Jan-Marten Seitz

Recent Advances in Biodegradable Metals for Medical Sutures: A Critical Review

Sutures that biodegrade and dissolve over a period of several weeks are in great demand to stitch wounds and surgical incisions. These new materials are receiving increased acceptance across surgical procedures whenever permanent sutures and long-term care are not needed. Unfortunately, both inflammatory responses and adverse local tissue reactions in the close-to-stitching environment are often reported for biodegradable polymeric sutures currently used by the medical community. While bioabsorbable metals are predominantly investigated and tested for vascular stent or osteosynthesis applications, they also appear to possess adequate bio-compatibility, mechanical properties, and corrosion stability to replace biodegradable polymeric sutures. In this Review, biodegradable alloys made of iron, magnesium, and zinc are critically evaluated as potential materials for the manufacturing of soft and hard tissue sutures. In the case of soft tissue closing and stitching, these metals have to compete against currently available degradable polymers. In the case of hard tissue closing and stitching, biodegradable sternal wires could replace the permanent sutures made of stainless steel or titanium alloys. This Review discusses the specific materials and degradation properties required by all suture materials, summarizes current suture testing protocols and provides a well-grounded direction for the potential future development of biodegradable metal based sutures.

Evaluation of wrought Zn–Al alloys (1, 3, and 5 wt % Al) through mechanical and in vivo testing for stent applications

Special high grade zinc and wrought zinc-aluminum (Zn-Al) alloys containing up to 5.5 wt % Al were processed, characterized, and implanted in rats in search of a new family of alloys with possible applications as bioabsorbable endovascular stents. These materials retained roll-induced texture with an anisotropic distribution of the second-phase Al precipitates following hot-rolling, and changes in lattice parameters were observed with respect to Al content. Mechanical properties for the alloys fell roughly in line with strength (190-240 MPa yield strength; 220-300 MPa ultimate tensile strength) and elongation (15-30%) benchmarks, and favorable elastic ranges (0.19-0.27%) were observed. Intergranular corrosion was observed during residence of Zn-Al alloys in the murine aorta, suggesting a different corrosion mechanism than that of pure zinc. This mode of failure needs to be avoided for stent applications because the intergranular corrosion caused cracking and fragmentation of the implants, although the composition of corrosion products was roughly identical between non- and Al-containing materials. In spite of differences in corrosion mechanisms, the cross-sectional reduction of metals in murine aorta was nearly identical at 30-40% and 40-50% after 4.5 and 6 months, respectively, for pure Zn and Zn-Al alloys. Histopathological analysis and evaluation of arterial tissue compatibility around Zn-Al alloys failed to identify areas of necrosis, though both chronic and acute inflammatory indications were present.

Susceptibility of metallic magnesium implants to bacterial biofilm infections.

Magnesium alloys have promising mechanical and biological properties as biodegradable medical implant materials for temporary applications during bone healing or as vascular stents. Whereas conventional implants are prone to colonization by treatment resistant microbial biofilms in which bacteria are embedded in a protective matrix, magnesium alloys have been reported to act antibacterial in vitro. To permit a basic assessment of antibacterial properties of implant materials in vivo an economic but robust animal model was established. Subcutaneous magnesium implants were inoculated with bacteria in a mouse model. Contrary to the expectations, bacterial activity was enhanced and prolonged in the presence of magnesium implants. Systemic antibiotic treatments were remarkably ineffective, which is a typical property of bacterial biofilms. Biofilm formation was further supported by electron microscopic analyses that revealed highly dense bacterial populations and evidence for the presence of extracellular matrix material. Bacterial agglomerates could be detected not only on the implant surface but also at a limited distance in the peri-implant tissue. Therefore, precautions may be necessary to minimize risks of metallic magnesium-containing implants in prospective clinical applications.

