Can Hardware Removal be Avoided Using Bioresorbable Mg-Zn-Ca Screws After Medial Malleolar Fracture Fixation? Mid-Term Results of a First-In-Human Study

Open AccessPublished:October 30, 2021DOI:https://doi.org/10.1016/j.injury.2021.10.025

      Highlights

      • No Mg-Zn-Ca screws were surgically removed.
      • Bioresorbable Mg screws show excellent PROMs, clinical and functional outcomes.
      • After one year, Mg screw heads in most of the patients could not be detected in the plane radiographs anymore.
      • Mg-based screws as nutrient implant solution may be a suitable alternative material for fracture fixation while avoiding hardware removal.

      ABSTRACT

      Ankle is the most common site of hardware removal, mainly performed within 12 months of the primary surgery. The prominence of the metallic hardware is a frequent cause of pain after fracture fixation. Over the last decade, the development of bioresorbable materials based on magnesium (Mg) has increased. Bioresorbable metals aim to avoid a second surgery for hardware removal.

      Methods

      Twenty patients with isolated, bimalleolar, or trimalleolar ankle fractures were treated with bioresorbable screws made of Mg, 0.45wt% calcium (Ca) and 0.45wt% zinc (Zn) (ZX00). Patient-reported outcome measures (PROMs) including visual analogue scale (VAS) for pain, the presence of complications 6 and 12 months after surgery and the AOFAS scale after 12 months were reported. The functional outcomes were analysed through the range of motion (ROM) of the ankle joint with a standard goniometer. Degradation products and the bioresorbability of the screws were evaluated using plane radiographs.

      Results

      One patient was lost to follow-up. All patients were free of pain, no complications, shoe conflict or misalignement were reported after 12 months of follow-up. No Mg screws were surgically removed. An additional fixation of the distal fibula or the dorsal tibial fragment with conventional titanium implants (Ti) was performed in 17 patients. Within 12 months after primary refixation, 12 of these patients (71%) underwent a second surgery for Ti hardware removal. The mean AOFAS score was 89.8±7.1 and the difference between the treated and the non-treated site in the ROM of the talocrural joint was 2°±11° after 12 months. Radiolucent areas around the screws were attributed to degradation and did not affect clinical or functional outcomes. After one year, the Mg screw heads could not be detected in the plane radiographs of 17 patients which suggests that the majority of the screw head is degraded without introducing adverse reactions.

      Conclusions

      At 6 and 12 months, the bioresorbable Mg screws show excellent PROMs without complications or need for screw removal. The resorbability of the screw heads in most of the patients after one year could also provide an advantage over conventional bio-inert implants by avoiding related skin irritation due for instance to shoe conflict.

