Frank Witte

The history of biodegradable magnesium implants: a review.

Today, more than 200years after the first production of metallic magnesium by Sir Humphry Davy in 1808, biodegradable magnesium-based metal implants are currently breaking the paradigm in biomaterial science to develop only highly corrosion resistant metals. This groundbreaking approach to temporary metallic implants is one of the latest developments in biomaterials science that is being rediscovered. It is a challenging topic, and several secrets still remain that might revolutionize various biomedical implants currently in clinical use. Magnesium alloys were investigated as implant materials long ago. A very early clinical report was given in 1878 by the physician Edward C. Huse. He used magnesium wires as ligature for bleeding vessels. Magnesium alloys for clinical use were explored during the last two centuries mainly by surgeons with various clinical backgrounds, such as cardiovascular, musculoskeletal and general surgery. Nearly all patients benefited from the treatment with magnesium implants. Although most patients experienced subcutaneous gas cavities caused by rapid implant corrosion, most patients had no pain and almost no infections were observed during the postoperative follow-up. This review critically summarizes the in vitro and in vivo knowledge and experience that has been reported on the use of magnesium and its alloys to advance the field of biodegradable metals.

Evaluation of short-term effects of rare earth and other elements used in magnesium alloys on primary cells and cell lines ☆

Degradable magnesium alloys for biomedical application are on the verge of being used clinically. Rare earth elements (REEs) are used to improve the mechanical properties of the alloys, but in more or less undefined mixtures. For some elements of this group, data on toxicity and influence on cells are sparse. Therefore in this study the in vitro cytotoxicity of the elements yttrium (Y), neodymium (Nd), dysprosium (Dy), praseodymium (Pr), gadolinium (Gd), lanthanum (La), cerium (Ce), europium (Eu), lithium (Li) and zirconium (Zr) was evaluated by incubation with the chlorides (10-2000 microM); magnesium (Mg) and calcium (Ca) were tested at higher concentrations (200 and 50mM, respectively). The influence on viability of human osteosarcoma cell line MG63, human umbilical cord perivascular (HUCPV) cells and mouse macrophages (RAW 264.7) was determined, as well as the induction of apoptosis and the expression of inflammatory factors (TNF-alpha, IL-1alpha). Significant differences between the applied cells could be observed. RAW exhibited the highest and HUCPV the lowest sensitivity. La and Ce showed the highest cytotoxicity of the analysed elements. Of the elements with high solubility in magnesium alloys, Gd and Dy seem to be more suitable than Y. The focus of magnesium alloy development for biomedical applications should include most defined alloy compositions with well-known tissue-specific and systemic effects.

Magnesium alloys as implant materials--principles of property design for Mg-RE alloys.

Magnesium alloys have attracted increasing interest in the past years due to their potential as implant materials. This interest is based on the fact that magnesium and its alloys are degradable during their time of service in the human body. Moreover magnesium alloys offer a property profile that is very close or even similar to that of human bone. The chemical composition triggers the resulting microstructure and features of degradation. In addition, the entire manufacturing route has an influence on the morphology of the microstructure after processing. Therefore the composition and the manufacturing route have to be chosen carefully with regard to the requirements of an application. This paper discusses the influence of composition and heat treatments on the microstructure, mechanical properties and corrosion behaviour of cast Mg-Gd alloys. Recommendations are given for the design of future degradable magnesium based implant materials.

In vivo corrosion and corrosion protection of magnesium alloy LAE442

The aim of this study was to investigate whether the extruded magnesium alloy LAE442 reacts in vivo with an appropriate host response and to investigate how an additional magnesium fluoride (MgF(2)) coating influences the in vivo corrosion rate. Forty cylinders were machined from extruded LAE442 and 20 of these were coated additionally with MgF(2) and implanted into the medial femur condyle of adult rabbits. Synchrotron-radiation-based X-ray computed micro-tomography (SRmicroCT) was used to quantitatively analyse corrosion non-destructively in vivo and comparisons were made to magnesium degradation rates based on area measurements of the remaining metal on uncalcified sections. Blood concentrations of the alloying elements were measured below toxicological limits. The MgF(2) layer was no longer detected after 4 weeks of implantation by particle-induced gamma emission, and the MgF(2) coating reduced the blood content of alloying elements during the first 6 weeks of implantation with no elevated fluoride concentration in the adjacent bone. Histopathological examinations of liver showed in 9 out of 40 cases minimal infiltrations of heterophil granulocytes of unknown origin (5 LAE442, 4 LAE442+MgF(2)). The kidneys were mainly regular in structure. The synovial tissue showed a granular cell infiltration as a temporary observation in the LAE442+MgF(2) group after 2 weeks. No subcutaneous gas cavities were observed clinically and on postoperative X-rays in all animals. All specimens were scanned by SRmicroCT at 2, 4, 6 and 12 weeks postoperatively before uncalcified sections were performed. All magnesium implants have been observed in direct bone contact and without a fibrous capsule. Localized pitting corrosion occurred in coated and uncoated magnesium implants. This study shows that the extruded magnesium alloy LAE442 provides low corrosion rates and reacts in vivo with an acceptable host response. The in vivo corrosion rate can be further reduced by additional MgF(2) coating.

