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Bone Morphogenetic Protein-Induced Repair of the Premaxillary Cleft
BASIC AND PATIENT-ORIENTED RESEARCH J Oral Maxillofac Surg 65:2136-2141, 2007
Bone Morphogenetic Protein-Induced Repair of the Premaxillary Cleft Alan S. Herford, DDS, MD,* Philip J. Boyne, DMD, MS, DSc(hon),† Rick Rawson, DDS, MS,‡ and Roland P. Williams, DDS§ Purpose: The purpose of this study is to evaluate the bony regeneration of premaxillary clefts in
humans using recombinant human bone morphogenetic protein type 2 in a collagen sponge carrier. Patients and Methods: Twelve patients with unilateral clefted premaxillas were evaluated preoperatively and 4 months postoperatively. Ten patients were repaired with recombinant human bone morphogenetic protein type 2 while 2 others were grafted with anterior iliac crest particulate marrow cancellous bone. Computed tomographic studies were used to evaluate preoperative alveolar cleft volumes, postoperative bone bridge volumes, and preoperative and postoperative volume ratios. Results: A preoperative and postoperative volume ratio for patients repaired with recombinant human bone morphogenetic protein type 2 ranged from 24.1% to 90.6% with a mean of 71.7%. Patients who were grafted with particulate marrow cancellous bone had similar preoperative and postoperative volume ratios ranging from 71.3% to 84.9% with a mean of 78.1%. Conclusions: Clefts of the anterior maxilla can have complete osseous regeneration induced by recombinant human bone morphogenetic protein type 2 as an effective alternative to conventional anterior iliac particulate marrow cancellous bone grafts. © 2007 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 65:2136-2141, 2007 The purpose of this study was to evaluate the bony regeneration of the premaxillary cleft in human subjects using recombinant human bone morphogenetic protein type 2 (rhBMP-2) in an absorbable collagen sponge carrier as an alternative method to autogenous bone grafting. Preoperative and postoperative computed tomograms were used to evaluate the repair progress of the cleft. These images were compared with cases in which autogenous grafting of the premaxillary cleft was done with iliac crest particulate Received from the Department of Oral and Maxillofacial Surgery, Loma Linda University Medical Center, Loma Linda, CA. *Chairman. †Professor Emeritus. ‡Former Chief Resident. §Research Intern. Address correspondence and reprint requests to Dr Herford: Department of Oral and Maxillofacial Surgery, Loma Linda University Medical Center, 11092 Anderson Street, Loma Linda, CA 92350; e-mail: [email protected] © 2007 American Association of Oral and Maxillofacial Surgeons
0278-2391/07/6511-0002$32.00/0 doi:10.1016/j.joms.2007.06.670
marrow cancellous bone (PMCB), which has been long considered to be the “gold standard.” A great benefit to patients in the use of rhBMP-2 is the avoidance of a second surgical site needed for the harvesting of PMCB autogenous bone. This translates into a shorter hospital stay, avoidance of possible complications such as gait and sensory disturbance, and a decreased number of sites for scar formation and possible infection.
Patients and Methods A chart review was undertaken of 10 patients who underwent premaxillary cleft grafting procedures with rhBMP-2 and repair of oral-nasal fistulas by the same surgeon (A.H.). In addition, 2 patients received traditional autogenous iliac crest bone grafted cleft repair. Patients had received presurgical and postsurgical computed tomography (CT) for bony fill measurement using a special imaging protocol. Supplementary data included the patients’ gender, age at time of treatment, and postoperative clinical exam. CT images were measured using identical protocols. The current “gold standard” of autogenous grafting
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FIGURE 3. Human recombinant bone morphogenetic protein-2 with collagen sponge in maxillary defect. FIGURE 1. Right cleft premaxillary ridge and patent oronasal fistula. Herford et al. BMP-Induced Repair of Premaxillary Cleft. J Oral Maxillofac Surg 2007.
was then compared with rhBMP-2 repair of the premaxillary cleft from both our study (n ⫽ 2) as well as a review of volume measurement data taken from the literature (Figs 1-7). The area of the grafted premaxillary defect studied was determined by the medial and distal cortical plates and the estimated ideal form of the alveolar ridge needed to provide sufficient bony support for eruption of the canine or orthodontic assessment of the central and lateral incisors. On the nasal aspect, the defect was calculated by measuring how much bony fill was needed to mirror the contralateral nonclefted piriform rim. CT evaluation of bone formation after grafting of premaxillary clefts was found to be accurate using the method described by Honma et al.1 The volume of the alveolar defect and grafted bone is calculated from the contiguous 1 mm slice sections. The margins of the maxillary segments at the grafting site
Herford et al. BMP-Induced Repair of Premaxillary Cleft. J Oral Maxillofac Surg 2007.
are discernible on the CT scan 4 months postoperatively. The volume of the cleft and bony bridge was then calculated from the area in the 1 mm slices using the optimal anticipated vertical dimensions of the cleft. Exact measurements were made directly on the radiographic studies utilizing maxillofacial CT images with axial 1 mm slices without contrast. The maxillary defect and bony bridge were then calculated using the “measure irregular area tool” on computer-assisted software (IMPAX; Afga-Gavaert, Mortsel, Belgium) which is accurate to 0.01 mm2. All measurements and clinical exams were done by 1 examiner in a blinded method. To assess the accuracy of this method, CT scans of a barium sulfate and resin block were taken 10 times in different positions. The volume was then calculated from each CT scan and compared with water displacement. Statistical analysis was formed using the paired t test and regression analysis. The source for rhBMP-2 was 4.2 mg of Infuse Bone Graft (Medtronic, Sofamor Danek, Memphis, TN) mixed with 4 cc sterile water and a 2.5 ⫻ 5 cm sterile
FIGURE 2. Creation of labial and palatal pockets with closure of nasal floor.
