The field of limb lengthening has undergone substantial progress in recent years with the introduction of various novel devices and technologies that further the application of core biomechanical principles1. Advancement has been noted with respect to the subjective patient experience, the rate of surgical complications, and the time required to achieve regenerate consolidation.
There are a number of devices that have facilitated the advancement toward motorized internal limb lengthening (MILL). One such device is the PRECICE Intramedullary Limb Lengthening System (NuVasive Specialized Orthopaedics). In 2011, the first-generation PRECICE nail was granted clearance for usage in Europe and the United States2. Since then, MILL devices have been integrated into the spectrum of limb-lengthening techniques with exceptional success. Figure 1 illustrates the excellent clinical outcomes that are achievable with the PRECICE nail. Figure 2 demonstrates the excellent remodeled healing of a lengthened femur after nail removal.
The initial internal lengthening devices that relied on ratchet mechanisms for the rotation of bone fragments have since been superseded by MILL devices3. This study focuses on these most recent additions to the limb-lengthening armamentarium. We aimed to assess the performance of these MILL devices when compared with alternative methods of limb lengthening via systematic review and meta-analysis.
Materials and Methods
Only studies that compared MILL methods with alternative methods of limb lengthening were included for systematic review. The following devices were considered under the domain of MILL: the PRECICE nail, the STRYDE nail (NuVasive Specialized Orthopaedics), and the FITBONE nail (WITTENSTEIN intens). Inclusion criteria were a minimum follow-up of 6 months, total time to regenerate union or details pertaining to the rate of regenerate union (e.g., consolidation index/bone-healing index), total length (centimeters) achieved, and details on loss to follow-up. A minimum of 6 months of follow-up was deemed appropriate as the regenerate is consolidated by this time in the majority of cases. All of the studies except 1 described a total time to regenerate union4. Szymczuk et al. compared regenerate healing rates using the consolidation index (days/cm) only4.
Details relating to “problems,” “obstacles,” and “sequelae” as described by Paley5 were preferred but were not an absolute indication for inclusion. Black et al. opted to describe complications using the classification system that had been designed in their own institution, with sufficient detail to allow these complications to be classified as problems, obstacles, or sequelae6. The PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines were adhered to for this study7.
On May 20, 2020, the following Medical Subject Headings (MeSH) terms were used to search a number of electronic bibliographic databases and clinical trial registries: “PRECICE,” “STRYDE,” “FITBONE,” “limb lengthening,” “Ilizarov,” “distraction osteogenesis,” and “motorized internal limb lengthening.” The locations that were searched included PubMed, the International Clinical Trials Registry Platform (ICTRP; World Health Organization [WHO]), the Cochrane Library, ClinicalTrials.gov, and the EU Clinical Trials Register. The abstracts of studies with appropriate titles were included depending on their compliance with the studies’ inclusion criteria. The text of the complete manuscripts was then assessed by 2 reviewers to ensure the accuracy of data extraction. Study selection was unblinded, and any contention was resolved through consensus with all of the authors.
All of the relevant data were extracted using an electronic data extraction form. Extracted information included author, year, journal, country of origin, total limbs, number of limbs undergoing MILL, number of limbs undergoing comparative lengthening, mean follow-up, sex, age, implant specifications, and complications (i.e., problems, obstacles, and sequelae).
All statistical analyses were conducted using Stata/IC 13.1 for Mac (64-bit Intel; StataCorp). The primary outcome measures were time to union (or time to full weight-bearing when this was reported as a surrogate for union) in weeks and the total length (centimeters) that was achieved. Two studies used time to full weight-bearing instead of time to union as the primary outcome measure6,8. Szymczuk et al. did not give an absolute time to union but instead used a consolidation index (days/cm) to describe the rate of regenerate union4. Kaplan-Meier survivorship curves were generated to compare the time to union for both cohorts. In order to detect a significant difference between both groups, the 2-sample t test with equal variances was utilized.