Biocompatibility of MgF2-coated MgNd2 specimens in contact with mucosa of the nasal sinus – A long term study

Up to now, different surgical techniques and stent systems have already been developed and tested for the continuous and adequate ventilation of the frontal sinuses. However, the results achieved still remain poor. Magnesium-based implants have been successfully used in numerous clinical applications. Offering excellent biocompatibility and biodegradability it may be the ideal material for the development of novel implants of the nasal sinus. Here, we present for the first time results on the behaviour of magnesium alloy in a unique environment, i.e. in contact to the nasal mucosa, air and nasal secretion. In a prospective longitudinal study, magnesium fluoride-coated MgNd2 specimens were implanted in the frontal sinuses of 12 minipigs for the investigation of biocompatibility and of the interface between the implant and the mucosa. Endoscopic examinations, histopathological evaluation and EDX measurements were performed regularly up to 180days. Endoscopic evaluation showed focal mucosal reaction, however, without affecting the patency of the sinus. In addition, no signs of bacterial infections were observed. The EDX analyses showed a marginal but steady increase in the Mg concentration in the mucosa over 180days. Histological analysis revealed a locally confined moderate mucosal hyperplasia and unspecific inflammatory reaction. Furthermore, we did not find any osteoinductive effects of the magnesium alloy. The results indicate the excellent biocompatibility of the MgNd2 alloy in contact with nasal mucosa and provide a novel material compound and solid proof-of-principle for the development of magnesium-based nasal stents.

APPLICABILITY OF DEGRADABLE MAGNESIUM LAE442 ALLOY PLATE-SCREW-SYSTEMS IN A RABBIT MODEL

Aim of this study was to assess the applicability of magnesium alloy plate-screw-systems in comparison to surgical steel. LAE442 plates (three different groups: implants made of LAE442 stored ≥ six months, treated with NaOH and stored ≤ 4 weeks) were fixed with four corresponding screws each on the medial surface of the tibia in NZW rabbits and a steel plate-screw-system on the contralateral tibia. For degradation analysis in vivo µ-computed tomography, X-ray and histology were per- formed. Around Mg implants massive gas formation and bone changes could be found. Volume and density of the implants decreased slightly. No differences were detected between the examined groups. Plate screw systems in large soft tissue contact are not applicable for osteosyn- thesis yet.

Evaluation of the inflammatory potential of implant materials in a mouse model by bioluminescent imaging of intravenously injected bone marrow cells.

To evaluate the inflammatory potential of implants a bioluminescent imaging assay was developed using luciferase-expressing bone marrow cells that were injected into the blood circulation of wild-type mice. After subcutaneous implantation of titanium discs as an example for a clinically established biocompatible material, the luminosity was modest. Similarly, low luminosity signals were generated by pure magnesium implants that were used to represent metallic alloys that are presently under investigation as novel degradable implant materials. Increased luminosity was observed in response to degradable polymeric PLGA implants. Surgical wounds induced a basic luminescent response even in the absence of an implant. However, the material-independent response to injury could be minimized using injectable microparticle suspensions. In parallel with the resorption of biodegradable microparticles, the signal induced by PLGA declined faster when compared to non-degradable polystyrene suspensions. By using an interferon type I inducible Mx2 promoter construct to drive luciferase gene expression, the highest luminosity was observed in response to bacteria, indicating that the system could also be employed to monitor implant infections. Overall, labeled bone marrow cells yielded specific, well-defined localized signals that correlated with the inflammatory responses to implants.

Differential magnesium implant corrosion coat formation and contribution to bone bonding