FIGURE 4. Closure of palatal and labial flaps.
Herford et al. BMP-Induced Repair of Premaxillary Cleft. J Oral Maxillofac Surg 2007.
Herford et al. BMP-Induced Repair of Premaxillary Cleft. J Oral Maxillofac Surg 2007.
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FIGURE 5. Six months postoperative healing. Herford et al. BMP-Induced Repair of Premaxillary Cleft. J Oral Maxillofac Surg 2007.
absorbable collagen sponge. Type I bovine collagen sponges were chosen for the carrier because of their favorable biodegradable properties and their ability to create and maintain space between the labial and palatal flaps. These collagen sponges also show no cross reactivity with rhBMP-2. Concomitant medications were also used during the perioperative period which included preoperative and postoperative antibiotics. All patients received either intravenous cefazolin or clindamycin on call to the operating room followed by a 7-day course of either oral cephalexin or clindamycin postoperatively.
Results The volume of the resin block obtained by volume displacement (direct measurement) was 4.11 cm3. The mean value ⫾ 1 SD calculated from the CT scans was 4.04 ⫾ 0.07 cm3, with a range of 3.76 to 4.21 cm3. Thus, the method was found to be accurate for
FIGURE 7. Demonstration of maxillary bony bridge measurement at 4 months. Herford et al. BMP-Induced Repair of Premaxillary Cleft. J Oral Maxillofac Surg 2007.
volume calculation of maxillary defect as well as alveolar bone bridging. The preoperative volume of the maxillary cleft ranged from 5.63 cm3 to 21.12 cm3 (Table 1). The mean preoperative cleft volume for patients receiving anterior iliac crest bone graft to the maxilla was 17.86 cm3, while it was 10.55 cm3 for those repaired with rhBMP-2 (Table 2). At 4 months after surgery, the postoperative volume of the bone bridging ranged from 2.96 cm3 to 14.63 cm3 with a mean of 7.57 cm3 in the rhBMP-2-repaired patients. For the same postoperative period, a range of 12.39 cm3 to 15.07 cm3 with a mean of 13.73 cm3 in bone bridging was seen in autogenous graft patients. The preoperative and postoperative volume ratio ranged from 24.1% to 90.6% with a mean of 71.7% in rhBMP-2-repaired patients. A preoperative and postoperative volume ratio range of 71.3% to 84.9% with a mean of 78.1% was calculated in the patients grafted with anterior iliac crest bone graft. No evidence of root resorption was seen with rhBMP-2 or autogenous bone-grafted patients. STATISTICAL ANALYSIS
The intraexaminer reliability of the measurements was determined by comparing triple assessments taken at least 2 weeks apart using 2-way random effects ANOVA and expressed as the intraclass correlation coefficient. Means and standard deviations were calculated for each parameter. Presurgical and postsurgical data were analyzed using t test and regression analysis. Statistical significance is denoted when P is less than .05.
FIGURE 6. Demonstration of maxillary defect measurement. Herford et al. BMP-Induced Repair of Premaxillary Cleft. J Oral Maxillofac Surg 2007.
Discussion Many techniques have been advocated by authors in the past for repair of the premaxillary cleft.2-15
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Table 1. VOLUME OF THE ALVEOLAR CLEFTS AND BONE BRIDGING
Gender
Diagnosis
Graft Type
Age at Surgery (yr)
M M M M M F M M M M F F
Left PMC Left PMC Left PMC Right PMC Left PMC Right PMC Left PMC Right PMC Left PMC Left PMC Right PMC Left PMC
AICBG AICBG rhBMP-2 rhBMP-2 rhBMP-2 rhBMP-2 rhBMP-2 rhBMP-2 rhBMP-2 rhBMP-2 rhBMP-2 rhBMP-2
9 11 8 7 8 9 7 8 10 8 7 8
Preoperative Volume of Alveolar Cleft (cm3)
4 Months Postoperative Volume of Bone Bridging (cm3)
Bone Fill in the Cleft (%)
21.12 14.60 14.17 16.15 7.89 12.30 16.15 7.89 5.63 13.65 13.32 12.01
15.07 12.39 3.34 14.63 6.77 2.96 14.63 6.77 2.82 10.08 7.49 6.23
71.3 84.9 24.3 90.6 85.8 24.1 90.6 85.8 50.4 73.8 56.23 51.9
Abbreviations: AICBG, anterior iliac crest bone graft; PMC, premaxillary cleft; F, female; M, male; rhBMP-2, recombinant human bone morphogenetic protein-2. Herford et al. BMP-Induced Repair of Premaxillary Cleft. J Oral Maxillofac Surg 2007.
