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Journal of Plastic, Reconstructive & Aesthetic Surgery (2014) xx, 1e8
Effect of maxillary alveolar reconstruction on nasal symmetry of cleft lip and palate patients: A study comparing iliac crest bone graft and recombinant human bone morphogenetic protein-2 Nivaldo Alonso a,*, Gabriel Henrique Risso a, Rafael Denadai b, Cassio Eduardo Raposo-Amaral b a Craniofacial Surgery Unit, Division of Plastic Surgery, Department of Surgery, Faculty of Medicine, Universidade de Sa˜o Paulo (USP), Sao Paulo, Brazil b Institute of Plastic and Craniofacial Surgery, SOBRAPAR Hospital, Campinas, Sao Paulo, Brazil
Received 24 November 2013; accepted 10 May 2014
KEYWORDS Alveolar cleft repair; Recombinant human bone morphogenetic protein; rhBMP-2; Iliac crest bone graft; Nasal symmetry; Nasal position
Summary Background: Recombinant human bone morphogenetic protein (rhBMP)-2 has been used in some craniofacial centers worldwide. However, its influence on nasal morphology is unknown. Thus, the objective of this investigation was to assess the effect of maxillary alveolar reconstruction on nasal position and symmetry in unilateral complete cleft lip patients who underwent traditional iliac crest bone grafting transferring versus reconstruction using rhBMP-2. Methods: Nineteen unilateral complete cleft lip patients were randomly divided into two groups. In group 1, patients underwent traditional iliac crest bone grafting transferring (n Z 11) and in group 2, patients underwent alveolar reconstruction using collagen matrix with lyophilized rhBMP-2 (n Z 8). Computerized tomography (CT) imaging was performed preoperatively and at 6 months postoperatively using a previously standardized protocol. Linear distances using anatomic landmarks were performed using tridimensional CT data reformatted by the OsiriX software. Quantitative and qualitative measurements to assess intra- and inter-group nasal position modifications were performed. Results: Intra-group pre- and postoperative comparisons showed significant differences (p < 0.05) in two linear measurements of group 1, while group 2 did not present a difference (p > 0.05). Group 2 presented significant postoperative enhancement (p < 0.05) in the
* Corresponding author. Craniofacial Surgery Unit, Division of Plastic Surgery, Faculty of Medicine, Universidade de Sa ˜o Paulo (USP), Rua Afonso Bra ¸˜ ao, Sa ´s, 473ecj. 65, Vila Nova Conceic ˜o Paulo 04511-011, Brazil. E-mail address: [email protected] (N. Alonso). http://dx.doi.org/10.1016/j.bjps.2014.05.014 1748-6815/ª 2014 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Alonso N, et al., Effect of maxillary alveolar reconstruction on nasal symmetry of cleft lip and palate patients: A study comparing iliac crest bone graft and recombinant human bone morphogenetic protein-2, Journal of Plastic, Reconstructive & Aesthetic Surgery (2014), http://dx.doi.org/10.1016/j.bjps.2014.05.014
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N. Alonso et al. quantitative nasal symmetry in one measurement. Qualitative analysis showed postoperative nasal symmetry enhancement in 75% of the measurements of group 2 and 36% of group 1. There was no statistically significant difference in the inter-group comparisons. Conclusions: Our study demonstrated that both groups showed similar effect on nasal symmetry. ª 2014 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
Introduction Unilateral cleft lip nasal repair is challenging because of the complexity of the deformity.1,2 This three-dimensional deformity involves several structures such as: the alar base, the alar cartilage (the medial and lateral crus), the nasal dome, the columella, the nasal septum, and the skeletal base, which includes the alveolus, maxillary segments, and palate.1 Thus, to obtain the realistic treatment goal (normal appearance and function, with better symmetry, balance, and less scarring), both skeletal and soft-tissue structures must be adequately managed.1,2 In fact, the open alveolar gap and the hypoplastic maxilla have been described as two major problems in achieving consistent, favorable results following cleft lip nasal repair.1 Alveolar bone grafting is an essential procedure in the overall osseous framework rehabilitation of patients with unilateral cleft lip alveolus, with or without cleft of the secondary palate.3 Among numerous donor sites, cancellous iliac crest bone grafting at the time of cuspid or lateral incisor root formation has proven to provide consistently excellent, stable long-term results and has become the standard approach for filling maxillary alveolar clefts.4,5 However, as donor-site morbidities such as acute and chronic pain, infection, hemorrhage, and nerve injury are quite significant,3 many investigations have been conducted to evaluate bone substitutes.6 In this context, our group7,8 and others9,10 have reported the successful use of the recombinant human bone morphogenetic protein (rhBMP)-2 for alveolar cleft repair in skeletally mature and immature patients. Alveolar cleft repair using rhBMP-2 had the same overall success as traditional iliac crest bone grafting.710 Additionally, this bone tissue engineering approach spares the need of a donor site, while excellent results can be obtained, with reduction of the surgical time and overall financial costs.7e10 Within the specific management of the cleft lip nasal deformity, the alveolar osseous graft has been used for restoring the maxilla at the piriform rim, providing improved stability and aesthetics by supporting the alar base.3 Even though previous studies11e19 have demonstrated nasal changes (nasal morphology, symmetry, and nostril shape) following alveolar bone grafting, it is unclear, however, how the rhBMP-2 influences the nasal symmetry. Such previous information led us to hypothesize that the positive effect on nasal symmetry generated by the inclusion of rhBMP-2 in the maxillary region does not differ from the effect yielded by autologous bone transferring from the iliac region. Thus, the purpose of this investigation was to
assess the effect of maxillary alveolar reconstruction on nasal position and symmetry in unilateral complete cleft lip patients during secondary dental eruption, comparing resorbable collagen matrix with rhBMP-2 versus traditional iliac crest bone grafting approaches.
Methods A retrospective study of 24 consecutive non-syndromic unilateral complete cleft lip patients, who underwent alveolar cleft repair between 9 and 12 years of age, was conducted at a single Brazilian Craniofacial Surgery Unit between 2010 and 2012. The data were started to be collected in 2010 resulting in a previous publication.7 All patients previously underwent primary rhinocheiloplasty between 3 and 6 months of age, according to the modified technique described by our group,20 and underwent palate repair at 1 year of age. Before secondary alveolar cleft repair, all subjects underwent preoperative orthodontic expansion of maxillary segments and were randomly assigned to group 1 (traditional iliac crest bone grafting transferring) or group 2 (reconstruction using collagen matrix with lyophilized rhBMP-2). No revision of lip surgical repair was performed during secondary alveolar cleft repair. All patients (n Z 5) who did not have adequate computed tomographic documentation, previous eruption of the canine, previous alveolar or nasal surgeries, and/or incomplete follow-up were excluded from the study. Additionally, complications such as infections, wound dehiscence leading to bone graft loss or rhBMP-2 exposure were recorded. All subjects were enrolled upon a consent form signed by their parents, in accordance with the Helsinki Declaration of 1975, as amended in 1983. A local institutional research ethics board approval was obtained for this study.
Surgical procedures All surgical interventions were performed by the same senior surgeon (N.A.) in a standard fashion. Key information included below and additional details were previously described by our group.7,8 Iliac crest bone graft (group 1) and collagen matrix with lyophilized rhBMP-2 (group 2) were placed in the maxillary alveolar defect after wide exposure of the cleft area. In group 1, through a 3-cm incision, a cortical bone trap door was raised and hinged on the inner edge of the iliac crest and enough chips of cancellous bone (20e40 mL) were then removed. In group 2, rhBMP-2 was reconstituted with distilled water and impregnated the supplied absorbable
Please cite this article in press as: Alonso N, et al., Effect of maxillary alveolar reconstruction on nasal symmetry of cleft lip and palate patients: A study comparing iliac crest bone graft and recombinant human bone morphogenetic protein-2, Journal of Plastic, Reconstructive & Aesthetic Surgery (2014), http://dx.doi.org/10.1016/j.bjps.2014.05.014
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Effect of maxillary alveolar reconstruction on nasal collagen sponge (Infuse Bone Graft kit; Medtronic, Memphis, TN, USA) for 20 min according to the manufacturer’s guidelines. The rhBMP-2-impregnated collagen matrix was then cut into several small parts that were used to fill in the alveolar cleft defect as necessary; approximately 3.2e4.2 mg of rhBMP-2 was used. Finally, a lateral mucoperiosteal flap was advanced to cover the cleft and then sutured to the medial flap and palatal flaps.
