Pullulan-dextran composite beads as bone fillers: from material design and industrial production to clinical...

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 250-300 µm pullulan-dextran-hydroxyapatite 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 in vitro biocompatibility and toxicology testing, along with in vivo 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 months 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-dextran-based biomaterial.