocompetent mice through microbead formulations based on sulfated or intermediate G alginates</title><title>Acta biomaterialia</title><addtitle>Acta Biomater</addtitle><description>[Display omitted]
Cell encapsulation in alginate microbeads is a promising approach to provide immune isolation in cell therapy without immunosuppression. However, the efficacy is hampered by pericapsular fibrotic overgrowth (PFO), causing encapsulated cells to lose function. Stability of the microbeads is important to maintain immune isolation in the long-term. Here, we report alginate microbeads with minimal PFO in immunocompetent C57BL/6JRj mice. Microbead formulations included either alginate with an intermediate (47 %) guluronate (G) content (IntG) or sulfated alginate (SA), gelled in Ca2+/Ba2+ or Sr2+. A screening panel of eleven microbead formulations were evaluated for PFO, yielding multiple promising microbeads. Two candidate formulations were evaluated for 112 days in vivo, exhibiting maintained stability and minimal PFO. Microbeads investigated in a human whole blood assay revealed low cytokine and complement responses, while SA microbeads activated coagulation. Protein deposition on microbeads explanted from mice investigated by confocal laser scanning microscopy (CLSM) showed minimal deposition of complement C3. Fibrinogen was positively associated with PFO, with a high deposition on microbeads of high G (68 %) alginate compared to IntG and SA microbeads. Overall, stable microbeads containing IntG or SA may serve in long-term therapeutic applications of cell encapsulation.
Alginate-based hydrogels in the format of micrometer size beads is a promising approach for the immunoisolation of cells in cell therapy. Clinical trials in type 1 diabetes have so far had limited success due to fibrotic responses that hinder the diffusion of nutrients and oxygen to the encapsulated cells, resulting in graft failure. In this study, minimal fibrotic response towards micrometer size alginate beads was achieved by chemical modification of alginate with sulfate groups. Also, the use of alginate with intermediate guluronic acid content resulted in minimally fibrotic microbeads. Fibrinogen deposition was revealed to be a good indicator of fibrosis. This study points to both new microsphere developments and novel insight in the mechanisms behind the fibrotic responses.</description><subject>Alginate</subject><subject>Alginates</subject><subject>Alginates - pharmacology</subject><subject>Alginic acid</subject><subject>Animals</subject><subject>Biocompatibility</subject><subject>Calcium alginate</subject><subject>Calcium ions</subject><subject>Cell therapy</subject><subject>Coagulation</subject><subject>Complement component C3</subject><subject>Confocal microscopy</subject><subject>Cytokines</subject><subject>Deposition</subject><subject>Encapsulation</subject><subject>Fibrinogen</subject><subject>Fibrosis</subject><subject>Glucuronic Acid</subject><subject>Hexuronic Acids</subject><subject>Immunocompetence</subject><subject>Immunosuppression</subject><subject>In vivo methods and tests</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Microbeads</subject><subject>Microspheres</subject><subject>Nanoparticles</subject><subject>Scanning microscopy</subject><subject>Stability analysis</subject><subject>Sulfates</subject><subject>Therapeutic applications</subject><issn>1742-7061</issn><issn>1878-7568</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc2OFSEQhYnROD_6BsaQuHHTV6Bpmt6YmImOJpPoQteEpos73HTDFegxPoWvbPXc0YULV1SKr05VziHkBWc7zrh6c9hZV8eQdoIJjq0dY_IROee6103fKf0Y616KpmeKn5GLUg6MtZoL_ZSctVK1smPDOfn1BXJw9ljW2Wbqw5hTDY6mO8j7nH7UW7qEGva2wkRDpGFZ1phcWo5QIVb8dEDrbU7rfiNdTiPYifqUFxSsIcVCR1twOEWKO_y9UMqoVSEvMAVs0Gtq532IWJZn5Im3c4HnD-8l-fbh_derj83N5-tPV-9uGteyrjZKda7z2nrP9eRtawfHJ6-dV5J7DV3fa6cFjH6SeuAgJicG9EePXvfKura9JK9Pusecvq9QqllCcTDPNkJaixHdZhUXakD01T_oIa054nVGKCEH3Q29REqeKPSglAzeHHNYbP5pODNbYOZgToGZLbCtiwfh2MsH8XVEO_4O_UkIgbcnANCNuwDZFBcgOrQug6tmSuH_G34DJ8Gs5g</recordid><startdate>20220101</startdate><enddate>20220101</enddate><creator>Coron, Abba E.</creator><creator>Kjesbu, Joachim S.</creator><creator>Kjærnsmo, Fredrikke</creator><creator>Oberholzer, José</creator><creator>Rokstad, Anne Mari A.