Magnesium hydroxide temporarily enhancing osteoblast activity and decreasing the osteoclast number in peri-implant bone remodelling.

Repeated observations of enhanced bone growth around various degradable magnesium alloys in vivo raise the question: what is the major mutual origin of this biological stimulus? Several possible origins, e.g. the metal surface properties, electrochemical interactions and biological effects of alloying elements, can be excluded by investigating the sole bone response to the purified major corrosion product of all magnesium alloys, magnesium hydroxide (Mg(OH)(2)). Isostatically compressed cylinders of pure Mg(OH)(2) were implanted into rabbit femur condyles for 2-6 weeks. We observed a temporarily increased bone volume (BV/TV) in the vicinity of Mg(OH)(2) at 4 weeks that returned to a level that was equal to the control at 6 weeks. The osteoclast surface (OcS/BS) was significantly reduced during the first four weeks around the Mg(OH)(2) cylinder, while an increase in osteoid surface (OS/BS) was observed at the same time. At 6 weeks, the OcS/BS adjacent to the Mg(OH)(2) cylinder was back within the same range of the control. The mineral apposition rate (MAR) was extensively enhanced until 4 weeks in the Mg(OH)(2) group before matching the control. Thus, the enhanced bone formation and temporarily decreased bone resorption resulted in a higher bone mass around the slowly dissolving Mg(OH)(2) cylinder. These data support the hypothesis that the major corrosion product Mg(OH)(2) from any magnesium alloy is the major origin of the observed enhanced bone growth in vivo. Further studies have to evaluate if the enhanced bone growth is mainly due to the local magnesium ion concentration or the local alkalosis accompanying the Mg(OH)(2) dissolution.

The morphology of anisotropic 3D-printed hydroxyapatite scaffolds

Three-dimensional (3D) scaffolds with tailored pores ranging from the nanometer to millimeter scale can support the reconstruction of centimeter-sized osseous defects. Three-dimensional-printing processes permit the voxel-wise fabrication of scaffolds. The present study rests upon 3D-printing with nano-porous hydroxyapatite granulates. The cylindrical design refers to a hollow bone with higher density at the periphery. The millimeter-wide central channel follows the symmetry axis and connects the perpendicularly arranged micro-pores. Synchrotron radiation-based micro computed tomography has served for the non-destructive characterization of the scaffolds. The 3D data treatment is essential, since, for example, the two-dimensional distance maps overestimate the mean distances to the material by 33-50% with respect to the 3D analysis. The scaffolds contain 70% micrometer-wide pores that are interconnected. Using virtual spheres, which might be related to the cells migrating along the pores, the central channel remains accessible through the micro-pores for spheres with a diameter of up to (350+/-35)mum. Registering the tomograms with their 3D-printing matrices has yielded the almost isotropic shrinking of (27+/-2)% owing to the sintering process. This registration also allows comparing the design and tomographic data in a quantitative manner to extract the quality of the fabricated scaffolds. Histological analysis of the scaffolds seeded with osteogenic-stimulated progenitor cells has confirmed the suitability of the 3D-printed scaffolds for potential clinical applications.

Implant-Derived Magnesium Induces Local Neuronal Production of CGRP to Improve Bone-Fracture Healing in Rats

