Is There a Role for Absorbable Metals in Surgery? A Systematic Review and Meta-Analysis of Mg/Mg Alloy Based Implants

Magnesium (Mg) alloys have received attention in the literature as potential biomaterials for use as absorbable implants in oral and maxillofacial and orthopedic surgery applications. This study aimed to evaluate the available clinical studies related to patients who underwent bone fixation (patients), and received conventional fixation (intervention), in comparison to absorbable metals (comparison), in terms of follow-up and complications (outcomes). A systematic review and meta-analysis were performed in accordance with the PRISMA statement and PROSPERO (CRD42020188654), PICO question, ROBINS-I, and ROB scales. The relative risk (RR) of complications and failures were calculated considering a confidence interval (CI) of 95%. Eight studies (three randomized clinical trial (RCT), one retrospective studies, two case-control studies, and two prospective studies) involving 468 patients, including 230 Mg screws and 213 Titanium (Ti) screws, were analyzed. The meta-analysis did not show any significant differences when comparing the use of Mg and Ti screws for complications (p = 0.868). The estimated complication rate was 13.3% (95% CI: 8.3% to 20.6%) for the comparison group who received an absorbable Mg screw. The use of absorbable metals is feasible for clinical applications in bone surgery with equivalent outcomes to standard metal fixation devices.


Introduction
One of the most significant public health concerns is the high incidence of traumatic accidents resulting in skeletal injuries with the need for bone reduction and fixation [1][2][3][4][5]. These traumatic events significantly affect the quality of life of these accident victims. Elderly patients and those suffering from chronic systemic conditions, such as diabetes, osteoporosis, and other bone metabolic disorders, follow-up, as well as complications (outcomes) will also be investigated [10,34]. Therefore, to understand the clinical behavior of these materials, this systematic review and meta-analysis will gather information from clinical studies regarding these issues. Additionally, in vivo studies are included to demonstrate the biological responses of these materials.

Standard Criteria and Type of Study
This systematic review followed the Cochrane criteria [35,36], and the PRISMA-P and PRISMA Statement [37,38] on systematic review and meta-analysis.

Protocol and Registration
The researchers registered this systematic review in the PROSPERO database, under submission: CRD42020188654 entitle "Is there viability in the use of absorbable metals in bone surgery? Systematic Review and Meta-analysis". The authors followed the PRISMA-P protocol for planning a systematic review [37].

Eligibility Criteria
The researchers performed the analyses based on the PICO index:

1.
Population: Patients undergoing surgical treatment of bone fractures or deformities with fixation devices.

2.
Intervention: Fixation using conventional metal plates and/or screws, such as Ti alloys. 3.
Comparison: Fixation using absorbable metal plates and/or screws (Mg).

4.
Outcome: Survival rates of the fixation systems, systemic complications, pain scale, quality of life, and functional analysis.

Inclusion Criteria
The studies were selected according to the search strategy with the following inclusion criteria: (1) English language; (2) clinical follow-up studies of at least 6 months including the following study types: retrospective, prospective, and controlled and randomized clinical trial (RCTs); (3) publication period analysis until 20 June 2020; (4) adults and children with no upper or lower age limit; (5) consecutive cases including over 5 patients.

Exclusion Criteria
The exclusion criteria included: studies related to in vitro methodology; animal studies; studies with less than 5 patients or with incomplete data; studies only related to the absorbable plates and/or screws from PLLA; review papers; studies that did not allow the collection of the required information.

Study Search Strategy
The databases used were: Medline/PubMed; Cochrane Library; EMBASE. These searches were carried out for articles published until 20 June 2020. Additional contact was made with the authors when it was not possible to locate the article via the national online system or COMUT.

Searches
The keywords based on MeSH/PubMed were: Surgery, Bone Plates, Absorbable implants. The articles were selected on the following bases (Cochrane, 46 articles; Embase, 517 articles; Pubmed, 556 articles; total = 1119 articles).
A manual search was also carried out in the specific journals in the area: Biomedical Engineering, Foot Ankle Surgurgery, Musculoskelet Disorders, Journal of Orthopaedic Science, Journal of Orthopaedic Research, Biomaterials and Journal of Oral and Maxillofacial Surgery, totalizing 9 articles and open grey.