      Keywords

      Introduction

      Ankle fractures are the second most common fracture requiring hospitalization while the incidence from different clinical trial varies from 71 to 187 per 100,000 person-years (1:800) [
      Selective fixation of the medial malleolus in unstable ankle fractures.
      ,
      • Carter T.H.
      • Oliver W.M.
      • Graham C.
      • Duckworth A.D.
      • White T.O.
      Medial malleolus: Operative Or Non-operative (MOON) trial protocol - a prospective randomised controlled trial of operative versus non-operative management of associated medial malleolus fractures in unstable fractures of the ankle.
      ,
      • Juto H.
      • Nilsson H.
      • Morberg P.
      Epidemiology of adult ankle fractures: 1756 cases identified in Norrbotten County during 2009-2013 and classified according to AO/OTA.
      ]. Medial malleolar (MM) fractures are frequently found and can be either isolated or associated with lateral or posterior malleolar fracture [
      • Court-Brown C.M.
      • Caesar B.
      Epidemiology of adult fractures: a review.
      ]. The treatment of MM fractures depends on the fracture type and stability of the fracture. Current treatment concepts recommend open reduction and internal fixation (ORIF) of unstable medial malleolar fractures [
      • Carter T.H.
      • Oliver W.M.
      • Graham C.
      • Duckworth A.D.
      • White T.O.
      Medial malleolus: Operative Or Non-operative (MOON) trial protocol - a prospective randomised controlled trial of operative versus non-operative management of associated medial malleolus fractures in unstable fractures of the ankle.
      ,
      • Carter T.H.
      • Duckworth A.D.
      • White T.O.
      Medial malleolar fractures: current treatment concepts.
      ]. Different surgical approaches including fixation with screws only or in combination with plates can be used [
      • Vandenborne K.
      • Elliott M.A.
      • Walter G.A.
      • Abdus S.
      • Okereke E.
      • Shaffer M.
      • et al.
      Longitudinal study of skeletal muscle adaptations during immobilization and rehabilitation.
      ], but the most commonly employed and accepted clinical technique is the open reduction of medial malleolar fractures and fixation with cancellous screws [
      • Barnes H.
      • Cannada L.K.
      • Watson J.T.
      A clinical evaluation of alternative fixation techniques for medial malleolus fractures.
      ]. Closed reduction and percutaneous fixation for MM fractures have been described, but is not generally recommended due to the lack of direct visualization and access to the fracture site for debridement [
      • Matson A.P.
      • Barchick S.R.
      • Adams S.B.
      Comparison of Open Reduction and Internal Fixation Versus Closed Reduction and Percutaneous Fixation for Medial Malleolus Fractures.
      ]. Conventional, bio-inert metallic implants (such as steel or titanium (Ti) alloys) are considered the gold standard in surgical fracture fixation. Recent clinical trials demonstrated that the MM fractures can be sucessfully stabilized with a single Ti screw [
      • Buckley R.
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      • Duffy P.
      • Korley R.
      • Puloski S.
      • Buckley A.
      • et al.
      Single-Screw Fixation Compared With Double Screw Fixation for Treatment of Medial Malleolar Fractures: A Prospective Randomized Trial.
      ,
      • Mandel J.
      • Behery O.
      • Narayanan R.
      • Konda S.R.
      • Egol K.A.
      Single- vs 2-Screw Lag Fixation of the Medial Malleolus in Unstable Ankle Fractures.
      ,
      • Böstman O.
      • Pihlajamäki H.
      Routine implant removal after fracture surgery: a potentially reducible consumer of hospital resources in trauma units.
      ]. Due to the persistence of the material in the operating site, complications such as pain, soft tissue irritation due to hardware prominence, deep late infection, metal allergy or toxicity, hardware migration and metal failure were reported post-operatively [
      • Böstman O.
      • Pihlajamäki H.
      Routine implant removal after fracture surgery: a potentially reducible consumer of hospital resources in trauma units.
      ,
      • Kasai T.
      • Matsumoto T.
      • Iga T.
      • Tanaka S.
      Complications of implant removal in ankle fractures.
      ,
      • Leyes M.
      • Torres R.
      • Guillén P.
      Complications of open reduction and internal fixation of ankle fractures.
      ]. Assessing patient's discomfort, it is sometimes difficult to determine, whether the pain or discomfort is due to the implant left in situ or patient's subjectivity. In many cases, metalwork is removed in both symptomatic but also asymptomatic patients for a variety of reasons, differing between surgeons and even countries and was recently estimated between 13% and 27% [
      • Fenelon C.
      • Murphy E.P.
      • Galbraith J.G.
      • Kearns S.R.
      The burden of hardware removal in ankle fractures: How common is it, why do we do it and what is the cost? A ten-year review.
      ,
      • Partio N.
      • Huttunen T.T.
      • Mäenpää H.M.
      • Mattila V.M.
      Reduced incidence and economic cost of hardware removal after ankle fracture surgery: a 20-year nationwide registry study.
      ]. In Germany, in about 80% of treated fractures, hardware was removed, which represents 176,257 surgeries in 2018 [

      Vollstationäre Patientinnen und Patienten der Krankenhäuser. Statistisches Bundesamt n.d. https://www.destatis.de/DE/Themen/Gesellschaft-Umwelt/Gesundheit/Krankenhaeuser/Tabellen/diagnose-kapitel-geschlecht.html (accessed January 4, 2021).

