{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T03:41:33Z","timestamp":1791517293698,"version":"4.3.4"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:p>\n                    Developing biomaterials from natural polysaccharides for medical applications presents significant challenges in terms of biocompatibility, scalability, and regulatory compliance. We report here the full development and preclinical validation of 250\u2013300\u00a0\u00b5m pullulan\u2013dextran\u2013hydroxyapatite microbeads for bone regeneration, intended for use in sinus lift procedures. This class III medical device was fabricated using two pharmaceutical-grade, biodegradable, and biocompatible polysaccharides (pullulan and dextran) that were crosslinked without the use of organic solvents and embedded with hydroxyapatite microparticles. Industrial-scale production of 59 batches achieved batch-to-batch reproducibility, comprehensive physicochemical characterizations, stability, sterilization, and packaging in syringes under Good Manufacturing Practices (GMP). Preclinical validation included\n                    <jats:italic>in vitro<\/jats:italic>\n                    biocompatibility and toxicology testing, along with\n                    <jats:italic>in vivo<\/jats:italic>\n                    demonstration of efficacy in a sheep model. The injected polysaccharide beads demonstrated performance comparable to commercial clinical bovine bone granules in a two-step sinus grafting surgery in six sheep, with dental implants successfully placed 6\u00a0months post-grafting. As a novel approach, the polysaccharide beads act as a temporary scaffold that could be easily injected into the sinus cavity, gradually degrading and being replaced by dense bone tissue. Clinical trial preparation, including protocol design and regulatory files submission, culminated in regulatory approval for human use in sinus lift procedures. This work illustrates a successful translation from the laboratory to the clinic, with the journey from conceptual design to clinical trial approval of a new pullulan\u2013dextran-based biomaterial.\n                  <\/jats:p>","DOI":"10.3389\/fbioe.2026.1791131","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T08:14:16Z","timestamp":1780560856000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Pullulan\u2013dextran composite beads as bone fillers: from material design and industrial production to clinical application in oral surgery"],"prefix":"10.3389","volume":"14","author":[{"given":"Sylvain","family":"Catros","sequence":"first","affiliation":[{"name":"Universit\u00e9 de Bordeaux, INSERM 1026, BioTis","place":["Bordeaux, France"]},{"name":"CHU de Bordeaux, Service de Chirurgie Orale","place":["Bordeaux, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Bidault","sequence":"additional","affiliation":[{"name":"Siltiss, SA, Zac de la Nau","place":["Saint-Viance, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Auget","sequence":"additional","affiliation":[{"name":"Siltiss, SA, Zac de la Nau","place":["Saint-Viance, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Pasquet","sequence":"additional","affiliation":[{"name":"Siltiss, SA, Zac de la Nau","place":["Saint-Viance, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Ehret","sequence":"additional","affiliation":[{"name":"Siltiss, SA, Zac de la Nau","place":["Saint-Viance, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachida","family":"Aid","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, Universit\u00e9 Sorbonne Paris Nord, INSERM 1148, LVTS, X Bichat Hospital","place":["Paris, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathilde","family":"Fenelon","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Bordeaux, INSERM 1026, BioTis","place":["Bordeaux, France"]},{"name":"CHU de Bordeaux, Service de Chirurgie Orale","place":["Bordeaux, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Christophe","family":"Fricain","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Bordeaux, INSERM 1026, BioTis","place":["Bordeaux, France"]},{"name":"CHU de Bordeaux, Service de Chirurgie