{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:28:11Z","timestamp":1792171691490,"version":"4.4.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T00:00:00Z","timestamp":1614211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000199","name":"U.S. Department of Agriculture","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000199","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013141","name":"Virginia Agricultural Experiment Station, Virginia Polytechnic Institute and State University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013141","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014523","name":"Institute for Critical Technology and Applied Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014523","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:p>3D-printed bone scaffolds hold great promise for the individualized treatment of critical-size bone defects. Among the resorbable polymers available for use as 3D-printable scaffold materials, poly(\u03b5-caprolactone) (PCL) has many benefits. However, its relatively low stiffness and lack of bioactivity limit its use in load-bearing bone scaffolds. This study tests the hypothesis that surface-oxidized cellulose nanocrystals (SO-CNCs), decorated with carboxyl groups, can act as multi-functional scaffold additives that (1) improve the mechanical properties of PCL and (2) induce biomineral formation upon PCL resorption. To this end, an <jats:italic>in vitro<\/jats:italic> biomineralization study was performed to assess the ability of SO-CNCs to induce the formation of calcium phosphate minerals. In addition, PCL nanocomposites containing different amounts of SO-CNCs (1, 2, 3, 5, and 10 wt%) were prepared using melt compounding extrusion and characterized in terms of Young's modulus, ultimate tensile strength, crystallinity, thermal transitions, and water contact angle. Neither sulfuric acid-hydrolyzed CNCs (SH-CNCs) nor SO-CNCs were toxic to MC3T3 preosteoblasts during a 24 h exposure at concentrations ranging from 0.25 to 3.0 mg\/mL. SO-CNCs were more effective at inducing mineral formation than SH-CNCs in simulated body fluid (1x). An SO-CNC content of 10 wt% in the PCL matrix caused a more than 2-fold increase in Young's modulus (stiffness) and a more than 60% increase in ultimate tensile strength. The matrix glass transition and melting temperatures were not affected by the SO-CNCs but the crystallization temperature increased by about 5.5\u00b0C upon addition of 10 wt% SO-CNCs, the matrix crystallinity decreased from about 43 to about 40%, and the water contact angle decreased from 87 to 82.6\u00b0. The abilities of SO-CNCs to induce calcium phosphate mineral formation and increase the Young's modulus of PCL render them attractive for applications as multi-functional nanoscale additives in PCL-based bone scaffolds.<\/jats:p>","DOI":"10.3389\/fbioe.2021.605924","type":"journal-article","created":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T09:09:59Z","timestamp":1614244199000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":36,"title":["Bioactive Cellulose Nanocrystal-Poly(\u03b5-Caprolactone) Nanocomposites for Bone Tissue Engineering Applications"],"prefix":"10.3389","volume":"9","author":[{"given":"Jung Ki","family":"Hong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelley L.","family":"Cooke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abby R.","family":"Whittington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maren","family":"Roman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1021\/la001070m","article-title":"Steric stabilization of a cellulose microcrystal suspension by poly(ethylene glycol) grafting","volume":"17","author":"Araki","year":"2001","journal-title":"Langmuir"},{"key":"B2","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1089\/107632700418083","article-title":"Fundamentals of biomechanics in tissue engineering of bone","volume":"6","author":"Athanasiou","year":"2000","journal-title":"Tissue Eng."},{"key":"B3","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1016\/j.jcis.2005.01.095","article-title":"Roughness and hydrophobicity studies of nanofiltration membranes using different modes of AFM","volume":"286","author":"Boussu","year":"2005","journal-title":"J. Colloid Interface Sci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1002\/mame.200800261","article-title":"A novel thermoformable bionanocomposite based on cellulose nanocrystal-graft-poly(epsilon-caprolactone)","volume":"294","author":"Chen","year":"2009","journal-title":"Macromol. Mater. Eng."