      ]. Similar numbers were also found in the USA [
      • Prediger B.
      • Mathes T.
      • Probst C.
      • Pieper D.
      Elective removal vs. retaining of hardware after osteosynthesis in asymptomatic patients-a scoping review.
      ]. These operations are associated with possible complications, such as intraoperative breakage of hardware, post-operative infection, compromised wound healing, and significant iatrogenic injuries [
      • Kasai T.
      • Matsumoto T.
      • Iga T.
      • Tanaka S.
      Complications of implant removal in ankle fractures.
      ,
      • Prediger B.
      • Mathes T.
      • Probst C.
      • Pieper D.
      Elective removal vs. retaining of hardware after osteosynthesis in asymptomatic patients-a scoping review.
      ]. Metalwork removal from the ankle is inextricably associated with significant health care costs, estimated for instance as a minimum of 1113 Euros per surgery in Europe for the removal of hardware under general anaesthetic as a day case procedure [
      • Fenelon C.
      • Murphy E.P.
      • Galbraith J.G.
      • Kearns S.R.
      The burden of hardware removal in ankle fractures: How common is it, why do we do it and what is the cost? A ten-year review.
      ]. Due to (i) the current increase of patients over the age of 65, which are expected to triple by 2030 [
      Increasing number and incidence of low-trauma ankle fractures in elderly people: finnish statistics during 1970–2000 and projections for the future.
      ], and the correlated increase of potential related fractures, (ii) the thinner and vulnerable tissues in elderly patients, (iii) the patient comfort and (iv) the associated costs, bioresorbable Mg-based materials which do not require a second stage surgery for hardware removal appear to be an urgent clinical need.
      Since some decades, new alternative and innovative material options for ankle fracture fixation, such as bioresorbable magnesium (Mg)-based alloys were developed. With an elastic modulus similar to that of cortical bone, these alloys minimize the stress shielding effect characterized by the resorption of surrounding bone tissue according to Wolff's laws [
      • Chen J.
      • Tan L.
      • Yu X.
      • Etim I.P.
      • Ibrahim M.
      • Yang K.
      Mechanical properties of magnesium alloys for medical application: A review.
      ]. Additionally, biocompatibility as well as antimicrobial and osteoconductive properties of Mg-based alloys have been exhibited [
      • Kamrani S.
      • Fleck C.
      Biodegradable magnesium alloys as temporary orthopaedic implants: a review.
      ]. Many biomedical Mg-alloy systems have been investigated, mainly focusing calcium (Ca), zinc (Zn), zirconium, strontium and/or rare earth elements (REE), such as lanthanum, yttrium, neodymium and gadolinium [
      • Feyerabend F.
      • Fischer J.
      • Holtz J.
      • Witte F.
      • Willumeit R.
      • Drücker H.
      • et al.
      Evaluation of short-term effects of rare earth and other elements used in magnesium alloys on primary cells and cell lines.
      ,
      • Gu X.
      • Zheng Y.
      • Cheng Y.
      • Zhong S.
      • Xi T.
      In vitro corrosion and biocompatibility of binary magnesium alloys.
      ,
      • Liu J.
      • Bian D.
      • Zheng Y.
      • Chu X.
      • Lin Y.
      • Wang M.
      • et al.
      Comparative in vitro study on binary Mg-RE (Sc, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu) alloy systems.
      ]. REE are used in Mg-based alloys to improve the corrosion resistance, hence reducing the degradation rate [
      • Dobatkin S.
      • Martynenko N.
      • Anisimova N.
      • Kiselevskiy M.
      • Prosvirnin D.
      • Terentiev V.
      • et al.
      Mechanical Properties, Biodegradation, and Biocompatibility of Ultrafine Grained Magnesium Alloy WE43.
      ]. However, some REE like yttrium previously showed cytotoxic effects on murine fibroblasts and osteoblasts [
      • Yamamoto A.
      • Honma R.
      • Sumita M.
      Cytotoxicity evaluation of 43 metal salts using murine fibroblasts and osteoblastic cells.
      ] as well as a concentration-dependent cell apoptosis in vitro [
      • Feyerabend F.
      • Fischer J.
      • Holtz J.
      • Witte F.
      • Willumeit R.
      • Drücker H.
      • et al.
      Evaluation of short-term effects of rare earth and other elements used in magnesium alloys on primary cells and cell lines.
      ,
      • Yu L.
      • Dai Y.
      • Yuan Z.
      • Li J.
      Effects of rare earth elements on telomerase activity and apoptosis of human peripheral blood mononuclear cells.
      ]. Only few studies focused on related biological effects of REE and there is a lack of high-quality research in the literature.
      Mg-based alloys composed of nutrient elements, such as the proposed Mg-alloy (Mg 0.45wt% Ca and 0.45wt% Zn; denoted as ZX00) exhibited suitable biomechanical properties, biocompatibility, bioresorbability and osteoconductivity in a large animal model [
      • Grün N.G.
      • Holweg P.
      • Tangl S.
      • Eichler J.
      • Berger L.
      • van den Beucken J.J.J.P.
      • et al.
      Comparison of a resorbable magnesium implant in small and large growing-animal models.
      ]. According to a “bench-to-bedside” approach, a pilot study investigating the use of ZX00 screws in medial malleolar fractures was designed. The 12 week results of the clinical trial have already been published [
      • Holweg P.
      • Herber V.
      • Ornig M.
      • Hohenberger G.
      • Donohue N.
      • Puchwein P.
      • et al.
      A lean bioabsorbable magnesium-zinc-calcium alloy ZX00 used for operative treatment of medial malleolus fractures: early clinical results of a prospective non-randomized first in man study.
      ]. Fracture union was successfully achieved without adverse events in all 20 patients [
      • Holweg P.
      • Herber V.
      • Ornig M.
      • Hohenberger G.
      • Donohue N.
      • Puchwein P.
      • et al.
      A lean bioabsorbable magnesium-zinc-calcium alloy ZX00 used for operative treatment of medial malleolus fractures: early clinical results of a prospective non-randomized first in man study.
      ]. As late patient's discomfort or complications after fracture healing occur generally within 12 months after primary surgery, mid-term clinical, patient reported outcomes measures and functional outcomes are essential in order to evaluate fractures treated with Mg-based implants [
      • Fenelon C.
      • Murphy E.P.
      • Galbraith J.G.
      • Kearns S.R.
      The burden of hardware removal in ankle fractures: How common is it, why do we do it and what is the cost? A ten-year review.
      ]. Therefore, the aim of this study was to evaluate the clinical, functional and radiographical outcomes of medial malleolus fractures treated with lean ZX00 compression screws after 6 and 12 months of follow-up.