However, the general consensus has been that autogenous bone grafting during the mixed dentition stage (ages 5-12) offers the best results. Advantages of the grafts include achieving stability of the arch and preventing collapse of the alveolar segments. This provides improved orthodontic stability. Grafting preserves the health of the dentition. Grafting provides room for the canine and lateral incisors to erupt into the arch into stable alveolar bone and maintains bony support of teeth adjacent to the cleft. Grafting restores continuity not only of the alveolus, but also of the maxilla at the piriform rim. This supports the ala and provides improved stability and support for the nose. This has a direct esthetic benefit and has been shown to be of long-term benefit when subsequent rhinoplasty procedures are performed. Palatal and nasolabial fistulas are often present even following posterior palatoplasty or velopharyngeal flaps. Grafting of the alveolar defect provides an opportunity for the surgeon to address the residual oronasal fistula. This has potential benefit for both hygiene and speech. Many cleft patients present with chronic upper respiratory and sinus disease, which may be related to reflux into the nasal cavity and sinus. Residual fistula, whether labial or palatal, can
have an effect on speech articulation and nasality and closure of the fistula and grafting the cleft defect can improve nasal emission and speech. Postoperative bone formation in alveolar clefts has been evaluated by dental, occlusal, and panoramic radiographs. With this 2-dimensional radiography, the marginal bone level was measured in association with adjacent teeth as criterion for success or failure of the procedure. According to Kochi et al,16 successful bone formation was achieved in 70.8% of clefts when grafted bone height exceeded the length of the central incisor root. Although bone grafting and 2-dimensional changes can be evaluated by conventional radiographs to some degree, these images do not assess well the changes in volume, morphology, and bony architecture. More recently, CT has been used to examine volume of alveolar cleft grafts status post anterior iliac crest bone grafting.1,17-21 Tai et al demonstrated that successful secondary bone grafts showed bony bridging with a volume of 0.9 to 3.6 cm3, with a mean volume of 2.10 cm3.19 Honma et al found the mean cleft volume of 15 patients to be 1.1 cm3 with a mean bony bridge of 1.2 cm3 at 3 months postoperatively.1 Both studies concluded that this bony bridge was
Table 2. MEAN OF VALUES
Graft Type
Age at Surgery (yr)
Preoperative Volume of Alveolar Cleft (cm3)
4 Months Postoperative Volume of Bone Bridging (cm3)
Bone Fill in the Cleft (%)
AICBG rhBMP-2
10.0 8.0
17.86 10.55
13.73 7.57
78.1 71.7
Abbreviations: AICBG, anterior iliac crest bone graft; rhBMP-2, recombinant human bone morphogenetic protein-2. Herford et al. BMP-Induced Repair of Premaxillary Cleft. J Oral Maxillofac Surg 2007.
2140 sufficient to support the eruption of an unerupted canine tooth. In our study, the 4-month preoperative and postoperative volume ratio of bone bridging is similar with anterior iliac crest bone graft versus repair with rhBMP-2 being 78.1% and 71.7%, respectively. These results are slightly less than those seen in Homna et al,1 in which a 115% preoperative and postoperative volume ratio was seen 3 months after unilateral cleft grafts. This could be secondary to Homna et al and Tai et al16 only measuring bone bridging to 1 mm past the apex of the central incisor and not accounting for restoration of the piriform rim. However, our results still meet the criteria set forth by Tai et al19 for a successful graft which include: 1) grafting must achieve stability of the arch and prevent collapse of the alveolar segments, 2) grafting must preserve the health of the dentition and maintain bony support of teeth adjacent to the cleft, 3) grafting must restore continuity not only of the alveolus but also the anterior hard palate and the maxilla at the piriform rim, 4) grafting must support the soft tissue closure of the oronasal fistula, and 5) grafting must have adequate volume of bone matrix for erupting teeth in the line of the cleft, and for orthodontic movement of the involved teeth into appropriate “nontorqued” position in the dental arch. No difference was seen clinically with the patients’ healing process except that the rhBMP-2-repaired patients tended to have slightly more postoperative swelling which resolved over 1 week. This increase in swelling can be attributed to the properties of rhBMP-2 being an inflammatory cytokine which induces mesenchymal stem cells to differentiate into osteoblasts. It must be noted that no increased pain was observed. PMCB grafting is considered to be the “gold standard” for osseous premaxillary cleft repair. The most common site for the autogenous graft is the iliac crest which has the advantage of a high volume of pluripotent stem cells. However, autogenous bone grafting does involve a second surgical site to obtain the graft which has disadvantages including possible gait disturbances, neurosensory disturbances, and postoperative pain.21-24 Additionally a secondary surgical site presents the possibility of infection and postoperative hemorrhage. The inadvertent surgical disruption of the cartilaginous cap overlying the crest theoretically could lead to growth disturbance. The plotting of the operative and postoperative percent of bone volumes in the cleftal area presented 2 data points that were obvious outliers. These were of the order of a 24% volume change. This could possibly be due to the patients being “non-responders” to the cytokine rhBMP-2. However the concept of “non-responder” to this particular cytokine is not given much support in the literature. It is our feeling that the lesser volume percent resulting
