Matrixmidface Preformed Orbital Implants for Three-Dimensional Reconstruction of Orbital Floor and Medial Wall Fractures: A Prospective Clinical Study

Abstract

Study Design: Prospective Interventional study. Objective: To evaluate the efficiency of Matrixmidface preformed Orbital plates for three-dimensional reconstruction of orbital floor and medial wall fractures. Methods: This prospective institutional clinical study was conducted on a group of 14 patients who underwent repair of orbital floor and medial wall fracture defects using Matrixmidface Preformed Orbital plates and open reduction and internal fixation of associated fractures. The following parameters were studied preoperative and postoperative enophthalmos, hypoglobus, orbital volume; correction of diplopia, intraoperative and postoperative complications. Results: All 14 patients were males aged between 19 and 42 years. The most common mode of injury was found to be road traffic accidents (RTAs) followed by self-fall and trauma at workplace. Orbital fractures were associated with other concomitant maxillofacial fractures in 12 patients (85.7%) while 2 patients (14.3%) had pure blowout fractures. Significant improvement of enophthalmos was noted from preoperative period to 1 week, 6 weeks, and 6 months postoperatively (P value .02, .01, and .01, respectively). Out of 11 patients with preoperative hypoglobus, 5 patients (45.45%) had persistent hypoglobus in the immediate postoperative period which reduced to 4 patients (36.36%) at 6 weeks postoperatively (p value .00). The postoperative orbital volume of fractured side ranged from 20.3 cm³ to 26.76 cm³ with a mean of 23.50 cm³ ± 1.74. The mean difference between the volumes of the repaired and uninjured sides was found to be .27 cm³ ± .39 (P value .02) denoting that the reconstruction of the orbit closely approximated that of the uninjured side. Conclusions: The Matrixmidface Preformed Orbital plate provides exceptional reconstruction of the orbital blowout fracture defects and ensures satisfactory results clinically and radiographically. The plate ensures an approximate recreation of topographical anatomy of the orbit and adequately restores the orbital volume. It provides adequate correction of asymmetry, hypoglobus, enophthalmos and attempts to restore eye movements, without causing any significant postoperative complication.

Introduction

The management of orbital fractures is one of the most challenging aspects of facial trauma. The pyramidal shape of the orbit with its quadrilateral base is analogous to a pear. The complex three-dimensional configuration of the orbital walls in combination with a weak bony framework and close proximity to vital structures makes anatomic reconstruction an extremely daunting task, more so in 2 wall fractures and when the deep orbital cone is affected [1].

The primary goal of orbital reconstruction is restoration of the orbital hard tissues to its pre-injury anatomy and to restore orbital volume by bridging the bony defect using suitable reconstructive implants in addition to restoration of facial fractures by internal fixation [1,2].

Titanium mesh implants have been extensively used to span large defects in the orbit and are known to reduce postoperative displacement and bring about adequate correction. Nonetheless, adapting the mesh to conform to the complex regional anatomy can be demanding and time-consuming. In comparison with the conventional mesh plate, a preformed mesh plate facilitates precise anatomical reconstruction of orbital shape and volume and hence restores the correct position of the eye [2,3].

The Matrixmidface Preformed Orbital plate is a pre-bent three-dimensional titanium implant that requires minimal cutting and contouring. It closely approximates the complex anatomical configuration of the orbital floor and medial wall. Thus, it helps in restoring the shape of the orbit [4].

The purpose of this study was to evaluate the efficiency of Matrixmidface Preformed Orbital plates for three-dimensional reconstruction of orbital floor and medial wall fractures. The primary objectives were to compare

• Preoperative and postoperative enophthalmos
• Preoperative and postoperative ocular dystopia
• Preoperative and postoperative orbital volume

The secondary objectives were to evaluate

• Correction of diplopia
• Intraoperative and postoperative complications.

Materials and Methods

This clinical study was conducted on patients attending the trauma and emergency unit of Goa Medical College & Hospital and OPD of Goa Dental College & Hospital, from November 2018 to November 2020. A total of 14 fractures patients were included in the clinical study after taking written informed consent for the same. This study included the cases with isolated Orbital blowout fractures and orbital blowout fractures associated with Zygomatic Maxillary Complex fractures and Lefort II and III fractures. An institutional review board (IRB) approval was obtained for the study protocol.

