{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:48:21Z","timestamp":1787028501005,"version":"build-2736575974"},"reference-count":49,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T00:00:00Z","timestamp":1675728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Project P2.02 OAcontrol of the research program of the BioMedical Materials institute","award":["PROG.167\/09-POLOPTEL"],"award-info":[{"award-number":["PROG.167\/09-POLOPTEL"]}]},{"name":"Dutch Ministry of Economic Affairs, Agriculture and Innovation","award":["PROG.167\/09-POLOPTEL"],"award-info":[{"award-number":["PROG.167\/09-POLOPTEL"]}]},{"name":"Fondazione Caripi","award":["PROG.167\/09-POLOPTEL"],"award-info":[{"award-number":["PROG.167\/09-POLOPTEL"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Poly(lactide) (PLA) and poly(ethylene glycol) (PEG)-based hydrogels were prepared by mixing phosphate buffer saline (PBS, pH 7.4) solutions of four-arm (PEG-PLA)2-R-(PLA-PEG)2 enantiomerically pure copolymers having the opposite chirality of the poly(lactide) blocks. Dynamic Light Scattering, rheology measurements, and fluorescence spectroscopy suggested that, depending on the nature of the linker R, the gelation process followed rather different mechanisms. In all cases, mixing of equimolar amounts of the enantiomeric copolymers led to micellar aggregates with a stereocomplexed PLA core and a hydrophilic PEG corona. Yet, when R was an aliphatic heptamethylene unit, temperature-dependent reversible gelation was mainly induced by entanglements of PEG chains at concentrations higher than 5 wt.%. When R was a linker containing cationic amine groups, thermo-irreversible hydrogels were promptly generated at concentrations higher than 20 wt.%. In the latter case, stereocomplexation of the PLA blocks randomly distributed in micellar aggregates is proposed as the major determinant of the gelation process.<\/jats:p>","DOI":"10.3390\/ijms24043327","type":"journal-article","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T03:01:45Z","timestamp":1675825305000},"page":"3327","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Aggregation and Gelation Behavior of Stereocomplexed Four-Arm PLA-PEG Copolymers Containing Neutral or Cationic Linkers"],"prefix":"10.3390","volume":"24","author":[{"given":"Francesca","family":"Signori","sequence":"first","affiliation":[{"name":"Department of Developmental BioEngineering, Faculty of Science and Technology, Tech Med Centre, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands"},{"name":"Consiglio Nazionale delle Ricerche\u2014Istituto per i Processi Chimico-Fisici, CNR-IPCF, Area della Ricerca di Pisa, Via Moruzzi 1, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos W. H.","family":"Wennink","sequence":"additional","affiliation":[{"name":"Department of Developmental BioEngineering, Faculty of Science and Technology, Tech Med Centre, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4832-7569","authenticated-orcid":false,"given":"Simona","family":"Bronco","sequence":"additional","affiliation":[{"name":"Consiglio Nazionale delle Ricerche\u2014Istituto per i Processi Chimico-Fisici, CNR-IPCF, Area della Ricerca di Pisa, Via Moruzzi 1, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Feijen","sequence":"additional","affiliation":[{"name":"Department of Polymer Chemistry and Biomaterials, Faculty of Science and Technology, Tech Med Centre, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0751-0604","authenticated-orcid":false,"given":"Marcel","family":"Karperien","sequence":"additional","affiliation":[{"name":"Department of Developmental BioEngineering, Faculty of Science and Technology, Tech Med Centre, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8222-2672","authenticated-orcid":false,"given":"Ranieri","family":"Bizzarri","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical and Molecular Pathology, and Critical Care Medicine, University of Pisa, Via Roma 65, 56126 Pisa, Italy"},{"name":"NEST, Scuola Normale Superiore and Istituto Nanoscienze-CNR, Piazza San Silvestro 12, 56127 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8455-1093","authenticated-orcid":false,"given":"Pieter J.","family":"Dijkstra","sequence":"additional","affiliation":[{"name":"Department of Developmental BioEngineering, Faculty of Science and Technology, Tech Med Centre, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5969","DOI":"10.1039\/c2cs35115c","article-title":"Self-assembly of block copolymers","volume":"41","author":"Mai","year":"2012","journal-title":"Chem. Soc. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1126\/science.1215368","article-title":"Multiblock Polymers: Panacea or Pandora\u2019s Box?","volume":"336","author":"Bates","year":"2012","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1021\/ma802138r","article-title":"Acid-Sensitive Polymeric Micelles Based on Thermoresponsive Block Copolymers with Pendent Cyclic Orthoester Groups","volume":"42","author":"Huang","year":"2009","journal-title":"Macromolecules"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"10852","DOI":"10.1021\/ja802609r","article-title":"Ion-Sensitive \u201cIsothermal\u201d Responsive Polymers Prepared in Water","volume":"130","author":"Magnusson","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"13151","DOI":"10.1021\/la901835z","article-title":"Photo-Cross-Linkable Polymer Micelles in Hydrogen-Bonding-Built Layer-By-Layer Films","volume":"25","author":"Zhao","year":"2009","journal-title":"Langmuir"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1021\/ma201865s","article-title":"Multicompartment Block Polymer Micelles","volume":"45","author":"Moughton","year":"2011","journal-title":"Macromolecules"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.1002\/pol.20210430","article-title":"Block copolymer solution self-assembly: Recent advances, emerging trends, and applications","volume":"59","author":"Karayianni","year":"2021","journal-title":"J. Polym. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kuperkar, K., Patel, D., Atanase, L.I., and Bahadur, P. (2022). Amphiphilic Block Copolymers: Their Structures, and Self-Assembly to Polymeric Micelles and Polymersomes as Drug Delivery Vehicles. Polymers, 14.","DOI":"10.3390\/polym14214702"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"645","DOI":"10.3389\/fchem.2018.00645","article-title":"Biomolecules Turn Self-Assembling Amphiphilic Block Co-Polymer Platforms into Biomimetic Interfaces","volume":"6","author":"Avsar","year":"2019","journal-title":"Front. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.addr.2012.09.009","article-title":"Novel crosslinking methods to design hydrogels","volume":"64","author":"Hennink","year":"2012","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Bustamante-Torres, M., Romero-Fierro, D., Arcentales-Vera, B., Palomino, K., Maga\u00f1a, H., and Bucio, E. (2021). Hydrogels Classification According to the Physical or Chemical Interactions and as Stimuli-Sensitive Materials. Gels, 7.","DOI":"10.3390\/gels7040182"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/s41392-021-00830-x","article-title":"Current hydrogel advances in physicochemical and biological response-driven biomedical application diversity","volume":"6","author":"Cao","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"S\u00e1nchez-Cid, P., Jim\u00e9nez-Rosado, M., Romero, A., and P\u00e9rez-Puyana, V. (2022). Novel Trends in Hydrogel Development for Biomedical Applications: A Review. Polymers, 14.","DOI":"10.3390\/polym14153023"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.jconrel.2014.03.052","article-title":"Hydrogels in a historical perspective: From simple networks to smart materials","volume":"190","author":"Buwalda","year":"2014","journal-title":"J. Control. Release"},{"key":"ref_15","unstructured":"Hart, D.S., Zhao, Y., and Forrest, M.L. (2020). Handbook of Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications, Jenny Stanford Publishing."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6844","DOI":"10.1021\/acs.chemrev.8b00199","article-title":"Block Copolymer Micelles in Nanomedicine Applications","volume":"118","author":"Cabral","year":"2018","journal-title":"Chem. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3021","DOI":"10.1039\/b701217a","article-title":"Recent advances in shell cross-linked micelles","volume":"38","author":"Read","year":"2007","journal-title":"Chem. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.2174\/1568026616666161222110600","article-title":"Advances in Micelle-Based Drug Delivery: Cross-Linked Systems","volume":"17","author":"Isoglu","year":"2017","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5294","DOI":"10.1021\/ma00119a019","article-title":"Formation of Polyion Complex Micelles in an Aqueous Milieu from a Pair of Oppositely-Charged Block Copolymers with Poly(ethylene glycol) Segments","volume":"28","author":"Harada","year":"1995","journal-title":"Macromolecules"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"13330","DOI":"10.1021\/acs.langmuir.2c02166","article-title":"Polyelectrolyte\u2014Surfactant