Orale","place":["Bordeaux, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joelle","family":"Amedee-Vilamitjana","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Bordeaux, INSERM 1026, BioTis","place":["Bordeaux, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Letourneur","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, Universit\u00e9 Sorbonne Paris Nord, INSERM 1148, LVTS, X Bichat Hospital","place":["Paris, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1089\/tea.2007.0134","article-title":"A biocompatible polysaccharide hydrogel\u2013embedded polypropylene mesh for enhanced tissue integration in rats","volume":"14","author":"Abed","year":"2008","journal-title":"Tissue Eng. Part A"},{"key":"B2","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1002\/jbm.a.33007","article-title":"Influence of polysaccharide composition on the biocompatibility of pullulan\/dextran-based hydrogels","volume":"96","author":"Abed","year":"2011","journal-title":"J. Biomed. Mater. Res. A"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.3390\/bioengineering10111257","article-title":"Development of novel polysaccharide membranes for guided bone regeneration: in vitro and in vivo evaluations","volume":"10","author":"Ahmed","year":"2023","journal-title":"Bioengineering"},{"key":"B4","doi-asserted-by":"publisher","first-page":"889481","DOI":"10.3389\/fbioe.2022.889481","article-title":"Recent advances of Pullulan and\/or Dextran-Based materials for bone tissue engineering strategies in preclinical studies: a systematic review","volume":"10","author":"Ahmed Omar","year":"2022","journal-title":"Front. Bioeng. Biotechnol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1494352","DOI":"10.3389\/fbioe.2025.1494352","article-title":"Challenges and limitations in developing of a new maxillary standardized rat alveolar bone defect model to study bone regenerative approaches in oral and maxillofacial surgery","volume":"13","author":"Ahmed Omar","year":"2025","journal-title":"Front. Bioeng. Biotechnol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"10760296211052293","DOI":"10.1177\/10760296211052293","article-title":"General considerations for diversifying heparin drug products by improving the Current heparin manufacturing process and reintroducing bovine sourced heparin to the US market","volume":"27","author":"Al-Hakim","year":"2021","journal-title":"Clin. Appl. Thromb."},{"key":"B7","doi-asserted-by":"publisher","first-page":"122124","DOI":"10.1016\/j.carbpol.2024.122124","article-title":"Sulfated polysaccharide as biomimetic biopolymers for tissue engineering scaffolds fabrication: challenges and opportunities","volume":"336","author":"Alizadeh","year":"2024","journal-title":"Carbohydr. Polym."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2000707","DOI":"10.1002\/adhm.202000707","article-title":"Membranes for guided bone regeneration: a road from bench to bedside","volume":"9","author":"Aprile","year":"2020","journal-title":"Adv. Healthc. Mater."},{"key":"B9","doi-asserted-by":"publisher","first-page":"3640","DOI":"10.1016\/j.actbio.2010.03.004","article-title":"Fabrication of porous polysaccharide-based scaffolds using a combined freeze-drying\/cross-linking process","volume":"6","author":"Autissier","year":"2010","journal-title":"Acta Biomater."},{"key":"B10","doi-asserted-by":"publisher","first-page":"117924","DOI":"10.1016\/j.carbpol.2021.117924","article-title":"Dextran-based scaffolds for in-situ hydrogelation: use for next generation of bioartificial cardiac tissues","volume":"262","author":"Banerjee","year":"2021","journal-title":"Carbohydr. Polym."},{"key":"B11","doi-asserted-by":"publisher","first-page":"407","DOI":"10.22203\/eCM.v021a31","article-title":"Osteoinductive biomaterials: current knowledge of properties, experimental models and biological mechanisms","volume":"21","author":"Barradas","year":"2011","journal-title":"Eur. Cell. Mater"},{"key":"B12","doi-asserted-by":"publisher","first-page":"2188","DOI":"10.1097\/SCS.0000000000008773","article-title":"A 3-Dimensional evaluation of bone density in alveolar cleft grafting methods: bone substitutes versus autologous bone","volume":"33","author":"Bianchi","year":"2022","journal-title":"J. Craniofac. Surg."