3 Table 1 Ten linear inter-landmark measurements (L1eL10) used to quantify nasal symmetry in this study. Linear items
Definitions
L1 L2
Distance from the prn point to the mipl point Distance from the cleft sbal point to the mipl point Distance from the noncleft sbal point to the mipl point Distance from the cleft al point to the mpf Distance from the noncleft al point to the mpf Distance between both al points (cleft al to noncleft al ) Distance from the cleft al point to the prn point Distance from the noncleft al point to the prn point Distance from the cleft al point to the sn point Distance from the noncleft al point to the sn point
L3
Anatomic landmarks and linear measurements Four bilateral and two median anatomic landmarks and one facial plane were defined according to the previous description by Farkas21: center point of the pupil (p); midpoint of the interpupillary line (mipl): defined by measuring interpupillary distance and marking the midpoint at the glabella; pronasale (prn): the most protruded point of the apex nasi; alare laterale (al): the most lateral point on each alar contour; subalare (sbal): the point of lower limit of each alar base, where the alar base disappears into the skin of the upper lip; subnasale (sn): midpoint of the angle at the columella base where the lower border of the nasal septum and the surface of the upper lip meet; median plane of the face (mpf): defined by three anatomical landmarks (root of the nose, subnasale (base of the columella), and the gnathion (lower edge of the mandible)) e the horizontal position of paired symmetrical features of the upper third of the face was aligned in order to obtain a vertical plane. After defining these landmarks, 10 linear (mm) inter-landmark measurements (L1eL10) were calculated in order to quantify nasal symmetry (Figure 1 and Table 1).
Three-dimensional computed tomography data Multislice computed tomography (CT) scans of the craniofacial region were performed preoperatively (1 month to 1 week prior to alveolar cleft repair) and postoperatively (6 months after alveolar cleft repair) for the evaluation of the
L4 L5 L6 L7 L8 L9 L10
prn, pronasale; mipl, midpoint of the interpupillary line; al, alare laterale; sbal, subalare; mpf, median plane of the face; sn, subnasale.
nasal region of cleft lip individuals. Patient data were obtained using 1 mm cut and images were reconstructed. All data were saved as a Digital Imaging and Communication in Medicine (DICOM) file and were then relabeled and reordered randomly to blind the rater. The data were then transferred to a workstation (Apple Mac OS X; Apple Computer, Inc., Cupertino, CA, USA) and analyzed using open-source OsiriX medical imaging software (version 7.6, www.osirix-viewer.com, OsiriX Foundation, Geneva, Switzerland) which is a fast DICOM viewer program22 with 0.05) in intra-investigator measures. Then, all the measurements were subsequently performed one time in each time period.
Quantitative and qualitative nasal symmetry analyses Eight (except L1 and L6) linear measurements were combined in pairs (ratio between the cleft and noncleft side measurements: L2/L3, L4/L5, L7/L8, and L9/L10) in order to measure quantitative nasal symmetry. Additionally, all linear measurements (L1eL10) were gathered and considered together in order to qualitatively quantify the overall nasal symmetry. For this, a score system that represented the variation (difference) of symmetry of the measurements in each period was defined. Initially, the variation (difference) of symmetry for each linear measurement in each period was individually performed for all patients. Afterwards, the 10 values obtained for each patient were summed and then a qualitative nasal symmetry analysis was performed on every individual in both groups. Positive values were considered enhancement (“gain”), and negative values were considered deterioration (“loss”) of nasal symmetry, while neutral values (difference equal to zero) were considered uninfluenced by the alveolar repair on nasal symmetry. Qualitative nasal symmetry enhancement
N. Alonso et al. and qualitative nasal symmetry deterioration were defined when positive values and negative values were achieved, respectively.
Statistical analysis In the descriptive analysis, data were summarized as means standard errors. Intra-group (preoperative vs. postoperative linear measurements and pre- and postoperative quantitative nasal symmetry) and inter-group (postoperative linear measurements and pre- and quantitative postoperative nasal symmetry) comparisons were performed with the aid of the paired t-test and the twosample t-test, respectively. All analyses were performed using the software program Statistical Package for Social Science (SPSS version 17.0 for Windows, Chicago, IL, USA). Values were considered significant for a confidence interval of 95% (p < 0.05) and tailed analysis was used as a supplement in the presence of statistical difference.
Results A total of 19 (79.17%) unilateral complete cleft lip patients (five females and 14 males, with average age of 11.75 years) met the inclusion criteria. Eleven (57.89%) patients underwent alveolar iliac crest bone grafting (group 1), and eight (42.11%) patients underwent alveolar cleft repair with resorbable collagen matrix with rhBMP-2 (group 2). Five (20.83%) patients were excluded because of an incomplete postoperative follow-up period, and therefore, did not undergo CT scans at 6 months after alveolar cleft lip repair. No complications were seen in these series of patients.
Intra-group comparisons Intra-group comparisons of the pre- and postoperative 3D CT linear measurements of the nasal area showed a
Figure 2 Computed tomography imaging of facial region (frontal and basal views; left and right, respectively) processed by OsiriX of a unilateral complete cleft lip patient illustrating seven linear inter-landmark measurements used to quantify nasal symmetry in this study.
Please cite this article in press as: Alonso N, et al., Effect of maxillary alveolar reconstruction on nasal symmetry of cleft lip and palate patients: A study comparing iliac crest bone graft and recombinant human bone morphogenetic protein-2, Journal of Plastic, Reconstructive & Aesthetic Surgery (2014), http://dx.doi.org/10.1016/j.bjps.2014.05.014
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Table 2 Intra-group (preoperative vs. postoperative measurements) and inter-group (postoperative measurements) comparative analysis. Linear measurements
Group 1 (Iliac crest bone graft) Pre
L1 L2 L3 L4 L5 L6 L7 L8 L9 L10
Group 2 (rhBMP-2)
Post
2.77 3.613 3.5559 1.6948 1.8345 3.529 2.029 2.0041 1.7925 1.8215
0.351 0.373 0.2978 0.2929 0.2275 0.432 0.341 0.2137 0.203 0.2758
2.8682 3.579 3.548 1.8146 1.779 3.594 2.094 1.9886 1.9092 1.8749
0.2327 0.378 0.362 0.3283 0.2708 0.524 0.333 0.2203 0.2165 0.2474
p-value*
Pre
0.287 0.752 0.928 0.171 0.386 0.438 0.034 0.489 0.013 0.63
2.828 3.61 3.584 1.7284 1.966 3.694 2.1333 1.941 1.8491 1.8931
Post
0.448 0.377 0.399 0.2096 0.462 0.498 0.1713 0.292 0.2155 0.1565
3.06 3.769 3.736 1.7944 1.826 3.6204 2.0769 1.9129 1.8664 1.9174
p-value*
0.394 0.357 0.377 0.1843 0.157 0.1819 0.1273 0.1826 0.1624 0.1279
0.097 0.218 0.106 0.25 0.403 0.63 0.271 0.771 0.768 0.664
rhBMP-2, recombinant human bone morphogenetic protein 2; Pre, preoperative; Post, postoperative. *, Intra-group pre- versus postoperative comparisons. Notes: (1) Inter-group postoperative comparative analysis showed no significant difference (p > 0.05 for all inter-group postoperative comparisons). (2) Data are presented as mean standard deviation in millimeter. (3) L1eL10 were defined in the Table 1.
significant enhancement in the postoperative period in the two cleft side distances (L7 and L9; p Z 0.034 and p Z 0.013, respectively), favoring patients of group 1 (traditional iliac crest bone graft transferring). There was a significant (p Z 0.014) enhancement in the postoperative quantitative nasal symmetry only in the L2/L3 measurement of the group 2 (rhBMP-2). The rest of the measurements revealed no intra-group significant differences (all p > 0.05) (Tables 2 and 3).
Inter-group comparisons Inter-group comparisons of the postoperative 3D CT linear measurements of the nasal area and pre- and postoperative quantitative nasal symmetry showed no inter-group significant differences (all p > 0.05) (Tables 2 and 3). Qualitative nasal symmetry analysis revealed better final nasal symmetry favoring group 2 (rhBMP-2), with 75% (n Z 6) of patients with positive values, meaning that all of these patients gained nasal symmetry in comparison to group 1 (traditional iliac crest bone graft), with 36.36% (n Z 4) of patients with positive values. Six (54.55%) patients of group 1 and two of group 2 (25%) showed negative
Table 3
Discussion The current study was designed to compare the effect of rhBMP-2 versus traditional iliac crest bone grafting on the nasal symmetry after alveolar reconstruction in cleft lip patients. In spite of the heterogeneous nature of cleft lip and palate, both groups were stratified with consecutive patients with unilateral complete cleft lip and palate that were randomly assigned between the groups. All patients followed the same surgical regimen, with the lip being operated at 3e6 months old and the palate being operated at 1 year of age, and alveolar grafting being performed with similar indication, immediately prior to canine eruption, with age varying from 9 to 12 years. Different 3D imaging techniques (e.g., 3D stereophotogrammetry, 3D optical scanner, 3D photogrammetry, and 3D-CT-scan, among others) have been used to assess nasal soft-tissue symmetry in cleft lip patients12,13,16,24; however, there is no gold standard tool to date.25
Intra-group and inter-group comparative analysis of the quantitative nasal symmetry.
