Abstract
Aims
This study aimed to evaluate the effectiveness of the induced membrane technique for treating infected bone defects, and to explore the factors that might affect patient outcomes.
Methods
A comprehensive search was performed in PubMed, Embase, and the Cochrane Central Register of Controlled Trials databases between 1 January 2000 and 31 October 2021. Studies with a minimum sample size of five patients with infected bone defects treated with the induced membrane technique were included. Factors associated with nonunion, infection recurrence, and additional procedures were identified using logistic regression analysis on individual patient data.
Results
After the screening, 44 studies were included with 1,079 patients and 1,083 segments of infected bone defects treated with the induced membrane technique. The mean defect size was 6.8 cm (0.5 to 30). After the index second stage procedure, 85% (797/942) of segments achieved union, and 92% (999/1,083) of segments achieved final healing. The multivariate analysis with data from 296 patients suggested that older age was associated with higher nonunion risk. Patients with external fixation in the second stage had a significantly higher risk of developing nonunion, increasing the need for additional procedures. The autografts harvested from the femur reamer-irrigator-aspirator increased nonunion, infection recurrence, and additional procedure rates.
Conclusion
The induced membrane technique is an effective technique for treating infected bone defects. Internal fixation during the second stage might effectively promote bone healing and reduce additional procedures without increasing infection recurrence. Future studies should standardize individual patient data prospectively to facilitate research on the affected patient outcomes.
Cite this article: Bone Joint Res 2023;12(9):546–558.
Article focus
-
The induced membrane technique is an effective method for managing infected bone defects.
Key messages
-
Internal fixation during the second stage might effectively promote bone healing and reduce additional procedures without increasing infection recurrence.
Strengths and limitations
-
Radical debridement is still an important cornerstone in the treatment of infected bone defects with the induced membrane technique.
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All studies included in this review were low-level evidence except one randomized controlled trial. Thus, the strength of the conclusions drawn from the multivariate analysis is limited.
Introduction
Managing infected bone defects is complex and challenging, and the surgeon faces two major challenges: infection control and defect reconstruction.1 In 2000, the French doctor Masquelet first reported the induced membrane technique,2 also known as the Masquelet technique, to treat infected bone defects. The induced membrane technique is a two-stage surgical procedure, combining the induction of functional biofilms with non-vascularized morcellized cancellous bone grafts to reconstruct segmental bone defects.2,3 Since the two-stage operation is consistent with first-stage infection control and second-stage bone reconstruction, it is especially advantageous in treating infected bone defects.4 Antibiotic bone cement can assist in infection control by eliminating dead space, being a local antibiotic carrier, and strengthening bone defect stability to some extent.5-7 The induced membrane technique has changed with its widespread clinical use.8,9 For example, antibiotics were added to the bone cement in the first stage,10,11 internal fixation was established as a stabilization method,12-14 osteoinductive factors were included, and allograft and osteoconductive scaffold for bone graft expender were added in the second stage.6,10,11 Although some systematic reviews and meta-analyses have discussed these changes, they included bone defects caused by various factors,6,10,11,15,16 or other treatment methods.17 Therefore, we conducted a systematic review to explore the factors affecting the patient outcomes of infected bone defect treated with the induced membrane technique.
Methods
This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.18
Search strategy
Two reviewers (JS, ZW) searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials databases between 1 January 2000 and 31 October 2021, using the terms “induced membrane technique” and “Masquelet technique”. Reference lists were also manually searched for relevant studies and reviews.
Inclusion and exclusion criteria
The inclusion criteria were: 1) patients with infected bone defects treated with the induced membrane technique; 2) publications in English; and 3) sample size ≥ five patients. The exclusion criteria were: 1) “review” and “digest”, “talk”, “letters”, “commentary”, “Conference article/abstract”, and “case report”; 2) animal studies; 3) basic research; 4) aseptic bone defects; and 5) bone transport in an induced membrane.
Study selection
Two authors (JS, ZW) independently performed the initial screening of titles and abstracts. If the study included septic and aseptic bone defects, the number of infected patients was determined based on the description in the Methods and Results sections of the article. A study was included for data extraction and analysis if at least five patients with infected bone defects were included. Studies with fewer than five patients, or unclear descriptions of septic and aseptic bone defects, were excluded. The study included in the qualitative synthesis should provide individual patient data. A third author (GW) independently assessed the full texts for eligibility. Any disagreements were resolved by discussion among the three authors.
Data extraction
The information retrieved included time, study design, number of patients, demographic characteristics, details of the operative technique, and outcomes. When available, the above information was extracted at the individual patient level for further analysis.
The infection diagnosis should be specified in the text. Additional procedures were defined as all surgical procedures performed to achieve bone healing after the second stage, including removing or exchanging the internal fixation, debridement, and duplicate bone grafting. Redebridement before the second stage was excluded from additional procedures. Union was defined as bone healing after the second stage without additional surgery, known as union after the index second stage procedure.10 Infection recurrence was defined as a deep infection requiring intravenous antibiotics and/or surgical procedures after grafting, excluding pin-track infections unless surgical intervention was required.
Statistical analysis
Statistical analyses were conducted with SPSS v22.0 (IBM, USA). The multivariate logistic regression analysis was conducted using individual patient data. The Hosmer-Lemeshow test determined the fit degree of the model. Statistical significance was set at p < 0.05.
Results
Literature search
Initially, we identified 1,092 studies. After removing duplicates, we screened 577 titles and abstracts. Among them, 519 articles did not fit the inclusion criteria, leaving 58 for full-text analysis. Overall, 14 full-text articles did not distinguish between septic and aseptic patients; thus, 44 studies were included for data extraction and analysis.7,12-14–19-58 Individual patient data were inaccessible in 14 full-text articles. In total, we included 30 studies in the qualitative synthesis (Figure 1).12,13,29-56
Fig. 1
Study flow diagram.
Demographic characteristics
Of the 44 included studies, 37 were retrospective and seven were prospective, including one randomized controlled trial. Among the 1,079 patients, 1,083 segments of infected bone defects were treated with the induced membrane technique; four patients had two infected bone defects in different locations, and underwent the same treatment.41,48 Additionally, 83% (851/1,031) of patients were male and 17% (180/1,031) were female, with a mean age of 40.3 years (4 to 88). Among the 1,083 segments, the most frequent location was the tibia (65%, n = 704), followed by the femur (24%, n = 258), forearm (ulna and radius; 8%, n = 86), and humerus (1%, n = 15). Other sites accounted for 2% (n = 20): five segments in the metatarsus, six in the fibula, two in the calcaneus, six in the phalanx, and one in the metacarpal.19,25,32,38,39,44,55 The mean bone defect length was 6.8 cm (0.5 to 30). Some studies reported the volume of bone defects rather than their length.21,36,58 Study and patient characteristics are summarized in Table I.
Table I.
Summary of study and patient characteristics.