The inclusion criteria were patients above 18 years of age belonging to ASA Class 1 and 2, unilateral pure orbital blowout fractures with or without associated fractures of facial skeleton, enophthalmos of more than 2 mm, ocular dystopia, extraocular muscle entrapment with positive forced duction test, significant diplopia that interferes with daily activities, increased bony orbital volume, soft tissue herniation into maxillary sinus, and healthy contralateral orbit. The exclusion criteria were infected fractures at the time of treatment, hyphema, retinal detachment, globe rupture, only functional eye, bilateral orbital fractures, and patients not giving informed consent.

The variables analyzed included patient age and gender, mechanism of injury, and fracture location. All patients underwent pre- and postoperative ophthalmological examinations. Preoperative examination also included thorough evaluation of facial fractures, measurement of enophthalmos using Hertel’s exophthalmometer, measurement of hypoglobus, range of extraocular muscle movement, forced duction test to rule out entrapment and diplopia charting. CT evaluation included measurement and comparison of orbital volume of injured and normal side. CT scan analysis was done using OsiriX MD software (US FDA approved). The region of interest was generated with axial slices using a 3D interpolation algorithm named Delaunay reconstruction. The 3D volume formula used: area under ROI x interslice thickness.

Surgical procedure was carried out under general anesthesia. Orbital floor and/or medial wall reconstruction was done using large or small sized three-dimensionally preformed Matrixmidface Orbital plate (.4 mm in thickness; Synthes, Oberdorf, Switzerland) [5], selected according to the size of the defect. It was secured with one or two 1.5 mm titanium monocortical non-compression self-drilling screws of length of 4 mm. Fixation of other associated midface fractures was carried out using miniplates and screws. Intraoperatively, the patients were evaluated with regards to the type of surgical approach, the size of plate used with or without medial extension and intraoperative complications (Figure 1).

Postoperatively, clinical and radiological follow-up of patients was done at 1 week, 6 weeks, and 6 months. The postoperative complications were noted. Preoperative and postoperative enophthalmos, ocular dystopia, and orbital volume were compared. Correction or improvement of diplopia was analyzed. CT scan analysis was done of postoperative CT scans by the same method as previously mentioned. The pre- and postoperative orbital volume was compared (Figure 2 and Figure 3).

Descriptive statistics such as mean and standard deviation (SD) for continuous variables and frequency and percentage for categorical variables were determined. Statistical analysis was carried out using SPSS 20.0 software.

Results

All 14 patients were males aged between 19 and 42 years with a mean of 28.21 ± 6.33. The peak incidence of the fracture was seen in the 3rd decade. The most common mode of injury was found to be road traffic accidents (RTAs) followed by self-fall and trauma at workplace. The site of involvement showed equal frequency of distribution in both sides. Orbital fractures were associated with other concomitant maxillofacial fractures in 12 patients (85.7%) while 2 patients (14.3%) had pure blowout fractures. In 6 patients (42.86%), the fractures were limited to the anterior and middle thirds of the orbit while it extended till the posterior third in 8 patients (57.14%).

• Preoperative evaluation

Enophthalmos was noted ranging from 2 mm to 5 mm (mean of 3.43 ± 1.01). Hypoglobus was present in 11 patients (78.57%), ranging from 10 mm to 2 mm (mean of 3.9 ± 2.73). Diplopia was noted in 6 patients (42.85%). Of which 2 had diplopia in all gazes (14.3%), 3 had diplopia in 6 gazes (21.4%) (primary, upward, laterals/medials) and 1 in 3 gazes (7.1%) (upward, laterals/medials) (

Table 1. Preoperative Clinical Assessment.

).

The orbital volume of the fractured side ranged from 21.04 cm³ to 33.3 cm³ (mean of 26.91 cm³ ± 3.41) while that of the uninjured side ranged from 20.19 to 25.9 cm³ (mean of 23.22 ± 1.59).

The mean expansion in orbital volume of the fractured side was 3.68 cm³ ± 2.45 (

Table 2. Preoperative Assessment of Orbital Volume.

).