Quantitative nasal symmetry
Group 1 (Iliac crest bone graft) Pre
L2/L3 L4/L5 L7/L8 L9/L10
values, meaning that all of these patients had nasal symmetry deterioration. One (9.09%) patient of group 1 showed a value equal to zero.
0.161 0.2487 0.383 0.1515
Group 2 (rhBMP-2)
Post
0.1076 0.2047 0.1673 0.0982
0.236 0.2455 0.2547 0.1059
0.1577 0.1525 0.1626 0.0765
p-value*
Pre
0.428 0.973 0.408 0.253
0.1741 0.424 0.2875 0.1633
Post
0.1156 0.354 0.1115 0.0837
0.109 0.1841 0.225 0.1307
p-value*
0.0962 0.2457 0.1198 0.0817
0.014 0.184 0.308 0.396
rhBMP-2, recombinant human bone morphogenetic protein 2; Pre, preoperative; Post, postoperative. *, Intra-group pre- versus postoperative comparisons. Notes: (1) Inter-group pre- and postoperative comparative analyses showed no significant difference (p > 0.05 for all inter-group comparisons). (2) Data are presented as mean standard deviation in millimeter. (3) L1eL10 were defined in the Table 1.
Please cite this article in press as: Alonso N, et al., Effect of maxillary alveolar reconstruction on nasal symmetry of cleft lip and palate patients: A study comparing iliac crest bone graft and recombinant human bone morphogenetic protein-2, Journal of Plastic, Reconstructive & Aesthetic Surgery (2014), http://dx.doi.org/10.1016/j.bjps.2014.05.014
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6 Therefore, all linear measurements were objectively obtained using 3D CT imaging processed by a previous validated computer-assisted software program.22,23 The observer was consistently trained to identify the anatomic landmarks using the axial, sagittal, and coronal cuts, in which measurements were performed two times, in two different periods to assess accuracy. Only after validation of the methodology were subsequent measurements performed once. Thus, any chance of error during measurements was reduced using this strategy previously described.7 All measurements were performed at 6 months after alveolar cleft repair to allow either bone induction or bone integration to its cleft bed.16 As during this time frame (from 9 to 12 years of age) the face may present significant growth, 6 months after surgery seems to be an ideal period to assess the effect of alveolar bone grafting on nasal symmetry by avoiding the insertion of facial growth variable into the nasal symmetry analysis. In addition, The Eurocleft project emphasized the need for minimum record taking to monitor the individual treatment and for quality improvement and research reasons.26 According to these recommendations,26 before and 6 months after alveolar bone grafting, an intraoral radiograph should be taken as a record. This radiograph, however, can only show the height of the reconstructed alveolar process and its relation to the teeth adjacent to the cleft. Thus, we performed a CT in order to assess the influence of the maxillary reestablishment on nasal symmetry in addition to facial growth and any possible teratoma formation. Historically, surgical teams around the world have been focusing on precocious cleft lip patients rehabilitation with less possible morbidity.1,2 Surgical attempts with primary bone grafting at the time of lip repair aim to provide early maxillary realignment and its subsequent long-term benefits on dental eruption and nasal symmetry.27 However, this procedure remains controversial due to donor-site morbidity and inherent side effects on the maxillary growth that this technique may pose.28 Although it has been stated that rhBMP-2 at the time of cleft lip repair reduced the amount of secondary surgery by inducing nature bone in the maxillary arch and cleft nasal floor and simultaneously avoid donor-site morbidity,29 we as others30,31 believe that any precocious intervention such as primary bone grafting or inclusion of rhBMP-2 or any other biomaterial on the maxillary arch at an early age may lead to a severe maxillary collapse. Further longitudinal randomized controlled studies may clarify this topic. Although the primary cleft lip nasal surgery has currently been performed at the time of lip repair,20 a residual (from minor to major) nasal deformity is usually found in all cohorts of patient with unilateral complete cleft lip and palate,32,33 regardless of surgeon’s skills. As final cleft lip nose repair is indicated after the completion of facial growth (after orthognatic surgery, if needed), all prior surgical interventions aimed to reduce nasal asymmetry.34 In this context, alveolar bone grafting imposes significant changes in the maxillary bone,9 somehow affecting nasal height and nasal width. Interestingly, our data have shown that the nasal height and nasal width in patients whose maxillary cleft received rhBMP-2 did not statistically differ from those who received iliac crest bone, although there are subtle differences in intra-group analysis. As rhBMP-2
N. Alonso et al. reduced the overall surgical cost of cleft lip patients’ rehabilitation and the requirement of donor site9 and simultaneously present similar interference on nasal symmetry in comparison of nature bone, it is possible to assume that rhBMP-2 can eventually be the standard adjunct element of the maxillary reestablishment during surgery in the cleft lip population. For a successful repair using rhBMP-2, a hermetic, watertight pocket needs to be created prior to its insertion. Any leak in the mucosa will compromise the outcome. Thus, it is important that only experienced surgeons use the rhBMP-2 for this purpose. On the other hand, autologous bone transferring tolerates minor leaks in the mucosa better, as only partial loss of bone graft may occur in the presence of minor dehiscence. Large prospective trials35e37 to determine the effect of rhBMP-2 on lower limbs fractures or lumbar inter-body fixation were conducted. Different doses (reaching up to 351 mg) of rhBMP-2 were used to speed up bone healing, to induce complete bone fusion, decrease secondary intervention, and reduce infection rate, among other outcomes.35e37 In the cleft lip management, different doses of rhBMP-2 were used to fulfill the alveolar cleft defect.7e10 These data showed that there is a paucity of guidelines in the current literature that can possibly optimize the minimum dose of rhBMP-2 to generate a targeted benefit in each specific clinical situation. Thus, in our study, we adopted a dose of rhBMP-2 previously used7,8,38 to induce bone formation in a congenital critical-sized osseous defect, in spite of relevant data showing bone healing in critical-sized calvarial defects in experiment studies using a lower-dose of rhBMP-2.39 In addition, acutely induced calvarial defects in experiments models, whose healing is influenced by the dura-mater, present a major regeneration capacity in comparison to a congenital osseous defect.40 Interestingly, in our study we did not observe ectopic bone formation42,43 or any side effect related to the dose of rhBMP-2 adopted, similar to other reports7,8,38 that used the same rhBMP-2 dose. Thus, we believe that the 3.2e4.2 mg of rhBMP-2 may be the standard dose to induce bone formation in congenital alveolar osseous defects in humans. However, further randomized prospective studies should be designed to investigate the effect of different doses of rhBMP-2 on both bone formation and nasal symmetry in cleft lip patients, and therefore, ratify or not our hypothesis. Our primary hypothesis has proven to be right, and both groups have shown similar quantitative influence on final nasal symmetry in the inter-group analysis. In addition, a qualitatively gain in nasal symmetry was seen in more patients of group 2 than group 1. Hence, other variables such as accessibility, technical difficulties, overall costs of patients’ rehabilitation in the long-term follow-up, and complication rates after using each material may support the final therapeutic decision. A limitation of our report is that we do not adopt all existing anatomical landmarks for nasal morphology assessment and, therefore, future studies should expand our findings by including additional linear measurements. The other caveat of our study is the lack of biomechanical testing in both cohorts of patients. Considering the inherent limitation of providing these tests in humans, in addition that all cleft lip patients have been followed up for long
Please cite this article in press as: Alonso N, et al., Effect of maxillary alveolar reconstruction on nasal symmetry of cleft lip and palate patients: A study comparing iliac crest bone graft and recombinant human bone morphogenetic protein-2, Journal of Plastic, Reconstructive & Aesthetic Surgery (2014), http://dx.doi.org/10.1016/j.bjps.2014.05.014
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postoperative periods, we observe that in both groups the canine/lateral incisor naturally erupted without problems, as also shown in previous reports.7,8 Thus, we assumed that the bone quality was sufficient to maintain dental eruption and sufficient stability for orthodontic treatment.
11.
Conclusion
12.
Our study demonstrated that unilateral complete cleft lip patients whose maxillary alveolar defect were repaired with rhBMP-2 showed similar nasal symmetry than those repaired with autologous iliac crest bone graft.
13.
Ethical approval
15.
All subjects were enrolled upon a consent form signed by their parents, in accordance with the Helsinki Declaration of 1975, as amended in 1983. A local institutional research ethics board approval was obtained for this study.
16.
Funding
17.
14.
None. FAPESP Project Number 2010-08175-6. 18.
Conflict of interest 19.
None.