| Study | Study design | Patients, n | Segments, n | Sex, n | Mean age, yrs (range) | Defect location, n | Mean defect size, cm (range) | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Male | Female | Femur | Tibia | Humerus | Forearm | Other* | ||||||
| Schöttle 200529 | Retrosp | 6 | 6 | 5 | 1 | 49.5 (37 to 61) |
0 | 6 | 0 | 0 | 0 | 6.5 (5 to 8) |
| Stafford 201030 | Retrosp | 7 | 7 | 6 | 1 | 39.7 (33 to 44) |
2 | 5 | 0 | 0 | 0 | 6.5 (2 to 17) |
| El-Alfy 201531 | Prosp | 17 | 17 | 15 | 2 | 43.1 (26 to 58) |
4 | 13 | 0 | 0 | 0 | 7.6 (5 to 11) |
| Scholz 201519 | Retrosp | 13 | 13 | 12 | 1 | 41.4 (16 to 69) |
3 | 5 | 0 | 1 | 4 | 8.1 (5.5 to 14.5) |
| Azi 20167 | Retrosp | 23 | 23 | NR | NR | 32.8 (18 to 54) |
10 | 13 | 0 | 0 | 0 | 7.2 (2.5 to 15.5) |
| Giannoudis 201632 | Prosp | 21 | 21 | 15 | 6 | 45.5 (18 to 80) |
7 | 7 | 1 | 5 | 1 | 4.7 (2 to 12) |
| Gupta 201633 | Prosp | 7 | 7 | 6 | 1 | 37.6 (22 to 55) |
0 | 7 | 0 | 0 | 0 | 5.3 (4 to 8.5) |
| Wang 201620 | Retrosp | 32 | 32 | 22 | 10 | 40.0 (19 to 72) |
12 | 20 | 0 | 0 | 0 | 5.0 (1.5 to 12.5) |
| Cho 201734 | Retrosp | 19 | 19 | 15 | 4 | 51.6 (20 to 80) |
6 | 11 | 2 | 0 | 0 | 8.7 (3.4 to 16.4) |
| Luo F 201714 | Retrosp | 67 | 67 | 58 | 9 | 37.0 (6 to 61) |
0 | 67 | 0 | 0 | 0 | 6.8 (2 to 16) |
| Luo TD 201735 | Retrosp | 7 | 10 | 3 | 4 | 47.1 (32 to 74) |
0 | 0 | 0 | 10 | 0 | 5.6 (4 to 8) |
| Mühlhäusser 201736 | Retrosp | 8 | 8 | 6 | 2 | NR (34 to 67) |
0 | 8 | 0 | 0 | 0 | NR |
| Qiu 201721 | Retrosp | 22 | 22 | 18 | 4 | 36.9 (22 to 68) |
0 | 22 | 0 | 0 | 0 | NR |
| Tong 201722 | Retrosp | 20 | 20 | 15 | 5 | 39.9 (NR) |
7 | 13 | 0 | 0 | 0 | 6.7 (NR) |
| Wang 201737 | Retrosp | 15 | 15 | 13 | 2 | 34 (6 to 51) |
0 | 15 | 0 | 0 | 0 | 5.1 (2 to 8.4) |
| Wu 201738 | Retrosp | 36 | 36 | 30 | 6 | 41.1 (21 to 68) |
16 | 19 | 0 | 0 | 1 | 5.5 (2 to 10.9) |
| Yu 201712 | Retrosp | 13 | 13 | 9 | 4 | 39.0 (16 to 69) |
13 | 0 | 0 | 0 | 0 | 9.8 (5 to 16) |
| Rousset 201839 | Retrosp | 8 | 8 | 6 | 2 | 12.8 (4 to 16) |
2 | 2 | 2 | 0 | 2 | 12.0 (4 to 30) |
| Sasaki 201840 | Retrosp | 7 | 7 | 6 | 1 | 42.9 (24 to 77) |
2 | 5 | 0 | 0 | 0 | 3.7 (2.4 to 6.5) |
| Siboni 201841 | Retrosp | 18 | 19 | 14 | 4 | 54.1 (24 to 88) |
0 | 19 | 0 | 0 | 0 | 5.3 (1.1 to 18) |
| Dhar 201942 | Retrosp | 12 | 12 | 11 | 1 | 37.9 (19 to 56) |
0 | 0 | 0 | 12 | 0 | 5 (3.5 to 7.0) |
| Gupta S 201923 | Prosp | 42 | 42 | 40 | 2 | 35.0 (18 to 67) |
24 | 16 | 2 | 0 | 0 | NR (4 to 12) |
| Masquelet 201943 | Retrosp | 14 | 14 | 12 | 2 | 32.8 (19 to 65) |
0 | 11 | 1 | 2 | 0 | 11.7 (3 to 25) |
| Raven 201924 | Retrosp | 54 | 54 | 43 | 11 | 48.6 (18 to 83) |
14 | 37 | 3 | 0 | 0 | 5.0 (0.5 to 26) |
| Wang 201944 | Retrosp | 21 | 21 | 15 | 6 | 37.9 (16 to 69) |
2 | 12 | 1 | 3 | 3 | 5.8 (2 to 10) |
| Choufani 202045 | Prosp | 13 | 13 | NR | NR | 33.7 (9 to 65) |
5 | 6 | 0 | 2 | 0 | 4.5 (2 to 10) |
| Gindraux 202056 | Retrosp | 13 | 13 | 9 | 4 | 46.8 (21 to 62) |
3 | 7 | 2 | 1 | 0 | 5.8 (2 to 11) |
| Inci 202046 | Retrosp | 24 | 24 | 22 | 2 | 38.1 (18 to 67) |
0 | 24 | 0 | 0 | 0 | 6.58 (4 to 10) |
| Jia 202025 | Retrosp | 183 | 183 | 154 | 29 | 42.8 (10 to 68) |
81 | 100 | 0 | 0 | 2 | 7.7 (1.5 to 22.7) |
| Mathieu 202047 | Retrosp | 8 | 8 | 7 | 1 | 58 (36 to 87) |
2 | 4 | 0 | 2 | 0 | 8.8 (5 to 20) |
| Mathieu 202048 | Retrosp | 11 | 11 | 8 | 3 | 36 (22 to 71) |
0 | 11 | 0 | 0 | 0 | 4.4 (2 to 11) |
| Mathieu 202049 | Retrosp | 12 | 12 | NR | NR | 37.2 (26 to 61) |
0 | 12 | 0 | 0 | 0 | 6.8 (3 to 12) |
| Meselhy 202026 | Prosp | 45 | 45 | 40 | 5 | 35 (22 to 51) |
27 | 18 | 0 | 0 | 0 | 8.16 (4 to 12) |
| Zhao 202050 | Retrosp | 12 | 12 | 9 | 3 | 39.5 (18 to 59) |
3 | 8 | 1 | 0 | 0 | 10 (6.1 to 17.2) |
| Commeil51 2021 | Retrosp | 6 | 6 | 5 | 1 | 43.8 (33 to 59) |
0 | 0 | 0 | 6 | 0 | 4.2 (2 to 8) |
| Lauthe 202152 | Retrosp | 6 | 6 | 6 | 0 | 40.3 (18 to 67) |
0 | 0 | 0 | 6 | 0 | 3.3 (1 to 9) |
| Lotzien 202153 | Retrosp | 31 | 31 | 30 | 1 | 45.8 (18 to 71) |
0 | 31 | 0 | 0 | 0 | 8.3 (1.7 to 28) |
| Ma 202127 | Retrosp | 32 | 32 | 20 | 12 | 43.2 (19 to 62) |
0 | 0 | 0 | 32 | 0 | 6.2 (3.6 to 8) |
| Pesciallo 202154 | Retrosp | 21 | 21 | 13 | 8 | 42.4 (18 to 68) |
8 | 13 | 0 | 0 | 0 | 5.3 (3.5 to 14) |
| Rohilla 202128 | RCT | 12 | 12 | 11 | 1 | 39.7 (25 to 60) |
0 | 12 | 0 | 0 | 0 | 3.8 (2 to 6) |
| Shen 202113 | Retrosp | 21 | 21 | 19 | 2 | 44 (19 to 60) |
0 | 21 | 0 | 0 | 0 | 6.1 (2.5 to 12) |
| Shen 202158 | Retrosp | 26 | 26 | 19 | 7 | 11.8 (4 to 18) |
5 | 17 | 0 | 4 | 0 | NR |
| Toyama 202155 | Retrosp | 7 | 7 | 6 | 1 | 56 (29 to 69) |
0 | 0 | 0 | 0 | 7 | NR |
| Xiao 202157 | Retrosp | 87 | 87 | 78 | 9 | 40.1 (13 to 65) |
0 | 87 | 0 | 0 | 0 | 7.2 (3 to 17) |
| Total | 7 Prosp, 37 Retrosp, 1 RCT |
1,079 | 1,083 | 851 /1,031 (83%) |
180 /1,031 (17%) |
40.3 (4 to 88) |
258 /1,083 (24%) |
704 /1,083 (65%) |
15 /1,083 (1%) |
86/1,083 (8%) |
20 /1,083 (2%) |
6.8 (0.5 to 30) |
-
*
Other: 5 metatarsus, 6 fibula, 2 calcaneus, 6 phalanx, and 1 metacarpal.
-
NR, not reported; Prosp, prospective study; RCT, randomized controlled trial; Retrosp, retrospective study.
Surgical parameters
The surgical parameters mainly included fixations, antibiotic bone cement, the interval between two stages, different autograft sources, osteoinductive adjunct, allograft, and osteoconductive scaffold (Table II).
Table II.
Summary of surgical parameters.