Secondary outcomes including problems, obstacles, and sequelae were compared using a random-effects meta-analysis5. To allow for missing data, a statistical command was used to explore the robustness of results to different assumptions about the missing data via sensitivity analysis for all of the available cases9. The relative risk (RR) for each outcome measure was calculated with a 95% confidence interval (CI), and a weighted percentage was attributed. A p value of <0.05 was considered to be significant. The results were illustrated on a forest plot.
The potential contribution of any interstudy heterogeneity was analyzed using the chi-square test and the I2 statistic. Variation in RR due to heterogeneity was expressed as a percentage, and a p value of >0.05 implied that heterogeneity had no significant impact on the described results.
To detect any evidence of publication bias, the effects of small studies were analyzed visually through the use of a funnel plot. To assess the funnel plot for significant asymmetry, the Egger test for small-study effects was used10. Again, a p value of <0.05 was considered significant.
Sixty-eight studies were originally identified for analysis. Fifty-three were excluded based on their titles, 9 were excluded based on their abstracts, and 1 was excluded based on a review of the complete text. All of the excluded studies were omitted from analysis since further review revealed that they were not comparative studies that were suitable for inclusion. This left 5 comparative studies that met the inclusion criteria (Fig. 3). Of the 5 included studies, 4 were from the U.S. and 1 was from the U.K. (Table I). The study by Richardson et al. did not include information on complications in the form of problems, obstacles, and sequelae11; therefore, this study was excluded from the meta-analyses that were performed to generate the respective forest plots to analyze these outcome measures. Szymczuk et al. did not include an absolute time to union; thus, this study was not included in the Kaplan-Meier curve generation4.
TABLE I -
Data Set for Included Limb-Lengthening Studies*
||Mean Age (MILL:Other) (yr)
||Total No. of MILL Limbs
||Total No. of Other Limbs
||Minimum Follow-up (MILL) (mo)
||Mean Length Achieved (MILL:Other) (cm)
||Mean Time to Union (MILL:Other) (wk)
||Mean Difference in Time to Union (wk)
||No. of Problems (MILL:Other)
||No. of Obstacles (MILL:Other)
||No. of Sequelae (MILL:Other)
||LRS Monorail Fixator
||LRS Monorail Fixator
*MILL = motorized internal limb lengthening, LON = lengthening over a nail, and LRS = limb reconstruction system.
We found no evidence of publication bias on review of the funnel plot (Fig. 4). The Egger test for small-study effects showed no significant asymmetry (p = 0.961), indicating no evidence of any publication bias.
A total of 143 limbs that were lengthened using MILL techniques were compared with 98 limbs that were lengthened using alternative techniques. In the comparison cohort, 3 different methods were utilized for lengthening. Lengthening over a nail (LON) (PRECICE) was used for comparison in 2 studies11,12. Two studies compared MILL with the Limb Reconstruction System (LRS) Monorail Fixator (Orthofix)4,8. Black et al. compared MILL with circular external fixation methods (Ilizarov apparatus [Smith & Nephew] or TrueLok [Orthofix])6. Four of the 5 studies used the PRECICE nail in the MILL cohort4,8,11,12. The MILL device that was used by Black et al. was the FITBONE Telescope Active Actuator (TAA) nail.
The indications for lengthening in 3 of the studies were congenital, developmental, and posttraumatic8,11,12. The indication for lengthening in 2 of the studies was exclusively congenital femoral deficiency4,6.
For all of the studies, the minimum follow-up period ranged from 6 to 24 months. The mean age was comparable between all of the groups in all of the studies. For most of the studies, the mean patient age was in the third and fourth decades of life. The mean age of patients who were included for congenital femoral deficiency was in the first and second decades of life4,6. In all of the studies, there was a male preponderance in both cohorts, except for the Szymczuk et al. study, where there was a female predominance in both cohorts. There was a 63% male majority in the MILL cohort for all of the studies overall.