      Materials and methods

      The study design was a prospective, non-randomized cohort study for the treatment of displaced fractures of the medial malleolus with ZX00 as a pilot first-in-human study [
      • Holweg P.
      • Herber V.
      • Ornig M.
      • Hohenberger G.
      • Donohue N.
      • Puchwein P.
      • et al.
      A lean bioabsorbable magnesium-zinc-calcium alloy ZX00 used for operative treatment of medial malleolus fractures: early clinical results of a prospective non-randomized first in man study.
      ].
      As previously described, this trial included 20 patients (11 males and 9 females with a mean age of 40.1 years (SD 14.5)) who were recruited between July 2018 and October 2019. The study was approved by the local Ethics Committee (28-071 ex 15/16) and was conducted according to the Good Clinical Practice standards and the Declaration of Helsinki. Inclusion criteria were subjects between 18 and 65 years old presenting with a displaced isolated medial malleolus fracture, a bimalleolar ankle fracture or a trimalleolar ankle fracture. Fracture displacement was defined as diastasis of the fracture in any direction of 2 mm or more. Exclusion criteria were pathological fractures, underlying diseases (in particularly bone diseases, kidney diseases, diabetes mellitus), poly-traumatized patients and pregnant or breastfeeding women. Fractures were classified using the Hersovici classification.
      Written informed consent was obtained from each patient before surgery. Bioresorbable, partially threaded, non-cannulated cortical screws with a diameter of 3.5 mm and a length of 40 mm were used as compression screws. The screws were made from ZX00 rods, consisting of 99.1 wt% Mg, 0.45 wt% Zn and 0.45 wt% Ca without any surface treatment. The screws were manufactured by computer numerical control machining from extruded rods (Fig. 1). Packaging and sterilization by gamma irradiation was performed after a cleaning process including immersion in an ultrasound bath of acetone. Under general anesthesia and after reduction of the fracture, two bioresorbable Mg screws were inserted to fix the fracture of the medial malleolus. In cases of combined fractures (bimalleolar and trimalleolar fracture) the other fragments were refixed with conventional Ti implants.
      Figure 1:
      Fig. 1Partially threaded, non-canulated compression screw used in the prospective trial. Implants had a diameter of 3,5 mm, a length of 40 mm and were threaded at the distal part for use as traction screws.
      PROMs including pain, assessed by a visual analog score (VAS) and the report of adverse events such as anormal vital signs, erythema, swelling, secretions, wound healing disorders, wound infections, implant infections, skin irritation, discomfort related to prominent screws, allergic reaction or screw failure were investigated after 6 and 12 months. The American Orthopedic Foot and Ankle Society (AOFAS) score was performed after 12 months. Blood analysis regarding Ca, Mg and renal function were recorded 6 and 12 months after the surgery. Functional outcomes were evaluated through range of motion (ROM) in dorsal and plantar flexion with a standard goniometer. Additionally, anterior–posterior and lateral ankle radiographs performed after 6 and 12 months were evaluated in regard to screw breakage, loosening, degradation, or any bony disorder including non union, delayed union, bone loss, or infection during the degradation of the screws. Degradation product building and screw integrity were assessed using postoperative X-ray after 24 and 52 weeks as a longitudinal investigation.
      A descriptive analysis of the data was performed using proportions, frequency and distributions and are given as mean ± and standard deviation (SD).

      Results