References 1. Salyer KE, Genecov ER, Genecov DG. Unilateral cleft lip-nose repair e long-term outcome. Clin Plast Surg 2004;31:191e208. 2. Mulliken JB, Martinez-Perez D. The principle of rotation advancement for repair of unilateral complete cleft lip and nasal deformity: technical variations and analysis of results. Plast Reconstr Surg 1999;104:1247e60. 3. Bajaj AK, Wongworawat AA, Punjabi A. Management of alveolar clefts. J Craniofac Surg 2003;14:840e6. 4. Baykul T, Aydin A, Nasir S, Turkkahraman H. Surgical rehabilitation of nasoalveolar complex in patients with alveolar clefts. J Craniofac Surg 2010;21:1512e5. 5. Meyer S, Molsted K. Long-term outcome of secondary alveolar bone grafting in cleft lip and palate patients: a 10-year followup cohort study. J Plast Surg Hand Surg 2013;47:503e8. 6. Engstrand T. Biomaterials and biologics in craniofacial reconstruction. J Craniofac Surg 2012;23:239e42. 7. Alonso N, Tanikawa DY, Freitas Rda S, et al. Evaluation of maxillary alveolar reconstruction using a resorbable collagen sponge with recombinant human bone morphogenetic protein2 in cleft lip and palate patients. Tissue Eng Part C Methods 2010;16:1183e9. 8. Canan Jr LW, da Silva Freitas R, Alonso N, et al. Human bone morphogenetic protein-2 use for maxillary reconstruction in cleft lip and palate patients. J Craniofac Surg 2012;23: 1627e33. 9. Dickinson BP, Ashley RK, Wasson KL, et al. Reduced morbidity and improved healing with bone morphogenic protein-2 in older patients with alveolar cleft defects. Plast Reconstr Surg 2008;121:209e17. 10. Francis CS, Mobin SS, Lypka MA, et al. rhBMP-2 with a demineralized bone matrix scaffold versus autologous iliac crest
20.
21. 22.
23.
24.
25.
26.
27.
28.
29.
bone graft for alveolar cleft reconstruction. Plast Reconstr Surg 2013;131:1107e15. Baeyens W, Daelemans A, Leloup T, De Mey A. Study of changes in nasal morphology in children with complete unilateral cleft lip and palate after secondary bone grafting measured with image analysis. Scand J Plast Reconstr Surg Hand Surg 2006;40: 345e51. Krimmel M, Kluba S, Bacher M, et al. Digital surface photogrammetry for anthropometric analysis of the cleft infant face. Cleft Palate Craniofac J 2006;43:350e5. Krimmel M, Schuck N, Bacher M, Reinert S. Facial surface changes after cleft alveolar bone grafting. J Oral Maxillofac Surg 2011;69:80e3. Li J, Shi B, Liu K, et al. A photogrammetric study of the effects of alveolar bone graft on nose symmetry among unilateral cleft patients. J Plast Reconstr Aesthet Surg 2011;64:1436e43. Nagasao T, Ogata H, Miyamoto J, et al. Alveolar bone grafting for patients with unilateral complete alveolar and palatal clefts improves the bony structure of the nose. Cleft Palate Craniofac J 2009;46:9e18. Sander M, Daskalogiannakis J, Tompson B, Forrest C. Effect of alveolar bone grafting on nasal morphology, symmetry, and nostril shape of patients with unilateral cleft lip and palate. Cleft Palate Craniofac J 2011;48:20e7. van der Wal KG, van der Meulen BD, van der Biezen JJ, Mulder JW. Bone grafting the piriform aperture deformity in isolated cleft lip patients: indication, technique, and results. J Oral Maxillofac Surg 1997;55:1089e93. Wu Y, Wang G, Yang Y, Zhang Y. Influence of alveolar-bone grafting on the nasal profile: unilateral cleft lips, alveoli, and palates. J Craniofac Surg 2010;21(6):1904e7. Kim SW, Park SO, Choi TH, Hai do T. Change in upper lip height and nostril sill after alveolar bone grafting in unilateral cleft lip alveolus patients. J Plast Reconstr Aesthet Surg 2012;65: 558e63. Tanikawa DY, Alonso N, Rocha DL. Evaluation of primary cleft nose repair: severity of the cleft versus final position of the nose. J Craniofac Surg 2010;21:1519e24. Farkas LG. Anthopometry of the head and face. New York: Raven Press, Ltd; 1994. Rosset A, Spadola L, Ratib O. OsiriX: an open-source software for navigating in multidimensional DICOM images. J Digit Imaging 2004;17:205e16. Kim G, Jung HJ, Lee HJ, et al. Accuracy and reliability of length measurements on three-dimensional computed tomography using open-source OsiriX software. J Digit Imaging 2012; 25:486e91. Bilwatsch S, Kramer M, Haeusler G, et al. Nasolabial symmetry following Tennison-Randall lip repair: a threedimensional approach in 10-year-old patients with unilateral clefts of lip, alveolus and palate. J Craniomaxillofac Surg 2006;34:253e62. Al-Omari I, Millett DT, Ayoub AF. Methods of assessment of cleft-related facial deformity: a review. Cleft Palate Craniofac J 2005;42:145e56. Shaw WC, Semb G, Nelson P, et al. The Eurocleft project 1996e2000: overview. J Craniomaxillofac Surg 2001;29: 131e40. Grisius TM, Spolyar J, Jackson IT, et al. Assessment of cleft lip and palate patients treated with presurgical orthopedic correction and either primary bone grafts, gingivoperiosteoplasty, or without alveolar grafting procedures. J Craniofac Surg 2006;17:468e73. Tomanova M, Mullerova Z. Effects of primary bone grafting on facial development in patients with unilateral complete cleft lip and palate. Acta Chir Plast 1994;36:38e41. Fallucco MA, Carstens MH. Primary reconstruction of alveolar clefts using recombinant human bone morphogenic protein-2:
Please cite this article in press as: Alonso N, et al., Effect of maxillary alveolar reconstruction on nasal symmetry of cleft lip and palate patients: A study comparing iliac crest bone graft and recombinant human bone morphogenetic protein-2, Journal of Plastic, Reconstructive & Aesthetic Surgery (2014), http://dx.doi.org/10.1016/j.bjps.2014.05.014
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30.
31.
32.
33.
34.
35.
N. Alonso et al. clinical and radiographic outcomes. J Craniofac Surg 2009;20: 1759e64. Salyer KE. Primary reconstruction of alveolar clefts using recombinant human bone morphogenic protein-2: clinical and radiographic outcomes. J Craniofac Surg 2009;20:1765. Friede H, Johanson B. Adolescent facial morphology of early bone-grafted cleft lip and palate patients. Scand J Plast Reconstr Surg 1982;16:41e53. Chang CS, Por YC, Liou EJ, et al. Long-term comparison of four techniques for obtaining nasal symmetry in unilateral complete cleft lip patients: a single surgeon’s experience. Plast Reconstr Surg 2010;126:1276e84. Freeman AK, Mercer NS, Roberts LM. Nasal asymmetry in unilateral cleft lip and palate. J Plast Reconstr Aesthet Surg 2013; 66:506e12. Haddock NT, McRae MH, Cutting CB. Long-term effect of primary cleft rhinoplasty on secondary cleft rhinoplasty in patients with unilateral cleft lip-cleft palate. Plast Reconstr Surg 2012;129:740e8. Govender S, Csimma C, Genant HK, et al. Recombinant human bone morphogenetic protein-2 for treatment of open tibial
36.
37.
38.
39.
40.
fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Jt Surg Am 2002;84: 2123e34. Mannion RJ, Nowitzke AM, Wood MJ. Promoting fusion in minimally invasive lumbar interbody stabilization with lowdose bone morphogenic protein-2 e but what is the cost? Spine J 2011;11:527e33. Mesfin A, Buchowski JM, Zebala LP, et al. High-dose rhBMP-2 for adults: major and minor complications: a study of 502 spine cases. J Bone Jt Surg Am 2013;95:1546e53. Herford AS, Boyne PJ, Rawson R, Williams RP. Bone morphogenetic protein-induced repair of the premaxillary cleft. J Oral Maxillofac Surg 2007;65:2136e41. Nguyen PD, Lin CD, Allori AC, et al. Scaffold-based rhBMP-2 therapy in a rat alveolar defect model: implications for human gingivoperiosteoplasty. Plast Reconstr Surg 2009;124: 1829e39. Cooper GM, Mooney MP, Gosain AK, et al. Testing the critical size in calvarial bone defects: revisiting the concept of a critical-size defect. Plast Reconstr Surg 2010;125: 1685e92.
