Longitudinal in vivo biodistribution of nano and micro sized hydroxyapatite particles implanted in a bone defect

Abstract

Hydroxyapatite (HA) has been widely used as a bone substitute and more recently as a carrier for local delivery of bone targeted drugs. Majority of the approved HA based biomaterials and drug carriers comprise of micrometer sized particulate HA (mHA) or granules and can therefore only be used for extracellular drug release. This shortcoming could be overcome with the use of cell penetrating HA nanoparticles (nHA) but a major concern with the clinical use of nHA is the lack of data on its in vivo biodistribution after implantation. In this study, we aimed to study the in vivo biodistribution of locally implanted nHA in a clinically relevant tibial void in rats and compare it with mHA or a combination of mHA and nHA. To enable in vivo tracking, HA particles were first labelled with 14C-zoledronic acid (14C-ZA), known to have a high binding affinity to HA. The labelled particles were then implanted in the animals and the radioactivity in the proximal tibia and vital organs was detected at various time points (Day 1, 7 and 28) post-implantation using scintillation counting. The local distribution of the particles in the bone was studied with micro-CT. We found that majority (>99.9%) of the implanted HA particles, irrespective of the size, stayed locally at the implantation site even after 28 days and the findings were confirmed using micro-CT. Less than 0.1% radioactivity was observed in the kidney and the spleen at later time points of day 7 and 28. No pathological changes in any of the vital organs could be observed histologically. This is the first longitudinal in vivo HA biodistribution study showing that the local implantation of nHA particles in bone is safe and that nHA could potentially be used for localized drug delivery.

Co-delivery of rhBMP-2 and zoledronic acid using calcium sulfate/hydroxyapatite carrier as a bioactive bone substitute to enhance and accelerate spinal fusion

“…Blood levels of bone biomarkers were not affected by local ZA application compared to the corresponding systemic ZA application group. A recent study of our team further confirmed this conclusion [ 43 ]. By loading 14 C-ZA into a micro- or nano-HA biomaterial, it was found that more than 99 % of 14 C ZA still was locally retained within the defect and less than 0.1 % of the ZA could be detected in other organs, regardless of particle size, after 4 weeks in a rat tibial defect model.…”

“…By loading 14 C-ZA into a micro- or nano-HA biomaterial, it was found that more than 99 % of 14 C ZA still was locally retained within the defect and less than 0.1 % of the ZA could be detected in other organs, regardless of particle size, after 4 weeks in a rat tibial defect model. ZA is tightly linked and chemically bound to the HA phase in a biphasic scaffold [ 15 , 43 ]. The targeted high biological effect of ZA significantly reduced the degradation of CaS/HA.…”

“…Previous studies showed that the CaS phase of CaS/HA biphasic carrier encapsulates rhBMP-2 by physical entrapment while preserving the biological activity of the protein [ 15 ]. In contrast, ZA chemically binds to the HA phase [ 15 , 43 ]. CaS/HA co-delivery of rhBMP-2 and ZA achieved significant bone formation in both an in vivo muscle pouch model [ 15 ] and a femoral defect model [ 26 ], in which rhBMP-2 loading of CaS/HA biomaterials promoted bone regeneration.…”

Endogenous Tissue Engineering for Chondral and Osteochondral Regeneration: Strategies and Mechanisms

“…Bioceramics can be synthesized from a range of materials, including alumina, zirconia, magnesia, carbon, silica-based compounds, calcium-based compounds, and various other chemicals . The initial development of bioceramics aimed to serve as bone substitutes for implantation for its superior biocompatibility, high mechanical strength, and corrosion resistance. , In recent years, through optimization of the material, processing methods, and physicochemical properties of bioceramics, the application of bioceramic scaffolds has expanded beyond bone regeneration to the integrated regeneration of OC tissue . For endogenous OC tissue engineering, bioceramic scaffolds can be functionalized to regulate stem cell functions, thus promoting AC and bone regeneration .…”

Cross Talk Between Cells and the Current Bioceramics in Bone Regeneration: A Comprehensive Review

“…Ceramic materials have proven successful in addressing bone tissue defects, falling under the umbrella of bioceramics. Bioceramics encompass inorganic, non-metallic materials with biocompatibility, high melting points, electrical resistance, and corrosion resistance 11 . While ceramic scaffolds offer promise for various applications in oral and maxillofacial surgery, periodontal treatments, and orthopedics, their brittle nature restricts their use to non-load-bearing applications 12 , 13 .…”