| Study | Segments, n | First-stage fixation | Second-stage fixation | Local antibiotic use, n | Mean time between stages, wks (range) | Autograft origin, n | Osteoinductive adjunct, n (%)* | Allograft, n (%) | Osteoconductive scaffold, n (%)† | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Plate | Nail | EF | Other‡ | Plate | Nail | P + N | EF | Other‡ | Total (%) | Single | Combination | ICBG | RIA | ICBG + RIA | Other§ | ||||||
| Schöttle 200529 | 6 | 0 | 0 | 6 | 0 | 0 | 0 | 0 | 6 | 0 | 6 (100) | 6 | 0 | 15 (13 to 17) |
6 | 0 | 0 | 0 | 0 (0) | 1 (16.7) | 0 (0) |
| Stafford 201030 | 7 | NR | NR | NR | NR | 3 | 2 | 2 | 0 | 0 | 7 (100) | NR | NR | NR | 0 | 6 | 1 | 0 | 7 (100) | 7 (100) | 0 (0) |
| El-Alfy 201531 | 17 | 0 | 0 | 17 | 0 | 0 | 0 | 0 | 17 | 0 | 0 (0) | 0 | 0 | 10.9 (4.3 to 17.4) |
17 | 0 | 0 | 0 | 0 (0) | 0 (0) | 0 (0) |
| Scholz 201519 | 13 | 0 | 0 | 13 | 0 | NR | NR | NR | 8 | 0 | 13 (100) | NR | NR | 9.8 (8 to 14) |
13 | 0 | 0 | 0 | 3 (23.1) | 0 (0) | 0 (0) |
| Azi 20167 | 23 | NR | NR | 20 | 0 | NR | NR | 0 | 13 | 0 | 23 (100) | 0 | 23 | 12.8 (7 to 25) |
23 | 0 | 0 | 0 | 0 (0) | 0 (0) | 0 (0) |
| Giannoudis 201632 | 21 | 0 | 0 | 21 | 0 | 15 | 5 | 0 | 0 | 1 | 21 (100) | 21 | 0 | 7 (6 to 8) |
3 | 18 | 0 | 0 | 19 (90.5) | 0 (0) | 0 (0) |
| Gupta G 201633 | 7 | 0 | 0 | 7 | 0 | 0 | 0 | 0 | 7 | 0 | 0 (0) | 0 | 0 | 5.3 (4.3 to 6.4) |
7 | 0 | 0 | 0 | 0 (0) | 0 (0) | 1 (14.3) |
| Wang 201620 | 32 | NR | NR | NR | NR | 19 | 0 | 10 | 3 | 0 | 32 (100) | 0 | 32 | 8.9 (6 to 14) |
32 | 0 | 0 | 0 | 0 (0) | NR | 0 (0) |
| Cho 201734 | 19 | NR | NR | NR | NR | 13 | 3 | 3 | 0 | 0 | 19 (100) |
0 | 19 | 17.1 (6 to 28) |
19 | 0 | 0 | 0 | 0 (0) | 0 (0) | 19 (100) |
| Luo F 201714 | 67 | 67 | 0 | 0 | 0 | 0 | 67 | 0 | 0 | 0 | 67 (100) |
0 | 67 | 8 (NR) | 67 | 0 | 0 | 0 | 0 (0) | 0 (0) | 0 (0) |
| Luo TD 201735 | 10 | 9 | 0 | 1 | 0 | 10 | 0 | 0 | 0 | 0 | 10 (100) |
NR | NR | 17.9 (NR) | 10 | 0 | 0 | 0 | 0 (0) | 0 (0) | 1 (10) |
| Mühlhäusser 201736 | 8 | 0 | 0 | 8 | 0 | 3 | 5 | 0 | 0 | 0 | 0 (0) | 0 | 0 | 13.3 (7 to 26) |
NR | NR | NR | NR | 3 (37.5) | NR | 0 (0) |
| Qiu 201721 | 22 | 0 | 0 | 18 | 4 | 0 | 0 | 0 | 18 | 4 | 22 (100) | 0 | 22 | 10.3 (NR) | 22 | 0 | 0 | 0 | 0 (0) | 11 (50) | 0 (0) |
| Tong 201722 | 20 | NR | NR | NR | NR | 9 | 0 | 0 | 11 | 0 | 20 (100) |
20 | 0 | 9.8 (8 to 11.3) |
20 | 0 | 0 | 0 | 20 (100) | 0 (0) | 0 (0) |
| Wang 201737 | 15 | 5 | 0 | 8 | 2 | 4 | 4 | 0 | 5 | 2 | 15 (100) |
15 | 0 | 7.1 (6.3 to 15) |
9 | 0 | 0 | 0 | 0 (0) | 12 (80) | 0 (0) |
| Wu 201738 | 36 | 12 | 0 | 24 | 0 | 5 | 22 | 0 | 9 | 0 | 36 (100) |
0 | 36 | 12.6 (6 to 36) |
36 | 0 | 0 | 0 | 0 (0) | 20 (55.6) | 0 (0) |
| Yu 201712 | 13 | 13 | 0 | 0 | 0 | 0 | 13 | 0 | 0 | 0 | 13 (100) | 0 | 13 | NR | 13 | 0 | 0 | 0 | 0 (0) | 0 (0) | 0 (0) |
| Rousset 201839 | 8 | 0 | 0 | 0 | 8 | 2 | 2 | 0 | 0 | 4 | 8 (100) | 8 | 0 | NR | 2 | 0 | 0 | 0 | 0 (0) | 2 (25) | 5 (62.5) |
| Sasaki 201840 | 7 | 4 | 0 | 0 | 3 | 4 | 3 | 0 | 0 | 0 | 7 (100) | 7 | 0 | 12.7 (6 to 28) |
7 | 0 | 0 | 0 | 0 (0) | 0 (0) | 7 (100) |
| Siboni 201841 | 19 | 0 | 0 | 15 | 4 | 8 | 0 | 0 | 6 | 5 | 19 (100) |
19 | 0 | 7.9 (NR) | 18 | 0 | 0 | 0 | 0 (0) | 9 (47.4) | 0 (0) |
| Dhar 201942 | 12 | 12 | 0 | 0 | 0 | 12 | 0 | 0 | 0 | 0 | 12 (100) |
12 | 0 | 6 (NR) |
12 | 0 | 0 | 0 | 0 (0) | 0 (0) | 0 (0) |
| Gupta S 201923 | 42 | NR | NR | 18 | 0 | NR | NR | NR | 0 | 0 | 42 (100) |
0 | 42 | 7.7 (5.1 to 12.4) |
42 | 0 | 0 | 0 | 0 (0) | 0 (0) | 27 (64.3) |
| Masquelet 201943 | 14 | 1 | 0 | 13 | 0 | 1 | 1 | 0 | 12 | 0 | 0 (0) |
0 | 0 | NR | 14 | 0 | 0 | 0 | 0 (0) | 0 (0) | 0 (0) |
| Raven 201924 | 54 | NR | NR | NR | NR | 25 | 27 | 0 | 0 | 2 | 54 (100) |
NR | NR | NR | 4 | 47 | 3 | 0 | 50 (92.6) | 0 (0) | 54 (100) |
| Wang 201944 | 21 | 2 | 0 | 16 | 3 | NR | NR | 0 | 3 | 3 | 21 (100) |
21 | 0 | 12 (NR) | NR | NR | NR | NR | 0 (0) | 0 (0) | 0 (0) |
| Choufani 2020 | 13 | 0 | 2 | 8 | 3 | 2 | 2 | 0 | 9 | 0 | 13 (100) |
13 | 0 | 9.1 (6 to 21.4) |
13 | 0 | 0 | 0 | 0 (0) | 0 (0) | 0 (0) |
| Gindraux 202056 | 13 | 5 | 6 | 1 | 1 | NR | NR | NR | NR | NR | 9 (69.2) | 9 | 0 | 30 (5.1 to 64) |
NR | NR | NR | NR | 0 (0) | 0 (0) | 0 (0) |
| Inci 202046 | 24 | 0 | 0 | 24 | 0 | 7 | 17 | 0 | 0 | 0 | 24 (100) |
NR | NR | 9.2 (6 to 16) |
NR | NR | NR | NR | 0 (0) | NR | NR |
| Jia 202025 | 183 | 183 | 0 | 0 | 0 | NR | NR | NR | 0 | 0 | 183 (100) |
0 | 183 | NR | 183 | 0 | 0 | 0 | 0 (0) | NR | 0 (0) |
| Mathieu 2020 | 8 | 0 | 5 | 0 | 3 | 4 | 4 | 0 | 0 | 0 | 8 (100) | 8 | 0 | 12 (8 to 20) |
4 | 1 | 3 | 0 | 0 (0) | 0 (0) | 0 (0) |
| Mathieu 2020 | 11 | 0 | 0 | 11 | 0 | 0 | 0 | 0 | 11 | 0 | 0 (0) | 0 | 0 | 11 (6 to 24) |
11 | 0 | 0 | 0 | 0 (0) | 0 (0) | 0 (0) |
| Mathieu 2020 | 12 | 1 | 0 | 11 | 0 | 1 | 2 | 0 | 9 | 0 | 12 (100) |
12 | 0 | 21.7 (8 to 49) |
NR | NR | 0 | 0 | 0 (0) | 0 (0) | 0 (0) |
| Meselhy 202026 | 45 | 0 | 0 | 45 | 0 | 0 | 0 | 0 | 45 | 0 | 45 (100) |
0 | 45 | 7.1 (6 to 9) |
45 | 0 | 0 | 0 | 0 (0) | 0 (0) | 0 (0) |
| Zhao 202050 | 12 | NR | NR | NR | NR | 3 | 3 | 2 | 2 | 2 | 12 (100) |
12 | 0 | NR | 12 | 0 | 0 | 0 | 0 (0) | 0 (0) | 12 (100) |
| Commeil 202151 | 6 | 3 | 0 | 3 | 0 | 5 | 0 | 1 | 0 | 0 | 6 (100) | 6 | 0 | 15 (8.6 to 21.4) |
6 | 0 | 0 | 0 | 0 (0) | 0 (0) | 0 (0) |
| Lauthe 202152 | 6 | 6 | 0 | 0 | 0 | 6 | 0 | 0 | 0 | 0 | 0 (0) | 0 | 0 | NR | 6 | 0 | 0 | 0 | 0 (0) | 0 (0) | 0 (0) |
| Lotzien 202153 | 31 | NR | NR | NR | NR | 0 | 0 | 0 | 31 | 0 | 31 (100) |
19 | 12 | 18.3 (4.5 to 63) |
1 | 13 | 17 | 0 | 20 (64.5) | 23 (74.2) | 0 (0) |
| Ma 2021 | 32 | 0 | 0 | 0 | 0 | 32 | 0 | 0 | 0 | 0 | 32 (100) |
26 | 6 | NR | 32 | 0 | 0 | 0 | 0 (0) | 0 (0) | 0 (0) |
| Pesciallo 202154 | 21 | 3 | 17 | 1 | 0 | 3 | 17 | 0 | 1 | 0 | 21 (100) | 17 | 4 | 11 (6 to 28) |
21 | 0 | 0 | 0 | 0 (0) | 21 (100) | 0 (0) |
| Rohilla 2021 | 12 | 0 | 0 | 12 | 0 | 0 | 0 | 0 | 12 | 0 | 12 (100) | NR | NR | NR | 12 | 0 | 0 | 0 | 0 (0) | 0 (0) | 0 (0) |
| Shen 2021 | 21 | 21 | 0 | 0 | 0 | 21 | 0 | 0 | 0 | 0 | 21 (100) | 0 | 21 | NR (6 to 8) |
21 | 0 | 0 | 0 | 0 (0) | 0 (0) | 0 (0) |
| Shen 2021 | 26 | NR | NR | NR | NR | 15 | 2 | 0 | 1 | 8 | 26 (100) | 0 | 26 | NR | 0 | 0 | 0 | 0 | 26 (100) | 26 (100) | 0 (0) |
| Toyama 202155 | 7 | NR | NR | NR | NR | 1 | 0 | 0 | 3 | 3 | 7 (100) | 0 | 7 | NR | 2 | 0 | 0 | 2 | 0 (0) | 0 (0) | 0 (0) |
| Xiao 2021 | 87 | 0 | 0 | 87 | 0 | 0 | 57 | 0 | 30 | 0 | 87 (100) | 87 | 0 | NR | 87 | 0 | 0 | 0 | 0 (0) | 11 (12.6) | 0 (0) |
| Total | 1,083 | 347 /816 (42%) |
30 /816 (4%) |
408 /816 (50%) |
31 /816 (4%) |
233 /815 (29%) |
258 /815 (32%) |
18 /815 (2%) |
272 /815 (33%) |
34 /815 (4%) |
1,016 /1,083 (94%) |
338 /896 (38%) |
558 /896 (62%) |
10.9 (4.3 to 64) |
852 /963 (88%) |
85 /963 (9%) |
24 /963 (3%) |
2 /963 (0%) |
148 /1,083 (14%) |
143 /1,083 (13%) |
126 /1,083 (12%) |
-
*
Includes bone morphogenetic proteins, bone marrow aspirate concentrate, platelet-rich plasma, and/or unspecified growth factors.