Time to Union
All 4 of the studies that reported time to union demonstrated an improvement in the MILL cohort (p = 0.77). Each of the 4 studies that reported this outcome demonstrated at least a 4-week reduction in overall time to union for the MILL group. Fragomen et al. reported the MILL time to union as 13.2 weeks compared with 18 weeks in the LON group12. Richardson et al. reported the MILL time to union as 14.3 weeks compared with 19.5 weeks in the LON group11. Laubscher et al. reported a time of 14.4 weeks to full weight-bearing in the MILL group compared with 19.2 weeks in the LRS Monorail Fixator group8. Black et al. reported a time of 30.8 weeks to full-weight-bearing in the MILL group compared with 35.2 weeks in the circular fixator group6. They defined the time to full weight-bearing as the interval between surgery and the postoperative clinic appointment at which full weight-bearing was permitted. This may explain the relatively higher figures that were reported in both groups for this study compared with the other 3 studies; however, the relative superiority of MILL techniques over comparative techniques was still demonstrated6.
Using Kaplan-Meier survival estimates, we noted that the mean time to union for the combined MILL cohort was 18 weeks (standard deviation [SD] = 8.43; 95% CI, 4.75 to 31.59) compared with 23 weeks in the combined comparative cohort (SD = 8.17; 95% CI, 9.96 to 35.98) (Fig. 5).
Szymczuk et al. did not report on total time to union but did demonstrate no significant difference in the consolidation index (days/cm) for both groups (p = 0.08)4. Fragomen et al. reported no significant difference in the bone-healing index (months/cm) for both groups (p = 0.101)12. Laubscher et al. used a healing index (days/cm) to describe the rate of regenerate consolidation8. Theirs was the only study to demonstrate a significant superiority of the MILL techniques when using indices to express the rate of regenerate healing (p < 0.001). The mean healing index in the MILL group was 31 days/cm compared with 47 days/cm in the comparative group for this study8.
Total Length Achieved
There was no significant difference in the mean total length that was achieved between both groups (p = 0.35). The accumulated mean length that was achieved in the MILL cohort was 4.6 cm (σ = 0.88; 95% CI, 3.45 to 5.65) compared with 4.7 cm in the comparative cohort (σ = 0.64; 95% CI, 3.93 to 5.53).
Complications (Problems, Obstacles, and Sequelae)
Regarding infection, Black et al. reported 2 deep infections in the comparative group and no deep infections in the MILL group6. Szymczuk et al. reported 1 deep infection in the comparative group and no deep infections in the MILL group4. There were 21 pin-site/superficial infections reported in the comparative group and only 1 superficial infection was reported in the MILL group (p < 0.0001)4. Laubscher et al. reported 7 cases of pin-site infection in the comparative group8. All of the cases with infection were managed with oral antimicrobial therapy, and no additional invasive intervention was required. Regarding post-lengthening regenerate deformity, mechanical axis deviation was reported in 19 (13.2%) of 144 cases of the MILL cohort and in 13 (13.0%) of 100 cases of the comparative cohort.
Complications that were specific to the MILL techniques included 1 internal lengthening nail device fracture, as described by Fragomen et al.12. Szymczuk et al. reported 2 rod failures in the MILL cohort4. Laubscher et al. described 2 cases of bolts backing out from their initial intraoperative position8. Black et al. reported 3 incidents that were specific to the MILL technique: 1 case of unrecognized telescopic nail settling, leading to a loss of lengthening from 4 cm to a final 2.5 cm; 1 case of intramedullary nail displacement during lengthening, leading to cessation of lengthening; and 1 case of a femoral fracture through the proximal locking bolt site secondary to noncompliant weight-bearing and a subsequent fall by the patient6.
Regarding the “problem” profile of both cohorts, the MILL cohort was found to have significantly fewer problems on random-effects meta-analysis (p < 0.001; RR = 0.31; 95% CI, 0.19 to 0.52) (Fig. 6).
