Calcium Phosphate Delivery Systems for Regeneration and Biomineralization of Mineralized Tissues of the Craniofacial Complex

Abstract

Calcium phosphate (CaP)-based materials have been extensively used for mineralized tissues in the craniofacial complex. Owing to their excellent biocompatibility, biodegradability, and inherent osteoconductive nature, their use as delivery systems for drugs and bioactive factors has several advantages. Of the three mineralized tissues in the craniofacial complex (bone, dentin, and enamel), only bone and dentin have some regenerative properties that can diminish due to disease and severe injuries. Therefore, targeting these regenerative tissues with CaP delivery systems carrying relevant drugs, morphogenic factors, and ions is imperative to improve tissue health in the mineralized tissue engineering field. In this review, the use of CaP-based microparticles, nanoparticles, and polymer-induced liquid precursor (PILPs) amorphous CaP nanodroplets for delivery to craniofacial bone and dentin are discussed. The use of these various form factors to obtain either a high local concentration of cargo at the macroscale and/or to deliver cargos precisely to nanoscale structures is also described. Finally, perspectives on the field using these CaP materials and next steps for the future delivery to the craniofacial complex are presented.

Keywords: biomineralization; calcium phosphates; craniofacial bone defects; dental decay; dentin; drug delivery; intrafibrillar mineralization.

Figure 1

Hierarchical structure and organization of Type-I collagen that composes bone and dentin tissues. Below, various sized drug delivery systems for bone and dentin applications.

Figure 2

Tunable dual growth factor delivery from hydroxyapatite microparticles. (A) Schematic of hydroxyapatite microparticles (HA MP) mineral coating with layer 1 (L1), then loaded with BMP-2 (BMP-2/L1). The second layer (L2) of mineral was coated on L1 by incubating HA MPs in mSBF, then VEGF was bound on the second layer of the mineral coating. (B–D) 1 mM fluoride mineral coating as L1 and % release: (B) BMP-2 release from L1, (C) VEGF release from L2, and (D) BMP-2/VEGF dual release. (E–G) 100 mM carbonate mineral coating as L1: (E) BMP-2 release from L1, (F) VEGF release from L2, and (G) BMP-2/VEGF dual release. Each condition was tested with 1 mM fluoride or 100 mM carbonate as the 2nd layer. Reprinted from ref (19). Copyright 2022 John Wiley and Sons.

Figure 3

Biphasic microparticles with collagen infiltration for BMP-2 drug delivery. (A–D) SEM of porous BCP microspheres (A, B) and porous BCP microspheres with collagen filtration (BCP-COLL) (C, D). (E) Percent release of BMP-2 from porous BCP microspheres (red) and BCP-COLL microspheres (blue). (F) Goldner trichrome staining of demineralized tissue sections postimplantation. Reprinted with permission from ref (58). Copyright 2022 Elsevier.

Figure 4

Dual-mode antimicrobial and ion delivery. (A–D) TEM of CDHA (A), zinc (Zn²⁺)-substituted CDHA (B), silver (Ag¹⁺)-substituted CDHA (C), and strontium (Sr²⁺)-substituted CDHA (D). (E) Doxycycline release from ion-substituted material. (F) Bacterial counts overtime after incubation with Ion-substituted CDHA. Reprinted with permission from ref (80). Copyright 2022 Frontiers.

Figure 5

PILP mineralization on periodontal tissues. (A–D) TEM of dentin, cementum, and periodontal ligament tissue sections remineralized with (A) CaP with no pAsp, (B) pAsp (MW 6), (C) pAsp (MW 10), or (D) pAsp (MW 100). Insets are selected area electron diffraction (SAED) of cementum. Used with permission from ref (90). Copyright 2018 The Royal Society, permission conveyed through Copyright Clearance Center, Inc.

Figure 6

Chlorhexidine-loaded ACP nanoparticles for MMP inhibition and collagen remineralization. (A–C) TEM micrographs of (A) ACP with no chlorhexidine, (B) C-ACP, and (C) G-ACP with SAED indicating ACP. Release of chlorhexidine from (D) C-ACP and (E) G-ACP. Intrafibrillar mineralization as seen with TEM and energy dispersive X-ray spectroscopy maps of collagen fibrils treated with (F) ACP with no chlorhexidine, (G) C-ACP, and (H) G-ACP. Reprinted with permission from ref (119). Copyright 2022 American Chemical Society.

Figure 7

PILP delivery and remineralization of dentin lesions. (A-C) SEM of artificial lesion restored with RMGI control (no PILP) (BC) (A), and PILP conditioner (con-BC) (B), and cement (con-lin-BC)(C). (D) Elastic modulus values versus lesion depth obtained from nanoindentations performed along lines from the lesion surface across the lesion toward normal dentin before (demin) and after treatment. Reprinted with permission from ref (141). Copyright 2022 Elsevier.