Orthopedic implants containing biodegradable magnesium have been used for fracture repair with considerable efficacy; however, the underlying mechanisms by which these implants improve fracture healing remain elusive. Here we show the formation of abundant new bone at peripheral cortical sites after intramedullary implantation of a pin containing ultrapure magnesium into the intact distal femur in rats. This response was accompanied by substantial increases of neuronal calcitonin gene-related polypeptide-α (CGRP) in both the peripheral cortex of the femur and the ipsilateral dorsal root ganglia (DRG). Surgical removal of the periosteum, capsaicin denervation of sensory nerves or knockdown in vivo of the CGRP-receptor-encoding genes Calcrl or Ramp1 substantially reversed the magnesium-induced osteogenesis that we observed in this model. Overexpression of these genes, however, enhanced magnesium-induced osteogenesis. We further found that an elevation of extracellular magnesium induces magnesium transporter 1 (MAGT1)-dependent and transient receptor potential cation channel, subfamily M, member 7 (TRPM7)-dependent magnesium entry, as well as an increase in intracellular adenosine triphosphate (ATP) and the accumulation of terminal synaptic vesicles in isolated rat DRG neurons. In isolated rat periosteum-derived stem cells, CGRP induces CALCRL- and RAMP1-dependent activation of cAMP-responsive element binding protein 1 (CREB1) and SP7 (also known as osterix), and thus enhances osteogenic differentiation of these stem cells. Furthermore, we have developed an innovative, magnesium-containing intramedullary nail that facilitates femur fracture repair in rats with ovariectomy-induced osteoporosis. Taken together, these findings reveal a previously undefined role of magnesium in promoting CGRP-mediated osteogenic differentiation, which suggests the therapeutic potential of this ion in orthopedics.

Fast escape of hydrogen from gas cavities around corroding magnesium implants.

Magnesium materials are of increasing interest in the development of biodegradable implants as they exhibit properties that make them promising candidates. However, the formation of gas cavities after implantation of magnesium alloys has been widely reported in the literature. The composition of the gas and the concentration of its components in these cavities are not known as only a few studies using non-specific techniques were done about 60 years ago. Currently many researchers assume that these cavities contain primarily hydrogen because it is a product of magnesium corrosion in aqueous media. In order to clearly answer this question we implanted rare earth-containing magnesium alloy disks in mice and determined the concentration of hydrogen gas for up to 10 days using an amperometric hydrogen sensor and mass spectrometric measurements. We were able to directly monitor the hydrogen concentration over a period of 10 days and show that the gas cavities contained only a low concentration of hydrogen gas, even shortly after formation of the cavities. This means that hydrogen must be exchanged very quickly after implantation. To confirm these results hydrogen gas was directly injected subcutaneously. Most of the hydrogen gas was found to exchange within 1h after injection. Overall, our results disprove the common misbelief that these cavities mainly contain hydrogen and show how quickly this gas is exchanged with the surrounding tissue.

Current status on clinical applications of magnesium-based orthopaedic implants: A review from clinical translational perspective

As a new generation of medical metallic material, magnesium (Mg) and its alloys with or without surface coating have attracted a great deal of attention due to its biodegradability and potential for avoiding a removal operation after the implant has fulfilled its function for surgical fixation of injured musculoskeletal tissues. Although a few clinical cases on Mg-based orthopaedic implants were reported more than a century ago, it was not until recently that clinical trials using these implants with improved physicochemical properties were carried out in Germany, China and Korea for bone fracture fixation. The promising results so far suggest a bright future for biodegradable Mg-based orthopaedic implants and would warrant large scale phase II/III studies. Given the increasing interest on this emerging biomaterials and intense effort to improve its properties for various clinical applications, this review covers the evolution, current strategies, and future perspectives in the development of Mg-based orthopaedic implants. We also highlight a few clinical cases performed in China that may be unfamiliar to the general orthopaedic community.

In vitro and in vivo evaluation of biodegradable, open-porous scaffolds made of sintered magnesium W4 short fibres

A cytocompatible and biocompatible, degradable, open-porous, mechanically adaptable metal scaffold made of magnesium alloy W4 melt-extracted short fibres was fabricated by liquid phase sintering. Cylindrical samples (3×5 mm) of sintered W4 short fibres were evaluated under in vitro (L929, HOB, eudiometer, weight loss) and in vivo conditions (rabbits: 6 and 12 weeks). The in vitro corrosion environment (e.g., temperature, flow, composition of corrosion solution, exposure time) significantly influenced the corrosion rates of W4 scaffolds compared with corrosion in vivo. Corrosion rates under cell culture conditions for 72 h varied from 1.05 to 3.43 mm y(-1) depending on the media composition. Corrosion rates measured in eudiometric systems for 24 h were ~24-27 times higher (3.88-4.43 mm y(-1)) than corrosion in vivo after 6 weeks (0.16 mm y(-1)). Moreover, it was found that the cell culture media composition significantly influences the ionic composition of the extract by selectively dissolving ions from W4 samples or their corrosion products. A pilot in vivo study for 6 and 12 weeks demonstrated active bone remodelling, no foreign body reaction and no clinical observation of gas formation during W4 scaffold implantation. Long-term in vivo studies need to be conducted to prove complete degradation of the W4 scaffold and total replacement by the host tissue.