-
†
Includes calcium sulphate, demineralized bone matrix, gelatin sponge, hydroxyapatite, and/or tricalcium phosphate.
-
‡
Kirschner wire, plaster, and brace.
-
§
Costal cartilage, radius.
-
EF, external fixation; ICBG, iliac crest bone graft; NR, not reported; P + N, plate + nail; RIA, reamer-irrigator-aspirator.
The addition of antibiotics to the polymethyl methacrylate spacer was reported in 38 studies, encompassing 94% (1,016/1,083) of segments. Among the patients with known antibiotics, 38% (338/896) used a single antibiotic, while 62% (558/896) used a mixture of two antibiotics in the polymethyl methacrylate spacer. Vancomycin was the most common antibiotic used alone, followed by gentamicin. The most common antibiotic combination was vancomycin and gentamicin, followed by vancomycin and tobramycin. The mean time between the two stages was 10.9 weeks (4.3 to 64).
Overall, 33 studies reported the fixation methods of first-stage surgery. External fixation was the most common (50%, 408/816), followed by internal plate fixation (42%, 347/816). However, intramedullary nails were rarely used as internal fixation (4%, 30/816) compared to plates. Other fixation methods included Kirschner wires (K-wires), braces, and plasters (4%, 31/816). A total of 39 studies reported the fixation methods of second-stage surgery. External fixation remained the most common fixation method (33%, 272/815), followed by intramedullary nail fixation (32%, 258/815) and plate internal fixation (29%, 233/815). Intramedullary nail and plate fixation was rarely used as internal fixation (2%, 18/815). Other fixation methods, including K-wires, plasters, and braces, accounted for 4% (34/815).
The autologous bone source was reported in 39 studies, and the most common bone harvest site was the iliac crest. Autologous bone graft was only obtained from the iliac crest bone graft in an estimated 88% (852/963) of segments, followed by the femur using a reamer-irrigator-aspirator system (9%, 85/963). Iliac crest bone graft was also combined with graft obtained using the reamer-irrigator-aspirator system (3%, 24/963). The use of allografts as a bone graft expander was reported in 11 studies, including 143 segments (13%, 143/1,083). In eight studies, including 148 segments (14%, 148/1,083), osteoinductive agents were added to the bone graft, with agents such as bone morphogenetic protein (BMP)-2, BMP-7, bone marrow aspirate concentrate, and platelet-rich plasma. Osteoconductive scaffolds, such as calcium sulphate, calcium phosphate, β-Tricalcium phosphate, and gelatin sponge, were used in eight studies (12%, 126/1,083).
Clinical indices
The clinical indices included final bone union, infection recurrence, union after the index second stage procedure, additional procedure, mean follow-up time, and mean bone healing time (Table III). Final bone union was achieved in 999 segments (92%, 999/1,083), and union after the index second stage procedure was achieved in 797 segments (85%, 797/942) without additional surgery. The infection recurrence rate was 10% (107/1,083). The mean follow-up time was 29.6 months (6 to 262), and the mean bone healing time was 7.5 months (2.3 to 49.9). Additional procedures, such as debridement, implant removal/exchange, and repeat grafting, were required to achieve bone healing in 142 segments (17%, 142/833).
Table III.
Summary of clinical indices.
| Study | Segments, n | Final union, n (%) | Union after index second stage procedure, n (%) | Mean time to union, mths (range) | Infection recurrence after grafting, n (%) | Mean follow-up time, mths (range) | Additional procedure, n (%) |
|---|---|---|---|---|---|---|---|
| Schöttle 200529 | 6 | 6 (100) | 5 (83.3) | 7 (6 to 8) | 0 (0) | 36 (18 to 60) | 1 (16.7) |
| Stafford 201030 | 7 | 5 (71.4) | 4 (57.1) | NR | 1 (14.3) | NR | 2 (28.6) |
| El-Alfy 201531 | 17 | 14 (82.4) | 8 (47.1) | 10 (6 to 19) | 2 (11.8) | 23 (14 to 38) | 10 (58.8) |
| Scholz 201519 | 13 | 13 (100) | 8 (61.5) | 4.4 (2.8 to 5.5) | 0 (0) | 13 (9 to 24) | 5 (38.5) |
| Azi 20167 | 23 | 20 (87.0) | 20 (87.0) | 8.6 (4 to 15) | 7 (30.4) | 30.1 (12 to 61) | 7 (30.4) |
| Giannoudis 201632 | 21 | 20 (95.2) | 19 (90.5) | 5.6 (2 to 11) | 1 (4.8) | NR | 3 (14.3) |
| Gupta G 201633 | 7 | 6 (85.7) | 5 (71.4) | 12.0 (8 to 16) | 1 (14.3) | NR | 2 (28.6) |
| Wang 2016 | 32 | 32 (100) | 32 (100) | 4.9 (3 to 9) | 0 (0) | 27.5 (24 to 32) | 2 (6.3) |
| Cho 201734 | 19 | 18 (94.7) | 16 (84.2) | 9.1 (6 to 12) | 1 (5.3) | NR | 3 (15.8) |
| Luo F 201714 | 67 | 66 (98.5) | 66 (98.5) | 5.6 (3 to 11) | 4 (6.0) | 22.5 (18 to 35) | NR |
| Luo TD 201735 | 10 | 10 (100) | 9 (90) | NR | 0 (0) | 86.7 (41 to 150) | 2 (20) |
| Mühlhäusser 201736 | 8 | 7 (87.5) | 6 (75) | 12.7 (6 to 21.4) | 0 (0) | NR | 2 (25) |
| Qiu 201721 | 22 | 20 (90.9) | 20 (90.9) | 7.5 (5 to 11) | 1 (4.5) | 31.2 (18 to 54) | 1 (4.5) |
| Tong 201722 | 20 | 20 (100) | 19 (95) | NR | 1 (5) | 23 (NR) | 1 (5) |
| Wang 201737 | 15 | 15 (100) | 15 (100) | 5.3 (3 to 8) | 0 (0) | 25 (24 to 28) | 0 (0) |
| Wu 201738 | 36 | 36 (100) | 36 (100) | 5.9 (4 to 8) | 1 (2.8) | 29.5 (24 to 45) | 0 (0) |
| Yu 201712 | 13 | 13 (100) | 12 (92.3) | 4.7 (4.1 to 6.9) | 1 (7.7) | 17.8 (12 to 24) | 1 (7.7) |
| Rousset 201839 | 8 | 8 (100) | 8 (100) | 4.6 (3 to 12) | 0 (0) | 28.5 (12 to 60) | 1 (12.5) |
| Sasaki 201840 | 7 | 7 (100) | 7 (100) | 5.7 (4 to 9) | 0 (0) | NR (12 to 19) | 0 (0) |
| Siboni 201841 | 19 | 17 (89.4) | 8 (42.1) | 17.1 (4 to 36) | 4 (21.1) | 34.0 (12 to 82) | 11 (57.9) |
| Dhar 201942 | 12 | 12 (100) | 12 (100) | 7.8 (6 to 12) | 0 (0) | NR | 0 (0) |
| Gupta S 201923 | 42 | 41 (97.6) | 34 (81.0) | 9.0 (6 to 15) | 4 (9.5) | 27.7 (12 to 48) | NR |
| Masquelet 201943 | 14 | 14 (100) | 14 (100) | 7.6 (3 to 16) | 0 (0) | N.R. (120 to 262) | 0 (0) |
| Raven 201924 | 54 | 39 (72.2) | NR | 10.4 (4.5 to 26.8) | 6 (11.1) | NR | NR |
| Wang 201944 | 21 | 21 (100) | 20 (95.2) | 5.5 (3 to 8) | 4 (19.0) | 19.5 (12 to 52) | 3 (14.3) |
| Choufani 2020 | 13 | 6 (46.1) | 5 (38.5) | 6.7 (4 to 12) | 5 (38.5) | NR | 6 (46.2) |
| Gindraux 202056 | 13 | 13 (100) | 13 (100) | 13.8 (4.6 to 49.9) | 0 (0) | NR | 0 (0) |
| Inci 202046 | 24 | 22 (91.7) | 22 (91.7) | 9.2 (5.6 to 14) | 2 (8.3) | 25.9 (12 to 48) | 2 (8.3) |
| Jia 202025 | 183 | 175 (95.6) | 159 (86.9) | 5.4 (4 to 12) | 24 (13.1) | 32 (12 to 66) | 24 (13.1) |
| Mathieu 2020 | 8 | 7 (87.5) | 6 (75) | 7 (5 to 10) | 2 (25) | 21 (12 to 36) | 2 (25) |
| Mathieu 2020 | 11 | 9 (81.8) | 5 (45.5) | NR | 5 (45.5) | 64 (52 to 94) | 6 (54.5) |
| Mathieu 2020 | 12 | 11 (91.7) | 6 (50) | 10.2 (8 to 12) | 3 (27.3) | NR | 6 (50) |
| Meselhy 202026 | 45 | 42 (93.3) | 42 (93.3) | 6.1 (3.7 to 14) | 3 (6.7) | 26 (17 to 37) | 3 (6.7) |
| Zhao 202050 | 12 | 12 (100) | 12 (100) | 29 (16 to 48) | 0 (0) | 69 (30 to 142) | 0 (0) |
| Commeil 202151 | 6 | 5 (83.3) | 5 (83.3) | 9.4 (4 to 13) | 0 (0) | 62.8 (48 to 74) | 1 (16.7) |
| Lauthe 202152 | 6 | 5 (83.3) | 5 (83.3) | 3.3 (3 to 6) | 0 (0) | NR | 0 (0) |
| Lotzien 202153 | 31 | 14 (45.2) | 5 (16.1) | 15.5 (6 to 49) | 17 (54.8) | 33 (13 to 69) | 26 (83.9) |
| Ma 2021 | 32 | 32 (100) | 32 (100) | 6.6 (4 to 9) | 0 (0) | NR | 0 (0) |
| Pesciallo 202154 | 21 | 21 (100) | 19 (90.5) | 8.3 (6 to 12) | 2 (9.5) | NR (13 to 54) | 4 (19) |
| Rohilla 2021 | 12 | 8 (66.7) | 6 (50) | NR | 0 (0) | 30.4 (24 to 36) | 4 (33.3) |
| Shen 2021 | 21 | 21 (100) | 21 (100) | 4.2 (2.3 to 11.2) | 0 (0) | NR | 0 (0) |
| Shen 2021 | 26 | 26 (100) | 25 (96.2) | 5.1 (3 to 10) | 0 (0) | 23.2 (12 to 60) | 1 (3.8) |
| Toyama 202155 | 7 | 7 (100) | 7 (100) | NR | 0 (0) | 9.6 (6 to 16) | 0 (0) |
| Xiao 2021 | 87 | 83 (95.4) | NR | 6.8 (3 to 16) | 5 (5.7) | NR | NR |
| Total | 1,083 | 999/1,083 (92) | 797/942 (85) | 7.5 (2.3 to 49.9) | 107/1,083 (10) | 29.6 (6 to 262) | 142/833 (17) |
-
NR, not reported.