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Journal of Plastic, Reconstructive & Aesthetic Surgery (2014) xx, 1e8
Effect of maxillary alveolar reconstruction on nasal symmetry of cleft lip and palate patients: A study comparing iliac crest bone graft and recombinant human bone morphogenetic protein-2 Nivaldo Alonso a,*, Gabriel Henrique Risso a, Rafael Denadai b, Cassio Eduardo Raposo-Amaral b a Craniofacial Surgery Unit, Division of Plastic Surgery, Department of Surgery, Faculty of Medicine, Universidade de Sa˜o Paulo (USP), Sao Paulo, Brazil b Institute of Plastic and Craniofacial Surgery, SOBRAPAR Hospital, Campinas, Sao Paulo, Brazil
Received 24 November 2013; accepted 10 May 2014
KEYWORDS Alveolar cleft repair; Recombinant human bone morphogenetic protein; rhBMP-2; Iliac crest bone graft; Nasal symmetry; Nasal position
Summary Background: Recombinant human bone morphogenetic protein (rhBMP)-2 has been used in some craniofacial centers worldwide. However, its influence on nasal morphology is unknown. Thus, the objective of this investigation was to assess the effect of maxillary alveolar reconstruction on nasal position and symmetry in unilateral complete cleft lip patients who underwent traditional iliac crest bone grafting transferring versus reconstruction using rhBMP-2. Methods: Nineteen unilateral complete cleft lip patients were randomly divided into two groups. In group 1, patients underwent traditional iliac crest bone grafting transferring (n Z 11) and in group 2, patients underwent alveolar reconstruction using collagen matrix with lyophilized rhBMP-2 (n Z 8). Computerized tomography (CT) imaging was performed preoperatively and at 6 months postoperatively using a previously standardized protocol. Linear distances using anatomic landmarks were performed using tridimensional CT data reformatted by the OsiriX software. Quantitative and qualitative measurements to assess intra- and inter-group nasal position modifications were performed. Results: Intra-group pre- and postoperative comparisons showed significant differences (p < 0.05) in two linear measurements of group 1, while group 2 did not present a difference (p > 0.05). Group 2 presented significant postoperative enhancement (p < 0.05) in the
* Corresponding author. Craniofacial Surgery Unit, Division of Plastic Surgery, Faculty of Medicine, Universidade de Sa ˜o Paulo (USP), Rua Afonso Bra ¸˜ ao, Sa ´s, 473ecj. 65, Vila Nova Conceic ˜o Paulo 04511-011, Brazil. E-mail address: [email protected] (N. Alonso). http://dx.doi.org/10.1016/j.bjps.2014.05.014 1748-6815/ª 2014 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Alonso N, et al., Effect of maxillary alveolar reconstruction on nasal symmetry of cleft lip and palate patients: A study comparing iliac crest bone graft and recombinant human bone morphogenetic protein-2, Journal of Plastic, Reconstructive & Aesthetic Surgery (2014), http://dx.doi.org/10.1016/j.bjps.2014.05.014
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N. Alonso et al. quantitative nasal symmetry in one measurement. Qualitative analysis showed postoperative nasal symmetry enhancement in 75% of the measurements of group 2 and 36% of group 1. There was no statistically significant difference in the inter-group comparisons. Conclusions: Our study demonstrated that both groups showed similar effect on nasal symmetry. ª 2014 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
Introduction Unilateral cleft lip nasal repair is challenging because of the complexity of the deformity.1,2 This three-dimensional deformity involves several structures such as: the alar base, the alar cartilage (the medial and lateral crus), the nasal dome, the columella, the nasal septum, and the skeletal base, which includes the alveolus, maxillary segments, and palate.1 Thus, to obtain the realistic treatment goal (normal appearance and function, with better symmetry, balance, and less scarring), both skeletal and soft-tissue structures must be adequately managed.1,2 In fact, the open alveolar gap and the hypoplastic maxilla have been described as two major problems in achieving consistent, favorable results following cleft lip nasal repair.1 Alveolar bone grafting is an essential procedure in the overall osseous framework rehabilitation of patients with unilateral cleft lip alveolus, with or without cleft of the secondary palate.3 Among numerous donor sites, cancellous iliac crest bone grafting at the time of cuspid or lateral incisor root formation has proven to provide consistently excellent, stable long-term results and has become the standard approach for filling maxillary alveolar clefts.4,5 However, as donor-site morbidities such as acute and chronic pain, infection, hemorrhage, and nerve injury are quite significant,3 many investigations have been conducted to evaluate bone substitutes.6 In this context, our group7,8 and others9,10 have reported the successful use of the recombinant human bone morphogenetic protein (rhBMP)-2 for alveolar cleft repair in skeletally mature and immature patients. Alveolar cleft repair using rhBMP-2 had the same overall success as traditional iliac crest bone grafting.710 Additionally, this bone tissue engineering approach spares the need of a donor site, while excellent results can be obtained, with reduction of the surgical time and overall financial costs.7e10 Within the specific management of the cleft lip nasal deformity, the alveolar osseous graft has been used for restoring the maxilla at the piriform rim, providing improved stability and aesthetics by supporting the alar base.3 Even though previous studies11e19 have demonstrated nasal changes (nasal morphology, symmetry, and nostril shape) following alveolar bone grafting, it is unclear, however, how the rhBMP-2 influences the nasal symmetry. Such previous information led us to hypothesize that the positive effect on nasal symmetry generated by the inclusion of rhBMP-2 in the maxillary region does not differ from the effect yielded by autologous bone transferring from the iliac region. Thus, the purpose of this investigation was to
assess the effect of maxillary alveolar reconstruction on nasal position and symmetry in unilateral complete cleft lip patients during secondary dental eruption, comparing resorbable collagen matrix with rhBMP-2 versus traditional iliac crest bone grafting approaches.
Methods A retrospective study of 24 consecutive non-syndromic unilateral complete cleft lip patients, who underwent alveolar cleft repair between 9 and 12 years of age, was conducted at a single Brazilian Craniofacial Surgery Unit between 2010 and 2012. The data were started to be collected in 2010 resulting in a previous publication.7 All patients previously underwent primary rhinocheiloplasty between 3 and 6 months of age, according to the modified technique described by our group,20 and underwent palate repair at 1 year of age. Before secondary alveolar cleft repair, all subjects underwent preoperative orthodontic expansion of maxillary segments and were randomly assigned to group 1 (traditional iliac crest bone grafting transferring) or group 2 (reconstruction using collagen matrix with lyophilized rhBMP-2). No revision of lip surgical repair was performed during secondary alveolar cleft repair. All patients (n Z 5) who did not have adequate computed tomographic documentation, previous eruption of the canine, previous alveolar or nasal surgeries, and/or incomplete follow-up were excluded from the study. Additionally, complications such as infections, wound dehiscence leading to bone graft loss or rhBMP-2 exposure were recorded. All subjects were enrolled upon a consent form signed by their parents, in accordance with the Helsinki Declaration of 1975, as amended in 1983. A local institutional research ethics board approval was obtained for this study.
Surgical procedures All surgical interventions were performed by the same senior surgeon (N.A.) in a standard fashion. Key information included below and additional details were previously described by our group.7,8 Iliac crest bone graft (group 1) and collagen matrix with lyophilized rhBMP-2 (group 2) were placed in the maxillary alveolar defect after wide exposure of the cleft area. In group 1, through a 3-cm incision, a cortical bone trap door was raised and hinged on the inner edge of the iliac crest and enough chips of cancellous bone (20e40 mL) were then removed. In group 2, rhBMP-2 was reconstituted with distilled water and impregnated the supplied absorbable
Please cite this article in press as: Alonso N, et al., Effect of maxillary alveolar reconstruction on nasal symmetry of cleft lip and palate patients: A study comparing iliac crest bone graft and recombinant human bone morphogenetic protein-2, Journal of Plastic, Reconstructive & Aesthetic Surgery (2014), http://dx.doi.org/10.1016/j.bjps.2014.05.014
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Effect of maxillary alveolar reconstruction on nasal collagen sponge (Infuse Bone Graft kit; Medtronic, Memphis, TN, USA) for 20 min according to the manufacturer’s guidelines. The rhBMP-2-impregnated collagen matrix was then cut into several small parts that were used to fill in the alveolar cleft defect as necessary; approximately 3.2e4.2 mg of rhBMP-2 was used. Finally, a lateral mucoperiosteal flap was advanced to cover the cleft and then sutured to the medial flap and palatal flaps.