BMP-INDUCED REPAIR OF PREMAXILLARY CLEFT
from the surgery is a technique phenomenon, ie, possible breakdown of the nasal soft tissue floor closure which is the most common postoperative complication from bone grafting and other types of procedures to regenerate bone in cleftal defects. This failure is due to the dependent drainage from the nose into the critical cleft area. In the case of bone grafts, the result may be fibrous tissue and scar formation rather than bony matrix. In the case of cytokine induction, the proper environment is not established for the rhBMP-2 to act appropriately on the critical mass of stem cells in the surgical defect. The time of evaluation was only 4 months and evidence of progressive calcification with further bone formation is seen over time. Orthodontic/orthopedic movement further enhances bone formation. Bone morphogenetic protein (BMP) is a growth factor belonging to the growth factor-B superfamily (TGF-B). Multiple BMPs have been identified. Those of interest to oral and maxillofacial surgery include BMP-2, ⫺4, and ⫺7. These have the ability to induce mesenchymal cells triggering their differentiation into osteoblasts. Recombinant technology has now made purified BMP readily available as a commercial product. BMP-2 is particularly efficacious in animal models and routinely induces bone repair when used with or even without an autogenous bone carrier graft. While anterior iliac PMCB grafting for repair of the premaxillary osseous cleft remains the “gold standard,” rhBMP-2 repair does offer significant advantages to the patient. These advantages may include shorter hospital stay, avoidance of gait and sensory disturbances, as well as decreased sites for scar formation and possible infection. Also, surgical time is reduced because the surgeon does not have to harvest autogenous bone from a secondary site. Continued long-term follow-up and a study with an increased sample size will determine the usefulness of this procedure. This 12-patient study suggests that premaxillary osseous clefts can have complete bony repair induced by rhBMP-2. This procedure offers an effective alternative to conventional (PMCB) grafting.
References 1. Honma K, Kobayashi T, Nakajima T: Computed tomographic evaluation of bone formation after secondary bone grafting of alveolar clefts. J Oral Maxillofac Surg 57:1209, 1999 2. Boyne PJ: Bone grafting in the osseous reconstruction of alveolar and palatal clefts. Oral Maxillofac Clin North Am 3:589, 1991 3. Bergland O, Semb G, Abyholm RD: Elimination of the residual alveolar cleft by secondary bone grafting and subsequent orthodontic treatment. Cleft Palate J 23:175, 1986 4. Horswell BB, Henderson JM: Secondary osteoplasty of the alveolar cleft defect. J Oral Maxillofac Surg 61:1082, 2003 5. Vig KWL: Alveolar bone grafts: The surgical/orthodontic management of the cleft maxilla. Ann Acad Med Singapore 28:721, 1999
HERFORD ET AL 6. Enemark H, Sindet-Pedersen S, Bundgaard M: Long-term results after secondary bone grafting of alveolar clefts. J Oral Maxillofac Surg 45:913, 1987 7. Kortebein MJ, Nelson CL, Sadove MA: Retrospective analysis of 135 secondary alveolar cleft grafts using iliac or calvarial bone. J Oral Maxillofac Surg 49:493, 1991 8. Sadove MA, Nelson CL, Epply BL, et al: An evaluation of calvearial and iliac donor sites in alveolar cleft grafting. Cleft Palate Craniofac J 27:225, 1990 9. Maxson BB, Baxter SD, Vig KW, et al: Allogeneic bone for secondary alveolar cleft osteoplasty. J Oral Maxillofac Surg 48:933, 1990 10. Schendel SA: Secondary cleft surgery. Selected readings. Oral Maxillofac Surg 3:1, 1994 11. Shafer DM: Secondary bone grafting for unilateral alveolar clefts: A review of surgical techniques. Atlas Oral Maxillofac Surg Clin North Am 3:29, 1995 12. Boyne PJ, Sands NR: Secondary bone grafting of residual alveolar and palatal clefts. J Oral Maxillofac Surg 30:87, 1972 13. Lino M, Kochi S, Matsui K: Secondary bone grafting of alveolar clefts using autogenous particulate cancellous bone and marrow harvested from illiac bone. J Jpn Cleft Palate Assoc 19:22, 1994 14. Borstlap WA, Heidbuchel KLWM: Early secondary bone grafting of alveolar cleft defects. J Craniomaxillofac Surg 18:201, 1990
2141 15. Long RE, Spangler BE, Yow M: Cleft width and secondary alveolar bone success. Cleft Palate Craniofac J 32:420, 1995 16. Kochi S, Toufukuji N, Matsui K: Bone graft in alveolar cleft with autogenous particulate cancellous bone: Evaluation of interdental bone height. J Oral Maxillofac Surg 39:735, 1993 17. Rosenstein SW, Long RE, Dado DV: Comparison of 2-D calculations from periapical and occlusal radiographs versus 3-D calculations from CAT scans in determining bone support cleft adjacent teeth following early alveolar bone grafts. Cleft Palate Craniofac J 34:199, 1997 18. van der Meij AJW, Baart JA, Prahl-Andersen B: Computed tomography in evaluation of early secondary bone grafting. Int J Oral Maxillofac Surg 23:132, 1994 19. Tai CE, Sutherland IS, McFadden L: Prospective analysis of secondary alveolar bone grafting using computed tomography. J Oral Maxillofac Surg 58:1241, 2000 20. Boyne PJ, Christiansen EL, Thompson JR: Advanced imaging of osseous maxillary clefts. Radiol Clin North Am 31:195, 1993 21. Crockford DA, Converse JM: The ilium as a source of bone grafts in children. Plast Reconstr Surg 50:270, 1972 22. Larsen PE: Sources of autogenous bone grafts in pediatric patients. Oral Maxillofac Clin North Am 6:137, 1994 23. Rudman RA: Prospective evaluation of morbidity associated with iliac crest harvest for alveolar cleft grafting. J Oral Maxillofac Surg 55:219, 1997 24. Wolfe SA, Kawamoto HK: Taking the iliac bone graft. J Bone Joint Surg 60:411, 1978