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2613","DOI":"10.1063\/1.121434","article-title":"Energy dissipation in tapping-mode atomic force microscopy","volume":"72","author":"Cleveland","year":"1998","journal-title":"Appl. Phys. Lett."},{"key":"B6","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1038\/nmat2911","article-title":"Biomineralization a crystal-clear view","volume":"9","author":"Colfen","year":"2010","journal-title":"Nat. Mater."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0304-3991(98)00024-2","article-title":"Direct visualization of surface charge in aqueous solution","volume":"74","author":"Czajkowsky","year":"1998","journal-title":"Ultramicroscopy"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1038\/nmat2900","article-title":"The role of prenucleation clusters in surface-induced calcium phosphate crystallization","volume":"9","author":"Dey","year":"2010","journal-title":"Nat. Mater."},{"key":"B9","doi-asserted-by":"publisher","first-page":"8893","DOI":"10.1016\/j.polymer.2004.10.037","article-title":"Isothermal crystallization in PCL\/clay nanocomposites investigated with thermal and rheometric methods","volume":"45","author":"Di Maio","year":"2004","journal-title":"Polymer"},{"key":"B10","doi-asserted-by":"publisher","first-page":"2327","DOI":"10.1021\/bm500524s","article-title":"The potential of cellulose nanocrystals in tissue engineering strategies","volume":"15","author":"Domingues","year":"2014","journal-title":"Biomacromolecules"},{"key":"B11","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1139\/v07-152","article-title":"Polysaccharide nano crystal reinforced nanocomposites","volume":"86","author":"Dufresne","year":"2008","journal-title":"Can. J. Chem. Rev. Can. Chim."},{"key":"B12","doi-asserted-by":"publisher","first-page":"5224","DOI":"10.1021\/ja000764e","article-title":"Cellulose crystallites: a new and robust liquid crystalline medium for the measurement of residual dipolar couplings","volume":"122","author":"Fleming","year":"2000","journal-title":"J. Am. Chem. Soc."},{"key":"B13","doi-asserted-by":"publisher","first-page":"016103","DOI":"10.1103\/PhysRevLett.97.016103","article-title":"Identification of nanoscale dissipation processes by dynamic atomic force microscopy","volume":"97","author":"Garcia","year":"2006","journal-title":"Phys. Rev. Lett."},{"key":"B14","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/nmat1925","article-title":"Nanoscale compositional mapping with gentle forces","volume":"6","author":"Garcia","year":"2007","journal-title":"Nat. Mater."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1569","DOI":"10.1016\/j.polymer.2003.12.028","article-title":"Surface silylation of cellulose microfibrils: preparation and rheological properties","volume":"45","author":"Gousse","year":"2004","journal-title":"Polymer"},{"key":"B16","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1023\/A:1021065905986","article-title":"Nanocomposites of cellulose acetate butyrate reinforced with cellulose nanocrystals","volume":"10","author":"Grunert","year":"2002","journal-title":"J. Polym. Environ."},{"key":"B17","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1007\/s10570-006-9075-y","article-title":"TEMPO-mediated surface oxidation of cellulose whiskers","volume":"13","author":"Habibi","year":"2006","journal-title":"Cellulose"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1974","DOI":"10.1021\/bm8001717","article-title":"Highly filled bionanocomposites from functionalized polysaccharide nanocrystals","volume":"9","author":"Habibi","year":"2008","journal-title":"Biomacromolecules"},{"key":"B19","doi-asserted-by":"publisher","first-page":"5002","DOI":"10.1039\/b809212e","article-title":"Bionanocomposites based on poly(epsilon-caprolactone)-grafted cellulose nanocrystals by ring-opening polymerization","volume":"18","author":"Habibi","year":"2008","journal-title":"J. Mater. Chem."