      One patient was lost to follow-up after 12 weeks. Concerning PROMs, all remaining 19 patients were free of pain 24 and 52 weeks after surgery. At clinical examination, all patients showed a regular postoperative scar at the 1-year follow-up. No adverse events or screw related complications including erythema, swelling, secretions, wound healing disorders, wound infections, soft tissue irritation or allergies were reported. At the final follow-up examination the mean AOFAS score was 89.8±7.1 points. No patient needed a second operation for Mg screws removal. In comparison, an additional fixation of the distal fibula or the dorsal tibial fragment with conventional Ti implants was performed in 17 patients (90%). Within 12 months after primary refixation, 12 of these patients (71%) underwent a second surgery for the removal of the additional Ti implants. The most common reason was a conflict with the soft tissue.
      Blood analysis assessed by the concentration of Mg and Ca demonstrated normal levels at all follow up visits with a Mg concentration between 0.700 and 1.100 mmol/L and a Ca concentration between 2.20 and 2.65 mmol/L. Moreover, renal function remained stable after 24 and 52 weeks with a normal glomerular filtration rate (GFR) equal to ∼130 ml/min/1.73 m2 in males and ∼120 ml/min/1.73 m2 in females.
      The mean difference in ROM between the operated site and the non-operated site of the talocrural joint (dorsal flexion/plantar flexion) was 7°±13° after 6 months and then decreased to 2°±11° after one year. Additionally, no misalignments of the ankle were reported.
      Between 6 and 12 months, no infections, encapsulation or screw failure including breakage, loosening or cracking were reported. In all antero-posterior and lateral plane radiographs the shaft of the screws were still visible after 6 and 12 months. Radiolucent zones localized around the screws were associated with gas formation (H2), considered as a product of the screw degradation (Fig. 2, Fig. 3). As shown in Fig. 3, these zones are persisted or sligthly decreased 6 to 12 months (white arrows). An associated line is observed at the border of the radiolucent zones after 6 and 12 months and is correlated with the formation of dense cortical-like bone at the interface. After one year of implantation, radiological disappearance of the screw head was observed in 17 patients (90%). As shown in Fig. 2 and 3, all screw heads were radiographically observable after 24 weeks in the medial malleolus. One year after implantation the head of the screws was mainly resorbed (blue arrows).
      Figure 2:
      Fig. 2Anteroposterior and lateral ankle radiographs of a 29-year-old male patient with a medial malleolar fracture (A) stabilized with two Mg-based screws after open anatomical reduction. After 6 months (B), a complete fracture consolidation is observed, with radiolucent zones within the bone surrounding the screws (white arrows). These radiolucent zones resulting from the degradation of the screws decreased slightly between 6 (B) and 12 months (C). The blue arrows show the screw heads 6 months after surgery (B). At the last follow-up time point, the heads of the screws are almost completely resorbed (blue arrows). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
      Figure 3:
      Fig. 3Anteroposterior ankle radiographs of two 45-year-old female patients (A and B) and a 30-year-old male patient (C). From left to right, anteroposterior ankle radiograph before surgery and after 6 and 12 months. All fractures were stabilized with two Mg-based screws aftre open anatomical reduction. After 6 months, radiolucent zones corresponding to the product of corrosion are homogeneously localized around the screws (white arrow). After 12 months, the radiolucent zones are still present but decrease slightly. Screw's heads are generally resorbed after 12 months (blue arrows).