There was no significant difference in the frequency of obstacles that were noted between the 2 groups, although there was a trend favoring the MILL group on random-effects meta-analysis (p = 0.51; RR = 0.91; 95% CI, 0.67 to 1.22) (Fig. 7).
A significantly higher number of sequelae were noted in the comparative group on random-effects meta-analysis (p = 0.002; RR = 0.57; 95% CI, 0.41 to 0.81) (Fig. 8).
Our results explore the benefits of MILL compared with a variety of alternative lengthening techniques. Recent evidence has suggested that both pediatric and adult populations experience excellent results with the use of MILL devices13,14. The results of the current study corroborate these claims. With MILL, the numbers of “problems” (p < 0.001) and “sequelae” (p = 0.002) were significantly lower.
Infectious complications were fewer with MILL procedures. Both Szymczuk et al. and Black et al. reported no deep infections in the MILL group4,6. Pin-site infections are eliminated with MILL techniques, but they do remain an issue with conventional circular fixation lengthening methods8. Szymczuk et al. reported 21 incidents of superficial/pin-site infections compared with 1 superficial infection in the MILL group4.
Regarding regenerate healing, recent meta-analyses have demonstrated a superior external fixation index and consolidation index when comparing integrated limb lengthening with conventional methods15. Our findings expand on this trend, stating that times to regenerate formation, union, and full weight-bearing with MILL are clinically superior, although not significantly so, to those for an array of alternative lengthening techniques. As demonstrated in Table I, the time to union for all 4 of the studies that reported this outcome was at least 4 weeks less in the MILL group. MILL techniques are therefore clinically superior to both conventional and integrated techniques of lengthening in relation to the time required to achieve regenerate union and full weight-bearing status. This finding, accompanied by the significant reduction in the complication profile of MILL, supports the claim that MILL techniques should be the gold standard for limb-lengthening surgery in the future.
There are a number of considerations with MILL devices. First, the comparative cost per procedure is higher. However, when considering the increased number of procedures that typically are required with conventional lengthening, the total cost of MILL then becomes comparable with conventional techniques12,16. Richardson et al. reported that patients with MILL required significantly fewer surgeries (p < 0.001) and incurred significantly lower surgeon fees (p < 0.001) when compared with patients undergoing integrated lengthening11. In addition to cost, implant-specific complications should be noted. Internal lengthening nails are highly advanced and complex devices. Retrieval analyses have demonstrated microscopic evidence of fretting and pitting corrosion with the formation of metal debris17. Device modification has improved these undesirable findings, but the issue of mechanical failure still remains. Many examples have been reported where MILL hardware has either failed or malfunctioned18-21. Black et al. reported 3 such implant-specific complications6. Despite the disadvantages that are associated with MILL devices, the evidence from this current meta-analysis suggests that MILL is becoming the gold standard of surgical care for patients who require limb-lengthening procedures.
We extended our inclusion criteria to retrospective comparative cohort studies, which introduced the inherent limitation that is associated with retrospective analysis. The comparative groups were heterogeneous but the MILL group was homogeneous, and our results consistently demonstrated the superiority of MILL, regardless of the techniques that were used in the comparative cohort. Fragomen et al. reported 1 patient (1 limb) from the MILL group and 2 patients (2 limbs) from the comparative group who were lost to follow-up12. These 3 limbs were excluded from the final analyses with use of statistical commands that controlled for missing data.
The number of included studies was small due to the emerging nature of this novel technique. With the addition of future comparative studies, MILL may demonstrate a significant improvement in time to union relative to comparative techniques. Despite the small number of eligible studies, it was still possible to demonstrate that MILL techniques are significantly superior to alternative methods of limb lengthening.
MILL is associated with fewer complications than alternative methods of limb lengthening. Because of the advancements in the field of limb lengthening toward fully implantable remote-controlled internal limb-lengthening devices, MILL techniques are likely to dominate the field of limb lengthening in the foreseeable future.
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