},{"key":"B20","doi-asserted-by":"publisher","first-page":"3705","DOI":"10.1016\/j.jnoncrysol.2006.02.124","article-title":"Montmorillonite (MMT) effect on the structure of poly(oxyethylene) (PEO)-MMT nanocomposites and silica-PEO-MMT hybrid materials","volume":"352","author":"Hikosaka","year":"2006","journal-title":"J. Non Cryst. Solids"},{"key":"B21","doi-asserted-by":"publisher","first-page":"17919","DOI":"10.1021\/la1028405","article-title":"Acid-catalyzed and solvolytic desulfation of H2SO4-hydrolyzed cellulose nanocrystals","volume":"26","author":"Jiang","year":"2010","journal-title":"Langmuir"},{"key":"B22","doi-asserted-by":"publisher","first-page":"4174","DOI":"10.1007\/s10853-015-8933-0","article-title":"Hierarchically decorated electrospun poly(epsilon-caprolactone)\/nanohydroxyapatite composite nanofibers for bone tissue engineering","volume":"50","author":"Jing","year":"2015","journal-title":"J. Mater. Sci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"2907","DOI":"10.1016\/j.biomaterials.2006.01.017","article-title":"How useful is SBF in predicting in vivo bone bioactivity?","volume":"27","author":"Kokubo","year":"2006","journal-title":"Biomaterials"},{"key":"B24","doi-asserted-by":"publisher","first-page":"255","DOI":"10.3109\/17435391003628713","article-title":"An Ecotoxicological characterization of nanocrystalline cellulose (NCC)","volume":"4","author":"Kovacs","year":"2010","journal-title":"Nanotoxicology"},{"key":"B25","doi-asserted-by":"publisher","first-page":"3160","DOI":"10.1021\/bm050479t","article-title":"Characterization of cellulose whiskers and their nanocomposites by atomic force and electron microscopy","volume":"6","author":"Kvien","year":"2005","journal-title":"Biomacromolecules"},{"key":"B26","doi-asserted-by":"publisher","first-page":"3274","DOI":"10.1039\/c2nr30260h","article-title":"Preparation, properties and applications of polysaccharide nanocrystals in advanced functional nanomaterials: a review","volume":"4","author":"Lin","year":"2012","journal-title":"Nanoscale"},{"key":"B27","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1002\/jbm.a.30734","article-title":"Increased osteoblast functions among nanophase titania\/poly(lactide-co-glycolide) composites of the highest nanometer surface roughness","author":"Liu","year":"2006","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"B28","doi-asserted-by":"publisher","first-page":"870","DOI":"10.1557\/jmr.2006.0105","article-title":"Cellulose micro\/nanocrystals reinforced polyurethane","volume":"21","author":"Marcovich","year":"2006","journal-title":"J. Mater. Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"3941","DOI":"10.1039\/c0cs00108b","article-title":"Cellulose nanomaterials review: structure, properties and nanocomposites","volume":"40","author":"Moon","year":"2011","journal-title":"Chem. Soc. Rev."},{"key":"B30","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1016\/j.colsurfb.2012.01.011","article-title":"Multiwall carbon nanotubes\/polycaprolactone composites for bone tissue engineering application","volume":"93","author":"Pan","year":"2012","journal-title":"Colloids Surf. B. Biointerfaces"},{"key":"B31","doi-asserted-by":"publisher","first-page":"3008","DOI":"10.1002\/jbm.a.34233","article-title":"In vitro mineralization and bone osteogenesis in poly(e-caprolactone)\/gelatin nanofibers","author":"Perez","year":"2012","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"B32","doi-asserted-by":"publisher","first-page":"3779","DOI":"10.1002\/app.1981.070261124","article-title":"Aliphatic polyesters .1. The degradation of poly(epsilon-caprolactone) in vivo","volume":"26","author":"Pitt","year":"1981","journal-title":"J. Appl. Polym. Sci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1016\/j.biomaterials.2008.10.022","article-title":"Biodegradable poly(epsilon-caprolactone) nanowires for bone tissue engineering applications","volume":"30","author":"Porter","year":"2009","journal-title":"Biomaterials"},{"key":"B34","doi-asserted-by":"publisher","first-page":"404","DOI":"10.3109\/03008200903329789","article-title":"Dentin sialophosphoprotein in biomineralization","volume":"51","author":"Prasad","year":"2010","journal-title":"Connect. Tissue Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.1016\/0021-9290(91)90006-9","article-title":"Tensile and compressive properties of cancellous bone","volume":"24","author":"Rohl","year":"1991","journal-title":"J. Biomech."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2949","DOI":"10.1016\/j.actbio.2010.02.006","article-title":"Osteogenic differentiation of bone marrow stromal cells on poly(epsilon-caprolactone) nanofiber scaffolds","volume":"6","author":"Ruckh","year":"2010","journal-title":"Acta Biomater."