Resorption of monetite granules in alveolar bone defects in human patients

Abstract

Bone grafting is often required to restore mandibular or maxillary bone volume prior to prosthetic tooth root implantation. Preclinical animal models are often used to study the in vivo properties of new bone graft products designed for human use. Although animal studies may offer valuable data regarding bioperformance, materials do not necessarily perform the same in human patients. In this study we implanted bovine hydroxyapatite (BH), a widely used porous apatite granule, and dicalcium phosphate anhydrous (monetite) granules, bilaterally in human patients post extraction alveolar sockets. After six months, histomorphometrical analysis of the biopsies revealed that the amount of bone regenerated with monetite (59.5 ± 13%) was significantly higher than that obtained with BH (33.1% ± 4.9), while the amount of unresorbed graft was higher in the sockets treated with BH (37.8 ± 6.1) than in those implanted with monetite (25.8 ± 14.3). Resorption of calcium phosphate ceramics is discussed by applying the Hixon–Crowell dissolution model.

Introduction

Dental implants are the restorations of choice in partially and completely edentulous patients due to their successful and predictable prognosis. However, most edentulous patients seeking this kind of treatment have insufficient bone volume to allow the placement of even the smallest implants, mainly due to age or chronic infections, and they require prior bone regeneration procedures [1], [2], [3]. Ideal graft materials for bone regeneration should combine osteogenesis, osteoconductive and osteoinductive properties, as well as being able to resorb in vivo to eventually be replaced by regenerated bone [1], [2], [3], [4]. Calcium phosphate biomaterials are excellent candidates for bone regeneration due to their proven biocompatitibility, osteconductive and sometimes osteoinductive properties. However, their resorption capacity in vivo is often reduced, and this is a limiting factor in restorations were the material is to be progressively replaced by functional autologous bone.

Calcium phosphate resorption in vivo is a combined mechanism of passive dissolution and cellular resorption [5], [6], [7]. Cellular mediated resorption is closely related to biological signals regulating osteoclast activity, such as factor RANKL [8], that synthetic bioceramics usually lack, unless deliberately added. Therefore, dissolution remains the major factor determining the resorption process in many calcium phosphate biomaterials and is important when designing bioresorbable ceramics.

Calcium phosphate ceramic materials dissolve into ions that are eventually cleared by the body [5], [6]. Under non-equilibrium conditions, a bioceramic crystal may grow or dissolve depending on the concentration of the solid in the medium (C) and the concentration at saturation (C_s) [9], [10], [11], hence that rate of bioceramic dissolution can be written as

$$\frac{dC}{dt}=k\left(C_{\text{s}}-C\right)$$

where k is the dissolution rate constant. Hixon and Crowell proposed [10], that the rate of dissolution of a given material in vivo depends on properties characteristic of the material it self, such as geometry and solubility, and on the properties of the dissolving medium, such as volume and temperature.

The kinetics of the dissolving system may be expressed as a change in mass by:

$$w_{\text{0}}^{\frac{1}{3}}-w_{\text{t}}^{\frac{1}{3}}=k_2·t$$

where w₀ is the mass of the particles at time zero, w_t is the undissolved mass at a time t, and k₂ is a constant that involves the solubility and geometry of the particles and its solvent volume. This can also be written as:

$$k_2=\frac{1.61·L·k·S·\left(n^{\frac{1}{3}}\right)}{{\rho }^{\frac{2}{3}}}$$

where k₂ is the same as in Eq. (2), L is the volume of dissolution medium, S is the solubility, n the total number of particles and ρ is the density of the material [11].

Mammals have a very stable temperature and concentration of ions in serum, therefore, when a biomaterial is implanted in vivo, its resorption rate would depend on its solubility, geometry (porosity and surface area), and on the rate of water exchange. Accordingly, the resorption rate of a resorbable biomaterial in vivo would be expected to be influenced by both the material it self and the species specific water exchange of the animal in which the material implanted.

A comparison between the resorption of two calcium phosphate biomaterials in different animal species and surgical sites is presented in Table 1.

The volume of water turnover in mammals depends on their caloric demand and presents and inverse logarithmic relation with their body mass. This explains the variable behavior of bioceramic materials when implanted in different animal species or in humans. Overall, resorption seems to occur faster in smaller animal species with lower body mass, and therefore, higher rate of water exchange (Table 1) [12], [13], [14], [15], [16], [17].

Calcined bovine bone hydroxyapatite (BH), is currently one of the most commonly used bone substitutes worldwide, however, its low solubility in serum results in almost no resorption in vivo. On the other hand, β-tricalcium phosphate (β-TCP), has higher solubility in physiological conditions, and subsequently, its resorption in vivo is much higher, as reported in both animal and clinical experiments (Table 1). Dicalcium phosphate dihydrate (brushite) reacts in vivo to form hydroxyapatite, and therefore its resorption rate in vivo is initially fast, but it slows down eventually as it re-precipitates into poorly resorbable HA, limiting its bioresorptive capacity [18], [19], [20], [21], [22], [23], [24].

Monetite is a dicalcium phosphate that can be prepared by the dehydration of brushite ceramics [25], [26]. Monetite is currently being used as a component of hydroxyapatite cements for orthopedic applications [25], [26], [28], [29], [30], [31], [32], [33], [34], [35], and its potential as bone regeneration material has been known since the early to mid 20th century [47], [48]. Recent development of brushite cements has awakened the interest in monetite since it has been found that custom-made monetite biomaterials can be prepared in adequate shapes and sizes by thermal dehydration of brushite preset cements [19], [49], [50]. Although both materials have similar chemical composition, their in vivo behavior is quite different, mainly due to differences in water solubility at physiological pH (see Table 1). Monetite does not reprecipitate into HA in vivo, and recent animal studies have demonstrated its good osteoconductive and osteoinductive properties, as well as being largely resorbable in vivo [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27]. Even though monetite resorption has been established in several small animal species, its behavior in human patients has yet to be determined.

This study reports the results of the first limited clinical trial of monetite and analyzes the effect of body weight on the resorption rate of calcium phosphates. This information has then been used to predict the resorption rate of monetite in humans. Subsequently we compare the predicted values with the data obtained from our clinical study and evaluate the extrapolation of animal data into human studies.