Bone Morphogenetic Protein-Induced Repair of the Premaxillary Cleft Alan S. Herford, DDS, MD,* Philip J. Boyne, DMD, MS, DSc(hon),† Rick Rawson, DDS, MS,‡ and Roland P. Williams, DDS§ Purpose: The purpose of this study is to evaluate the bony regeneration of premaxillary clefts in
humans using recombinant human bone morphogenetic protein type 2 in a collagen sponge carrier. Patients and Methods: Twelve patients with unilateral clefted premaxillas were evaluated preoperatively and 4 months postoperatively. Ten patients were repaired with recombinant human bone morphogenetic protein type 2 while 2 others were grafted with anterior iliac crest particulate marrow cancellous bone. Computed tomographic studies were used to evaluate preoperative alveolar cleft volumes, postoperative bone bridge volumes, and preoperative and postoperative volume ratios. Results: A preoperative and postoperative volume ratio for patients repaired with recombinant human bone morphogenetic protein type 2 ranged from 24.1% to 90.6% with a mean of 71.7%. Patients who were grafted with particulate marrow cancellous bone had similar preoperative and postoperative volume ratios ranging from 71.3% to 84.9% with a mean of 78.1%. Conclusions: Clefts of the anterior maxilla can have complete osseous regeneration induced by recombinant human bone morphogenetic protein type 2 as an effective alternative to conventional anterior iliac particulate marrow cancellous bone grafts. © 2007 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 65:2136-2141, 2007 The purpose of this study was to evaluate the bony regeneration of the premaxillary cleft in human subjects using recombinant human bone morphogenetic protein type 2 (rhBMP-2) in an absorbable collagen sponge carrier as an alternative method to autogenous bone grafting. Preoperative and postoperative computed tomograms were used to evaluate the repair progress of the cleft. These images were compared with cases in which autogenous grafting of the premaxillary cleft was done with iliac crest particulate Received from the Department of Oral and Maxillofacial Surgery, Loma Linda University Medical Center, Loma Linda, CA. *Chairman. †Professor Emeritus. ‡Former Chief Resident. §Research Intern. Address correspondence and reprint requests to Dr Herford: Department of Oral and Maxillofacial Surgery, Loma Linda University Medical Center, 11092 Anderson Street, Loma Linda, CA 92350; e-mail: [email protected] © 2007 American Association of Oral and Maxillofacial Surgeons
0278-2391/07/6511-0002$32.00/0 doi:10.1016/j.joms.2007.06.670
marrow cancellous bone (PMCB), which has been long considered to be the “gold standard.” A great benefit to patients in the use of rhBMP-2 is the avoidance of a second surgical site needed for the harvesting of PMCB autogenous bone. This translates into a shorter hospital stay, avoidance of possible complications such as gait and sensory disturbance, and a decreased number of sites for scar formation and possible infection.
Patients and Methods A chart review was undertaken of 10 patients who underwent premaxillary cleft grafting procedures with rhBMP-2 and repair of oral-nasal fistulas by the same surgeon (A.H.). In addition, 2 patients received traditional autogenous iliac crest bone grafted cleft repair. Patients had received presurgical and postsurgical computed tomography (CT) for bony fill measurement using a special imaging protocol. Supplementary data included the patients’ gender, age at time of treatment, and postoperative clinical exam. CT images were measured using identical protocols. The current “gold standard” of autogenous grafting
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FIGURE 3. Human recombinant bone morphogenetic protein-2 with collagen sponge in maxillary defect. FIGURE 1. Right cleft premaxillary ridge and patent oronasal fistula. Herford et al. BMP-Induced Repair of Premaxillary Cleft. J Oral Maxillofac Surg 2007.
was then compared with rhBMP-2 repair of the premaxillary cleft from both our study (n ⫽ 2) as well as a review of volume measurement data taken from the literature (Figs 1-7). The area of the grafted premaxillary defect studied was determined by the medial and distal cortical plates and the estimated ideal form of the alveolar ridge needed to provide sufficient bony support for eruption of the canine or orthodontic assessment of the central and lateral incisors. On the nasal aspect, the defect was calculated by measuring how much bony fill was needed to mirror the contralateral nonclefted piriform rim. CT evaluation of bone formation after grafting of premaxillary clefts was found to be accurate using the method described by Honma et al.1 The volume of the alveolar defect and grafted bone is calculated from the contiguous 1 mm slice sections. The margins of the maxillary segments at the grafting site
Herford et al. BMP-Induced Repair of Premaxillary Cleft. J Oral Maxillofac Surg 2007.