Multivariate analysis
Furthermore, we analyzed the patient and surgical factors, and determined the independent risk factors affecting the prognosis. Individual patient data were reported in 30 studies, encompassing 421 patients (425 segments). However, complete data were unavailable for some patients due to the lack of standardization and unity in individual patient data reporting. Therefore, 296 segments were finally included for multivariate logistic regression analysis. The multivariate analysis suggested that older age was associated with higher nonunion risk (OR 1.032, 95% CI 1.006 to 1.058; p = 0.015). Patients with external fixation in the second stage had a significantly higher risk of developing nonunion (OR 6.740, 95% CI 2.043 to 22.238; p = 0.002; OR 10.188, 95% CI 2.685 to 38.657; p = 0.001), and increasing need of additional procedures (OR 6.399, 95% CI 2.030 to 20.177; p = 0.002; OR 5.784, 95% CI 1.759 to 19.021; p = 0.004). Meanwhile, harvesting autografts from the femur reamer-irrigator-aspirator increased the risk of nonunion (OR 14.057, 95% CI 2.280 to 86.664; p = 0.004), infection recurrence (OR 19.312, 95% CI 3.142 to 118.691; p = 0.001), and additional procedure (OR 8.975, 95% CI 1.509 to 53.388; p = 0.016) (Table IV).
Table IV.
Summary of multivariate logistic regression analysis.
| Variable | Nonunion after index second stage procedure, OR (95% CI) | p-value | Infection recurrence after grafting, OR (95% CI) | p-value | Additional procedure, OR (95% CI) | p-value |
|---|---|---|---|---|---|---|
| Sex — male vs female | 2.953 (0.862 to 10.117) | 0.085 | 3.964 (0.434 to 36.165) | 0.222 | 2.097 (0.691 to 6.366) | 0.191 |
| Age (per year) | 1.032 (1.006 to 1.058) | 0.015 | 1.009 (0.977 to 1.043) | 0.574 | 1.019 (0.994 to 1.044) | 0.134 |
| Location — tibia vs femur | 1.037 (0.356 to 3.020) | 0.947 | 2.471 (0.431 to 14.174) | 0.310 | 1.634 (0.563 to 4.740) | 0.366 |
| Size of defect (per cm) | 1.033 (0.947 to 1.127) | 0.464 | 1.080 (0.973 to 1.199) | 0.150 | 1.039 (0.955 to 1.131) | 0.376 |
| Type of fixation (second stage) | ||||||
| Nail vs Plate | 0.662 (0.178 to 2.453) | 0.537 | 2.674 (0.397 to 18.002) | 0.312 | 1.106 (0.329 to 3.715) | 0.870 |
| EF vs Plate | 6.740 (2.043 to 22.238) | 0.002 | 4.262 (0.724 to 25.102) | 0.109 | 6.399 (2.030 to 20.177) | 0.002 |
| EF vs Nail | 10.188 (2.685 to 38.657) | 0.001 | 1.594 (0.333 to 7.636) | 0.560 | 5.784 (1.759 to 19.021) | 0.004 |
| Antibiotics used in spacer | 0.525 (0.165 to 1.672) | 0.276 | 0.939 (0.147 to 6.003) | 0.947 | 0.777 (0.248 to 2.432) | 0.665 |
| Autograft origin — RIA vs ICBG | 14.057 (2.280 to 86.664) | 0.004 | 19.312 (3.142 to 118.691) | 0.001 | 8.975 (1.509 to 53.388) | 0.016 |
| Osteoinductive adjunct* | 0.625 (0.110 to 3.553) | 0.596 | 0.309 (0.059 to 1.606) | 0.163 | 0.663 (0.116 to 3.782) | 0.643 |
| Allograft | 1.927 (0.779 to 4.770) | 0.156 | 1.458 (0.465 to 4.576) | 0.518 | 1.718 (0.719 to 4.108) | 0.223 |
| Osteoconductive scaffold† | 1.299 (0.363 to 4.648) | 0.687 | 0.363 (0.032 to 4.156) | 0.415 | 1.075 (0.309 to 3.735) | 0.910 |
-
*
Includes bone morphogenetic proteins, bone marrow aspirate concentrate, platelet-rich plasma, and/or unspecified growth factors.
-
†
Includes calcium sulphate, demineralized bone matrix, gelatin sponge, hydroxyapatite, and/or tricalcium phosphate.
-
CI, confidence interval; OR, odds ratio; EF, external fixation; ICBG, iliac crest bone graft; RIA, reamer-irrigator-aspirator
Discussion
Since its first report to treat large segment bone defects by Masquelet in 2000,2 the induced membrane technique has been widely used in clinical practice because of its remarkable effects. Many changes have occurred to improve patient outcomes.9,31 In this systematic review, final bone union was achieved in 999 segments (92%, 999/1,083), and the infection recurrence rate was 10% (107/1,083). The mean bone healing time was 7.5 months (2.3 to 49.9), and additional procedures were required to achieve bone healing in 142 segments (17%, 142/833). These results were consistent with other reviews which confirmed that the induced membrane technique is reliable and effective for managing infected bone defects.6,10 However, patients with tibial defects treated with the induced membrane technique had a high infection rate and a low union rate.59 Morris et al59 showed that patients who underwent initial surgery in a smaller unit had an increased rate of complications and required revision surgery more frequently. Therefore, patients transferred from peripheral hospitals should receive a careful assessment of the quality of initial debridement, and the treatment team should be confident that there is no residual infection before proceeding with the induced membrane technique.
Radical debridement is an important cornerstone for the treatment of infected bone defects with the induced membrane technique.4,5,15,17,43,60 Preoperative evaluation and judgment of lesion boundary, ‘pepper sign’ in intraoperative bone debridement, repeated flushing, and elimination of dead space have been reported in many studies.13,50,61 In 2010, Apard et al62 and Stafford et al30 added antibiotics to bone cement to improve the efficiency of infection control during the first stage induced membrane technique. A recent systematic review and meta-analysis suggested that adding antibiotics to bone cement can reduce infection recurrence and reoperation rate after the second stage of the induced membrane technique.10,11 However, we found that the antibiotics used in the bone cement spacer did not reduce the infection recurrence rate, which might be related to our enrolled infected bone defect patients. Therefore, antibiotic bone cement cannot be considered capable of treating bone infection while neglecting the importance of radical debridement.63
External fixators are the first choice for local stabilization in Masquelet’s clinical patients involving post-traumatic septic nonunions, occasionally requiring iterative excisions.2 Using an external fixator often impacts the patient’s ability to carry out daily activities,64 and negatively affects their mental health.65 In contrast, internal fixation might improve the patient’s quality of life and avoid potential complications associated with the pin-track.10 A recent study comparing treatment outcomes with internal and external fixation in the second stage of the induced membrane technique showed no difference in infection control and bone healing. However, higher complication rates were detected in the external fixation group.57 Lotzien et al53 reported unsatisfactory results during the reconstruction of septic tibial bone defects with the induced membrane technique and external ring fixation. Siboni et al41 also believed that a lack of rigid fixation (in the case of an external fixator) after the second stage would lead to nonunion or delayed union. Our results indicated that external fixation in second-stage surgery is an independent risk factor for nonunion and additional procedures, and did not reduce the risk of infection recurrence. These results may be associated with the relative stability of the external fixator.66 Additionally, pin-track infection, the most common complication of external fixation, is correlated with loose pins,67 which might further reduce external fixation stability. Hence, Azi et al4 recommend selecting internal fixation for definitive bone stabilization whenever possible. Meanwhile, in contrast to Morwood et al,68 we did not find any differential effect of the internal fixation method (plate vs intramedullary nail) on outcomes. In their study, acute bone loss after open fracture was the major aetiology of bone defects (67%) rather than infected bone defects. Moreover, there is a lack of comparative studies on second-stage internal fixation (nail vs plate) in the management of infected bone defects with the induced membrane technique.