• Intraoperative evaluation

A lateral canthotomy with transconjunctival approach was taken in 5 patients while a combined lateral canthotomy with transconjunctival and transcaruncular approach was preferred due to its ease of access in 9 patients. The small sized implant with its medial extension was used in majority of cases (10), while a large sized implant with its medial extension was used in 4 cases. Out of 5 cases with positive FDT preoperatively, 3 remained positive postoperatively. No significant statistical difference was noted between pre- and postoperative FDT (P value 1.00).

Intra operative complications noted were corneal abrasion, optic nerve damage, pus discharge from fracture site (each in 1 patient or 7.1%), eyelid edema (57.1%), chemosis (50%), excessive bleeding, abnormal pupillary reflexes, damage to IR muscle, deformation and malposition of implant (28.57% each); 21.4% had cautery burns. Selection of implants was incorrect with regards to its size and use of medial extension in 2 patients with pure blowout fractures and had to undergo secondary intervention for the rectification of the same. 1 patient developed medial rectus iatrogenic injury due to excessive manipulation during secondary orbital exploration which manifested as persistent diplopia postoperatively. This was managed with a long course of oral steroids and seemed to have resolved by 6 months postoperative follow-up.

• Postoperative evaluation

Enophthalmos

Significant improvement of enophthalmos was noted from preoperative to 1 week, 6 weeks, and 6 months postoperatively (P value .02, .01, and .01, respectively) and had high statistical significance (P value .00). Difference in improvement between the postoperative intervals was statistically insignificant (1 week to 6 weeks P value .13; 1 week to 6 months P value .068; and 6 weeks to 6 months P value .317). Out of 12 patients, it was seen to have completely resolved in 9 patients (64.3%) at 6 months postoperatively. Persistent enophthalmos was noted in 5 patients (35.7%) off which 2 showed significant improvement from preoperative period while 3 had minimal improvement. Correction of enophthalmos was seen in more than 60% cases but found to be statistically not significant (P value .13) (

Table 3. Comparison of Pre- and Postoperative Enophthalmos.

).

Hypoglobus

Out of 11 patients with preoperative hypoglobus (range of 2–10 mm), 5 patients (45.45%) (range 0–6 mm) had persistent hypoglobus in the immediate postoperative period which reduced to 4 patients (36.36%) (0–6 mm) at 6 weeks postoperatively and showed high statistical significance (p value .00). The improvement from preoperative to immediate postoperative and preoperative to 6 weeks postoperative was found to be statistically significant (P value .007 and .004, respectively), while the improvement in hypoglobus from immediate postoperative to 6 weeks postoperative was statistically insignificant (P value .31). Correction of hypoglobus was seen in 7 patients (63.6%) while 4 (36.4%) showed mild improvement of the same and was not statistically significant (P value .2) (

Table 4. Comparison of pre- and postoperative hypoglobus.

).

Diplopia

Diplopia was noted in 5 (35.6%), 3 (21.4%), and 2 (14.3%) patients at postoperative 1 week, 6 weeks and 6 months respectively. At 1 week postoperatively, 1 patient complained of diplopia in all gazes; 2 patients in 6 gazes and 1 in 1 gaze and 2 gazes each. At 6 weeks postoperatively, 2 patients complained of diplopia in 2 gazes while 1 patient had diplopia in 6 gazes. Persistent diplopia was noted 2 patients (14.3%) in 2 gazes after 6 months of postoperative period. A good improvement in frequency of diplopia was noted from preoperative to 6 months postoperative periods but it was found to be statistically not significant (P value .66). Diplopia was corrected in 5 patients (71.4%) while adequate improvement but not complete correction was seen in 2 patients (28.6%). This too was statistically insignificant (P value .12) (

Table 5. Comparison of pre- and postoperative diplopia.

).

Postoperative complications included persistent hypoglobus, diplopia (14.3%), enophthalmos (35.71%) and ocular motility restriction (7.1%), lagophthalmos (42.85%); abnormal pupillary reflex, scarring (28.5%); wound dehiscence (21.4%) of the lateral crease portion of the incision; entropion (14.3%); ectropion (7.1%) and a persistent post-traumatic headache in 1 patient (7.1%). The incision and eyelid-related complications were most likely due to contracture of the preexisting scars.

