Elise Verron

Calcium phosphate biomaterials as bone drug delivery systems: a review.

A short review is proposed on the existing literature for the research performed in calcium phosphate (CaP) biomaterials used as drug delivery systems. In the first part, a brief update is given on the performance of both CaP ceramics and CaP cements. Second, a review of the research and clinical situation is developed for CaP materials already used as drug delivery systems. Experimental works performed for local delivery are reported. In particular, a description is given of the in vitro and in vivo studies in which these materials are loaded with various proteins and drugs.

In vivo bone augmentation in an osteoporotic environment using bisphosphonate-loaded calcium deficient apatite

Resorbable calcium phosphate (CaP) biomaterials have demonstrated considerable efficacy in bone reconstructive surgery. Furthermore, bisphosphonates (BPs) are well known anti-resorptive agents largely used in clinical treatments for osteoporosis. An injectable BP-combined CaP matrix has been developed in order to biologically reinforce osteoporotic bone by increasing the bone fraction and improving bone micro-architecture. Our previous in vitro studies have shown that CaP is effective for loading and releasing BPs at doses that can inhibit excessive bone resorption without affecting osteoblasts. In vivo studies in relevant animal models are necessary to explore the effect of our injectable BP-combined biomaterial on femur bone structure by performing three-dimensional microtomography analysis, histological studies and SEM observations. Firstly, in rat model, our BP-combined CaP matrix significantly improved the bone micro-architecture as compared to CaP alone. The implantation of the BP-loaded biomaterial within proximal femurs of osteoporotic ewes led to a significant increase in relative bone content and an improvement of its micro-architecture. These modifications were confirmed by histological and SEM observations, which revealed CaP granule resorption and new bone trabeculae formation. This approach could be considered in the future for preventing osteoporotic fractures that are preferentially localized in the proximal femur, vertebral bodies or wrist.

Controlled release of bisphosphonate from a calcium phosphate biomaterial inhibits osteoclastic resorption in vitro

Calcium phosphate biomaterials such as calcium deficient apatite (CDA) have been contemplated as carrier for delivery of bisphosphonate in bone tissues. In the present work, we have investigated the in vitro biological properties of Zoledronate-loaded CDA. CDA was loaded with zoledronate according to a previously described coating process. 31P MAS NMR spectra demonstrated the effective loading of zoledronate onto CDA. Using 14C labeled zoledronate, we then demonstrated the in vitro release of zoledronate from CDA. In a first set of experiments, we confirmed that Zoledronate reduced the number of TRAP-, vitronectin receptor-, and F-actin ring-positive cells as well as the resorption activity of osteoclasts obtained from a total rabbit bone cell culture. Interestingly, Zoledronate-loaded CDA and its extractive solutions decreased the osteoclastic resorption. Finally, zoledronate-loaded CDA did not affect the viability and alkaline phosphatase activity of primary osteoblastic cells. These data demonstrate that CDA is effective for loading and release of zoledronate. The released zoledronate inhibited osteoclastic resorption without affecting osteoblasts. Our findings therefore suggest that such a drug delivery system would allow an increase in the efficiency of bisphosphonates by being locally available. Further experiments are now required to evaluate the in vivo antiresorptive activity of this concept.

Controlling the biological function of calcium phosphate bone substitutes with drugs

There is a growing interest in bone tissue engineering for bone repair after traumatic, surgical or pathological injury, such as osteolytic tumor or osteoporosis. In this regard, calcium phosphate (CaP) bone substitutes have been used extensively as bone-targeting drug-delivery systems. This localized approach improves the osteogenic potential of bone substitutes by delivering bone growth factors, thus extending their biofunctionality to any pathological context, including infection, irradiation, tumor and osteoporosis. This review briefly describes the physical and chemical processes implicated in the preparation of drug-delivering CaPs. It also describes the impact of these processes on the intrinsic properties of CaPs, especially in terms of the drug-release profile. In addition, this review focuses on the potential influence of drugs on the resorption rate of CaPs. Interestingly, by modulating the resorption parameters of CaP biomaterials, it should be possible to control the release of bone-stimulating ions, such as inorganic phosphate, in the vicinity of bone cells. Finally, recent in vitro and in vivo evaluations are extensively reported.

Biphasic calcium phosphate ceramics for bone reconstruction: A review of biological response

