Mg-Zn-Ca Alloy (ZX00) Screws Are Resorbed at a Mean of 2.5 Years After Medial Malleolar Fracture Fixation: Follow-up of a First-in-humans Application and Insights From a Sheep Model

Abstract

Background: In the ongoing development of bioresorbable implants, there has been a particular focus on magnesium (Mg)-based alloys. Several Mg alloys have shown promising properties, including a lean, bioresorbable magnesium-zinc-calcium (Mg-Zn-Ca) alloy designated as ZX00. To our knowledge, this is the first clinically tested Mg-based alloy free from rare-earth elements or other elements. Its use in medial malleolar fractures has allowed for bone healing without requiring surgical removal. It is thus of interest to assess the resorption behavior of this novel bioresorbable implant.

Questions/purposes: (1) What is the behavior of implanted Mg-alloy (ZX00) screws in terms of resorption (implant volume, implant surface, and gas volume) and bone response (histologic evaluation) in a sheep model after 13 months and 25 months? (2) What are the radiographic changes and clinical outcomes, including patient-reported outcome measures, at a mean of 2.5 years after Mg-alloy (ZX00) screw fixation in patients with medial malleolar fractures?

Methods: A sheep model was used to assess 18 Mg-alloy (ZX00) different-length screws (29 mm, 24 mm, and 16 mm) implanted in the tibiae and compared with six titanium-alloy screws. Micro-CT was performed at 13 and 25 months to quantify the implant volume, implant surface, and gas volume at the implant sites, as well as histology at both timepoints. Between July 2018 and October 2019, we treated 20 patients with ZX00 screws for medial malleolar fractures in a first-in-humans study. We considered isolated, bimalleolar, or trimalleolar fractures potentially eligible. Thus, 20 patients were eligible for follow-up. However, 5% (one patient) of patients were excluded from the analysis because of an unplanned surgery for a pre-existing osteochondral lesion of the talus performed 17 months after ZX00 implantation. Additionally, another 5% (one patient) of patients were lost before reaching the minimum study follow-up period. Our required minimum follow-up period was 18 months to ensure sufficient time to observe the outcomes of interest. At this timepoint, 10% (two patients) of patients were either missing or lost to follow-up. The follow-up time was a mean of 2.5 ± 0.6 years and a median of 2.4 years (range 18 to 43 months).

Results: In this sheep model, after 13 months, the 29-mm screws (initial volume: 198 ± 1 mm 3 ) degraded by 41% (116 ± 6 mm 3 , mean difference 82 [95% CI 71 to 92]; p < 0.001), and after 25 months by 65% (69 ± 7 mm 3 , mean difference 130 [95% CI 117 to 142]; p < 0.001). After 13 months, the 24-mm screws (initial volume: 174 ± 0.2 mm 3 ) degraded by 51% (86 ± 21 mm 3 , mean difference 88 [95% CI 52 to 123]; p = 0.004), and after 25 months by 72% (49 ± 25 mm 3 , mean difference 125 [95% CI 83 to 167]; p = 0.003). After 13 months, the 16-mm screws (initial volume: 112 ± 5 mm 3 ) degraded by 57% (49 ± 8 mm 3 , mean difference 63 [95% CI 50 to 76]; p < 0.001), and after 25 months by 61% (45 ± 10 mm 3 , mean difference 67 [95% CI 52 to 82]; p < 0.001). Histologic evaluation qualitatively showed ongoing resorption with new bone formation closely connected to the resorbing screw without an inflammatory reaction. In patients treated with Mg-alloy screws after a mean of 2.5 years, the implants were radiographically not visible in 17 of 18 patients and the bone had homogenous texture in 15 of 18 patients. No clinical or patient-reported complications were observed.

Conclusion: In this sheep model, Mg-alloy (ZX00) screws showed a resorption to one-third of the original volume after 25 months, without eliciting adverse immunologic reactions, supporting biocompatibility during this period. Mg-alloy (ZX00) implants were not detectable on radiographs after a mean of 2.5 years, suggesting full resorption, but further studies are needed to assess environmental changes regarding bone quality at the implantation site after implant resorption.

Clinical relevance: The study demonstrated successful healing of medial malleolar fractures using bioresorbable Mg-alloy screws without clinical complications or revision surgery, resulting in pain-free ankle function after 2.5 years. Future prospective studies with larger samples and extended follow-up periods are necessary to comprehensively assess the long-term effectiveness and safety of ZX00 screws, including an exploration of limitations when there is altered bone integrity, such as in those with osteoporosis. Additional use of advanced imaging techniques, such as high-resolution CT, can enhance evaluation accuracy.