Morcellized cancellous bone autograft has always been considered to be the ideal bone graft.69,70 Herein, the most commonly used autografts were harvested from the anterior or posterior iliac crests (88%, 852/963). However, the complication rate of the iliac crest as the donor site can be as high as 10%.71 Compared to iliac crest bone graft harvesting, reamer-irrigator-aspirator bone graft harvesting produces sufficient graft and has low donor site morbidity.72,73 Here, 9% (85/963) of patients only obtained autogenous bones using the reamer-irrigator-aspirator. Stafford and Norris30 reported good results from combining reamer-irrigator-aspirator and the induced membrane technique in treating infected bone defects. However, the multivariate analysis suggested that the reamer-irrigator-aspirator is an independent risk factor for poor outcomes, which might be related to the heterogeneity of the included studies. In Lotzien et al’s study,53 nine different orthopaedic surgeons operated, which might have led to different operating techniques. Therefore, among the patients who obtained bone autograft through reamer-irrigator-aspirator (97%), the initial healing rate was only 17%, the infection recurrence rate was as high as 53%, and the reoperation rate reached 83%. A recent study showed that the success rate of segmental bone defect reconstruction with autogenous bone obtained by reamer-irrigator-aspirator was 54%,74 far from our expectations. The defect size might be a key factor affecting the final result.74 Another factor that must be considered is whether preoperative infections are related to the ultimate effect of reamer-irrigator-aspirator bone graft reconstruction on bone defects, which requires further research. Therefore, autogenous iliac bone grafts remain the gold standard for treating bone defects,75 especially infected ones.
Supplementary allografts and osteoconductive scaffolds are often used when the harvested autograft quantity is insufficient. Our review found that 25% (269/1,083) of segments used these two bone graft expanders. The multivariate analysis did not show a significant negative effect, which might be related to the fact that the bone graft expender to autograft ratio was ≤ 1:3 in some included studies.20,25,36,38,50,57 Some scholars believe that a percentage of bone graft expander volume between 25%3,5,9,76 and 40%70 does not increase the rate of complications (e.g. nonunion, graft resorption). However, good results have also been reported for the complete use of allograft58 or osteoconductive scaffold,39 but were limited to immature patients.
Additionally, the use of osteoinductive adjuncts such as BMP, platelet-rich plasma, and/or bone marrow aspirate concentrate concurrently with the induced membrane technique has emerged as a recent trend in an effort to increase union rates.77 However, our multivariate analysis did not reach that conclusion, which is significantly different from the clinical effects reported in previous studies.58,78 Masquelet even believed that adding BMP-7 leads to a poor prognosis of infected bone defects.3
Age is a recognized factor affecting bone healing.79,80 However, to treat bone defects, our results regarding age conflicted with other systematic reviews.6,10,11 Two reasons can be considered: the first might be related to the presence of children (4 to 16 years old) who accounted for a certain proportion of the patients included in this study; the second is the increased comorbidities that come with age.81 A recent systematic review suggested that old age (age ≥ 65 years) might be a risk factor for final nonunion status for managing femoral bone defects with the induced membrane technique.16 Therefore, for elderly patients with other risk factors for bone healing, second-stage reconstruction should be performed cautiously, and even second-stage surgery should be delayed indefinitely. Cierny82 and Shen et al13 reported a method using permanent spacers, composed of various antibiotic-impregnated bone cement reinforced with a nail, pin, or plate, to treat infected bone defects successfully, which might be effective, but long-term follow-up observations are needed.
Our systematic review has some limitations. First, all studies included had low-level evidence, with only one randomized controlled trial, which limited the capacity to control for confounding variables and selection bias. Moreover, some statistically significant differences have wide confidence intervals, indicating that the effect size estimate is imprecise. Second, the complexity of microbial culture results and the difference in follow-up periods makes it impossible to include them in the multivariate analysis, which is a potential confounder limiting comparability. Third, the studies included in the multivariate analysis lack uniform standards for individual patient data reporting, which makes extraction and follow-up analysis difficult. Missing data included smoking, diabetes, deprivation, and nutrition, which negatively affect bone healing time and union. Thus, the strength of conclusions drawn from the multivariate analysis is limited.
In conclusion, the induced membrane technique is an effective treatment for infected bone defects. Second-stage internal fixation might promote bone healing and reduce additional procedures without increasing infection recurrence. Additionally, reamer-irrigator-aspirator bone grafts might not be suitable for infected bone defects. Nevertheless, future studies should standardize individual patient data reporting – including sex; age; smoking; diabetes; deprivation; nutrition; defect location and size; two-stage fixation methods; local antibiotic use; time between stages; autograft origin; osteoinductive adjunct, allograft, and osteoconductive scaffold use; final union; initial union; union time; infection recurrence; follow-up time; and additional procedure – in a prospective fashion to facilitate research on the influence of relevant factors on patient outcomes.
References
1. McNally MA , Small JO , Tofighi HG , Mollan RA . Two-stage management of chronic osteomyelitis of the long bones. The Belfast technique . J Bone Joint Surg Br . 1993 ; 75-B ( 3 ): 375 – 380 . Crossref PubMed Google Scholar
2. Masquelet AC , Fitoussi F , Begue T , Muller GP . Reconstruction of the long bones by the induced membrane and spongy autograft . Ann Chir Plast Esthet . 2000 ; 45 ( 3 ): 346 – 353 . PubMed Google Scholar
3. Masquelet AC , Begue T . The concept of induced membrane for reconstruction of long bone defects . Orthop Clin North Am . 2010 ; 41 ( 1 ): 27 – 37 . Crossref PubMed Google Scholar
4. Azi ML , Teixeira A de AA , Cotias RB , Joeris A , Kfuri M . Induced-membrane technique in the management of posttraumatic bone defects . JBJS Essent Surg Tech . 2019 ; 9 ( 2 ): e22 . Crossref PubMed Google Scholar
5. Mauffrey C , Hake ME , Chadayammuri V , Masquelet AC . Reconstruction of long bone infections using the induced membrane technique: Tips and tricks . J Orthop Trauma . 2016 ; 30 ( 6 ): e188 – 93 . Crossref PubMed Google Scholar
6. Morelli I , Drago L , George DA , Gallazzi E , Scarponi S , Romanò CL . Masquelet technique: myth or reality? A systematic review and meta-analysis . Injury . 2016 ; 47 Suppl 6 : S68 – S76 . Crossref PubMed Google Scholar
7. Azi ML , Teixeira AA de A , Cotias RB , Joeris A , Kfuri M Jr . Membrane induced osteogenesis in the management of posttraumatic bone defects . J Orthop Trauma . 2016 ; 30 ( 10 ): 545 – 550 . Crossref PubMed Google Scholar
8. Chadayammuri V , Hake M , Mauffrey C . Innovative strategies for the management of long bone infection: a review of the Masquelet technique . Patient Saf Surg . 2015 ; 9 : 32 . Crossref PubMed Google Scholar
9. Han W , Shen J , Wu H , Yu S , Fu J , Xie Z . Induced membrane technique: Advances in the management of bone defects . Int J Surg . 2017 ; 42 : 110 – 116 . Crossref PubMed Google Scholar
10. Fung B , Hoit G , Schemitsch E , Godbout C , Nauth A . The induced membrane technique for the management of long bone defects . Bone Joint J . 2020 ; 102-B ( 12 ): 1723 – 1734 . Crossref PubMed Google Scholar
11. Hsu CA , Chen SH , Chan SY , Yu YH . The induced membrane technique for the management of segmental tibial defect or nonunion: A systematic review and meta-analysis . Biomed Res Int . 2020 ; 2020 : 5893642 . Crossref PubMed Google Scholar
12. Yu X , Wu H , Li J , Xie Z . Antibiotic cement-coated locking plate as a temporary internal fixator for femoral osteomyelitis defects . Int Orthop . 2017 ; 41 ( 9 ): 1851 – 1857 . Crossref PubMed Google Scholar
13. Shen J , Sun D , Fu J , Wang S , Wang X , Xie Z . Management of surgical site infection post-open reduction and internal fixation for tibial plateau fractures . Bone Joint Res . 2021 ; 10 ( 7 ): 380 – 387 . Crossref PubMed Google Scholar