</creator><creator>Strand, Berit L.</creator><general>Elsevier Ltd</general><general>Elsevier BV</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QF</scope><scope>7QO</scope><scope>7QQ</scope><scope>7SC</scope><scope>7SE</scope><scope>7SP</scope><scope>7SR</scope><scope>7T7</scope><scope>7TA</scope><scope>7TB</scope><scope>7U5</scope><scope>8BQ</scope><scope>8FD</scope><scope>C1K</scope><scope>F28</scope><scope>FR3</scope><scope>H8D</scope><scope>H8G</scope><scope>JG9</scope><scope>JQ2</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>P64</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-9951-0355</orcidid></search><sort><creationdate>20220101</creationdate><title>Pericapsular fibrotic overgrowth mitigated in immunocompetent mice through microbead formulations based on sulfated or intermediate G alginates</title><author>Coron, Abba E. ; 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Cell encapsulation in alginate microbeads is a promising approach to provide immune isolation in cell therapy without immunosuppression. However, the efficacy is hampered by pericapsular fibrotic overgrowth (PFO), causing encapsulated cells to lose function. Stability of the microbeads is important to maintain immune isolation in the long-term. Here, we report alginate microbeads with minimal PFO in immunocompetent C57BL/6JRj mice. Microbead formulations included either alginate with an intermediate (47 %) guluronate (G) content (IntG) or sulfated alginate (SA), gelled in Ca2+/Ba2+ or Sr2+. A screening panel of eleven microbead formulations were evaluated for PFO, yielding multiple promising microbeads. Two candidate formulations were evaluated for 112 days in vivo, exhibiting maintained stability and minimal PFO. Microbeads investigated in a human whole blood assay revealed low cytokine and complement responses, while SA microbeads activated coagulation. Protein deposition on microbeads explanted from mice investigated by confocal laser scanning microscopy (CLSM) showed minimal deposition of complement C3. Fibrinogen was positively associated with PFO, with a high deposition on microbeads of high G (68 %) alginate compared to IntG and SA microbeads. Overall, stable microbeads containing IntG or SA may serve in long-term therapeutic applications of cell encapsulation.
Alginate-based hydrogels in the format of micrometer size beads is a promising approach for the immunoisolation of cells in cell therapy. Clinical trials in type 1 diabetes have so far had limited success due to fibrotic responses that hinder the diffusion of nutrients and oxygen to the encapsulated cells, resulting in graft failure. In this study, minimal fibrotic response towards micrometer size alginate beads was achieved by chemical modification of alginate with sulfate groups. Also, the use of alginate with intermediate guluronic acid content resulted in minimally fibrotic microbeads. Fibrinogen deposition was revealed to be a good indicator of fibrosis. This study points to both new microsphere developments and novel insight in the mechanisms behind the fibrotic responses.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>34634509</pmid><doi>10.1016/j.actbio.2021.10.004</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-9951-0355</orcidid></addata></record> |
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| ispartof | Acta biomaterialia, 2022-01, Vol.137, p.172-185 |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Alginate Alginates Alginates - pharmacology Alginic acid Animals Biocompatibility Calcium alginate Calcium ions Cell therapy Coagulation Complement component C3 Confocal microscopy Cytokines Deposition Encapsulation Fibrinogen Fibrosis Glucuronic Acid Hexuronic Acids Immunocompetence Immunosuppression In vivo methods and tests Mice Mice, Inbred C57BL Microbeads Microspheres Nanoparticles Scanning microscopy Stability analysis Sulfates Therapeutic applications |
| title | Pericapsular fibrotic overgrowth mitigated in immunocompetent mice through microbead formulations based on sulfated or intermediate G alginates |
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