Data Collection Process
This research was carried out by methods used by previously calibrated researchers. The selection of articles and data collection was performed by a calibrated reviewers (T.J.L.-N.and L.P.F.). All titles and abstracts evaluated as eligible were separated and analyzed thoroughly to assess the titles and abstracts found, to obtain a concordance thesis value for the articles selected in both databases, and to reduce the possibility of bias in selecting articles. A meeting was required to reach consensus, and discrepancies were discussed and resolved by the third reviewer (J.F.S.Jr.).

Items to Be Extracted
The extracted data from each study were analyzed in an orderly manner, and the needed information was obtained in a standardized fashion. The following data were collected from the articles: authors, type of study, number of patients, age, sex, operated region of the body, type of screw, number of screws, surgery time, follow up, radiologic measures, functional recovery, laboratory values (mertal ion release), and complications. All data were collected by one reviewer (T.J.L.-N.) was then verified by another reviewer (L.P.F.). The data collection was entered in Excel spreadsheet (Excel, Microsoft, Washington, DC, USA).

Assessment of Study Quality and Risk of Bias
The ROBINS-I scale was applied for Non-Randomized studies of the effects of interventions [39]. This scale was developed by members of the Cochrane Bias Methods Group and the Cochrane Non-Randomised Studies Methods Group. For RCTs studies, the risk of bias in randomized trials was applied [35,40,41]. The online Robvis website (https://mcguinlu.shinyapps.io/robvis/) (accessed: 29 June 2020), was used to prepare responses for the seven areas presented in ROBINS-I and for the 5 domains presented on the ROB scale [40]. Analyses of radiologic measures, functional recovery, and laboratory results of the metal ions released.

Additional Analysis
Sensitivity tests for subgroup analysis were performed in order to avoid the potential for heterogeneity considering, for example, possible differences in the different bone regions rehabilitated [42,43].

Summary Measures
Quantitative data were grouped for some variables: the number of complications in patients who received absorbable Mg screws compared to the control group (Ti screws or bone grafting), the prevalence of severe complications, and failure in the Mg screw group was also calculated. This grouped information was evaluated for the event rate considering 95% CI. The number of treated patients who received surgical treatment was considered for data analysis (dichotomous data), which was used as a risk ratio (RR) [44,45].
A p value < 0.05 was considered significance. For event rate analyzes, the total number of patients who received absorbable Mg screws, and the total number of complications and failures were considered. The contribution weight of each study was also assessed. The Comprehensive Meta-Analysis software (Software version 3.0-Biostat, Englewood, NJ, USA) was used to construct the Forest plot [46].

Qualitative Analysis
In the initial search, 1199 articles were found according to the flowchart represented in Figure 1. After analysis of the inclusion criteria, eight articles were eligible, which 468 patients were included (control group or experimental group), with 230 screws of Mg. The age of patients included in all studies was 48.14 years [7,10,11,21,22,33,34,47]. The main results are summarized in Table 1. patients who received surgical treatment was considered for data analysis (dichotomous data), which was used as a risk ratio (RR) [44,45]. A p value < 0.05 was considered significance. For event rate analyzes, the total number of patients who received absorbable Mg screws, and the total number of complications and failures were considered. The contribution weight of each study was also assessed. The Comprehensive Meta-Analysis software (Software version 3.0-Biostat, Englewood, NJ, USA) was used to construct the Forest plot [46].

Qualitative Analysis
In the initial search, 1199 articles were found according to the flowchart represented in Figure 1. After analysis of the inclusion criteria, eight articles were eligible, which 468 patients were included (control group or experimental group), with 230 screws of Mg. The age of patients included in all studies was 48.14 years [7,10,11,21,22,33,34,47]. The main results are summarized in Table 1.

Experimental Design
From eight studies selected, three were RCT studies [10,11,33], one were retrospective studies [34], two were case-control studies [11,22], and lastly, two were prospective case series [21,47]. All of these studies were published between 2013-2020. These studies are unclear about the specific location of the surgeries, but the report stated that surgeons were well-trained in their respective fields (Table  1).