3 Table 1 Ten linear inter-landmark measurements (L1eL10) used to quantify nasal symmetry in this study. Linear items
Definitions
L1 L2
Distance from the prn point to the mipl point Distance from the cleft sbal point to the mipl point Distance from the noncleft sbal point to the mipl point Distance from the cleft al point to the mpf Distance from the noncleft al point to the mpf Distance between both al points (cleft al to noncleft al ) Distance from the cleft al point to the prn point Distance from the noncleft al point to the prn point Distance from the cleft al point to the sn point Distance from the noncleft al point to the sn point
L3
Anatomic landmarks and linear measurements Four bilateral and two median anatomic landmarks and one facial plane were defined according to the previous description by Farkas21: center point of the pupil (p); midpoint of the interpupillary line (mipl): defined by measuring interpupillary distance and marking the midpoint at the glabella; pronasale (prn): the most protruded point of the apex nasi; alare laterale (al): the most lateral point on each alar contour; subalare (sbal): the point of lower limit of each alar base, where the alar base disappears into the skin of the upper lip; subnasale (sn): midpoint of the angle at the columella base where the lower border of the nasal septum and the surface of the upper lip meet; median plane of the face (mpf): defined by three anatomical landmarks (root of the nose, subnasale (base of the columella), and the gnathion (lower edge of the mandible)) e the horizontal position of paired symmetrical features of the upper third of the face was aligned in order to obtain a vertical plane. After defining these landmarks, 10 linear (mm) inter-landmark measurements (L1eL10) were calculated in order to quantify nasal symmetry (Figure 1 and Table 1).
Three-dimensional computed tomography data Multislice computed tomography (CT) scans of the craniofacial region were performed preoperatively (1 month to 1 week prior to alveolar cleft repair) and postoperatively (6 months after alveolar cleft repair) for the evaluation of the
L4 L5 L6 L7 L8 L9 L10
prn, pronasale; mipl, midpoint of the interpupillary line; al, alare laterale; sbal, subalare; mpf, median plane of the face; sn, subnasale.
nasal region of cleft lip individuals. Patient data were obtained using 1 mm cut and images were reconstructed. All data were saved as a Digital Imaging and Communication in Medicine (DICOM) file and were then relabeled and reordered randomly to blind the rater. The data were then transferred to a workstation (Apple Mac OS X; Apple Computer, Inc., Cupertino, CA, USA) and analyzed using open-source OsiriX medical imaging software (version 7.6, www.osirix-viewer.com, OsiriX Foundation, Geneva, Switzerland) which is a fast DICOM viewer program22 with 0.05) in intra-investigator measures. Then, all the measurements were subsequently performed one time in each time period.
Quantitative and qualitative nasal symmetry analyses Eight (except L1 and L6) linear measurements were combined in pairs (ratio between the cleft and noncleft side measurements: L2/L3, L4/L5, L7/L8, and L9/L10) in order to measure quantitative nasal symmetry. Additionally, all linear measurements (L1eL10) were gathered and considered together in order to qualitatively quantify the overall nasal symmetry. For this, a score system that represented the variation (difference) of symmetry of the measurements in each period was defined. Initially, the variation (difference) of symmetry for each linear measurement in each period was individually performed for all patients. Afterwards, the 10 values obtained for each patient were summed and then a qualitative nasal symmetry analysis was performed on every individual in both groups. Positive values were considered enhancement (“gain”), and negative values were considered deterioration (“loss”) of nasal symmetry, while neutral values (difference equal to zero) were considered uninfluenced by the alveolar repair on nasal symmetry. Qualitative nasal symmetry enhancement
N. Alonso et al. and qualitative nasal symmetry deterioration were defined when positive values and negative values were achieved, respectively.
Statistical analysis In the descriptive analysis, data were summarized as means standard errors. Intra-group (preoperative vs. postoperative linear measurements and pre- and postoperative quantitative nasal symmetry) and inter-group (postoperative linear measurements and pre- and quantitative postoperative nasal symmetry) comparisons were performed with the aid of the paired t-test and the twosample t-test, respectively. All analyses were performed using the software program Statistical Package for Social Science (SPSS version 17.0 for Windows, Chicago, IL, USA). Values were considered significant for a confidence interval of 95% (p < 0.05) and tailed analysis was used as a supplement in the presence of statistical difference.
Results A total of 19 (79.17%) unilateral complete cleft lip patients (five females and 14 males, with average age of 11.75 years) met the inclusion criteria. Eleven (57.89%) patients underwent alveolar iliac crest bone grafting (group 1), and eight (42.11%) patients underwent alveolar cleft repair with resorbable collagen matrix with rhBMP-2 (group 2). Five (20.83%) patients were excluded because of an incomplete postoperative follow-up period, and therefore, did not undergo CT scans at 6 months after alveolar cleft lip repair. No complications were seen in these series of patients.
Intra-group comparisons Intra-group comparisons of the pre- and postoperative 3D CT linear measurements of the nasal area showed a
Figure 2 Computed tomography imaging of facial region (frontal and basal views; left and right, respectively) processed by OsiriX of a unilateral complete cleft lip patient illustrating seven linear inter-landmark measurements used to quantify nasal symmetry in this study.
Please cite this article in press as: Alonso N, et al., Effect of maxillary alveolar reconstruction on nasal symmetry of cleft lip and palate patients: A study comparing iliac crest bone graft and recombinant human bone morphogenetic protein-2, Journal of Plastic, Reconstructive & Aesthetic Surgery (2014), http://dx.doi.org/10.1016/j.bjps.2014.05.014
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Effect of maxillary alveolar reconstruction on nasal
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Table 2 Intra-group (preoperative vs. postoperative measurements) and inter-group (postoperative measurements) comparative analysis. Linear measurements
Group 1 (Iliac crest bone graft) Pre
L1 L2 L3 L4 L5 L6 L7 L8 L9 L10
Group 2 (rhBMP-2)
Post
2.77 3.613 3.5559 1.6948 1.8345 3.529 2.029 2.0041 1.7925 1.8215
0.351 0.373 0.2978 0.2929 0.2275 0.432 0.341 0.2137 0.203 0.2758
2.8682 3.579 3.548 1.8146 1.779 3.594 2.094 1.9886 1.9092 1.8749
0.2327 0.378 0.362 0.3283 0.2708 0.524 0.333 0.2203 0.2165 0.2474
p-value*
Pre
0.287 0.752 0.928 0.171 0.386 0.438 0.034 0.489 0.013 0.63
2.828 3.61 3.584 1.7284 1.966 3.694 2.1333 1.941 1.8491 1.8931
Post
0.448 0.377 0.399 0.2096 0.462 0.498 0.1713 0.292 0.2155 0.1565
3.06 3.769 3.736 1.7944 1.826 3.6204 2.0769 1.9129 1.8664 1.9174
p-value*
0.394 0.357 0.377 0.1843 0.157 0.1819 0.1273 0.1826 0.1624 0.1279
0.097 0.218 0.106 0.25 0.403 0.63 0.271 0.771 0.768 0.664
rhBMP-2, recombinant human bone morphogenetic protein 2; Pre, preoperative; Post, postoperative. *, Intra-group pre- versus postoperative comparisons. Notes: (1) Inter-group postoperative comparative analysis showed no significant difference (p > 0.05 for all inter-group postoperative comparisons). (2) Data are presented as mean standard deviation in millimeter. (3) L1eL10 were defined in the Table 1.
significant enhancement in the postoperative period in the two cleft side distances (L7 and L9; p Z 0.034 and p Z 0.013, respectively), favoring patients of group 1 (traditional iliac crest bone graft transferring). There was a significant (p Z 0.014) enhancement in the postoperative quantitative nasal symmetry only in the L2/L3 measurement of the group 2 (rhBMP-2). The rest of the measurements revealed no intra-group significant differences (all p > 0.05) (Tables 2 and 3).
Inter-group comparisons Inter-group comparisons of the postoperative 3D CT linear measurements of the nasal area and pre- and postoperative quantitative nasal symmetry showed no inter-group significant differences (all p > 0.05) (Tables 2 and 3). Qualitative nasal symmetry analysis revealed better final nasal symmetry favoring group 2 (rhBMP-2), with 75% (n Z 6) of patients with positive values, meaning that all of these patients gained nasal symmetry in comparison to group 1 (traditional iliac crest bone graft), with 36.36% (n Z 4) of patients with positive values. Six (54.55%) patients of group 1 and two of group 2 (25%) showed negative
Table 3
Discussion The current study was designed to compare the effect of rhBMP-2 versus traditional iliac crest bone grafting on the nasal symmetry after alveolar reconstruction in cleft lip patients. In spite of the heterogeneous nature of cleft lip and palate, both groups were stratified with consecutive patients with unilateral complete cleft lip and palate that were randomly assigned between the groups. All patients followed the same surgical regimen, with the lip being operated at 3e6 months old and the palate being operated at 1 year of age, and alveolar grafting being performed with similar indication, immediately prior to canine eruption, with age varying from 9 to 12 years. Different 3D imaging techniques (e.g., 3D stereophotogrammetry, 3D optical scanner, 3D photogrammetry, and 3D-CT-scan, among others) have been used to assess nasal soft-tissue symmetry in cleft lip patients12,13,16,24; however, there is no gold standard tool to date.25
Intra-group and inter-group comparative analysis of the quantitative nasal symmetry.