},{"key":"B37","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/S0076-695X(08)60760-7","article-title":"Polymers - crystal structure and morphology 9. Thermal analysis of polymers","volume":"16","author":"Runt","year":"1980","journal-title":"Methods Exp. Phys."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1386","DOI":"10.1021\/ma030532a","article-title":"Preparation of cellulose whiskers reinforced nanocomposites from an organic medium suspension","volume":"37","author":"Samir","year":"2004","journal-title":"Macromolecules"},{"key":"B39","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1006\/jcis.2001.7617","article-title":"Crystal orientation of hydroxyapatite induced by ordered carboxyl groups","volume":"240","author":"Sato","year":"2001","journal-title":"J. Colloid Interface Sci."},{"key":"B40","doi-asserted-by":"publisher","first-page":"2581","DOI":"10.1016\/S0142-9612(01)00002-3","article-title":"Biomaterials and bone mechanotransduction","volume":"22","author":"Sikavitsas","year":"2001","journal-title":"Biomaterials"},{"key":"B41","doi-asserted-by":"publisher","first-page":"3009","DOI":"10.1016\/S0006-3495(01)76266-2","article-title":"From images to interactions: high-resolution phase imaging in tapping-mode atomic force microscopy","volume":"80","author":"Stark","year":"2001","journal-title":"Biophys. J."},{"key":"B42","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-642-34802-0","volume-title":"Biodegradable Polymer-Based Scaffolds for Bone Tissue Engineering","author":"Sultana","year":"2013"},{"key":"B43","doi-asserted-by":"publisher","first-page":"2394","DOI":"10.1063\/1.120039","article-title":"Effects of elastic and inelastic interactions on phase contrast images in tapping-mode scanning force microscopy","volume":"71","author":"Tamayo","year":"1997","journal-title":"Appl. Phys. Lett."},{"key":"B44","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1002\/(SICI)1097-4636(19970305)34:3<305::AID-JBM5>3.0.CO;2-O","article-title":"Surface functional group dependence on apatite formation on self-assembled monolayers in a simulated body fluid","volume":"34","author":"Tanahashi","year":"1997","journal-title":"J. Biomed. Mater. Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1021\/bm061104q","article-title":"Preparation of homogeneous dispersions of tunicate cellulose whiskers in organic solvents","volume":"8","author":"van den Berg","year":"2007","journal-title":"Biomacromolecules"},{"key":"B46","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1002\/jbm.a.32139","article-title":"Preparation and characterization of bioactive calcium silicate and poly(epsilon-caprolactone) nanocomposite for bone tissue regeneration","author":"Wei","year":"2009","journal-title":"J. Biomed. Materials Res. Part A"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1515\/9781501509346-006","article-title":"An overview of biomineralization processes and the problem of the vital effect","volume":"54","author":"Weiner","year":"2003","journal-title":"Biomineralization"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1089\/ten.2005.11.1","article-title":"Mediation of biomaterial-cell interactions by adsorbed proteins: a review","volume":"11","author":"Wilson","year":"2005","journal-title":"Tissue Eng."},{"key":"B49","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1002\/mabi.200500150","article-title":"Preparation and characterization of novel bone scaffolds based on electrospun polycaprolactone fibers filled with nanoparticles","volume":"6","author":"Wutticharoenmongkol","year":"2006","journal-title":"Macromol. Biosci."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1571","DOI":"10.1002\/jbm.a.34462","article-title":"Mineralization induction effects of osteopontin, bone sialoprotein, and dentin phosphoprotein on a biomimetic collagen substrate","volume":"101","author":"Zurick","year":"2013","journal-title":"J. Biomed. Mater. Res. Part A"}],"container-title":["Frontiers in Bioengineering and Biotechnology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2021.605924\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T09:10:04Z","timestamp":1614244204000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2021.605924\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,25]]},"references-count":50,"alternative-id":["10.3389\/fbioe.2021.605924"],"URL":"https:\/\/doi.org\/10.3389\/fbioe.2021.605924","relation":{},"ISSN":["2296-4185"],"issn-type":[{"value":"2296-4185","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,25]]},"article-number":"605924"}}