Experimental Design
From eight studies selected, three were RCT studies [10,11,33], one were retrospective studies [34], two were case-control studies [11,22], and lastly, two were prospective case series [21,47]. All of these studies were published between 2013-2020. These studies are unclear about the specific location of the surgeries, but the report stated that surgeons were well-trained in their respective fields (Table 1).

Patient Selection
The studies analyzed reported various inclusion criteria for patient selection. Inclusion criteria were: age between 18 and 79 years, no medical contraindications, and surgical procedures that require fixation using screws [10,22]. The exclusion criteria included: patients with neurological diseases, surgeries in the same body region operated previously, allergies against the materials used for testing components of the screws [33,34] (Table 1).

Operated Region
Of the eight studies selected, six studies were related to the hallux region [7,10,21,22,33,34], one related to the treatment of necrosis of the femoral head [11] and last one related to mandibular condyle fracture [47]. All studies used screws for fixation. For each region operated, the most appropriate surgical procedure had a follow-up to evaluate the success of the treatment (Table 1).

Type of Screws
Five studies compared Mg and Ti screws related to the treatment of hallux fracture [7,10,22,33,34], one study used Mg screw compared to a control group with no graft fixation [11], and two studies had no control or comparison group [21,47] (Table 1).

Radiologic Measures
All studies did some method of radiologic evaluation, and only one study described significant changes between the Mg and Ti group. In the Mg group, the authors classified 60% of the radiographs as satisfactory and 40% with some alteration, but these alterations were not specified. They only described areas of radiolucency, lytic areas, signs of plate or screw loosening, and bone resorption areas of demineralization, but no patients demonstrated any painful symptoms [34].
In the other studies, the radiographic evaluation showed no difference between the Mg and Ti group [7,10,22,33] (Table 2).

Follow-Up
The follow-up period ranged from 6 months to 36 months [10,33]. The mean postoperative follow-up was 12 months [7,11,21,22,34,47]. Despite the variation in follow-up time, the authors reported that it was enough to notice possible complications ( Table 2).

Functional Recovery
All studies did some type of postoperative recovery assessment. Only one study reported positive results for Ti compared to the Mg group [7], whereas other studies showed similar results between the Mg group and the Ti group [10,22,33,34] (Table 2).

Laboratory Results
Only two studies reported Mg blood level assessment. Regarding the lab alterations, there was no difference between the groups [11,33] (Table 2).

Complications
The studies described the number of complications, one patient for Ti group with a screw head displayed, but the patient declined a re-operation surgery [34]. One patient in another study had a prominence of the screw, but no re-treatment was performed [22].
Regarding the evaluation of infections and postoperative healing, two studies reported patients with postoperative infection [7,34]. Klauser reported three patients had healing problems without signs of infection, two patients in the Mg group and one patient in the Ti group, and complications healed during the follow-up [34]. Thirteen patients had some type of infection of the surgical site, six from the Mg group and seven from the Ti group. The treatment for those infections ranged from the prescription of systemic antibiotic therapy to surgical treatment [7,22].
Regarding postoperative pain, one study [7] was very clear to discuss the pain evaluation between groups. In the Mg group, there were three cases of infection and one case of local pain. In the Ti group there were three cases of cellulitis; one case of regional pain; and one patient required implant removal. One study [5] reported that three patients for the Ti group had residual postoperative pain, while no patient in the Mg group reported any type of pain. In two other studies [11,47], no complications were related to the Mg group (Table 2).

Complications in the Absorbable Mg Screws vs. Control Group
Five studies [7,10,11,33,34] involving a total of 156 patients who received Mg screws identified 15 complications, and 213 patients received Ti screws or bone grafting, with 18 complications. The meta-analysis did not indicate a significant difference in this comparison (RR 1.071; 95% CI 0.475 to 2.417, p = 0.868, Figure 2). The heterogeneity was Q-value: 5.442, p = 0.245, I 2 = 26.499.

Complications in the Absorbable Mg Screws vs. Control Group
Five studies [7,10,11,33,34] involving a total of 156 patients who received Mg screws identified 15 complications, and 213 patients received Ti screws or bone grafting, with 18 complications. The meta-analysis did not indicate a significant difference in this comparison (RR 1.071; 95% CI 0.475 to 2.417, p = 0.868, Figure 2). The heterogeneity was Q-value: 5.442, p = 0.245, I 2 = 26.499.