Complexes As a Formulation Tool for Drug Delivery","volume":"38","author":"Gradzielski","year":"2022","journal-title":"Langmuir ACS J. Surf. Colloids"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1007\/s11051-006-9103-8","article-title":"Enantiomeric PLA-PEG block copolymers and their stereocomplex micelles used as rifampin delivery","volume":"9","author":"Chen","year":"2007","journal-title":"J. Nanoparticle Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Im, S.H., Im, D.H., Park, S.J., Chung, J.J., Jung, Y., and Kim, S.H. (2021). Stereocomplex Polylactide for Drug Delivery and Biomedical Applications: A Review. Molecules, 26.","DOI":"10.3390\/molecules26102846"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1021\/la0623580","article-title":"pH-Controlled, Polymer-Mediated Assembly of Polymer Micelle Nanoparticles","volume":"23","author":"Lee","year":"2006","journal-title":"Langmuir"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1021\/bm901080d","article-title":"Influence of Amide versus Ester Linkages on the Properties of Eight-Armed PEG-PLA Star Block Copolymer Hydrogels","volume":"11","author":"Buwalda","year":"2009","journal-title":"Biomacromolecules"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6699","DOI":"10.1016\/S0032-3861(99)00004-X","article-title":"Stereocomplex formation between enantiomeric poly(lactic acid)s. XI. Mechanical properties and morphology of solution-cast films","volume":"40","author":"Tsuji","year":"1999","journal-title":"Polymer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1080\/15583724.2015.1111380","article-title":"A Mini Review on the Functional Biomaterials Based on Poly(lactic acid) Stereocomplex","volume":"56","author":"Jing","year":"2016","journal-title":"Polym. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3680","DOI":"10.1021\/ma992067g","article-title":"Novel Self-Assembled Hydrogels by Stereocomplex Formation in Aqueous Solution of Enantiomeric Lactic Acid Oligomers Grafted To Dextran","volume":"33","author":"Wahls","year":"2000","journal-title":"Macromolecules"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2790","DOI":"10.1021\/bm060630e","article-title":"In-Situ Formation of Biodegradable Hydrogels by Stereocomplexation of PEG-(PLLA)8 and PEG-(PDLA)8 Star Block Copolymers","volume":"7","author":"Hiemstra","year":"2006","journal-title":"Biomacromolecules"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1002\/1616-5195(20010701)1:5<204::AID-MABI204>3.0.CO;2-H","article-title":"Novel thermo-responsive formation of a hydrogel by stereo-complexation between PLLA-PEG-PLLA and PDLA-PEG-PDLA block copolymers","volume":"1","author":"Fujiwara","year":"2001","journal-title":"Macromol. Biosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8008","DOI":"10.1021\/ma034734i","article-title":"Synthesis, Characterization, and Stereocomplex-Induced Gelation of Block Copolymers Prepared by Ring-Opening Polymerization of l(d)-Lactide in the Presence of Poly(ethylene glycol)","volume":"36","author":"Li","year":"2003","journal-title":"Macromolecules"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"19759","DOI":"10.1039\/D0RA01790F","article-title":"Synthesis and properties of a temperature-sensitive hydrogel based on physical crosslinking via stereocomplexation of PLLA-PDLA","volume":"10","author":"Shi","year":"2020","journal-title":"RSC Adv."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"8502","DOI":"10.1039\/C7SM01491K","article-title":"Stereocomplexed physical hydrogels with high strength and tunable crystallizability","volume":"13","author":"Cao","year":"2017","journal-title":"Soft Matter"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.addr.2016.07.004","article-title":"Poly(lactic acid) based hydrogels","volume":"107","author":"Basu","year":"2016","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/S0168-3659(01)00228-0","article-title":"Physically crosslinked dextran hydrogels by stereocomplex formation of lactic acid oligomers: Degradation and protein release behavior","volume":"71","author":"Bosch","year":"2001","journal-title":"J. Control. Release"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.jconrel.2007.03.014","article-title":"In vitro and in vivo protein delivery from in situ forming poly(ethylene glycol)\u2014poly(lactide) hydrogels","volume":"119","author":"Hiemstra","year":"2007","journal-title":"J. Control. Release"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7255","DOI":"10.1039\/C8SM01559G","article-title":"Impact of stereochemistry on rheology and nanostructure of