title: Long-term controlled delivery of rhBMP-2 from collagen-hydroxyapatite scaffolds for superior bone tissue regeneration.
abstract: The clinical utilization of recombinant human bone morphogenetic protein 2 (rhBMP-2) delivery systems for bone regeneration has been associated with very severe side effects, which are due to the non-controlled and non-targeted delivery of the growth factor from its collagen sponge carrier post-implantation which necessitates supraphysiological doses. However, rhBMP-2 presents outstanding regenerative properties and thus there is an unmet need for a biocompatible, fully resorbable delivery system for the controlled, targeted release of this protein. With this in mind, the purpose of this work was to design and develop a delivery system to release low rhBMP-2 doses from a collagen-hydroxyapatite (CHA) scaffold which had previously been optimized for bone regeneration and recently demonstrated significant healing in vivo. In order to enhance the potential for clinical translation by minimizing the design complexity and thus upscaling and regulatory hurdles of the device, a microparticle and chemical functionalization-free approach was chosen to fulfill this aim. RhBMP-2 was combined with a CHA scaffold using a lyophilization fabrication process to produce a highly porous CHA scaffold supporting the controlled release of the protein over the course of 21days while maintaining in vitro bioactivity as demonstrated by enhanced alkaline phosphatase activity and calcium production by preosteoblasts cultured on the scaffold. When implanted in vivo, these materials demonstrated increased levels of healing of critical-sized rat calvarial defects 8weeks post-implantation compared to an empty defect and unloaded CHA scaffold, without eliciting bone anomalies or adjacent bone resorption. These results demonstrate that it is possible to achieve bone regeneration using 30 times less rhBMP-2 than INFUSE®, the current clinical gold standard; thus, this work represents the first step of the development of a rhBMP-2 eluting material with immense clinical potential.
authors: Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland, Dublin, Ireland; Trinity Centre for Bioengineering, Trinity College Dublin, Ireland; Advanced Materials Bio-Engineering Research Centre (AMBER), RCSI and Trinity College Dublin, Dublin, Ireland.
authors: Elaine
authors: E
authors: Quinlan
authors: Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland, Dublin, Ireland; Trinity Centre for Bioengineering, Trinity College Dublin, Ireland; Advanced Materials Bio-Engineering Research Centre (AMBER), RCSI and Trinity College Dublin, Dublin, Ireland.
authors: Emmet M
authors: EM
authors: Thompson
authors: Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland, Dublin, Ireland; Trinity Centre for Bioengineering, Trinity College Dublin, Ireland; Advanced Materials Bio-Engineering Research Centre (AMBER), RCSI and Trinity College Dublin, Dublin, Ireland.
authors: Amos
authors: A
authors: Matsiko
authors: Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland, Dublin, Ireland; Trinity Centre for Bioengineering, Trinity College Dublin, Ireland; Advanced Materials Bio-Engineering Research Centre (AMBER), RCSI and Trinity College Dublin, Dublin, Ireland.
authors: Fergal J
authors: FJ
authors: O'Brien
authors: School of Pharmacy, Royal College of Surgeons in Ireland, Dublin, Ireland; Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland, Dublin, Ireland; Trinity Centre for Bioengineering, Trinity College Dublin, Ireland; Advanced Materials Bio-Engineering Research Centre (AMBER), RCSI and Trinity College Dublin, Dublin, Ireland. Electronic address: adolfolnoriega@rcsi.ie.
authors: Adolfo
authors: A
authors: López-Noriega
mesh_terms: D016475:3T3 Cells; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage* / Q000737:chemistry; D001861:Bone Regeneration / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D003094:Collagen / Q000737:chemistry*; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D006801:Humans; D006882:Hydroxyapatites / Q000378:metabolism*; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D016062:Porosity; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000737:chemistry; D012886:Skull / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors; D054457:Tissue Scaffolds; D055114:X-Ray Microtomography
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D006882:Hydroxyapatites; D011994:Recombinant Proteins; D003094:Collagen; D000469:Alkaline Phosphatase; D002118:Calcium
keywords: Bone tissue regeneration; Collagen–hydroxyapatite; Controlled release; Osteogenesis; Rat calvarial defect model; RhBMP-2