Quantitative nasal symmetry
Group 1 (Iliac crest bone graft) Pre
L2/L3 L4/L5 L7/L8 L9/L10
values, meaning that all of these patients had nasal symmetry deterioration. One (9.09%) patient of group 1 showed a value equal to zero.
0.161 0.2487 0.383 0.1515
Group 2 (rhBMP-2)
Post
0.1076 0.2047 0.1673 0.0982
0.236 0.2455 0.2547 0.1059
0.1577 0.1525 0.1626 0.0765
p-value*
Pre
0.428 0.973 0.408 0.253
0.1741 0.424 0.2875 0.1633
Post
0.1156 0.354 0.1115 0.0837
0.109 0.1841 0.225 0.1307
p-value*
0.0962 0.2457 0.1198 0.0817
0.014 0.184 0.308 0.396
rhBMP-2, recombinant human bone morphogenetic protein 2; Pre, preoperative; Post, postoperative. *, Intra-group pre- versus postoperative comparisons. Notes: (1) Inter-group pre- and postoperative comparative analyses showed no significant difference (p > 0.05 for all inter-group comparisons). (2) Data are presented as mean standard deviation in millimeter. (3) L1eL10 were defined in the Table 1.
Please cite this article in press as: Alonso N, et al., Effect of maxillary alveolar reconstruction on nasal symmetry of cleft lip and palate patients: A study comparing iliac crest bone graft and recombinant human bone morphogenetic protein-2, Journal of Plastic, Reconstructive & Aesthetic Surgery (2014), http://dx.doi.org/10.1016/j.bjps.2014.05.014
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6 Therefore, all linear measurements were objectively obtained using 3D CT imaging processed by a previous validated computer-assisted software program.22,23 The observer was consistently trained to identify the anatomic landmarks using the axial, sagittal, and coronal cuts, in which measurements were performed two times, in two different periods to assess accuracy. Only after validation of the methodology were subsequent measurements performed once. Thus, any chance of error during measurements was reduced using this strategy previously described.7 All measurements were performed at 6 months after alveolar cleft repair to allow either bone induction or bone integration to its cleft bed.16 As during this time frame (from 9 to 12 years of age) the face may present significant growth, 6 months after surgery seems to be an ideal period to assess the effect of alveolar bone grafting on nasal symmetry by avoiding the insertion of facial growth variable into the nasal symmetry analysis. In addition, The Eurocleft project emphasized the need for minimum record taking to monitor the individual treatment and for quality improvement and research reasons.26 According to these recommendations,26 before and 6 months after alveolar bone grafting, an intraoral radiograph should be taken as a record. This radiograph, however, can only show the height of the reconstructed alveolar process and its relation to the teeth adjacent to the cleft. Thus, we performed a CT in order to assess the influence of the maxillary reestablishment on nasal symmetry in addition to facial growth and any possible teratoma formation. Historically, surgical teams around the world have been focusing on precocious cleft lip patients rehabilitation with less possible morbidity.1,2 Surgical attempts with primary bone grafting at the time of lip repair aim to provide early maxillary realignment and its subsequent long-term benefits on dental eruption and nasal symmetry.27 However, this procedure remains controversial due to donor-site morbidity and inherent side effects on the maxillary growth that this technique may pose.28 Although it has been stated that rhBMP-2 at the time of cleft lip repair reduced the amount of secondary surgery by inducing nature bone in the maxillary arch and cleft nasal floor and simultaneously avoid donor-site morbidity,29 we as others30,31 believe that any precocious intervention such as primary bone grafting or inclusion of rhBMP-2 or any other biomaterial on the maxillary arch at an early age may lead to a severe maxillary collapse. Further longitudinal randomized controlled studies may clarify this topic. Although the primary cleft lip nasal surgery has currently been performed at the time of lip repair,20 a residual (from minor to major) nasal deformity is usually found in all cohorts of patient with unilateral complete cleft lip and palate,32,33 regardless of surgeon’s skills. As final cleft lip nose repair is indicated after the completion of facial growth (after orthognatic surgery, if needed), all prior surgical interventions aimed to reduce nasal asymmetry.34 In this context, alveolar bone grafting imposes significant changes in the maxillary bone,9 somehow affecting nasal height and nasal width. Interestingly, our data have shown that the nasal height and nasal width in patients whose maxillary cleft received rhBMP-2 did not statistically differ from those who received iliac crest bone, although there are subtle differences in intra-group analysis. As rhBMP-2
N. Alonso et al. reduced the overall surgical cost of cleft lip patients’ rehabilitation and the requirement of donor site9 and simultaneously present similar interference on nasal symmetry in comparison of nature bone, it is possible to assume that rhBMP-2 can eventually be the standard adjunct element of the maxillary reestablishment during surgery in the cleft lip population. For a successful repair using rhBMP-2, a hermetic, watertight pocket needs to be created prior to its insertion. Any leak in the mucosa will compromise the outcome. Thus, it is important that only experienced surgeons use the rhBMP-2 for this purpose. On the other hand, autologous bone transferring tolerates minor leaks in the mucosa better, as only partial loss of bone graft may occur in the presence of minor dehiscence. Large prospective trials35e37 to determine the effect of rhBMP-2 on lower limbs fractures or lumbar inter-body fixation were conducted. Different doses (reaching up to 351 mg) of rhBMP-2 were used to speed up bone healing, to induce complete bone fusion, decrease secondary intervention, and reduce infection rate, among other outcomes.35e37 In the cleft lip management, different doses of rhBMP-2 were used to fulfill the alveolar cleft defect.7e10 These data showed that there is a paucity of guidelines in the current literature that can possibly optimize the minimum dose of rhBMP-2 to generate a targeted benefit in each specific clinical situation. Thus, in our study, we adopted a dose of rhBMP-2 previously used7,8,38 to induce bone formation in a congenital critical-sized osseous defect, in spite of relevant data showing bone healing in critical-sized calvarial defects in experiment studies using a lower-dose of rhBMP-2.39 In addition, acutely induced calvarial defects in experiments models, whose healing is influenced by the dura-mater, present a major regeneration capacity in comparison to a congenital osseous defect.40 Interestingly, in our study we did not observe ectopic bone formation42,43 or any side effect related to the dose of rhBMP-2 adopted, similar to other reports7,8,38 that used the same rhBMP-2 dose. Thus, we believe that the 3.2e4.2 mg of rhBMP-2 may be the standard dose to induce bone formation in congenital alveolar osseous defects in humans. However, further randomized prospective studies should be designed to investigate the effect of different doses of rhBMP-2 on both bone formation and nasal symmetry in cleft lip patients, and therefore, ratify or not our hypothesis. Our primary hypothesis has proven to be right, and both groups have shown similar quantitative influence on final nasal symmetry in the inter-group analysis. In addition, a qualitatively gain in nasal symmetry was seen in more patients of group 2 than group 1. Hence, other variables such as accessibility, technical difficulties, overall costs of patients’ rehabilitation in the long-term follow-up, and complication rates after using each material may support the final therapeutic decision. A limitation of our report is that we do not adopt all existing anatomical landmarks for nasal morphology assessment and, therefore, future studies should expand our findings by including additional linear measurements. The other caveat of our study is the lack of biomechanical testing in both cohorts of patients. Considering the inherent limitation of providing these tests in humans, in addition that all cleft lip patients have been followed up for long
Please cite this article in press as: Alonso N, et al., Effect of maxillary alveolar reconstruction on nasal symmetry of cleft lip and palate patients: A study comparing iliac crest bone graft and recombinant human bone morphogenetic protein-2, Journal of Plastic, Reconstructive & Aesthetic Surgery (2014), http://dx.doi.org/10.1016/j.bjps.2014.05.014
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Effect of maxillary alveolar reconstruction on nasal
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postoperative periods, we observe that in both groups the canine/lateral incisor naturally erupted without problems, as also shown in previous reports.7,8 Thus, we assumed that the bone quality was sufficient to maintain dental eruption and sufficient stability for orthodontic treatment.
11.
Conclusion
12.
Our study demonstrated that unilateral complete cleft lip patients whose maxillary alveolar defect were repaired with rhBMP-2 showed similar nasal symmetry than those repaired with autologous iliac crest bone graft.
13.
Ethical approval
15.
All subjects were enrolled upon a consent form signed by their parents, in accordance with the Helsinki Declaration of 1975, as amended in 1983. A local institutional research ethics board approval was obtained for this study.
16.
Funding
17.
14.
None. FAPESP Project Number 2010-08175-6. 18.
Conflict of interest 19.
None.