      Discussion

      Hardware removal is mainly performed during the first year after the primary surgery [
      • Fenelon C.
      • Murphy E.P.
      • Galbraith J.G.
      • Kearns S.R.
      The burden of hardware removal in ankle fractures: How common is it, why do we do it and what is the cost? A ten-year review.
      ]. Mid-term results, 6 and 12 months after MM fracture reduction with bioresorbable ZX00 screws exhibit excellent clinical and functional outcomes without complications. According to a recent systematic review and meta-analysis including eight clinical trials and reviewing a total number of 230 patients, the estimated complication rate for Mg-based implants was 13.3% [
      • Sukotjo C.
      • Lima-Neto T.J.
      • Santiago Júnior J.F.
      • Faverani L.P.
      • Miloro M.
      Is There a Role for Absorbable Metals in Surgery? A Systematic Review and Meta-Analysis of Mg/Mg Alloy Based Implants.
      ]. In the current literature a total of five clinical studies including prospective and retrospective clinical trials investigating Mg-based alloys implanted in foot ankles are registered and exhibit similar clinical and functional outcomes [
      • Acar B.
      • Unal M.
      • Turan A.
      • Kose O.
      Isolated Lateral Malleolar Fracture Treated with a Bioabsorbable Magnesium Compression Screw.
      ,
      • Kose O.
      • Turan A.
      • Unal M.
      • Acar B.
      • Guler F.
      Fixation of medial malleolar fractures with magnesium bioabsorbable headless compression screws: short-term clinical and radiological outcomes in eleven patients.
      ,
      • Xie K.
      • Wang L.
      • Guo Y.
      • Zhao S.
      • Yang Y.
      • Dong D.
      • et al.
      Effectiveness and safety of biodegradable Mg-Nd-Zn-Zr alloy screws for the treatment of medial malleolar fractures.
      ,
      • Acar B.
      • Kose O.
      • Unal M.
      • Turan A.
      • Kati Y.A.
      • Guler F.
      Comparison of magnesium versus titanium screw fixation for biplane chevron medial malleolar osteotomy in the treatment of osteochondral lesions of the talus.
      ,
      • May H.
      • Alper Kati Y.
      • Gumussuyu G.
      • Yunus Emre T.
      • Unal M.
      • Kose O.
      Bioabsorbable magnesium screw versus conventional titanium screw fixation for medial malleolar fractures.
      ]. All of these studies aimed on the clinical implementation of Mg implants alloyed with REEs. Amongst them, compression screws (CS) based on Mg with yttrium, zirconium and other REEs were used for lateral malleolar fractures [
      • Acar B.
      • Unal M.
      • Turan A.
      • Kose O.
      Isolated Lateral Malleolar Fracture Treated with a Bioabsorbable Magnesium Compression Screw.
      ] and for biplane chevron MM osteotomy in the treatment of osteochondral lesions of the talus [
      • Acar B.
      • Kose O.
      • Unal M.
      • Turan A.
      • Kati Y.A.
      • Guler F.
      Comparison of magnesium versus titanium screw fixation for biplane chevron medial malleolar osteotomy in the treatment of osteochondral lesions of the talus.
      ]. Two retrospective studies for MM fracture fixation and reported fracture union associated to retrieved ankle function without complications in a follow-up between 12 and 24 months [
      • Kose O.
      • Turan A.
      • Unal M.
      • Acar B.
      • Guler F.
      Fixation of medial malleolar fractures with magnesium bioabsorbable headless compression screws: short-term clinical and radiological outcomes in eleven patients.
      ,
      • May H.
      • Alper Kati Y.
      • Gumussuyu G.
      • Yunus Emre T.
      • Unal M.
      • Kose O.
      Bioabsorbable magnesium screw versus conventional titanium screw fixation for medial malleolar fractures.
      ]. May et al. (2020) retrospectively reviewed a cohort studying MM fractures. 23 patients were treated with bioresorbable Mg-based screws and 25 patients with Ti screws [
      • May H.
      • Alper Kati Y.
      • Gumussuyu G.
      • Yunus Emre T.
      • Unal M.
      • Kose O.
      Bioabsorbable magnesium screw versus conventional titanium screw fixation for medial malleolar fractures.
      ]. A similar therapeutic efficacy in MM fracture fixation was shown between the two materials. No Mg-based screws were removed while five patients treated with Ti screws underwent screw removal 12 - 19 months after surgery [
      • May H.
      • Alper Kati Y.
      • Gumussuyu G.
      • Yunus Emre T.
      • Unal M.
      • Kose O.
      Bioabsorbable magnesium screw versus conventional titanium screw fixation for medial malleolar fractures.
      ]. Xie et al. (2021) explored the clinical use of an alloy made with Mg, neomydium, zinc and zirconium for MM fracture fixation. During the one year of follow-up, no infection, failure of internal fixation, malunion, or other complications were shown and a similar AOFAS score (90.4±8.9) after one year was reported [