Magnesium alloys are presently under investigation as promising biodegradable implant materials with osteoconductive properties. To study the molecular mechanisms involved, the potential contribution of soluble magnesium corrosion products to the stimulation of osteoblastic cell differentiation was examined. However, no evidence for the stimulation of osteoblast differentiation could be obtained when cultured mesenchymal precursor cells were differentiated in the presence of metallic magnesium or in cell culture medium containing elevated magnesium ion levels. Similarly, in soft tissue no bone induction by metallic magnesium or by the corrosion product magnesium hydroxide could be observed in a mouse model. Motivated by the comparatively rapid accumulation solid corrosion products physicochemical processes were examined as an alternative mechanism to explain the stimulation of bone growth by magnesium-based implants. During exposure to physiological solutions a structured corrosion coat formed on magnesium whereby the elements calcium and phosphate were enriched in the outermost layer which could play a role in the established biocompatible behavior of magnesium implants. When magnesium pins were inserted into avital bones, corrosion lead to increases in the pull out force, suggesting that the expanding corrosion layer was interlocking with the surrounding bone. Since mechanical stress is a well-established inducer of bone growth, volume increases caused by the rapid accumulation of corrosion products and the resulting force development could be a key mechanism and provide an explanation for the observed stimulatory effects of magnesium-based implants in hard tissue.

Biodegradable nasal stents (MgF2‐coated Mg–2 wt %Nd alloy)—A long‐term in vivo study

Despite innovative surgical techniques and use of current frontal sinus stents from different materials, the problem of treatment failure with consecutive reoperation remains present. The aim of our study is to investigate biocompatibility, degradation kinetics, and functionality of a newly developed fluoride-coated magnesium-based nasal stent. A minipig anatomy of frontal sinus adapted design and an external surgical approach were developed and established. The functionality of the stents was evaluated endoscopically. The stent-tissue blocks were analysed after 90 and 180 days using microcomputed tomography (µ-CT), histology, scanning electron microscopy (SEM), and energy-dispersive X-ray spectroscopy (EDS). Functional evaluation revealed an unobstructed stent lumen in all cases. Histological analysis showed moderate mucosal hyperplasia with a mild, nonspecific inflammatory response, and nonosteoconductive effect. Rejection reactions or necrosis did not occur. The volumetric analysis of the stents showed 51% volume loss after 180 days. The EDS analysis did not detect any neodymium (Nd) in the mucosa or bone. The Mg-2 wt % Nd stents are a promising option when treating the narrow passages following paranasal sinus surgery. In particular, its good biocompatibility and good functionality facilitate the re-epithelization of these constricted passages.

Influence of Heat Treatment on the Degradation Behaviour of Degradable Magnesium Based Implants

Aim of the study was to characterise the influence of heat treatment on the degradation behaviour and stability of degradable magnesium based implants. For this purpose two groups (untreated/ heat treated) of LAE442 pins were separately analysed in an in vitro and in vivo study. The corrosion behaviour was evaluated during 8 weeks degrada- tion in SBF (in vitro) and 48 weeks degradation intrame- dullary in the rabbit tibia (in vivo). The analyses were made by using µ-computed tomography and three-point-bending tests. Heat treatment led to altered mechanical and corro- sion properties of LAE442.While the initial stability declined significantly a reduction of the degradation rate over either in vitro and in vivo evaluation period is determined. If these alterations are still reasonable for osteosynthesis implants remains to be investigated in further projects.

Phosphate conversion coating reduces the degradation rate and suppresses side effects of metallic magnesium implants in an animal model.

Magnesium alloys have promising mechanical and biological properties for the development of degradable implants. However, rapid implant corrosion and gas accumulations in tissue impede clinical applications. With time, the implant degradation rate is reduced by a highly biocompatible, phosphate-containing corrosion layer. To circumvent initial side effects after implantation it was attempted to develop a simple in vitro procedure to generate a similarly protective phosphate corrosion layer. To this end magnesium samples were pre-incubated in phosphate solutions. The resulting coating was well adherent during routine handling procedures. It completely suppressed the initial burst of corrosion and it reduced the average in vitro magnesium degradation rate over 56 days almost two-fold. In a small animal model phosphate coatings on magnesium implants were highly biocompatible and abrogated the appearance of gas cavities in the tissue. After implantation, the phosphate coating was replaced by a layer with an elemental composition that was highly similar to the corrosion layer that had formed on plain magnesium implants. The data demonstrate that a simple pre-treatment could improve clinically relevant properties of magnesium-based implants.