References 1. Salyer KE, Genecov ER, Genecov DG. Unilateral cleft lip-nose repair e long-term outcome. Clin Plast Surg 2004;31:191e208. 2. Mulliken JB, Martinez-Perez D. The principle of rotation advancement for repair of unilateral complete cleft lip and nasal deformity: technical variations and analysis of results. Plast Reconstr Surg 1999;104:1247e60. 3. Bajaj AK, Wongworawat AA, Punjabi A. Management of alveolar clefts. J Craniofac Surg 2003;14:840e6. 4. Baykul T, Aydin A, Nasir S, Turkkahraman H. Surgical rehabilitation of nasoalveolar complex in patients with alveolar clefts. J Craniofac Surg 2010;21:1512e5. 5. Meyer S, Molsted K. Long-term outcome of secondary alveolar bone grafting in cleft lip and palate patients: a 10-year followup cohort study. J Plast Surg Hand Surg 2013;47:503e8. 6. Engstrand T. Biomaterials and biologics in craniofacial reconstruction. J Craniofac Surg 2012;23:239e42. 7. Alonso N, Tanikawa DY, Freitas Rda S, et al. Evaluation of maxillary alveolar reconstruction using a resorbable collagen sponge with recombinant human bone morphogenetic protein2 in cleft lip and palate patients. Tissue Eng Part C Methods 2010;16:1183e9. 8. Canan Jr LW, da Silva Freitas R, Alonso N, et al. Human bone morphogenetic protein-2 use for maxillary reconstruction in cleft lip and palate patients. J Craniofac Surg 2012;23: 1627e33. 9. Dickinson BP, Ashley RK, Wasson KL, et al. Reduced morbidity and improved healing with bone morphogenic protein-2 in older patients with alveolar cleft defects. Plast Reconstr Surg 2008;121:209e17. 10. Francis CS, Mobin SS, Lypka MA, et al. rhBMP-2 with a demineralized bone matrix scaffold versus autologous iliac crest
20.
21. 22.
23.
24.
25.
26.
27.
28.
29.
bone graft for alveolar cleft reconstruction. Plast Reconstr Surg 2013;131:1107e15. Baeyens W, Daelemans A, Leloup T, De Mey A. Study of changes in nasal morphology in children with complete unilateral cleft lip and palate after secondary bone grafting measured with image analysis. Scand J Plast Reconstr Surg Hand Surg 2006;40: 345e51. Krimmel M, Kluba S, Bacher M, et al. Digital surface photogrammetry for anthropometric analysis of the cleft infant face. Cleft Palate Craniofac J 2006;43:350e5. Krimmel M, Schuck N, Bacher M, Reinert S. Facial surface changes after cleft alveolar bone grafting. J Oral Maxillofac Surg 2011;69:80e3. Li J, Shi B, Liu K, et al. A photogrammetric study of the effects of alveolar bone graft on nose symmetry among unilateral cleft patients. J Plast Reconstr Aesthet Surg 2011;64:1436e43. Nagasao T, Ogata H, Miyamoto J, et al. Alveolar bone grafting for patients with unilateral complete alveolar and palatal clefts improves the bony structure of the nose. Cleft Palate Craniofac J 2009;46:9e18. Sander M, Daskalogiannakis J, Tompson B, Forrest C. Effect of alveolar bone grafting on nasal morphology, symmetry, and nostril shape of patients with unilateral cleft lip and palate. Cleft Palate Craniofac J 2011;48:20e7. van der Wal KG, van der Meulen BD, van der Biezen JJ, Mulder JW. Bone grafting the piriform aperture deformity in isolated cleft lip patients: indication, technique, and results. J Oral Maxillofac Surg 1997;55:1089e93. Wu Y, Wang G, Yang Y, Zhang Y. Influence of alveolar-bone grafting on the nasal profile: unilateral cleft lips, alveoli, and palates. J Craniofac Surg 2010;21(6):1904e7. Kim SW, Park SO, Choi TH, Hai do T. Change in upper lip height and nostril sill after alveolar bone grafting in unilateral cleft lip alveolus patients. J Plast Reconstr Aesthet Surg 2012;65: 558e63. Tanikawa DY, Alonso N, Rocha DL. Evaluation of primary cleft nose repair: severity of the cleft versus final position of the nose. J Craniofac Surg 2010;21:1519e24. Farkas LG. Anthopometry of the head and face. New York: Raven Press, Ltd; 1994. Rosset A, Spadola L, Ratib O. OsiriX: an open-source software for navigating in multidimensional DICOM images. J Digit Imaging 2004;17:205e16. Kim G, Jung HJ, Lee HJ, et al. Accuracy and reliability of length measurements on three-dimensional computed tomography using open-source OsiriX software. J Digit Imaging 2012; 25:486e91. Bilwatsch S, Kramer M, Haeusler G, et al. Nasolabial symmetry following Tennison-Randall lip repair: a threedimensional approach in 10-year-old patients with unilateral clefts of lip, alveolus and palate. J Craniomaxillofac Surg 2006;34:253e62. Al-Omari I, Millett DT, Ayoub AF. Methods of assessment of cleft-related facial deformity: a review. Cleft Palate Craniofac J 2005;42:145e56. Shaw WC, Semb G, Nelson P, et al. The Eurocleft project 1996e2000: overview. J Craniomaxillofac Surg 2001;29: 131e40. Grisius TM, Spolyar J, Jackson IT, et al. Assessment of cleft lip and palate patients treated with presurgical orthopedic correction and either primary bone grafts, gingivoperiosteoplasty, or without alveolar grafting procedures. J Craniofac Surg 2006;17:468e73. Tomanova M, Mullerova Z. Effects of primary bone grafting on facial development in patients with unilateral complete cleft lip and palate. Acta Chir Plast 1994;36:38e41. Fallucco MA, Carstens MH. Primary reconstruction of alveolar clefts using recombinant human bone morphogenic protein-2:
Please cite this article in press as: Alonso N, et al., Effect of maxillary alveolar reconstruction on nasal symmetry of cleft lip and palate patients: A study comparing iliac crest bone graft and recombinant human bone morphogenetic protein-2, Journal of Plastic, Reconstructive & Aesthetic Surgery (2014), http://dx.doi.org/10.1016/j.bjps.2014.05.014
+
MODEL
8
30.
31.
32.
33.
34.
35.
N. Alonso et al. clinical and radiographic outcomes. J Craniofac Surg 2009;20: 1759e64. Salyer KE. Primary reconstruction of alveolar clefts using recombinant human bone morphogenic protein-2: clinical and radiographic outcomes. J Craniofac Surg 2009;20:1765. Friede H, Johanson B. Adolescent facial morphology of early bone-grafted cleft lip and palate patients. Scand J Plast Reconstr Surg 1982;16:41e53. Chang CS, Por YC, Liou EJ, et al. Long-term comparison of four techniques for obtaining nasal symmetry in unilateral complete cleft lip patients: a single surgeon’s experience. Plast Reconstr Surg 2010;126:1276e84. Freeman AK, Mercer NS, Roberts LM. Nasal asymmetry in unilateral cleft lip and palate. J Plast Reconstr Aesthet Surg 2013; 66:506e12. Haddock NT, McRae MH, Cutting CB. Long-term effect of primary cleft rhinoplasty on secondary cleft rhinoplasty in patients with unilateral cleft lip-cleft palate. Plast Reconstr Surg 2012;129:740e8. Govender S, Csimma C, Genant HK, et al. Recombinant human bone morphogenetic protein-2 for treatment of open tibial
36.
37.
38.
39.
40.
fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Jt Surg Am 2002;84: 2123e34. Mannion RJ, Nowitzke AM, Wood MJ. Promoting fusion in minimally invasive lumbar interbody stabilization with lowdose bone morphogenic protein-2 e but what is the cost? Spine J 2011;11:527e33. Mesfin A, Buchowski JM, Zebala LP, et al. High-dose rhBMP-2 for adults: major and minor complications: a study of 502 spine cases. J Bone Jt Surg Am 2013;95:1546e53. Herford AS, Boyne PJ, Rawson R, Williams RP. Bone morphogenetic protein-induced repair of the premaxillary cleft. J Oral Maxillofac Surg 2007;65:2136e41. Nguyen PD, Lin CD, Allori AC, et al. Scaffold-based rhBMP-2 therapy in a rat alveolar defect model: implications for human gingivoperiosteoplasty. Plast Reconstr Surg 2009;124: 1829e39. Cooper GM, Mooney MP, Gosain AK, et al. Testing the critical size in calvarial bone defects: revisiting the concept of a critical-size defect. Plast Reconstr Surg 2010;125: 1685e92.
Please cite this article in press as: Alonso N, et al., Effect of maxillary alveolar reconstruction on nasal symmetry of cleft lip and palate patients: A study comparing iliac crest bone graft and recombinant human bone morphogenetic protein-2, Journal of Plastic, Reconstructive & Aesthetic Surgery (2014), http://dx.doi.org/10.1016/j.bjps.2014.05.014