Fig. 1

This illustration shows the screw location in sheep tibiae. The right leg of both animals had a ZX00 screw in the proximal epiphysis (29-mm monocortical) and proximal metaphysis (24-mm bicortical), and three screws were placed in the diaphysis (16-mm bicortical) as well as one in the distal metaphysis (16-mm monocortical) and distal epiphysis (16-mm monocortical). The left legs of both animals received ZX00 screws in the proximal epiphysis (29-mm monocortical) and proximal metaphysis (24-mm bicortical), and three Ti-6Al-4V screws were placed bicortically in the diaphysis as a control, except for the 25-month animal, in which most distal diaphysis Ti screw was monocortical.

Fig. 2

This figure shows the evaluation and comparison of ZX00 and Ti-6Al-4V implant properties obtained by ex vivo high-resolution micro-CT. Different lengths of ZX00 and Ti-6Al-4V screws were implanted in sheep tibiae. (A) Implant volume, (B) implant surface area, and (C) gas volume were obtained by ex vivo micro-CT and previewed with mean and standard deviation analyzed by Mimics software. In comparison to initial values, all three types of implanted ZX00 screws showed a decrease in (A) volume and (B) surface area after 13 and 25 months. The coronal view of ex vivo micro-CT images shows (D) the 16-mm ZX00 screw after 13 months, (E) the 18-mm Ti-6Al-4V screw after 25 months, and (F) the 16-mm ZX00 screw after 25 months. (D, F) The black arrows indicate new bone formation, with qualitatively increased endosteal and periosteal bone volume, and bone formation around the ZX00 screw in the medullary cavity, the black arrowhead indicates a narrow bone-implant interface of ZX00 screws, and the black asterisk indicates gas formation around the ZX00 screw. (E) The white arrow indicates absence of osteoconduction in the medullary cavity, the white arrowhead indicates the visible area between the bone-implant interface, and the white asterisk shows common artefacts after Ti-6Al-4V imaging. (G) 3D images of different length screws after degradation at 13 and 25 months are shown. A color image accompanies the online version of this article.

Fig. 3

(A-C) Histologic evaluation of the 24-mm ZX00 screw after the 25-month period in sheep tibiae with (D) respective micro-CT. (A) New bone formation, “bony bridges,” within the medullary cavity is marked with a black arrow, and reactive woven bone formation on the periosteum adjacent to the screw head is marked with a white asterisk. (B) Osteocytes and osteoblasts are marked with black and white arrowheads, respectively. (C) The fat necrosis area is shown with white arrows, and air pockets are marked with black asterisks (Laczko-Levai stain; original magnification, x10).

Fig. 4

(A-C) Histologic evaluation of the 18-mm Ti-6Al-4V screw after the 25-month period in sheep tibiae with (D) respective micro-CT. (A) Newly formed bone in the medullary cavity is marked with a black arrow, and reactive woven bone formation on the periosteum adjacent to the screw head is labeled with a white asterisk. (B) Osteocytes and osteoblasts are marked with black and white arrowheads, respectively, whereas the (C) fat necrosis area is shown with a white arrow (Laczko-Levai stain; original magnification, x10).

Fig. 5

(A-D) Radiographic evaluation of a 47-year-old female patient who underwent surgery for a Maisonneuve fracture. Postoperative radiographs were obtained at (A) 6 weeks, (B) 1 year, and (C) 3 years and 7 months after surgical fixation. The patient received ZX00 screws for the medial malleolus fracture and a fibulo-tibial positioning screw (titanium) for syndesmotic instability, which was removed 6 weeks postoperatively (white arrow indicating screw hole). (D) Axial CT images at four levels reveal implant sites after ZX00 screw resorption at the medial malleolus and the titanium positioning screw site (white arrow) at the distal tibia. Both sites show changes or a lack of trabecular structures. The visibility of the ZX00 screws was rated as (+++) at 6 weeks, (+/++) at 1 year, and (-) at the final follow-up (reprinted with permission from the authors [10]).

Fig. 6

(A-C) Radiographic evaluation of a 20-year-old male patient who was surgically treated for a trimalleolar fracture. Postoperative radiographs were obtained at (A) 6 weeks, (B) 1 year, and (C) 2 years and 10 months after injury and surgery. The patient received two ZX00 screws for the medial malleolus fracture and locking compression plates for the lateral and posterior malleolus fractures. The locking compression plates were removed 1 year and 6 months postoperatively. The visibility of the ZX00 screws was rated as (+++) at 6 weeks, (+/++) at 1 year, and (-) at the final follow-up.