Complications in the Absorbable Mg Screw vs. Ti Screw Group and Hallux Valgus Deformity Surgery
Four studies [7,10,33,34] involving a total of 145 patients who received absorbable Mg screws identified 13 complications and 188 patients received Ti screws in addition to being specifically for the region: Hallux valgus deformity, with 12 complications. The meta-analysis did not indicate a significant difference in this comparison (RR 1.476; 95% CI 0.693 to 3.144, p = 0.313, Figure 3). The heterogeneity was Q-value: 2.748, p = 0.432, I 2 = 00.000.

Complications in the Absorbable Mg Screw vs. Ti Screw Group and Hallux Valgus Deformity Surgery
Four studies [7,10,33,34] involving a total of 145 patients who received absorbable Mg screws identified 13 complications and 188 patients received Ti screws in addition to being specifically for the region: Hallux valgus deformity, with 12 complications. The meta-analysis did not indicate a significant difference in this comparison (RR 1.476; 95% CI 0.693 to 3.144, p = 0.313, Figure 3). The heterogeneity was Q-value: 2.748, p = 0.432, I 2 = 00.000.

Complications in the Absorbable Mg Screws vs. Control Group
Five studies [7,10,11,33,34] involving a total of 156 patients who received Mg screws identified 15 complications, and 213 patients received Ti screws or bone grafting, with 18 complications. The meta-analysis did not indicate a significant difference in this comparison (RR 1.071; 95% CI 0.475 to 2.417, p = 0.868, Figure 2). The heterogeneity was Q-value: 5.442, p = 0.245, I 2 = 26.499.

Complications in the Absorbable Mg Screw vs. Ti Screw Group and Hallux Valgus Deformity Surgery
Four studies [7,10,33,34] involving a total of 145 patients who received absorbable Mg screws identified 13 complications and 188 patients received Ti screws in addition to being specifically for the region: Hallux valgus deformity, with 12 complications. The meta-analysis did not indicate a significant difference in this comparison (RR 1.476; 95% CI 0.693 to 3.144, p = 0.313, Figure 3). The heterogeneity was Q-value: 2.748, p = 0.432, I 2 = 00.000.

Failure in the Mg vs. Absorbable Screw Group Control (Ti Screw and Region: Hallux Valgus Deformity)
Four studies [7,10,33,34] involving a total of 145 patients who received absorbable Mg screws identified 1 failure and 188 patients received Ti screw or bone grafting, showing four failures. The meta-analysis did not indicate a significant difference in this comparison (RR 0.548; 95% CI 0.122 to 2.463, p = 0.433, Figure 4). The heterogeneity was de Q-value: 0.622, p = 0.891, I 2 = 00.000.

Failure in the Mg vs. Absorbable Screw Group Control (Ti Screw and Region: Hallux Valgus Deformity)
Four studies [7,10,33,34] involving a total of 145 patients who received absorbable Mg screws identified 1 failure and 188 patients received Ti screw or bone grafting, showing four failures. The meta-analysis did not indicate a significant difference in this comparison (RR 0.548; 95% CI 0.122 to 2.463, p = 0.433, Figure 4). The heterogeneity was de Q-value: 0.622, p = 0.891, I 2 = 00.000.

The Event Rate for Complications in Absorbable Mg Screw-in Operated Patients
Eight studies [7,10,11,21,22,33,34,47] involving a total of 230 patients who received absorbable Mg screws identified 25 complications. Event rate data ranged from 8.3% to 20.6%. The overall pooled for event rate was 13.3% (random; 95% CI: 8.3% to 20.6%; Figure 5). Regions considered: Hallux valgus deformity, osteosynthesis of the mandibular condyle, osteonecrosis of the femoral head. The heterogeneity of the event rate for complications was considered to be Q-value: 9.448, p = 0.222, I 2 = 25.907.

