title: Cell-mediated BMP-2 release from a novel dual-drug delivery system promotes bone formation.
abstract: OBJECTIVE
  In this study, a novel biomimetic calcium phosphate bone substitute (BioCaP) is introduced as a dual-drug release system with two drug/protein delivery modes: protein is incorporated into (i) the interior of BioCaP (an internal depot); and (ii) a superficial calcium phosphate coating on BioCaP (a surface-coated depot). Our aim is to investigate each of the two delivery modes of BioCaP. Our hypotheses are that (i) both of the drug delivery modes, in in vitro as well as in vivo environment, can achieve a sustained cell-mediated protein release; and (ii) BioCaP with these two delivery modes with incorporated bone morphogenetic protein-2 (BMP-2) promotes bone formation.
  
  
  METHODS
  Tablets of BioCaP were prepared with different carrying modes using bovine serum albumin (BSA) as model protein. The release of this protein was analysed (n = 6 per group). Granules of BioCaP with different carrying modes of BMP-2 were implanted subcutaneously in rats (n = 6 animals per group). Samples were collected after 5 weeks for histomorphometric analysis.
  
  
  RESULTS
  In vitro data showed that the internal and surface-coated depots of BSA resulted in a sustained osteoclast-mediated release, while the adsorbed BSA was rapidly released, and this release was not affected by osteoclasts. In vivo data showed that the volume densities of bone, bone marrow, and blood vessels were significantly higher in samples where BMP-2 was incorporated internally or in the coating compared with granules with adsorbed growth factor. Osteoclast-like cells were associated with the granules, and resorption lacunae were frequently observed.
  
  
  CONCLUSIONS
  It is shown that different modes of incorporation of BMP-2 on and in BioCaP granules have a beneficial effect on the formation of ectopic bone. This dual-drug release system makes BioCaP granule a promising tool for delivering multiple therapeutic agents for different clinical applications.
authors.forename: Tie
authors.initials: T
authors.lastname: Liu
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.forename: Yuanna
authors.initials: Y
authors.lastname: Zheng
authors.forename: Daniel
authors.initials: D
authors.lastname: Wismeijer
authors.forename: Vincent
authors.initials: V
authors.lastname: Everts
authors.forename: Yuelian
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000327:Adsorption; D000818:Animals; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry*; D001808:Blood Vessels / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage* / Q000494:pharmacology; D018786:Bone Substitutes / Q000138:chemical synthesis / Q000737:chemistry*; D002130:Calcium Phosphates / Q000138:chemical synthesis / Q000737:chemistry*; D002478:Cells, Cultured; D020099:Coated Materials, Biocompatible / Q000737:chemistry; D004337:Drug Carriers; D016503:Drug Delivery Systems; D008297:Male; D008422:Materials Testing; D051379:Mice; D009999:Ossification, Heterotopic / Q000473:pathology; D010010:Osteoclasts / Q000502:physiology; D010012:Osteogenesis / Q000187:drug effects; D010316:Particle Size; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000737:chemistry*; D013499:Surface Properties
chemical_list: D055396:Bone Morphogenetic Protein 2; D018786:Bone Substitutes; D002130:Calcium Phosphates; D020099:Coated Materials, Biocompatible; D004337:Drug Carriers; D012709:Serum Albumin; C020243:calcium phosphate