14. Luo F , Wang X , Wang S , Fu J , Xie Z . Induced membrane technique combined with two-stage internal fixation for the treatment of tibial osteomyelitis defects . Injury . 2017 ; 48 ( 7 ): 1623 – 1627 . Crossref PubMed Google Scholar
15. Andrzejowski P , Masquelet A , Giannoudis PV . Induced membrane technique (Masquelet) for bone defects in the distal tibia, foot, and ankle: systematic review, case presentations, tips, and techniques . Foot Ankle Clin . 2020 ; 25 ( 4 ): 537 – 586 . Crossref PubMed Google Scholar
16. Lu Y , Lai CY , Lai PJ , Yu YH . Induced membrane technique for the management of segmental femoral defects: A systematic review and meta-analysis of individual participant data . Orthop Surg . 2023 ; 15 ( 1 ): 28 – 37 . Crossref PubMed Google Scholar
17. Bezstarosti H , Metsemakers WJ , van Lieshout EMM , et al. Management of critical-sized bone defects in the treatment of fracture-related infection: a systematic review and pooled analysis . Arch Orthop Trauma Surg . 2021 ; 141 ( 7 ): 1215 – 1230 . Crossref PubMed Google Scholar
18. Moher D , Liberati A , Tetzlaff J , Altman DG , PRISMA Group . Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement . BMJ . 2009 ; 339 : b2535 . Crossref PubMed Google Scholar
19. Scholz AO , Gehrmann S , Glombitza M , et al. Reconstruction of septic diaphyseal bone defects with the induced membrane technique . Injury . 2015 ; 46 Suppl 4 : S121 – 4 . Crossref PubMed Google Scholar
20. Wang X , Luo F , Huang K , Xie Z . Induced membrane technique for the treatment of bone defects due to post-traumatic osteomyelitis . Bone Joint Res . 2016 ; 5 ( 3 ): 101 – 105 . Crossref PubMed Google Scholar
21. Qiu X-S , Chen Y-X , Qi X-Y , Shi H-F , Wang J-F , Xiong J . Outcomes of cement beads and cement spacers in the treatment of bone defects associated with post-traumatic osteomyelitis . BMC Musculoskelet Disord . 2017 ; 18 ( 1 ): 256 . Crossref PubMed Google Scholar
22. Tong K , Zhong Z , Peng Y , et al. Masquelet technique versus Ilizarov bone transport for reconstruction of lower extremity bone defects following posttraumatic osteomyelitis . Injury . 2017 ; 48 ( 7 ): 1616 – 1622 . Crossref PubMed Google Scholar
23. Gupta S , Malhotra A , Jindal R , Garg SK , Kansay R , Mittal N . Role of beta tri-calcium phosphate-based composite ceramic as bone-graft expander in Masquelet’s-induced membrane technique . Indian J Orthop . 2019 ; 53 ( 1 ): 63 – 69 . Crossref PubMed Google Scholar
24. Raven TF , Moghaddam A , Ermisch C , et al. Use of Masquelet technique in treatment of septic and atrophic fracture nonunion . Injury . 2019 ; 50 Suppl 3 : 40 – 54 . Crossref PubMed Google Scholar
25. Jia C , Wang X , Yu S , et al. An antibiotic cement-coated locking plate as a temporary fixation for treatment of infected bone defects: A new method of stabilization . J Orthop Surg Res . 2020 ; 15 ( 1 ): 44 . Crossref PubMed Google Scholar
26. Meselhy MA , Elhammady AS . Induced membrane technique using combined free fibular and iliac graft for the treatment of infected nonunion of long bones of the lower limb . SN Compr Clin Med . 2020 ; 2 ( 8 ): 1184 – 1190 . Crossref Google Scholar
27. Ma XY , Liu B , Yu HL , Zhang X , Xiang LB , Zhou DP . Induced membrane technique for the treatment of infected forearm nonunion: A retrospective study . J Hand Surg Am . 2022 ; 47 ( 6 ): 583 . Crossref PubMed Google Scholar
28. Rohilla R , Sharma PK , Wadhwani J , Das J , Singh R , Beniwal D . Prospective randomized comparison of bone transport versus Masquelet technique in infected gap nonunion of tibia . Arch Orthop Trauma Surg . 2022 ; 142 ( 8 ): 1923 – 1932 . Crossref PubMed Google Scholar
29. Schöttle PB , Werner CML , Dumont CE . Two-stage reconstruction with free vascularized soft tissue transfer and conventional bone graft for infected nonunions of the tibia: 6 patients followed for 1.5 to 5 years . Acta Orthop . 2005 ; 76 ( 6 ): 878 – 883 . Crossref PubMed Google Scholar
30. Stafford PR , Norris BL . Reamer-irrigator-aspirator bone graft and bi Masquelet technique for segmental bone defect nonunions: a review of 25 cases . Injury . 2010 ; 41 Suppl 2 : S72 – 7 . Crossref PubMed Google Scholar
31. El-Alfy BS , Ali AM . Management of segmental skeletal defects by the induced membrane technique . Indian J Orthop . 2015 ; 49 ( 6 ): 643 – 648 . Crossref PubMed Google Scholar
32. Giannoudis PV , Harwood PJ , Tosounidis T , Kanakaris NK . Restoration of long bone defects treated with the induced membrane technique: protocol and outcomes . Injury . 2016 ; 47 Suppl 6 : S53 – S61 . Crossref PubMed Google Scholar
33. Gupta G , Ahmad S , Khan AH , Sherwani MKA , Khan AQ . Management of traumatic tibial diaphyseal bone defect by “induced-membrane technique.” Indian J Orthop . 2016 ; 50 ( 3 ): 290 – 296 . Crossref PubMed Google Scholar
34. Cho J-W , Kim J , Cho W-T , et al. Circumferential bone grafting around an absorbable gelatin sponge core reduced the amount of grafted bone in the induced membrane technique for critical-size defects of long bones . Injury . 2017 ; 48 ( 10 ): 2292 – 2305 . Crossref PubMed Google Scholar
35. Luo TD , Nunez FA , Lomer AA , Nunez FA . Management of recalcitrant osteomyelitis and segmental bone loss of the forearm with the Masquelet technique . J Hand Surg Eur Vol . 2017 ; 42 ( 6 ): 640 – 642 . Crossref PubMed Google Scholar
36. Mühlhäusser J , Winkler J , Babst R , Beeres FJP . Infected tibia defect fractures treated with the Masquelet technique . Medicine (Baltimore) . 2017 ; 96 ( 20 ): e6948 . Crossref PubMed Google Scholar
37. Wang X , Wang Z , Fu J , Huang K , Xie Z . Induced membrane technique for the treatment of chronic hematogenous tibia osteomyelitis . BMC Musculoskelet Disord . 2017 ; 18 ( 1 ): 33 . Crossref PubMed Google Scholar
38. Wu H , Shen J , Yu X , et al. Two stage management of Cierny-Mader type IV chronic osteomyelitis of the long bones . Injury . 2017 ; 48 ( 2 ): 511 – 518 . Crossref PubMed Google Scholar
39. Rousset M , Walle M , Cambou L , et al. Chronic infection and infected non-union of the long bones in paediatric patients: preliminary results of bone versus beta-tricalcium phosphate grafting after induced membrane formation . Int Orthop . 2018 ; 42 ( 2 ): 385 – 393 . Crossref PubMed Google Scholar
40. Sasaki G , Watanabe Y , Miyamoto W , Yasui Y , Morimoto S , Kawano H . Induced membrane technique using beta-tricalcium phosphate for reconstruction of femoral and tibial segmental bone loss due to infection: technical tips and preliminary clinical results . Int Orthop . 2018 ; 42 ( 1 ): 17 – 24 . Crossref PubMed Google Scholar
41. Siboni R , Joseph E , Blasco L , et al. Management of septic non-union of the tibia by the induced membrane technique. What factors could improve results? Orthop Traumatol Surg Res . 2018 ; 104 ( 6 ): 911 – 915 . Crossref PubMed Google Scholar
42. Dhar SA , Dar TA , Mir NA . Management of infected nonunion of the forearm by the Masquelet technique . Strategies Trauma Limb Reconstr . 2019 ; 14 ( 1 ): 1 – 5 . Crossref PubMed Google Scholar
43. Masquelet AC , Kishi T , Benko PE . Very long-term results of post-traumatic bone defect reconstruction by the induced membrane technique . Orthop Traumatol Surg Res . 2019 ; 105 ( 1 ): 159 – 166 . Crossref PubMed Google Scholar
44. Wang J , Yin Q , Gu S , Wu Y , Rui Y . Induced membrane technique in the treatment of infectious bone defect: A clinical analysis . Orthop Traumatol Surg Res . 2019 ; 105 ( 3 ): 535 – 539 . Crossref PubMed Google Scholar
45. Choufani C , Demoures T , de l’Escalopier N , Chapon M-P , Barbier O , Mathieu L . Application of the Masquelet technique in austere environments: experience from a French forward surgical unit deployed in Chad . Eur J Trauma Emerg Surg . 2022 ; 48 ( 1 ): 593 – 599 . Crossref PubMed Google Scholar
46. Inci F , Yildirim AO , Kocak C , et al. Treatment strategies of defect nonunion with vascular damaged by induced membrane technique: Is two-stage treatment sufficient? Injury . 2020 ; 51 ( 4 ): 1103 – 1108 . Crossref PubMed Google Scholar
47. Mathieu L , Tossou-Odjo L , de l’Escalopier N , et al. Induced membrane technique with sequential internal fixation: use of a reinforced spacer for reconstruction of infected bone defects . Int Orthop . 2020 ; 44 ( 9 ): 1647 – 1653 . Crossref PubMed Google Scholar
48. Mathieu L , Potier L , Ndiaye R , Choufani C , Mbaye E , Niang CD . Challenges of the induced-membrane technique in the reconstruction of traumatic tibial defect with limited resources: A cohort study . Acta Orthop Belg . 2020 ; 86 ( 4 ): 606 – 613 . PubMed Google Scholar
49. Mathieu L , Bilichtin E , Durand M , et al. Masquelet technique for open tibia fractures in a military setting . Eur J Trauma Emerg Surg . 2020 ; 46 ( 5 ): 1099 – 1105 . Crossref PubMed Google Scholar