are discernible on the CT scan 4 months postoperatively. The volume of the cleft and bony bridge was then calculated from the area in the 1 mm slices using the optimal anticipated vertical dimensions of the cleft. Exact measurements were made directly on the radiographic studies utilizing maxillofacial CT images with axial 1 mm slices without contrast. The maxillary defect and bony bridge were then calculated using the “measure irregular area tool” on computer-assisted software (IMPAX; Afga-Gavaert, Mortsel, Belgium) which is accurate to 0.01 mm2. All measurements and clinical exams were done by 1 examiner in a blinded method. To assess the accuracy of this method, CT scans of a barium sulfate and resin block were taken 10 times in different positions. The volume was then calculated from each CT scan and compared with water displacement. Statistical analysis was formed using the paired t test and regression analysis. The source for rhBMP-2 was 4.2 mg of Infuse Bone Graft (Medtronic, Sofamor Danek, Memphis, TN) mixed with 4 cc sterile water and a 2.5 ⫻ 5 cm sterile
FIGURE 2. Creation of labial and palatal pockets with closure of nasal floor.
FIGURE 4. Closure of palatal and labial flaps.
Herford et al. BMP-Induced Repair of Premaxillary Cleft. J Oral Maxillofac Surg 2007.
Herford et al. BMP-Induced Repair of Premaxillary Cleft. J Oral Maxillofac Surg 2007.
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FIGURE 5. Six months postoperative healing. Herford et al. BMP-Induced Repair of Premaxillary Cleft. J Oral Maxillofac Surg 2007.
absorbable collagen sponge. Type I bovine collagen sponges were chosen for the carrier because of their favorable biodegradable properties and their ability to create and maintain space between the labial and palatal flaps. These collagen sponges also show no cross reactivity with rhBMP-2. Concomitant medications were also used during the perioperative period which included preoperative and postoperative antibiotics. All patients received either intravenous cefazolin or clindamycin on call to the operating room followed by a 7-day course of either oral cephalexin or clindamycin postoperatively.
Results The volume of the resin block obtained by volume displacement (direct measurement) was 4.11 cm3. The mean value ⫾ 1 SD calculated from the CT scans was 4.04 ⫾ 0.07 cm3, with a range of 3.76 to 4.21 cm3. Thus, the method was found to be accurate for
FIGURE 7. Demonstration of maxillary bony bridge measurement at 4 months. Herford et al. BMP-Induced Repair of Premaxillary Cleft. J Oral Maxillofac Surg 2007.
volume calculation of maxillary defect as well as alveolar bone bridging. The preoperative volume of the maxillary cleft ranged from 5.63 cm3 to 21.12 cm3 (Table 1). The mean preoperative cleft volume for patients receiving anterior iliac crest bone graft to the maxilla was 17.86 cm3, while it was 10.55 cm3 for those repaired with rhBMP-2 (Table 2). At 4 months after surgery, the postoperative volume of the bone bridging ranged from 2.96 cm3 to 14.63 cm3 with a mean of 7.57 cm3 in the rhBMP-2-repaired patients. For the same postoperative period, a range of 12.39 cm3 to 15.07 cm3 with a mean of 13.73 cm3 in bone bridging was seen in autogenous graft patients. The preoperative and postoperative volume ratio ranged from 24.1% to 90.6% with a mean of 71.7% in rhBMP-2-repaired patients. A preoperative and postoperative volume ratio range of 71.3% to 84.9% with a mean of 78.1% was calculated in the patients grafted with anterior iliac crest bone graft. No evidence of root resorption was seen with rhBMP-2 or autogenous bone-grafted patients. STATISTICAL ANALYSIS
The intraexaminer reliability of the measurements was determined by comparing triple assessments taken at least 2 weeks apart using 2-way random effects ANOVA and expressed as the intraclass correlation coefficient. Means and standard deviations were calculated for each parameter. Presurgical and postsurgical data were analyzed using t test and regression analysis. Statistical significance is denoted when P is less than .05.
FIGURE 6. Demonstration of maxillary defect measurement. Herford et al. BMP-Induced Repair of Premaxillary Cleft. J Oral Maxillofac Surg 2007.
Discussion Many techniques have been advocated by authors in the past for repair of the premaxillary cleft.2-15
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Table 1. VOLUME OF THE ALVEOLAR CLEFTS AND BONE BRIDGING
Gender
Diagnosis
Graft Type
Age at Surgery (yr)
M M M M M F M M M M F F
Left PMC Left PMC Left PMC Right PMC Left PMC Right PMC Left PMC Right PMC Left PMC Left PMC Right PMC Left PMC
AICBG AICBG rhBMP-2 rhBMP-2 rhBMP-2 rhBMP-2 rhBMP-2 rhBMP-2 rhBMP-2 rhBMP-2 rhBMP-2 rhBMP-2
9 11 8 7 8 9 7 8 10 8 7 8
Preoperative Volume of Alveolar Cleft (cm3)
4 Months Postoperative Volume of Bone Bridging (cm3)
Bone Fill in the Cleft (%)
21.12 14.60 14.17 16.15 7.89 12.30 16.15 7.89 5.63 13.65 13.32 12.01
15.07 12.39 3.34 14.63 6.77 2.96 14.63 6.77 2.82 10.08 7.49 6.23
71.3 84.9 24.3 90.6 85.8 24.1 90.6 85.8 50.4 73.8 56.23 51.9
Abbreviations: AICBG, anterior iliac crest bone graft; PMC, premaxillary cleft; F, female; M, male; rhBMP-2, recombinant human bone morphogenetic protein-2. Herford et al. BMP-Induced Repair of Premaxillary Cleft. J Oral Maxillofac Surg 2007.