Autologous bone graft is considered as the gold standard in bone reconstructive surgery. However, the quantity of bone available is limited and the harvesting procedure requires a second surgical site resulting in severe complications. Due to these limits, scientists and clinicians have considered alternatives to autologous bone graft. Calcium phosphates (CaPs) biomaterials including biphasic calcium phosphate (BCP) ceramics have proven efficacy in numerous clinical indications. Their specific physico-chemical properties (HA/TCP ratio, dual porosity and subsequent interconnected architecture) control (regulate/condition) the progressive resorption and the bone substitution process. By describing the most significant biological responses reported in the last 30years, we review the main events that made their clinical success. We also discuss about their exciting future applications as osteoconductive scaffold for delivering various bioactive molecules or bone cells in bone tissue engineering and regenerative medicine. STATEMENT OF SIGNIFICANCE Nowadays, BCPs are definitely considered as the gold standard of bone substitutes in bone reconstructive surgery. Among the numerous clinical studies in literature demonstrating the performance of BCP, Passuti et al. and Randsford et al. studies largely contributed to the emergence of the BCPs. It could be interesting to come back to the main events that made their success and could explain their large adhesion from scientists to clinicians. This paper aims to review the most significant biological responses reported in the last 30years, of these BCP-based materials. We also discuss about their exciting future applications as osteoconductive scaffold for delivering various bioactive molecules or bone cells in bone tissue engineering and regenerative medicine.

Gallium modulates osteoclastic bone resorption in vitro without affecting osteoblasts

Background and purpose:  Gallium (Ga) has been shown to be effective in the treatment of disorders associated with accelerated bone loss, including cancer‐related hypercalcemia and Pagets disease. These clinical applications suggest that Ga could reduce bone resorption. However, few studies have studied the effects of Ga on osteoclastic resorption. Here, we have explored the effects of Ga on bone cells in vitro.

Is bisphosphonate therapy compromised by the emergence of adverse bone disorders

Bisphosphonates (BPs) are the preferred class of antiresorptive agents used for the treatment of osteoporosis and bone metastases. Recently, an increasing number of clinical reports concerning osteonecrosis of the jaw and atypical fractures have suggested a link between prolonged use of BPs and these adverse bone events, which are exceptionally difficult to treat. Even though these side effects were mainly observed in patients with metastases, osteoporotic patients might become increasingly affected by these conditions with the increasing use of injectable BPs. Could these severe adverse bone events compromise the use of BPs? The development of these unfavorable conditions as a consequence of oversuppression of bone resorption could raise concern regarding the use of therapeutic strategies involving antiresorptive drugs.

Vertebroplasty using bisphosphonate-loaded calcium phosphate cement in a standardized vertebral body bone defect in an osteoporotic sheep model.

In the context of bone regeneration in an osteoporotic environment, the present study describes the development of an approach based on the use of calcium phosphate (CaP) bone substitutes that can promote new bone formation and locally deliver in situ bisphosphonate (BP) directly at the implantation site. The formulation of a CaP material has been optimized by designing an injectable apatitic cement that (i) hardens in situ despite the presence of BP and (ii) provides immediate mechanical properties adapted to clinical applications in an osteoporotic environment. We developed a large animal model for simulating lumbar vertebroplasty through a two-level lateral corpectomy on L3 and L4 vertebrae presenting a standardized osteopenic bone defect that was filled with cements. Both 2-D and 3-D analysis of microarchitectural parameters demonstrated that implantation of BP-loaded cement in such vertebral defects positively influenced the microarchitecture of the adjacent trabecular bone. This biological effect was dependent on the distance from the implant, emphasizing the in situ effect of the BP and its release from the cement. As a drug device combination, this BP-containing apatitic cement shows good promise as a local approach for the prevention of osteoporotic vertebral fractures through percutaneous vertebroplasty procedures.

Design and properties of novel gallium-doped injectable apatitic cements

UNLABELLED Different possible options were investigated to combine an apatitic calcium phosphate cement with gallium ions, known as bone resorption inhibitors. Gallium can be either chemisorbed onto calcium-deficient apatite or inserted in the structure of β-tricalcium phosphate, and addition of these gallium-doped components into the cement formulation did not significantly affect the main properties of the biomaterial, in terms of injectability and setting time. Under in vitro conditions, the amount of gallium released from the resulting cement pellets was found to be low, but increased in the presence of osteoclastic cells. When implanted in rabbit bone critical defects, a remodeling process of the gallium-doped implant started and an excellent bone interface was observed. STATEMENT OF SIGNIFICANCE The integration of drugs and materials is a growing force in the medical industry. The incorporation of pharmaceutical products not only promises to expand the therapeutic scope of biomaterials technology but to design a new generation of true combination products whose therapeutic value stem equally from both the structural attributes of the material and the intrinsic therapy of the drug. In this context, for the first time an injectable calcium phosphate cement containing gallium was designed with properties suitable for practical application as a local delivery system, implantable by minimally invasive surgery. This important and original paper reports the design and in-depth chemical and physical characterization of this groundbreaking technology.

Therapeutic strategies for treating osteolytic bone metastases.

The recent progress in oncologic management of patients with localized cancer or metastatic disease has permitted a significant improvement in life expectancy. Nevertheless, bone metastases and their consequent skeletal-related events (SREs) are still associated with unfavorable prognosis and greatly affect quality of life. Global management of these bone metastases includes traditional local approaches (surgery, radiotherapy, etc.) and systemic administration of chemotherapeutic agents. This review focuses on treatments specific for bone metastases and, in particular, on inhibitors of bone resorption that are effective for preventing and delaying the development of SREs.