PLA-PEO-PLA triblocks: Stiff gels at intermediate l\/d-lactide ratios","volume":"14","author":"Yin","year":"2018","journal-title":"Soft Matter"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6471","DOI":"10.1021\/acs.jpcb.5b03610","article-title":"In Situ Formation and Gelation Mechanism of Thermoresponsive Stereocomplexed Hydrogels upon Mixing Diblock and Triblock Poly(Lactic Acid)\/Poly(Ethylene Glycol) Copolymers","volume":"119","author":"Mao","year":"2015","journal-title":"J. Phys. Chem. B"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1039\/C7QM00502D","article-title":"Poly(lactic acid)\/poly(ethylene glycol) stereocomplexed physical hydrogels showing thermally-induced gel-sol-gel multiple phase transitions","volume":"2","author":"Mao","year":"2018","journal-title":"Mater. Chem. Front."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4628","DOI":"10.1039\/C6SM00517A","article-title":"Thermoresponsive physical hydrogels of poly(lactic acid)\/poly(ethylene glycol) stereoblock copolymers tuned by stereostructure and hydrophobic block sequence","volume":"12","author":"Mao","year":"2016","journal-title":"Soft Matter"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.1016\/j.polymer.2012.05.006","article-title":"Stereocomplexed 8-armed poly(ethylene glycol)-poly(lactide) star block copolymer hydrogels: Gelation mechanism, mechanical properties and degradation behavior","volume":"53","author":"Buwalda","year":"2012","journal-title":"Polymer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3857","DOI":"10.1002\/pat.5297","article-title":"Star-shaped copolymers with PLA-PEG arms and their potential applications as biomedical materials","volume":"32","author":"Kubisa","year":"2021","journal-title":"Polym. Adv. Technol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3662","DOI":"10.1021\/acs.macromol.5b00168","article-title":"Effects of Molecular Weight and Its Distribution of PEG Block on Micellization and Thermogellability of PLGA-PEG-PLGA Copolymer Aqueous Solutions","volume":"48","author":"Chen","year":"2015","journal-title":"Macromolecules"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1021\/bm300325v","article-title":"Controlled Thermoresponsive Hydrogels by Stereocomplexed PLA-PEG-PLA Prepared via Hybrid Micelles of Pre-Mixed Copolymers with Different PEG Lengths","volume":"13","author":"Abebe","year":"2012","journal-title":"Biomacromolecules"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1002\/mabi.200300112","article-title":"Hydrogel Formation between Enantiomeric B-A-B-Type Block Copolymers of Polylactides(PLLA or PDLA: A) and Polyoxyethylene(PEG: B); PEG-PLLA-PEG and PEG-PDLA-PEG","volume":"4","author":"Mukose","year":"2004","journal-title":"Macromol. Biosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6894","DOI":"10.1016\/j.polymer.2013.11.007","article-title":"Introducing small cationic groups into 4-armed PLLA-PEG copolymers leads to preferred micellization over thermo-reversible gelation","volume":"54","author":"Wennink","year":"2013","journal-title":"Polymer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1039\/c3cc38071h","article-title":"Imaging the static dielectric constant in vitro and in living cells by a bioconjugable GFP chromophore analog","volume":"49","author":"Signore","year":"2013","journal-title":"Chem. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1016\/j.bpj.2018.02.032","article-title":"Simultaneous Detection of Local Polarizability and Viscosity by a Single Fluorescent Probe in Cells","volume":"114","author":"Abbandonato","year":"2018","journal-title":"Biophys. J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6026","DOI":"10.1063\/1.1784774","article-title":"Solvation dynamics in triton-X-100 and triton-X-165 micelles: Effect of micellar size and hydration","volume":"121","author":"Kumbhakar","year":"2004","journal-title":"J. Chem. Phys."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.cocis.2010.07.007","article-title":"Rheology of associative polymer solutions","volume":"16","author":"Chassenieux","year":"2011","journal-title":"Curr. Opin. Colloid Interface Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3327\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:27:02Z","timestamp":1760120822000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3327"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,7]]},"references-count":49,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24043327"],"URL":"https:\/\/doi.org\/10.3390\/ijms24043327","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,7]]}}}