},{"key":"B13","doi-asserted-by":"publisher","first-page":"845735","DOI":"10.3389\/fbioe.2022.845735","article-title":"Polysaccharide-Based hydrogels for wound dressing: design considerations and clinical applications","volume":"10","author":"Cui","year":"2022","journal-title":"Front. Bioeng. Biotechnol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"131809","DOI":"10.1016\/j.ijbiomac.2024.131809","article-title":"Advanced application of carbohydrate-based micro\/nanoparticles for rheumatoid arthritis","volume":"269","author":"Cui","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"123138","DOI":"10.1016\/j.carbpol.2024.123138","article-title":"Functional polysaccharide-based hydrogel in bone regeneration: from fundamentals to advanced applications","volume":"352","author":"Du","year":"2025","journal-title":"Carbohydr. Polym."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.carbpol.2003.12.006","article-title":"Hyaluronan-based hydrogels particles prepared by crosslinking with trisodium trimetaphosphate. Synthesis and characterization","volume":"57","author":"Dulong","year":"2004","journal-title":"Carbohydr. Polym."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e0184663","DOI":"10.1371\/journal.pone.0184663","article-title":"Strontium-doped hydroxyapatite polysaccharide materials effect on ectopic bone formation","volume":"12","author":"Ehret","year":"2017","journal-title":"PloS One"},{"key":"B18","doi-asserted-by":"publisher","first-page":"139845","DOI":"10.1016\/j.ijbiomac.2025.139845","article-title":"Application prospect of polysaccharide in the development of vaccine adjuvants","volume":"297","author":"Feng","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"4117","DOI":"10.3390\/ma16114117","article-title":"Bone grafts in dental medicine: an overview of autografts, allografts and synthetic materials","volume":"16","author":"Ferraz","year":"2023","journal-title":"Materials"},{"key":"B20","doi-asserted-by":"publisher","first-page":"116457","DOI":"10.1016\/j.carbpol.2020.116457","article-title":"Gd(DOTA)-grafted submicronic polysaccharide-based particles functionalized with fucoidan as potential MR contrast agent able to target human activated platelets","volume":"245","author":"Forero Ramirez","year":"2020","journal-title":"Carbohydr. Polym."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2947","DOI":"10.1016\/j.biomaterials.2013.01.049","article-title":"A nano-hydroxyapatite \u2013 pullulan\/dextran polysaccharide composite macroporous material for bone tissue engineering","volume":"34","author":"Fricain","year":"2013","journal-title":"Biomaterials"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1016\/j.dental.2018.03.021","article-title":"In-vitro and in-vivo design and validation of an injectable polysaccharide-hydroxyapatite composite material for sinus floor augmentation","volume":"34","author":"Fricain","year":"2018","journal-title":"Dent. Mater."},{"key":"B23","doi-asserted-by":"publisher","first-page":"3557","DOI":"10.1016\/j.actbio.2014.04.017","article-title":"Potential lack of \u201cstandardized\u201d processing techniques for production of allogeneic and xenogeneic bone blocks for application in humans","volume":"10","author":"Ghanaati","year":"2014","journal-title":"Acta Biomater."},{"key":"B24","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.actbio.2019.05.070","article-title":"Mechanisms of pore formation in hydrogel scaffolds textured by freeze-drying","volume":"94","author":"Grenier","year":"2019","journal-title":"Acta Biomater."},{"key":"B25","doi-asserted-by":"publisher","first-page":"212973","DOI":"10.1016\/j.bioadv.2022.212973","article-title":"Interplay between crosslinking and ice nucleation controls the porous structure of freeze-dried hydrogel scaffolds","volume":"139","author":"Grenier","year":"2022","journal-title":"Biomater. Adv."},{"key":"B26","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1080\/21691401.2024.2436350","article-title":"Recent advances in polysaccharide-based drug delivery systems for cancer therapy: a comprehensive review","volume":"52","author":"Hsu","year":"2024","journal-title":"Artif. Cells Nanomedicine Biotechnol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"490","DOI":"10.31616\/asj.2024.0520","article-title":"Bone fusion materials: past, present, and future","volume":"19","author":"Kim","year":"2025","journal-title":"Asian Spine J."