Calcium phosphate ceramic systems in growth factor and drug delivery for bone tissue engineering: a review

Abstract

Calcium phosphates (CaPs) are the most widely used bone substitutes in bone tissue engineering due to their compositional similarities to bone mineral and excellent biocompatibility. In recent years, CaPs, especially hydroxyapatite and tricalcium phosphate, have attracted significant interest in simultaneous use as bone substitute and drug delivery vehicle, adding a new dimension to their application. CaPs are more biocompatible than many other ceramic and inorganic nanoparticles. Their biocompatibility and variable stoichiometry, thus surface charge density, functionality, and dissolution properties, make them suitable for both drug and growth factor delivery. CaP matrices and scaffolds have been reported to act as delivery vehicles for growth factors and drugs in bone tissue engineering. Local drug delivery in musculoskeletal disorder treatments can address some of the critical issues more effectively and efficiently than the systemic delivery. CaPs are used as coatings on metallic implants, CaP cements, and custom designed scaffolds to treat musculoskeletal disorders. This review highlights some of the current drug and growth factor delivery approaches and critical issues using CaP particles, coatings, cements, and scaffolds towards orthopedic and dental applications.

Fig. 1

Application approaches of calcium phosphates in drug delivery and biomolecule.

Fig. 2

Schematic of CaP NPs for drug delivery applications: single shell (a and b), multi-shell (c), and surface functionalization approach (d). Fluorophore agents can be entrapped/doped into CaP core as shown in (b) for imaging. The multi-shell approach (c) is more effective for nuclear transfection than the single shell as in (a). Drugs or biomolecules that are poorly adsorbed on CaP can also be adsorbed on the surface functionalized polymer coating as shown in (d).

Fig. 3

Schematic of the interaction of a nucleic acid on the CaP NP surface (Copyright (2008) Wiley-VCH Verlag GmbH & Co. KGaA. Reprinted from Ref. [84] with permission).

Fig. 4

Schematic of transfection/intracellular delivery of drugs and biomolecules by CaP particles.

Fig. 5

(a) Release profiles of AD from CaP/AD nanocomposite in PBS of pH 5.0 and pH 7.4; (b) dissolution of Ca²⁺ from CaP/AD nanocomposite after 72 h (^*P < 0.05); (c) release profiles of RDB from RDB-CaP/AD nanocomposite at different pH; (d) TRAP activity of osteoclast cells after 28 days of culture showing a threefold decrease in TRAP expression by CaP/AD nanocomposite compared to bare CaP nanoparticles (P < 0.05) (Copyright (2011) John Wiley and Sons Inc. Reprinted from Ref. [92] with permission).

Fig. 6

(a) Schematic showing the interaction between HA and BSA. Lengthening of the c-site of doped HA crystal lattice facilitated increased in situ BSA loading, (b) BSA release profile from the BSA loaded undoped (HA-BSA), magnesium-doped HA (Mg-HA-BSA), and zinc-doped HA (Zn-HA-BSA) nanoparticles (Copyright (2010) American Chemical Society. Reprinted from Ref. [94] with permission).

Fig. 7

(a) Dependence of the zeta potential on the type of nanoparticles, demonstrating the addition of the differently charged outer layers (single shell and triple shell: DNA; double-shell: calcium phosphate); (b) comparison of the transfection efficiency of T-HUVEC in quantums medium by different methods. The error bars represent the standard deviation (N = 3). There were significant differences between single shell and triple shell (P < 0.01) and triple shell and the standard calcium phosphate method (P < 0.05) (Copyright (2006) Elsevier. Reprinted from Ref. [95] with permission).

Fig. 8

Schematic of biomimetic coating: (a) simple biomimetic coating of an amorphous calcium deficient carbonated apatite from SBF (usually the SBF ion concentration for biomimetic coating is 5 to 10 times higher than the normal SBF ion concentration); (b) biomimetic co-precipitation of drug/growth factor.

Fig. 9

(a) Incorporation of antibiotic into the carbonated hydroxyapatite coating vs. the concentration in coating solution, (b) antibiotic release from carbonated hydroxyapatite coatings into PBS pH 7.3 (Copyright (2004) Elsevier. Reprinted from Ref. [109] with permission).

Fig. 10

Structural similarities between inorganic pyrophosphate and bisphosphonates. Substitution of different functional groups at R¹ and R² positions generates a family of bisphosphonate drugs, here only showing alendronate.

Fig. 11

(i) Porous BCP scaffolds with 92–94% volume fraction porosity, and interconnected macropore size 360–440 μm and 900–1150 μm (A), and 0.4–4 μm micropore size in the strut (B); (ii) ESEM (environmental scanning electron microscopy) images of explanted BCP scaffolds stimulated with BMP-7 (A), and corresponding segmented image for the detection of newly formed bone (B). The grey values are assigned to different colors (ceramic: red, new bone: blue) and the area ratio of ceramic/new bone was calculated. New bone formation observed both at the surface (white arrows) and inside the pores (white stars) (B). A control BCP scaffold without any additives is presented in (C), with the corresponding image used for histomorphometric analysis (D) (Copyright (2010) Elsevier. Reprinted from Ref. [151] with permission).

Fig. 12

(a) SEM morphologies of the scaffolds: (i) TCP, (ii) TCP coated with 2.5% PCL w/v in dichloromethane, (iii) TCP coated with 5.0% PCL w/v in dichloromethane; (b) release profile of BSA: (i) from BSA incorporated into PCL-coated samples, (ii) from superficially BSA adsorbed samples. BSA incorporation into polymer (PCL) coating showed a relatively controlled release than the superficially adsorbed BSA samples (Copyright (2009) John Wiley and Sons. Reprinted from the reference. [153] with permission); (c) Schematic of 3D printing and some 3D printed parts (fabricated at Washington State University) showing the versatility of 3D printing technology for ceramic scaffolds fabrication with complex architectural features.

Fig. 13

Schematic representation of drug loading approaches on CaP scaffolds: (a) adsorption on bare CaP scaffold; (b) adsorption of drugs on bare CaP scaffolds followed by polymer coating to prevent burst release and have a sustained release; (c) polymer coating on bare CaP scaffolds followed by surface treatment of the coating, then adsorption of drugs or conjugation of drug molecules by chemical treatment; and (d) drugs can be encapsulated into the polymer coating itself.

Fig. 14

Schematic of drug release: from uncoated (a), and polymer-coated (b) CaP scaffolds, and a CPC loaded with drug molecules (red zig-zags) (c); blue arrows indicate the drug release.

Fig. 15

Schematic representation of the chemical association of bisphosphonates onto the surface of CDA particles, via a reversible BP for phosphate exchange (Copyright (2008) American Chemical Society. Reprinted from Ref. [173] with permission).

Fig. 16

In vitro release profile of human growth hormone (hGH) from macroporous biphasic calcium phosphate (MBCP) ceramic: (a) cumulated hGH amount released; (b) Higuchi plot of the hGH release profile; (n = 3) (Copyright (1998) John Wiley and Sons. Reprinted from Ref. [139] with permission).

Fig. 17

Two different types of pore distribution in a α-TCP cement measured by mercury intrusion porosimetry, and also observed in SEM image. Porosity between aggregates (a), and porosity between crystallites. These intrinsic porosities play a key role in drug adsorption and release (Copyright (2009) Elsevier. Reprinted from Ref. [183] with permission).