      • Xie K.
      • Wang L.
      • Guo Y.
      • Zhao S.
      • Yang Y.
      • Dong D.
      • et al.
      Effectiveness and safety of biodegradable Mg-Nd-Zn-Zr alloy screws for the treatment of medial malleolar fractures.
      ].
      This prospective clinical trial using screws made of Mg and nutrient elements (Ca and Zn) confirm that this alloying system presents the same excellent clinical and functional outcomes as previously shown in other retrospective studies.
      During the one year follow-up study, several important results were found, in particular concerning the bioresorbable behavior of the Mg-based screws. This bioresorbability can be divided into two stages: during the early stage up to 24 weeks, ZX00 degradation is associated with the gradual increase of gas volume around the screw and is characterized by the extension of radiolucent areas [
      • Holweg P.
      • Herber V.
      • Ornig M.
      • Hohenberger G.
      • Donohue N.
      • Puchwein P.
      • et al.
      A lean bioabsorbable magnesium-zinc-calcium alloy ZX00 used for operative treatment of medial malleolus fractures: early clinical results of a prospective non-randomized first in man study.
      ]; during the second stage between 24 and 52 weeks, the radiolucent areas are still present around the srew but the gas evolution has slightly diminished.
      Due to their composition, ZX00 compression screws have the same radio-opacity as cortical bone. After implantation of Mg in the physiological environment, it corrodes through electrochemical and chemical processes. The hydrogen evolution reaction is the main cathodic reaction during Mg corrosion [
      • Seitz J.-M.
      • Eifler R.
      • Bach F.-W.
      • Maier H.J.
      Magnesium degradation products: effects on tissue and human metabolism.
      ,
      • Pogorielov M.
      • Husak E.
      • Solodivnik A.
      • Zhdanov S.
      Magnesium-based biodegradable alloys: Degradation, application, and alloying elements.
      ]. The hydrogen (H2) production occurs spontaneously after implantation and is characterized radiographically by the appearance of radiolucent zones. After 6 and 12 months, a homogeneous degradation process of the screw shafts characterized by radiolucent zones localized around the screws was observed in all patients. To reduce and control the corrosion rate, various strategies such as purification, alloying, and surface modification were developed. Xie et al. (2021) explored the clinical use of calcium phosphate coating on the Mg-based alloy surface to reduce the degradation products formation (H2) [
      • Xie K.
      • Wang L.
      • Guo Y.
      • Zhao S.
      • Yang Y.
      • Dong D.
      • et al.
      Effectiveness and safety of biodegradable Mg-Nd-Zn-Zr alloy screws for the treatment of medial malleolar fractures.
      ]. Similar clinical outcomes were reported, still revealing radiolucent areas in the radiographic outcomes up to one year after implantation. Though, further clinical investigations need to be done, as the cited study included only 9 subjects.
      The ZX00 screws used in this study were designed as partially threaded, non-cannulated cortical screws that where used as compression screws. After radiographical examination at the final follow-up, the representative radiographs showed that corrosion occurred predominantly at the head of the Mg screws in approximately 90% of the patients. This could be due to pronounced blood supply and shear forces present in the soft tissue area, adjacent to the screw head, which might lead to accelerated degradation. On the medial side of the ankle, screw prominence can cause irritation of the posteriortibialis tendon or other soft-tissue irritation [
      • Femino J.E.
      • Gruber B.F.
      • Karunakar M.A.
      Safe zone for the placement of medial malleolar screws.
      ]. As the screw head can cause skin irritations due for instance to shoe conflict, the resorption of the screw heads after one year is a big advantage.
      One year after implantation of ZX00 screws for MM fracture fixation, no Mg hardware removal was necessary. Thus, Mg-based implant can avoid related costs, potential complications and the associated stress for the patient due to the second stage surgery for hardware removal. In contrast, in 71% percent of the patients who received an additional fragment refixation with conventional Ti implants, a second surgery for implant removal was performed. In most cases, skin irritation was the reason for conventional implant removal.
      This study has some limitations. Following a “bench-to-bedside” approach, this study is the first investigation of this alloying system (made only with nutrient elements) in human beings. A randomized study was not allowed per definitionem, as the safety is not to be proven in a randomized control study group. Additionally, only 20 patients were included in this clinical trial.