The Event Rate for Complications in Absorbable Mg Screw-in Operated Patients
Eight studies [7,10,11,21,22,33,34,47] involving a total of 230 patients who received absorbable Mg screws identified 25 complications. Event rate data ranged from 8.3% to 20.6%. The overall pooled for event rate was 13.3% (random; 95% CI: 8.3% to 20.6%; Figure 5). Regions considered: Hallux valgus deformity, osteosynthesis of the mandibular condyle, osteonecrosis of the femoral head. The heterogeneity of the event rate for complications was considered to be Q-value: 9.448, p = 0.222, I 2 = 25.907.

The Event Rate for Complications in Absorbable Mg Screw-in Operated Patients
Eight studies [7,10,11,21,22,33,34,47] involving a total of 230 patients who received absorbable Mg screws identified 25 complications. Event rate data ranged from 8.3% to 20.6%. The overall pooled for event rate was 13.3% (random; 95% CI: 8.3% to 20.6%; Figure 5). Regions considered: Hallux valgus deformity, osteosynthesis of the mandibular condyle, osteonecrosis of the femoral head. The heterogeneity of the event rate for complications was considered to be Q-value: 9.448, p = 0.222, I 2 = 25.907.

Risk of Bias in the Studies
Heterogeneity was used using the Q method and the value of I 2 was analyzed [45,48] heterogeneity above 75 (0-100) may reflect greater significance [45,49], we adopted analysis random for all meta-analyzes in order to reduce the potential for heterogeneity [50]. Particularities of the sample designs of each study were also evaluated and particularities of each forest plot were considered, considering, for example, specific analysis for hallux valgus deformity disregarding other regions, a control group containing only Ti screw was also considered, disregarding other materials.

Non-Randomized Studies
For non-randomized clinical studies [7,10,22,34,47], some studies either lacked the sample design, data were not proportional, or used retrospective data for test or control groups, which may all have influenced the outcomes. Limitations on the follow-up and lacking tomographic analysis for all the groups were also noted in some studies. Lastly, a lack of identification of the size of the screws in all studies, and only one study showed a sample size calculation. Figures 7 and 8 show the main data on the risk of bias scale.

Randomized Studies
For randomized clinical studies [10,11,33], there was a limitation in the randomization methods. There was a lack of organization of the failures differently from the complications on each step of the evaluation. A short period of follow-up, or lack of information about systemic disorders or etiological factors also were noted. The main results for the evaluated domains are shown in Figures 9 and 10, related to individual and general valuation, respectively.

Randomized Studies
For randomized clinical studies [10,11,33], there was a limitation in the randomization methods. There was a lack of organization of the failures differently from the complications on each step of the evaluation. A short period of follow-up, or lack of information about systemic disorders or etiological factors also were noted. The main results for the evaluated domains are shown in Figures 9 and 10, related to individual and general valuation, respectively.

Randomized Studies
For randomized clinical studies [10,11,33], there was a limitation in the randomization methods. There was a lack of organization of the failures differently from the complications on each step of the evaluation. A short period of follow-up, or lack of information about systemic disorders or etiological factors also were noted. The main results for the evaluated domains are shown in Figures 9 and 10, related to individual and general valuation, respectively.  Other methodologies information was also assessed, and it was noticed limitations related to data organization and identification of the sample size calculation (Table 3).  Other methodologies information was also assessed, and it was noticed limitations related to data organization and identification of the sample size calculation (Table 3). Other methodologies information was also assessed, and it was noticed limitations related to data organization and identification of the sample size calculation (Table 3).