The postoperative orbital volume of fractured side ranged from 20.3 cm³ to 26.76 cm³ with a mean of 23.50 cm³ ± 1.74. The mean volume of the uninjured side was 23.22 cm³ ± 1.59. The mean difference between the volumes of the repaired and uninjured sides was found to be .27 cm³ ± .39 (P value .02) and was statistically significant denoting that the reconstruction of the orbit closely approximated that of the uninjured side. The mean difference between the preoperative and postoperative volumes was 3.36 cm³ ± 2.30 (P value .00) and was statistically highly significant (

Table 6. Orbital volume assessment.

and Figure 4).

Statistical Analysis

Data was analyzed using Microsoft Office Excel 2016 and SPSS Version 20. Descriptive statistics like mean, standard deviation, range, frequency, and percentages were used to summarize the data. Normality was tested by using Shapiro–Wilk test. Data was not normally distributed. McNemar’s test was used to assess significant differences between preoperative and postoperative forced duction test. Friedman’s test was used to assess preoperative and postoperative enophthalmos, hypoglobus, and diplopia and at different time intervals. Paired t test was used for comparison of orbital volumes. One sample t test was used the for comparison of difference between orbital volumes of reconstructed and uninjured side. A P-value of <.05 was considered to be statistically significant (

Table 7. Comparison of Change in Enophthalmos Pre- and Postoperatively Using Friedman’s Test.

,

Table 8. Comparison of Change in Enophthalmos Pre- and Postoperatively Using Wilcoxon Signed Ranks Test.

,

Table 9. Comparison of Change in Hypoglobus Pre- and Postoperatively Using Friedman’s Test.

,

Table 10. Comparison of Change in Hypoglobus Pre- and Postoperatively Using Wilcoxon Signed Ranks Test.

,

Table 11. Descriptive Statistics of Diplopia.

,

Table 12. Comparison of Change in Diplopia Pre- and Postoperatively Using Friedman’s Test.

and

Table 13. Paired t Test for Comparison of Reconstructed Side With Uninjured Side.

).

Discussion

The restoration of the preinjury three-dimensional bony anatomy is fundamentally imperative for a cosmetic and functional recovery of the integrity of the orbit. This is of supreme importance in case of large defects involving more than 1 orbital wall, as these defects are highly challenging to repair [6,7,8,9,10,11,12,13].

Over the years, the evolution of titanium mesh implants for reconstruction of orbital defects has been adequately described in literature. Four techniques have been reported [9]. The first technique was to use mesh plates that were trimmed and contoured to the shape of the orbit intraoperatively [6,14,15]. The second technique involved the fabrication of a preformed titanium mesh produced individually by computer-assisted stereolithography followed by its navigation-guided placement [10,11,16]. This lead to the evolution of the third technique whereby the plates were specially designed from CT scan data of the general population (Metzger et al. 2007), which thoroughly approximated the mean topographic anatomy of the human orbits. The MPOP were the result of a balanced compromise between the first 2 reported techniques. These preformed three-dimensional meshes had a unique design and structure that made intraoperative manipulations like bending and trimming quite redundant [16]. Last, the recent and most accepted advancement was the fabrication of patient specific implants that are computer designed and custom made based on individual three-dimensional models [17].

The advent of patient-specific implants has revolutionized the management of orbital fractures on account of the advancements of mirror imaging and also their customizability to definite size of the defect. A PSI is tailored to measure, based on the individual’s orbital shape and is incomparable both functionally and esthetically in its treatment outcomes. It has been noted that there is no significant difference in the orbital shape unless there is a coexisting deformity or a prior surgical intervention; hence, no major variation is seen with regard to anatomy and contour of the orbital floor. However, considering the financial and economical burdens that accompany the use of these implants along with the tedious process of planning and printing of stereolithographic models, it is difficult to use PSIs for all patients.

In this study, the efficiency of the Matrixmidface Preformed Orbital Plates was evaluated. This plate was introduced by Synthes (Switzerland). It is 0.4 mm thick, malleable, made of pure Titanium, and consists of a rigid zone that helps in maintaining the correct position of the globe by restoring the shape of the posterior orbital floor.

These plates have been designed with an S shape contour to match the contour of the floor of the orbit and also closely approximate the 45° angulation of the same [18]. This contour incorporates a pre-designed posterior retrobulbar bulge that contributes the critical area of support to the globe. It plays a vital role in providing projection to the globe and hence aids in preventing postoperative enophthalmos [9].