      Conclusion

      Outcomes after one year reveal excellent PROMs and functional outcomes after implantation of bioresorbable screws based on Mg and nutrient elements. The resorbability of the screw heads after one year could also provide an advantage over conventional bio-inert implants by avoiding related complications which normally appear after fracture healing and resumption of daily activities inbetween the month 6 and 12. No Mg hardware removal was necessary up to one year of follow-up suggesting implant safety. Due to its bioresorbability and therefore the avoidance of (i) hardware removal surgeries, (ii) related costs and (iii) the reduction of associated comorbidities, Mg-based screws as nutrient implant solution may be a suitable alternative material for future fracture fixation.

      Declaration of Competing Interest

      Valentin Herber, Viktor Labmayr, Nicole G. Sommer, Romy Marek, Ulrike Wittig, Franz Seibert and Patrick Holweg certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. Andreas Leithner declares institutional educational grants from Johnson & Johnson, Alphamed, Implantec and Medacta.

      Funding/support statement

      One of the authors (P.H.) has received funding from LORENZ BÖHLER Fond.

      Acknowledgements

      The Laura Bassi Center BRIC (Medical University Graz, Graz, Austria) support the study by performing the needed preclinical studies (FFG (Austrian fund)). Bri.Tech GmbH (Austria) supported the study by knowledge transfer.

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