},{"key":"B28","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1016\/j.carres.2007.01.011","article-title":"High-resolution nuclear magnetic resonance spectroscopy studies of polysaccharides crosslinked by sodium trimetaphosphate: a proposal for the reaction mechanism","volume":"342","author":"Lack","year":"2007","journal-title":"Carbohydr. Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1007\/s10856-018-6085-x","article-title":"Effect of cross-linking on the physicochemical and in vitro properties of pullulan\/dextran microbeads","volume":"29","author":"Lanouar","year":"2018","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1978","DOI":"10.3390\/pharmaceutics14091978","article-title":"3D bioprinted Chitosan-Based Hydrogel Scaffolds in tissue engineering and localised drug delivery","volume":"14","author":"Lazaridou","year":"2022","journal-title":"Pharmaceutics"},{"key":"B31","doi-asserted-by":"publisher","first-page":"114570","DOI":"10.1016\/j.colsurfb.2025.114570","article-title":"Recent progress in alginate-based nanocomposites for bone tissue engineering applications","volume":"250","author":"Lekhavadhani","year":"2025","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"B32","doi-asserted-by":"publisher","first-page":"2001237","DOI":"10.1002\/adhm.202001237","article-title":"Enabling MedTech translation in academia: redefining value proposition with updated regulations","volume":"10","author":"Letourneur","year":"2021","journal-title":"Adv. Healthc. Mater."},{"key":"B33","doi-asserted-by":"publisher","first-page":"e2400854","DOI":"10.1002\/ardp.202400854","article-title":"Advances in polysaccharide\u2010based materials for biomedical and pharmaceutical applications: a comprehensive review","volume":"358","author":"Li","year":"2025","journal-title":"Arch. Pharm. Weinh."},{"key":"B34","doi-asserted-by":"publisher","first-page":"12766","DOI":"10.3390\/ijms252312766","article-title":"The future of bone repair: emerging technologies and biomaterials in bone regeneration","volume":"25","author":"\u0141uczak","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1111\/prd.12165","article-title":"Sinus floor elevation procedures to enable implant placement and integration: techniques, biological aspects and clinical outcomes","volume":"73","author":"Lundgren","year":"2017","journal-title":"Periodontology"},{"key":"B36","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1016\/j.tibtech.2016.07.005","article-title":"Calcium phosphates and angiogenesis: implications and advances for bone regeneration","volume":"34","author":"Malhotra","year":"2016","journal-title":"Trends Biotechnol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"225","DOI":"10.2174\/2213476X06666191129094236","article-title":"Nanotechnology: regulatory outlook on nanomaterials and nanomedicines in United States, Europe and India","volume":"7","author":"Malik","year":"2020","journal-title":"Appl. Clin. Res. Clin. Trials Regul. Aff."},{"key":"B38","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.foodhyd.2012.09.017","article-title":"Sterilization treatments on polysaccharides: effects and side effects on pectin","volume":"31","author":"Munarin","year":"2013","journal-title":"Food Hydrocoll."},{"key":"B39","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1615\/CritRevBiomedEng.2023043780","article-title":"Modification and functionalization of polymers for targeting to bone cancer and bone regeneration","volume":"51","author":"Nimbalkar","year":"2023","journal-title":"Crit. Rev. Biomed. Eng."},{"key":"B40","doi-asserted-by":"publisher","first-page":"121655","DOI":"10.1016\/j.carbpol.2023.121655","article-title":"Exploring polysaccharide-based bio-adhesive topical film as a potential platform for wound dressing application: a review","volume":"327","author":"Priya","year":"2024","journal-title":"Carbohydr. Polym."