The preformed three-dimensional shape of the implant is designed for minimal contouring and cutting, in order to reduce the amount of time required to manipulate the plate intraoperatively. Its segmented design allows customization of the size. Limited literature exists on the clinical in-vivo evaluation of this particular plate.

The dimensional specifications of the implant closely follow the results obtained in topographical CT data studies of the orbital floor [8,11,16]. No specific measurements have been quoted in literature with regard to the dimensions of the implant. However, we have recorded the measurements of the same using a scale. The small sized implant measured approximately 3.5 cm in length along its long axis and 3 cm in width while the large sized implant measured approximately 3.5 cm in length and 4 cm in width. The medial wall extension or flange is shorter in length compared to the rest of the implant. It measures around 2 cm in length and 1 cm in height in the small sized implant and 1.8 cm in length and 2.4 cm in height in the large sized implant. It is positioned in a slightly posteromedial direction in order to accommodate the presence of the lacrimal sac and prevent any injury to the same.

The present study consisted of 14 male subjects in the 2nd to 5th decade of life. The male preponderance was in accordance with a study conducted by Sabharwal et al. in South India [19]. The predominant cause for orbital fracture in this study was road traffic accidents which is also the leading cause of the same in most countries as noted by Cruz et al. and Khojastepour et al. [20,21]. This distribution of the mode of injury can be demonstrated by the fact that currently 2 wheeler vehicles are the most popular mode of transport which is further compounded by lax enforcement of road safety rules and measures.

In this study, 12 patients (85.7%) had orbital fractures that were associated with other concomitant maxillofacial fractures like ZMC (11 patients), NOE (5 patients), frontal bone (3 patients) and LeFort fractures (1 patient), while 2 patients (14.3%) had isolated blowout fractures. This study also showed that right and left sides had equal distribution as compared to studies that suggest a higher prevalence of fractures of the left orbit [22]. Isolated fractures of the floor (57.14%) were found to be slightly more common than floor with medial wall fractures with or without roof fractures (42.86%) in this study.

In the present study, a transconjunctival approach was used in 5 patients (35.71%) while a combined transconjunctival and transcaruncular approach was used in 9 patients (64.2%). Kim et al., in their study successfully used the transcaruncular approach for repair of isolated medial wall fractures (32.5%) and its combination with the transconjunctival approach for combined medial wall and floor fractures (67.5%) which was also seen in other studies [9,23,24].

In a study by Bitterman et al., anatomical information as per Metzger’s CT analysis study was incorporated into the design of the preformed plate such that they are available in 2 different sizes for each side and preoperative planning could be used adequately for plate selection [16,25]. Scolozzi et al. in their study selected plate size according to size of the defect and also revised the size of the plates intraoperatively [9]. In the current study, the small sized implant with its medial extension was used in 10 cases, while a large sized implant with its medial extension was used in 4 cases.

In this study, all patients belonged to an age group of 19 years and above. As adult dimensions are attained by 7 years and the growth of the orbit ceases by 8–10 years, not many variations were expected. However subtle differences between individuals were noted and were recompensed by preplanning and using either small or a large sized implant as indicated. These differences were not statistically significant [26]. In our experience, we encountered no problem with regards to the fit and positioning of the plate in most of our patients. This may be attributed to the universal design of this plate. Minimal variations in anatomy were noted in fewer patients intraoperatively and only required subtle adjustments in the plate. We did not encounter any cases with non-conformation issues when applying this plate.

Studies have identified that the primary distinction between the anatomy of the orbits of males and females lies characteristically in the structure of the posteromedial bulge. It has been reported that males demonstrate a larger and higher posteromedial bulge than females. The other differences included a smaller anteromedial portion of the inferior orbital rim. Also the width of the orbital cavity was reported to be lesser in females [16]. As this study did not include any female patients and the entire study sample consisted of male patients, we did not notice any major differences in size and shape and hence cannot comment on the gender differences.

In a retrospective study conducted by Simon et al., postoperative vertical ductions improved after fracture repair with no significant difference in the surgical outcomes on comparing early and late surgical repair [27]. In this study out of the 5 cases with positive FDT preoperatively, 3 remained positive postoperatively and all were candidates of a late surgical repair.

