Synergistic effects of bisphosphonate and calcium phosphate nanoparticles on peri-implant bone responses in osteoporotic rats
Introduction
The use of bone implants in dental or orthopedic rehabilitation is generally successful as reflected by 10-year survival rates of 95% in healthy patients [1]. In the clinic, however, the aging patient population challenges the use of implants due to general as well as oral health issues in modern societies. For instance, osteoporosis, a common systemic bone disease, develops with age and is more prevalent in women and men aged above 50 years [2]. The prevalence of osteoporosis has been reported to increase up to 70% in patients at 80 years old. Worldwide, osteoporosis affects approximately 200 million people and the national osteoporosis foundation (NOF) estimates that over 40 million people in the USA already have osteoporosis or are at high risk in 2020 [3], [4]. Osteoporosis is characterized by a severe decrease in bone mass and alteration of trabecular bone microstructure due to an imbalance between bone resorption (by osteoclasts) and bone formation (by osteoblasts) [5]. Further, it has been shown that bone healing in osteoporosis is impaired and the biological activity of bone cells is negatively influenced [6]. For bone implant treatment in osteoporotic patients, the osteoporotic condition impedes primary stability, biological fixation and final osseointegration [7]. As such, the application of bone implants in osteoporotic patients remains a clinical challenge in dental and orthopedic surgery.
For successful implant osseointegration, the bone-implant interface has to interact optimally with the bone tissue in the implant vicinity. For medically healthy patients, new bone (i.e. woven bone) is formed directly in contact with the implant surface by osteoblastic cells, where after it transforms into mature bone [8]. This interaction can be improved by implant-related factors, such as implant design, surgical technique, and osteophilicity of the implant surface [9]. Because the implant surface directly interacts with bone tissue, a variety of surface modifications have been explored [10]. The currently available surface modifications aim to combine advantages of physical properties (e.g. roughness) with bioactive cues (i.e. bone-bonding) to improve implant integration [11]. Over the past two decades, calcium phosphate (CaP) coatings have demonstrated to favor the healing response to the implant surface and hence to enhance peri-implant bone formation [12], [13]. The presence of a CaP coating at the implant surface is anticipated to facilitate colonization by mesenchymal precursor cells and upregulate specific gene expression in the vicinity of the implant [14]. Recently, it was shown that electrostatic spray deposition (ESD) enables the functionalization of implant surfaces with CaP nanoparticles (nCaP) that mimic the mineral component of natural bone [15]. An additional advantage of ESD is that it enables the deposition of nCaP in combination with organic biomolecules such as collagen proteins, growth factors, peptides, or other therapeutic agents [16]. As a consequence, a novel generation of therapeutic implant coatings can be synthesized that instruct bone cells by releasing drug molecules locally around the implant surface, especially for compromised conditions such as osteoporosis [17], [18]. In clinical practice, the deposition of nCaP in combination with therapeutic implant coatings might have a dual effect during bone-implant integration, and their concomitant use may offer a simultaneous targeting of peri-implant bone anabolic/catabolic processes. Particularly bisphosphonates (BPs) are appealing for such purpose, as their therapeutic function to inhibit osteoclast proliferation and activity can be exploited for local effects in the vicinity of an implant surface toward improved implant fixation [19]. In view of this, the idea for therapeutic nCaP/BP coatings for bone implants represents an appealing approach to improve bone responses and implant integration in osteoporotic conditions.
The present study aimed to evaluate the efficacy of an ESD-derived nCaP/BP coating on peri-implant bone response in osteoporotic as well as healthy conditions using an established rat femoral condyle implantation model [20], [21]. At 4 weeks post-implantation, histological, histomorphometrical, and microcomputed tomography (μCT) were performed. In addition to conventional histological analysis, we also performed real-time polymerase chain reaction (RT-PCR) after 4 weeks of healing to evaluate osteogenic gene expression in the peri-implant bone in osteoporotic and healthy conditions.
Section snippets
Preparation of implants
Pin-shaped implants were made of commercially-pure titanium with main diameter of 3.1 mm and length of 7.0 mm. The implant model was featured by a pin part (diameter: 1.5 mm and length: 4 mm) to facilitate a standard method of harvesting bone-implant tissues for histological and genetic analyses. All implants were grit-blasted (roughness, Ra = 0.5 μm) and cleaned ultrasonically in nitric acid 10% (15 min), acetone (15 min), and ethanol (15 min) and thereafter air-dried.
Electrostatic spray deposition (ESD) of coatings
ESD coatings were
Rat osteoporotic model
In vivo, 6-weeks monitoring of trabecular bone in femoral condyles (i.e. implantation site) via the in-vivo μCT imaging showed rapid bone morphological changes for hypo-gonadism rats. The measurements revealed significantly lower trabecular bone volume (%BV), trabecular thickness (Tb.Th mm), trabecular number (Tb.N mm−1), and significantly higher trabecular spacing (Tb.Sp mm) for hypo-gonadism compared to healthy rats (Table 2).
Bone-implant interfacial histology after 4 weeks
The morphology of the bone tissue in the peri-implant area was
Discussion
In the present study, a combination of calcium phosphate nanoparticles (nCaP) and bisphosphonate (BP) was used to generate coatings onto titanium implants in an approach to enhance bone-implant integration for osteoporotic and healthy patients. Interestingly, by detailed histomorphometrical and μCT analyses, a significant increase in bone-to-implant contact (%BIC) and bone volume (%BV) was observed in association with the deposition of nCaP/BP onto implant surfaces at 4-weeks post-implantation
Conclusion
The results of this study demonstrate that the combined use of nCaP and bisphosphonate increases both bone formation and bone-to-implant contact compared to non-coated implants. It is suggested that simultaneous targeting of bone formation (by nCaP) and bone resorption (by BP) using nCaP/BP surface coatings represents an effective strategy for improving bone implant integration, especially in osteoporotic conditions. On the molecular level, real-time PCR analysis at 4-weeks revealed similar
Acknowledgments
We would like to acknowledge Dr. E.M. Bronkhorst for his assistance with the statistical analysis, Vincent Cuijpers for his technical assistance on μCT imaging and 3-dimentional animations, and Natasja van Dijk for her assistance with histological preparation. This research forms part of the Project P2.04 BONE-IP of the research program of the BioMedical Materials institute, co-funded by the Dutch Ministry of Economic Affairs, Agriculture and Innovation. This study was also supported by Saudi
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H.S. Alghamdi and R. Bosco contributed equally to this work.