However, the general consensus has been that autogenous bone grafting during the mixed dentition stage (ages 5-12) offers the best results. Advantages of the grafts include achieving stability of the arch and preventing collapse of the alveolar segments. This provides improved orthodontic stability. Grafting preserves the health of the dentition. Grafting provides room for the canine and lateral incisors to erupt into the arch into stable alveolar bone and maintains bony support of teeth adjacent to the cleft. Grafting restores continuity not only of the alveolus, but also of the maxilla at the piriform rim. This supports the ala and provides improved stability and support for the nose. This has a direct esthetic benefit and has been shown to be of long-term benefit when subsequent rhinoplasty procedures are performed. Palatal and nasolabial fistulas are often present even following posterior palatoplasty or velopharyngeal flaps. Grafting of the alveolar defect provides an opportunity for the surgeon to address the residual oronasal fistula. This has potential benefit for both hygiene and speech. Many cleft patients present with chronic upper respiratory and sinus disease, which may be related to reflux into the nasal cavity and sinus. Residual fistula, whether labial or palatal, can
have an effect on speech articulation and nasality and closure of the fistula and grafting the cleft defect can improve nasal emission and speech. Postoperative bone formation in alveolar clefts has been evaluated by dental, occlusal, and panoramic radiographs. With this 2-dimensional radiography, the marginal bone level was measured in association with adjacent teeth as criterion for success or failure of the procedure. According to Kochi et al,16 successful bone formation was achieved in 70.8% of clefts when grafted bone height exceeded the length of the central incisor root. Although bone grafting and 2-dimensional changes can be evaluated by conventional radiographs to some degree, these images do not assess well the changes in volume, morphology, and bony architecture. More recently, CT has been used to examine volume of alveolar cleft grafts status post anterior iliac crest bone grafting.1,17-21 Tai et al demonstrated that successful secondary bone grafts showed bony bridging with a volume of 0.9 to 3.6 cm3, with a mean volume of 2.10 cm3.19 Honma et al found the mean cleft volume of 15 patients to be 1.1 cm3 with a mean bony bridge of 1.2 cm3 at 3 months postoperatively.1 Both studies concluded that this bony bridge was
Table 2. MEAN OF VALUES
Graft Type
Age at Surgery (yr)
Preoperative Volume of Alveolar Cleft (cm3)
4 Months Postoperative Volume of Bone Bridging (cm3)
Bone Fill in the Cleft (%)
AICBG rhBMP-2
10.0 8.0
17.86 10.55
13.73 7.57
78.1 71.7
Abbreviations: AICBG, anterior iliac crest bone graft; rhBMP-2, recombinant human bone morphogenetic protein-2. Herford et al. BMP-Induced Repair of Premaxillary Cleft. J Oral Maxillofac Surg 2007.
2140 sufficient to support the eruption of an unerupted canine tooth. In our study, the 4-month preoperative and postoperative volume ratio of bone bridging is similar with anterior iliac crest bone graft versus repair with rhBMP-2 being 78.1% and 71.7%, respectively. These results are slightly less than those seen in Homna et al,1 in which a 115% preoperative and postoperative volume ratio was seen 3 months after unilateral cleft grafts. This could be secondary to Homna et al and Tai et al16 only measuring bone bridging to 1 mm past the apex of the central incisor and not accounting for restoration of the piriform rim. However, our results still meet the criteria set forth by Tai et al19 for a successful graft which include: 1) grafting must achieve stability of the arch and prevent collapse of the alveolar segments, 2) grafting must preserve the health of the dentition and maintain bony support of teeth adjacent to the cleft, 3) grafting must restore continuity not only of the alveolus but also the anterior hard palate and the maxilla at the piriform rim, 4) grafting must support the soft tissue closure of the oronasal fistula, and 5) grafting must have adequate volume of bone matrix for erupting teeth in the line of the cleft, and for orthodontic movement of the involved teeth into appropriate “nontorqued” position in the dental arch. No difference was seen clinically with the patients’ healing process except that the rhBMP-2-repaired patients tended to have slightly more postoperative swelling which resolved over 1 week. This increase in swelling can be attributed to the properties of rhBMP-2 being an inflammatory cytokine which induces mesenchymal stem cells to differentiate into osteoblasts. It must be noted that no increased pain was observed. PMCB grafting is considered to be the “gold standard” for osseous premaxillary cleft repair. The most common site for the autogenous graft is the iliac crest which has the advantage of a high volume of pluripotent stem cells. However, autogenous bone grafting does involve a second surgical site to obtain the graft which has disadvantages including possible gait disturbances, neurosensory disturbances, and postoperative pain.21-24 Additionally a secondary surgical site presents the possibility of infection and postoperative hemorrhage. The inadvertent surgical disruption of the cartilaginous cap overlying the crest theoretically could lead to growth disturbance. The plotting of the operative and postoperative percent of bone volumes in the cleftal area presented 2 data points that were obvious outliers. These were of the order of a 24% volume change. This could possibly be due to the patients being “non-responders” to the cytokine rhBMP-2. However the concept of “non-responder” to this particular cytokine is not given much support in the literature. It is our feeling that the lesser volume percent resulting