50. Zhao Z , Wang G , Zhang Y , et al. Induced membrane technique combined with antibiotic-loaded calcium sulfate-calcium phosphate composite as bone graft expander for the treatment of large infected bone defects: preliminary results of 12 cases . Ann Transl Med . 2020 ; 8 ( 17 ): 1081 . Crossref PubMed Google Scholar
51. Commeil P , Seguineau A , Delesque A , et al. Post-traumatic forearm bone defect reconstruction using the induced membrane technique . Orthop Traumatol Surg Res . 2021 ; 107 ( 8 ): 103036 . Crossref PubMed Google Scholar
52. Lauthe O , Gaillard J , Cambon-Binder A , Masquelet AC . Induced membrane technique applied to the forearm: Technical refinement, indications and results of 13 cases . Orthop Traumatol Surg Res . 2021 ; 107 ( 8 ): 103074 . Crossref PubMed Google Scholar
53. Lotzien S , Rosteius T , Reinke C , et al. Reconstruction of septic tibial bone defects with the Masquelet technique and external ring fixation- A low healing rate and high complication and revision rates . J Orthop Trauma . 2021 ; 35 ( 9 ): e328 – e336 . Crossref PubMed Google Scholar
54. Pesciallo CA , Garabano G , Dainotto T , Ernst G . Masquelet technique in post-traumatic infected femoral and tibial segmental bone defects. Union and reoperation rates with high proportions (up to 64%) of allograft in the second stage . Injury . 2021 ; 52 ( 11 ): 3471 – 3477 . Crossref PubMed Google Scholar
55. Toyama T , Hamada Y , Horii E , Kinoshita R , Saito T . Finger rescue using the induced membrane technique for osteomyelitis of the hand . J Hand Surg Asian-Pac Vol . 2021 ; 26 ( 02 ): 235 – 239 . Crossref PubMed Google Scholar
56. Gindraux F , Loisel F , Bourgeois M , et al. Correction to: Induced membrane maintains its osteogenic properties even when the second stage of Masquelet’s technique is performed later . Eur J Trauma Emerg Surg . 2020 ; 46 ( 2 ): 313 – 315 . Crossref PubMed Google Scholar
57. Xiao H , Wang S , Wang F , Dong S , Shen J , Xie Z . Locking compression plate as an external fixator for the treatment of tibia infected bone defects . Z Orthop Unfall . 2023 ; 161 ( 3 ): 311 – 317 . Crossref PubMed Google Scholar
58. Shen J , Sun D , Yu S , et al. Radiological and clinical outcomes using induced membrane technique combined with bone marrow concentrate in the treatment of chronic osteomyelitis of immature patients . Bone Joint Res . 2021 ; 10 ( 1 ): 31 – 40 . Crossref PubMed Google Scholar
59. Morris R , Hossain M , Evans A , Pallister I . Induced membrane technique for treating tibial defects gives mixed results . Bone Joint J . 2017 ; 99-B ( 5 ): 680 – 685 . Crossref PubMed Google Scholar
60. Masquelet AC , Kanakaris NK , Obert L , Stafford P , Giannoudis PV . Bone repair using the Masquelet technique . J Bone Joint Surg Am . 2019 ; 101-A ( 11 ): 1024 – 1036 . Crossref PubMed Google Scholar
61. Metsemakers W-J , Fragomen AT , Moriarty TF , et al. Evidence-based recommendations for local antimicrobial strategies and dead space management in fracture-related infection . J Orthop Trauma . 2020 ; 34 ( 1 ): 18 – 29 . Crossref PubMed Google Scholar
62. Apard T , Bigorre N , Cronier P , Duteille F , Bizot P , Massin P . Two-stage reconstruction of post-traumatic segmental tibia bone loss with nailing . Orthop Traumatol Surg Res . 2010 ; 96 ( 5 ): 549 – 553 . Crossref PubMed Google Scholar
63. Masquelet AC . Induced membrane technique: Pearls and pitfalls . J Orthop Trauma . 2017 ; 31 Suppl 5 : S36 – S38 . Crossref PubMed Google Scholar
64. Wang Y , Jiang H , Deng Z , et al. Comparison of monolateral external fixation and internal fixation for skeletal stabilisation in the management of small tibial bone defects following successful treatment of chronic osteomyelitis . Biomed Res Int . 2017 ; 2017 : 6250635 . Crossref PubMed Google Scholar
65. Abulaiti A , Yilihamu Y , Yasheng T , Alike Y , Yusufu A . The psychological impact of external fixation using the Ilizarov or Orthofix LRS method to treat tibial osteomyelitis with a bone defect . Injury . 2017 ; 48 ( 12 ): 2842 – 2846 . Crossref PubMed Google Scholar
66. Bible JE , Mir HR . External fixation: Principles and applications . J Am Acad Orthop Surg . 2015 ; 23 ( 11 ): 683 – 690 . Crossref PubMed Google Scholar
67. Mahan J , Seligson D , Henry SL , Hynes P , Dobbins J . Factors in pin tract infections . Orthopedics . 1991 ; 14 ( 3 ): 305 – 308 . PubMed Google Scholar
68. Morwood MP , Streufert BD , Bauer A , et al. Intramedullary nails yield superior results compared with plate fixation when using the Masquelet technique in the femur and tibia . J Orthop Trauma . 2019 ; 33 ( 11 ): 547 – 552 . Crossref PubMed Google Scholar
69. Giannoudis PV , Faour O , Goff T , Kanakaris N , Dimitriou R . Masquelet technique for the treatment of bone defects: tips-tricks and future directions . Injury . 2011 ; 42 ( 6 ): 591 – 598 . Crossref PubMed Google Scholar
70. Aurégan JC , Bégué T . Induced membrane for treatment of critical sized bone defect: a review of experimental and clinical experiences . Int Orthop . 2014 ; 38 ( 9 ): 1971 – 1978 . Crossref PubMed Google Scholar
71. Arrington ED , Smith WJ , Chambers HG , Bucknell AL , Davino NA . Complications of iliac crest bone graft harvesting . Clin Orthop Relat Res . 1996 ; 1996 ( 329 ): 300 – 309 . Crossref PubMed Google Scholar
72. Han F , Peter L , Lau ETC , Thambiah J , Murphy D , Kagda FHY . Reamer Irrigator Aspirator bone graft harvesting: complications and outcomes in an Asian population . Injury . 2015 ; 46 ( 10 ): 2042 – 2051 . Crossref PubMed Google Scholar
73. Dimitriou R , Mataliotakis GI , Angoules AG , Kanakaris NK , Giannoudis PV . Complications following autologous bone graft harvesting from the iliac crest and using the RIA: a systematic review . Injury . 2011 ; 42 Suppl 2 : S3 – 15 . Crossref PubMed Google Scholar
74. Metsemakers WJ , Claes G , Terryn PJ , Belmans A , Hoekstra H , Nijs S . Reamer-Irrigator-Aspirator bone graft harvesting for treatment of segmental bone loss: analysis of defect volume as independent risk factor for failure . Eur J Trauma Emerg Surg . 2019 ; 45 ( 1 ): 21 – 29 . Crossref PubMed Google Scholar
75. Sen MK , Miclau T . Autologous iliac crest bone graft: should it still be the gold standard for treating nonunions? Injury . 2007 ; 38 Suppl 1 : S75 – 80 . Crossref PubMed Google Scholar
76. Mathieu L , Durand M , Collombet J-M , de Rousiers A , de l’Escalopier N , Masquelet A-C . Induced membrane technique: A critical literature analysis and proposal for a failure classification scheme . Eur J Trauma Emerg Surg . 2021 ; 47 ( 5 ): 1373 – 1380 . Crossref PubMed Google Scholar
77. Nauth A , Lee M , Gardner MJ , et al. Principles of nonunion management: State of the art . J Orthop Trauma . 2018 ; 32 Suppl 1 : S52 – S57 . Crossref PubMed Google Scholar
78. Piacentini F , Ceglia MJ , Bettini L , Bianco S , Buzzi R , Campanacci DA . Induced membrane technique using enriched bone grafts for treatment of posttraumatic segmental long bone defects . J Orthop Traumatol . 2019 ; 20 ( 1 ): 13 . Crossref PubMed Google Scholar
79. Hak DJ , Fitzpatrick D , Bishop JA , et al. Delayed union and nonunions: epidemiology, clinical issues, and financial aspects . Injury . 2014 ; 45 Suppl 2 : S3 – 7 . Crossref PubMed Google Scholar
80. Ekegren CL , Edwards ER , de Steiger R , Gabbe BJ . Incidence, costs and predictors of non-union, delayed union and mal-union following long bone fracture . Int J Environ Res Public Health . 2018 ; 15 ( 12 ): 12 . Crossref PubMed Google Scholar
81. Zura R , Mehta S , Della Rocca GJ , Steen RG . Biological risk factors for nonunion of bone fracture . JBJS Rev . 2016 ; 4 ( 1 ): e5 . Crossref PubMed Google Scholar
82. Cierny G . Surgical treatment of osteomyelitis . Plast Reconstr Surg . 2011 ; 127 Suppl 1 : 190S – 204S . Crossref PubMed Google Scholar
Author contributions
J. Shen: Conceptualization, Investigation, Data curation, Methodology, Formal analysis, Writing – original draft.
Z. Wei: Investigation, Data curation, Methodology, Formal analysis, Writing – original draft.
S. Wang: Data curation. Writing – review & editing.
X. Wang: Writing – review & editing.
W. Lin: Conceptualization, Writing – review & editing.
L. Liu: Conceptualization, Funding acquisition, Writing – review & editing.
G. Wang: Conceptualization, Funding acquisition, Writing – review & editing.
Funding statement
The authors disclose receipt of the following financial or material support for the research, authorship, and/or publication of this article: this work was supported by the National Natural Science Foundation of China (81874002, 82272515, 82202707).
ICMJE COI statement
All the authors declare that there is no conflict of interest.
Data sharing
The data that support the findings for this study are available to other researchers from the corresponding author upon reasonable request.
Open access funding
The open access funding for this article was supported by the National Natural Science Foundation of China (81874002).
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