Discussion
This systematic review with a meta-analysis yielded that absorbable metals used for bone surgery, especially Mg alloys, were clinically useful and biologically acceptable compared to standard Ti implants. Of the 468 patients assessed in the studies selected, 230 Mg-alloys screws were used to stabilize a bone fracture [47], bone graft fixation [11], or correction of bone deformity [7,10,21,22,33,34]. Similar statistical data were noted for comparison between Ti and Mg screws (p = 0.433), as shown in Figure 1, showing acceptable biological responses for these applications.
Previous animal studies have found interesting results for absorbable metals in bone surgeries [34,51,52]. Most studies have suggested that Mg increases osteoblastic activity and has anti-inflammatory properties during the degradation process [26,53,54]. The vascular endothelial grown factor (VEGF), one of the most important factors to vascular proliferation, was significantly increased around Mg implants placed in bone marrow defects of rats [54]. The osteogenic and angiogenic properties with its degradation were achieved because of Mg ion and a co-enzyme of more than 200 enzymes from the organism which can be responsible to improve bone healing [55]. A few parts of Mg were distributed in the adjacent muscles, and other parts were metabolized by the kidney and liver without any postoperative blood chemistry alteration, as noticed by Windhagen et al., 2013 [33] and Choo et al., 2019 [7] ( Table 2). The serum levels of calcium, Mg, and phosphorus were normal [11,26,33,[56][57][58][59][60].
One of the concerns during Mg degradation is the hydrogen gas release. Some studies have speculated that the corrosion occurs with non-absorbable and absorbable metals. The particles around the bone and soft tissues could cause inflammation and bone resorption, including hypersensitivity reactions. However, none of the investigations found any evidence of allergenic effects in the presence of Mg-alloys [10,61,62]. One possible complication could be edema and emphysema during hydrogen gas release. Some cases indicated some radiographic signals of peri-implant gas radiolucencies.
In regards to the biomechanical properties, Mg screws have Young' modulus very similar to bone tissue. However, over time, Mg could fatigue, especially when it requires a higher insertion torque. Recent studies have added other ions or metal particles, such as iron and zinc, to increase the mechanical resistance features [26]. Regardless, most of the clinical studies have found similar fatigue complications in the comparison between Mg and Ti materials for bone fixation [65,66]. One clinical strategy to decrease that complication is to use a countersink drill before screw insertion, since Mg screws are not self-drilling or self-tapping. Although this process may increase the time of surgery, the studies did not show a significant difference between Ti or Mg fixation, with only five-six minutes more time required for Mg surgeries [22,33,34] (Table 1).
The use of absorbable metals is very applicable in oral and maxillofacial surgery. For instance, in mandibular condyle fractures, when there is any instability of the temporomandibular joint complex during the postoperative period, an absorbable fixation system may avoid the development of some TMJ disorders or pathologies. Mg-MgHA/collagen-based scaffolds have been successfully used for sinus augmentation procedures. However, the result should be interpreted carefully as controls were not used for comparison [67]. The use of conventional Ti fixation in children is still controversial. Many studies suggested fixation removal after at least six months postoperatively, leading to more indirect costs related to the surgery and additional days for recovery of the patients. Therefore, an absorbable metal fixation becomes useful in children, with no necessity for a second surgery only to remove the fixation system. Although this study does not focus on an analysis of children, further research needs to be performed in the area [68][69][70][71][72].
In the orthopedic field, no significant differences were found between Ti and Mg screws used to bone fixation in all studies that assessed postoperative clinical parameters such as pain, walking/standing, and social interaction through standard scales demonstrated. In regards to better postoperative function, both treatments were effective [22].
Another important finding in the studies is the use of absorbable polymers, especially from the PLLA and poly-glycolic acid (PGA). Although the studies did not demonstrate significant differences in postoperative complications, absorbable polymers are mechanically weaker, and their degradation process through hydrolysis resulted in acidic elements, which can increase infections and bone resorption osteoclasts activation. The findings indicated that the use of PLLA and PGA might not be applicable for clinical applications, and the search for other degradable materials is warranted [14,[73][74][75].
Several limitations were noticed in this systematic review as described above in the results section. These are fundamental to achieve an acceptable level of evidence for a clinical problem. The first one is the number of well-designed clinical investigations, including lack of clear methods of randomization, equality in the size of the sample for each experimental group (absence of sample calculations), limited follow-up, and different periods of follow-up among studies, limited organization of the failure's assessment. Future studies should be designed following those standard parameters, especially through RCTs, involving control groups within the same study, and finally increasing the level of evidence of the results. Numerous studies have investigated Mg screws for fracture fixation of the maxillofacial and orthopedic bone surgeries. Future studies evaluating Mg plates for bioactivity properties should be warranted.

Conclusions
The use of Mg-based implants as absorbable metals for osteosynthesis show feasible applications in bone surgery procedures. There are no differences in a comparison between Mg-implants and conventional implants (Ti) with regards to biocompatibility or complication rates. Therefore, Mg-based implants should be considered for clinical applications in oral and orthopedic reconstructive surgery. Funding: Study financed with own resources.