Magnesium alloys for temporary implants in osteosynthesis: In vivo studies of their degradation and interaction with bone

Abstract

This study investigates the bone and tissue response to degrading magnesium pin implants in the growing rat skeleton by continuous in vivo microfocus computed tomography (μCT) monitoring over the entire pin degradation period, with special focus on bone remodeling after implant dissolution. The influence of gas release on tissue performance upon degradation of the magnesium implant is also addressed. Two different magnesium alloys – one fast degrading (ZX50) and one slowly degrading (WZ21) – were used for evaluating the bone response in 32 male Sprague–Dawley rats. After femoral pin implantation μCTs were performed every 4 weeks over the 24 weeks of the study period. ZX50 pins exhibited early degradation and released large hydrogen gas volumes. While considerable callus formation occurred, the bone function was not permanently harmed and the bone recovered unexpectedly quickly after complete pin degradation. WZ21 pins kept their integrity for more than 4 weeks and showed good osteoconductive properties by enhancing bone accumulation at the pin surface. Despite excessive gas formation, the magnesium pins did not harm bone regeneration. At smaller degradation rates, gas evolution remained unproblematic and the magnesium implants showed good biocompatibility. Online μCT monitoring is shown to be suitable for evaluating materials degradation and bone response in vivo, providing continuous information on the implant and tissue performance in the same living animal.

Introduction

In recent years extensive research on magnesium and its alloys as potential biodegradable implant materials has been carried out [1], [2], [3], [4], [5], [6], [7]. Biodegradable magnesium alloys are more suitable for load-bearing implant applications than their polymeric counterparts due to their superior mechanical strength. Moreover, since their elastic properties resemble those of bone, they are considered ideal for hard tissue implants employed in fracture stabilization because stress shielding is avoided and bone regeneration is enhanced [1], [2]. Previous in vivo and in vitro studies have shown that magnesium alloys exhibit good biocompatibility with no systemic inflammatory reaction or affection of the cellular blood composition [3], [4], [5], [6]. In addition, high mineral apposition rates and increased bone mass were found around degrading Mg implants in bone [7]. The beneficial influence of magnesium has been emphasized further in a study showing that the bone–implant interface strength and osseointegration are significantly greater for magnesium than for conventional titanium materials [8]. Using materials that degrade in physiological environments renders subsequent surgical intervention for implant removal after tissues healing [1], [3]. This is of great benefit because morbidity related to repeated surgery is reduced and additional health costs are avoided. It makes temporary implants also very attractive in pediatric cases – which are, as potential end application, in the focus of this study – where the growing bone is less interfered with and its regeneration after fracture is supported.

Specific properties must be fulfilled in order to use biodegradable implants as material for osteosynthesis in a growing skeleton. The key issues include (i) an adequate stability during fracture healing, requiring sufficient strength to hold the replaced fracture; (ii) degradation and full regeneration of the bone structure within 12–15 months, requiring a moderate and homogeneous degradation performance in equilibrium with the bone healing process; and (iii) biocompatibility, requiring an adequate biological response. Magnesium is considered to meet many of these requirements. However, the fact that its degradation is accompanied by hydrogen gas formation (Mg + 2H₂O → Mg(OH)₂ + H₂, [9]) has abated the optimistic predictions for its use in osteosynthesis, because its degradation generally results in considerable gas accumulations in the surrounding tissue [7]. Therefore, recent studies focused mainly on assessing the corrosion performance of various Mg alloys in vitro and in vivo and finding compositions that enable slow and homogeneous degradation [5], [10], [11]. It has remained unclear, however, to what extent gas accumulations are harmful and whether bone healing is thus negatively affected. To our knowledge, studies focusing on the bone behavior at the end of the degradation process are also lacking as most studies were concluded before entire implant degradation was achieved. Thus, in this study we investigate the bone behavior during and after complete degradation of Mg pin implants by continuous microfocus computed tomography (μCT) monitoring in the same living animal and by histological analysis.

Since its introduction by Feldcamp et al. [12], μCT has gained enormous significance in the quantitative assessment of cancellous bone [13]. In anthropology, this method of microarchitecture imaging finds widespread application, besides histological sectioning, planar radiography, and medical computed tomography [13]. The high-resolution imaging, with a resolution of tens of microns, is a pivotal advantage of μCT over previously used methods, since studies have indeed demonstrated that accurate assessment of trabecular architecture depends on image resolution [14]. Moreover, μCT based on quantitative bone morphometry is key for three-dimensional (3-D) measurements of trabecular bone structure [15].

The animal model deployed in our study is the growing rat skeleton. This model was chosen for two reasons: (i) the anatomical size of the laboratory rat is considered appropriate for bone implant experiments in small animals, and (ii) feasibility of μCT examination is guaranteed within the entire growth process of the rat and even on full-grown animals. For gaining information on the influence of the degradation rate and thus the gas formation rate on bone healing, two different Mg alloys were evaluated: the alloy ZX50 and the alloy WZ21 (their compositions are listed in Table 1). Both alloys have similar mechanical performance and a chemical composition considered promising for temporary implant applications [5], [16], [17]; however, they considerably differ in their degradation performance. The alloy ZX50 degrades rather rapidly in vitro in physiological solutions and was deliberately chosen to achieve complete degradation in an appropriate time period. It represents also a material that evolves considerable amounts of hydrogen gas in short time periods. For Mg alloys to be used as viable implant materials, their degradation rates should not exceed the healing rate of the affected tissue, however. For adults they should maintain their mechanical integrity at least for 12–18 weeks [1], [7], while in pediatric trauma patients a shorter presence in the bone is tolerated. To study the effect of gas evolution besides the fast degrading ZX50 material, the alloy WZ21 was used as reference material degrading slowly and thus exhibiting much smaller gas formation rates than ZX50 [5].

Based on this concept the present study aims at answering the following essential questions: (i) How fast do the selected alloys degrade in vivo and how long do they maintain their integrity, respectively? (ii) To what extent does the hydrogen gas evolved upon degradation of the magnesium implants irritate the surrounding tissues? (iii) Is the living organism able to remodel the alterations caused by the degradation after complete absorption of the implant? And (iv), is μCT the appropriate method for evaluating the degradation performance of such temporary implants and studying the related tissue response?