BMP-INDUCED REPAIR OF PREMAXILLARY CLEFT
from the surgery is a technique phenomenon, ie, possible breakdown of the nasal soft tissue floor closure which is the most common postoperative complication from bone grafting and other types of procedures to regenerate bone in cleftal defects. This failure is due to the dependent drainage from the nose into the critical cleft area. In the case of bone grafts, the result may be fibrous tissue and scar formation rather than bony matrix. In the case of cytokine induction, the proper environment is not established for the rhBMP-2 to act appropriately on the critical mass of stem cells in the surgical defect. The time of evaluation was only 4 months and evidence of progressive calcification with further bone formation is seen over time. Orthodontic/orthopedic movement further enhances bone formation. Bone morphogenetic protein (BMP) is a growth factor belonging to the growth factor-B superfamily (TGF-B). Multiple BMPs have been identified. Those of interest to oral and maxillofacial surgery include BMP-2, ⫺4, and ⫺7. These have the ability to induce mesenchymal cells triggering their differentiation into osteoblasts. Recombinant technology has now made purified BMP readily available as a commercial product. BMP-2 is particularly efficacious in animal models and routinely induces bone repair when used with or even without an autogenous bone carrier graft. While anterior iliac PMCB grafting for repair of the premaxillary osseous cleft remains the “gold standard,” rhBMP-2 repair does offer significant advantages to the patient. These advantages may include shorter hospital stay, avoidance of gait and sensory disturbances, as well as decreased sites for scar formation and possible infection. Also, surgical time is reduced because the surgeon does not have to harvest autogenous bone from a secondary site. Continued long-term follow-up and a study with an increased sample size will determine the usefulness of this procedure. This 12-patient study suggests that premaxillary osseous clefts can have complete bony repair induced by rhBMP-2. This procedure offers an effective alternative to conventional (PMCB) grafting.
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HERFORD ET AL 6. Enemark H, Sindet-Pedersen S, Bundgaard M: Long-term results after secondary bone grafting of alveolar clefts. J Oral Maxillofac Surg 45:913, 1987 7. Kortebein MJ, Nelson CL, Sadove MA: Retrospective analysis of 135 secondary alveolar cleft grafts using iliac or calvarial bone. J Oral Maxillofac Surg 49:493, 1991 8. Sadove MA, Nelson CL, Epply BL, et al: An evaluation of calvearial and iliac donor sites in alveolar cleft grafting. Cleft Palate Craniofac J 27:225, 1990 9. Maxson BB, Baxter SD, Vig KW, et al: Allogeneic bone for secondary alveolar cleft osteoplasty. J Oral Maxillofac Surg 48:933, 1990 10. Schendel SA: Secondary cleft surgery. Selected readings. Oral Maxillofac Surg 3:1, 1994 11. Shafer DM: Secondary bone grafting for unilateral alveolar clefts: A review of surgical techniques. Atlas Oral Maxillofac Surg Clin North Am 3:29, 1995 12. Boyne PJ, Sands NR: Secondary bone grafting of residual alveolar and palatal clefts. J Oral Maxillofac Surg 30:87, 1972 13. Lino M, Kochi S, Matsui K: Secondary bone grafting of alveolar clefts using autogenous particulate cancellous bone and marrow harvested from illiac bone. J Jpn Cleft Palate Assoc 19:22, 1994 14. Borstlap WA, Heidbuchel KLWM: Early secondary bone grafting of alveolar cleft defects. J Craniomaxillofac Surg 18:201, 1990
2141 15. Long RE, Spangler BE, Yow M: Cleft width and secondary alveolar bone success. Cleft Palate Craniofac J 32:420, 1995 16. Kochi S, Toufukuji N, Matsui K: Bone graft in alveolar cleft with autogenous particulate cancellous bone: Evaluation of interdental bone height. J Oral Maxillofac Surg 39:735, 1993 17. Rosenstein SW, Long RE, Dado DV: Comparison of 2-D calculations from periapical and occlusal radiographs versus 3-D calculations from CAT scans in determining bone support cleft adjacent teeth following early alveolar bone grafts. Cleft Palate Craniofac J 34:199, 1997 18. van der Meij AJW, Baart JA, Prahl-Andersen B: Computed tomography in evaluation of early secondary bone grafting. Int J Oral Maxillofac Surg 23:132, 1994 19. Tai CE, Sutherland IS, McFadden L: Prospective analysis of secondary alveolar bone grafting using computed tomography. J Oral Maxillofac Surg 58:1241, 2000 20. Boyne PJ, Christiansen EL, Thompson JR: Advanced imaging of osseous maxillary clefts. Radiol Clin North Am 31:195, 1993 21. Crockford DA, Converse JM: The ilium as a source of bone grafts in children. Plast Reconstr Surg 50:270, 1972 22. Larsen PE: Sources of autogenous bone grafts in pediatric patients. Oral Maxillofac Clin North Am 6:137, 1994 23. Rudman RA: Prospective evaluation of morbidity associated with iliac crest harvest for alveolar cleft grafting. J Oral Maxillofac Surg 55:219, 1997 24. Wolfe SA, Kawamoto HK: Taking the iliac bone graft. J Bone Joint Surg 60:411, 1978