},{"key":"B41","doi-asserted-by":"publisher","first-page":"e110251","DOI":"10.1371\/journal.pone.0110251","article-title":"Pullulan\/dextran\/nHA macroporous composite beads for bone repair in a femoral condyle defect in rats","volume":"9","author":"Schlaubitz","year":"2014","journal-title":"PloS One"},{"key":"B42","doi-asserted-by":"publisher","first-page":"3199","DOI":"10.1021\/acsbiomaterials.2c00194","article-title":"Criteria, challenges, and opportunities for acellularized Allogeneic\/Xenogeneic bone grafts in bone repairing","volume":"8","author":"Sharifi","year":"2022","journal-title":"ACS Biomater. Sci. Eng."},{"key":"B43","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.carbpol.2014.06.010","article-title":"Polysaccharide-based strategies for heart tissue engineering","volume":"116","author":"Silva","year":"2015","journal-title":"Carbohydr. Polym."},{"key":"B44","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1055\/s-0032-1328970","article-title":"Market entry of biosimilar low-molecular-weight heparins in Europe: opportunities and challenges","volume":"39","author":"Simoens","year":"2012","journal-title":"Semin. Thromb. Hemost."},{"key":"B45","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1016\/j.carbpol.2016.07.118","article-title":"Recent insights on applications of pullulan in tissue engineering","volume":"153","author":"Singh","year":"2016","journal-title":"Carbohydr. Polym."},{"key":"B46","doi-asserted-by":"publisher","first-page":"140820","DOI":"10.1016\/j.ijbiomac.2025.140820","article-title":"A review on polysaccharide-based tumor targeted drug nanodelivery systems","volume":"304","author":"Tu","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"3366","DOI":"10.1039\/D1FO00122A","article-title":"Effects of fungal beta-glucans on health \u2013 a systematic review of randomized controlled trials","volume":"12","author":"Vlassopoulou","year":"2021","journal-title":"Food Funct."},{"key":"B48","doi-asserted-by":"publisher","first-page":"5186","DOI":"10.1016\/j.biomaterials.2006.05.051","article-title":"In vivo behavior of calcium phosphate scaffolds with four different pore sizes","volume":"27","author":"Von Doernberg","year":"2006","journal-title":"Biomaterials"},{"key":"B49","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.bjoms.2009.04.032","article-title":"Bone regeneration in sinus lifts: comparing tissue-engineered bone and iliac bone","volume":"48","author":"Voss","year":"2010","journal-title":"Br. J. Oral Maxillofac. Surg."},{"key":"B50","doi-asserted-by":"publisher","first-page":"2357","DOI":"10.1016\/S0142-9612(98)00154-9","article-title":"Hydroxyapatite-polyethylene composites for bone substitution: effects of ceramic particle size and morphology","volume":"19","author":"Wang","year":"1998","journal-title":"Biomaterials"},{"key":"B51","doi-asserted-by":"publisher","first-page":"101395","DOI":"10.1016\/j.mtbio.2024.101395","article-title":"Polysaccharide-based biomaterials for regenerative therapy in intervertebral disc degeneration","volume":"30","author":"Wang","year":"2025","journal-title":"Mater. Today Bio"},{"key":"B52","doi-asserted-by":"publisher","first-page":"950","DOI":"10.3390\/polym14050950","article-title":"Polysaccharide-Drug conjugates: a tool for enhanced cancer therapy","volume":"14","author":"Yadav","year":"2022","journal-title":"Polymers"},{"key":"B53","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1902\/jop.2007.060055","article-title":"Ossification of a novel cross\u2010linked porcine collagen barrier in guided bone regeneration in dogs","volume":"78","author":"Zubery","year":"2007","journal-title":"J. Periodontol."}],"container-title":["Frontiers in Bioengineering and Biotechnology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2026.1791131\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T08:14:21Z","timestamp":1780560861000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2026.1791131\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,4]]},"references-count":53,"alternative-id":["10.3389\/fbioe.2026.1791131"],"URL":"https:\/\/doi.org\/10.3389\/fbioe.2026.1791131","relation":{},"ISSN":["2296-4185"],"issn-type":[{"value":"2296-4185","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,4]]},"article-number":"1791131"}}