The most significant intra operative complication noted was damage to IR muscle and deformation and malposition of implant (28.57% each). Selection of a wrong size of implant with use of medial extension in 2 patients required a secondary exploration to change the implant and caused inadvertent damage to the medial rectus muscles in 1 patient. No intraoperative complications were noted with use of preformed implants in studies conducted by Suke-gawa et al. and Scolozzi et al. Sukegawa et al. reported that the operating time was shortened by the use of preformed implants and that only minimal manipulation of the optic nerve was involved [2,9]. It may be inferred that the use of these implants satisfactorily accompanies a steep learning curve and a certain amount of experience in orbital trauma is imperative.

Significant improvement of enophthalmos was noted in the current study from preoperative to postoperative periods. Of 14 patients, it completely resolved in 9 patients (64.3%) while, persistent enophthalmos was noted in 5 patients (35.7%). 2 showed significant improvement from preoperative period while 3 had minimal improvement. According to a study by Degala et al., correction of enophthalmos was seen in 87.5% of the patients while 1 patient had persistent enophthalmos on the 6th week following surgery which resolved by the 1 year follow-up [28]. In another study by Chen et al., incidence of residual enophthalmos post-surgery was found to be significantly higher (P < .001) in patients with 2-walled fractures [29]. This correlation can also be made in the current study. Fat atrophy is contemplated to be a common cause for this finding, but it may be due to inadequate reconstruction of the orbit [30,31,32].

With regards to hypoglobus, according to Lu et al., it is more common in combined ZMC and orbital fractures. Out of 46 cases, 40 had more than 2-mm (mean 3 mm) hypoglobus preoperatively and all were completely corrected postoperatively [33]. In the study by Ramphul et al., 30 patients had no hypoglobus post-surgery, 9 had hypoglobus that had improved but not entirely resolved while 3 had no visible changes from their preoperative status. There was no worsening of dystopia post-surgery [34]. In our study, out of 11 patients with preoperative hypoglobus, correction of hypoglobus was seen in 7 patients (63.6%) while 4 (36.4%) showed mild improvement. Satisfactory improvement was noted from preoperative to postoperative periods.

Jin et al. in their retrospective study of 63 patients evaluated CT scan for possible risk factors for residual postoperative diplopia. An increase in the diameter of IR muscle or medial rectus due to swelling was significantly associated with persistent postoperative diplopia. They contended that EOM injury at the time of trauma plays a larger role in the recovery from diplopia than the extent of periorbital herniation [35]. Shah et al. noted that there was a strong association between diplopia, restriction of ocular motility and the use of porous titanium mesh implants. In their study, repair of fractures significantly improved diplopia in all except 1 patient. They proposed that the need for a strabismus surgery can be avoided by performing a thorough fracture repair and the use of non-porous implants primarily or secondarily [36].

The findings of our study with regards to orbital volume measurements were in congruence with the findings of a study by Scolozzi et al. and Sukegawa et al [2,9]. Scolozzi et al. (2009) substantiated that with the use of AO orbital titanium mesh plates the orbital volume of the reconstructed orbit paralleled that of the contralateral uninjured orbit with an accuracy of within 1.85 cm³ (2.19–2.5 cm³) [37]. In the study by Sukegawa et al., this difference in volume matched by .75 cm³ (range —1.88 to 1.10 cm³). There was found to be no significant difference between the 2 variables [2]. In the current study, the mean difference between the volumes of the reconstructed and uninjured sides was found to be .27 cm³ ± .39 denoting that the reconstruction of the orbit closely approximated that of the uninjured side.

Conclusion

The Matrixmidface Preformed Orbital plate can be considered as a safe and reliable option for the three-dimensional reconstruction of orbital floor and medial wall fractures. It provides exceptional reconstruction of the orbital blowout fracture defects and ensures satisfactory results clinically and radiographically. The plate ensures an approximate recreation of topographical anatomy of the orbit and adequately restores the orbital volume. It provides adequate correction of Enophthalmos, hypoglobus and attempts to restore eye movements. It adequately serves its purpose of isolating the orbital contents from the nasal and antral cavities and also provides sufficient support to reduce or even prevent enophthalmos. However, incorrect selection of size of the plate can have untoward outcomes of persistent enophthalmos and inadequate restoration of orbital volume. Excessive manipulation can lead to deformation of the plate. The plate does not cause any significant postoperative complications. Further improvements in the study design with respect to the sample size would have led to more clinically relevant conclusions.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.