SCIENTIFIC FOUNDATION
Treatment of Large Calvarial Defects With Bone Transport Osteogenesis: A Preclinical Sheep Model Patrick A. Gerety, MD, Jason D. Wink, MD, MTR, Rami D. Sherif, BA, Nadya Clarke, MD, Hyun-Duck Nah, DMD, PhD, and Jesse A. Taylor, MD Background: Bone transport osteogenesis (BTO), distraction of a free portion of bone across a defect, offers an autologous solution to large cranial defects that may allow treatment without permanent hardware implantation. This study establishes a sheep model to evaluate the feasibility and distraction kinetics of BTO. Methods: Subtotal cranial defects (3.5 3.5 cm) were created in 10 young adult sheep and a transport segment (3.5 2 cm) traversed the defect at varying distraction rates (0, 0.5, 1.0, and 1.5 mm/ day) using semi-buried cranial distractors. After a 6-week consolidation period, sheep were euthanized and the resultant bone was analyzed by CT, histology, and mechanical testing. Results: Gross examination, histology, and 3D CT revealed that control animals had fibrous nonunion whereas distraction animals had ossified defects with fibrous nonunion at the distal docking site. There was one premature consolidation in the 0.5 mm/day group. The volume of bony regenerate in the 0.5, 1.0, and 1.5 mm/day distraction rate groups was statistically indistinct (P = 0.16). The mean flexural moduli (MPa) of non-decalcified samples from the control cranium, transport segment, and bone regenerate were found to be 4.50 ± 4.9, 6.17 ± 2.1, and 4.14 ± 4.8, respectively (P = 0.24). Conclusions: This experiment provides proof of concept for BTO for large calvarial defects in a sheep model. Distraction at a rate of 0.5 mm per day may place individuals at higher risk for premature consolidation, but distraction rates did not have significant effects on regenerate quantity or quality. Future work will include the use of curvilinear distraction devices for 3-dimensional contour. Key Words: Calvarial defect, bone transport osteogenesis, sheep model, critical-sized defect, osteodistraction (J Craniofac Surg 2014;25: 1917–1922)
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arge cranial defects place patients at risk for cerebral injury, acute and chronic neurologic symptoms related to perturbed intracranial pressure (“Syndrome of the Trephined”), and contour irregularities.1–3 Cranioplasty aims to restore contour and mechanical protection. Physical properties of an ideal cranioplasty are biocompatibility, infection resistance, and biomechanical properties similar to bone. If available, such as in the trauma setting, the replacement of a banked cranial bone flap is an option.4 When the native cranial bone flap is unavailable, many have advocated for the use of autologous bone graft despite numerous reports of significant resorption and contour irregularities.5 For most surgeons, alloplastic materials including methylmethacrylate, PEEK, titanium mesh, and hydroxyapatite cement are the next line of treatment for patients failing bone grafting.6–10 Alloplasts have the advantage of no additional donor site, but their use may be complicated by erosion, mechanical failure, migration, and infection necessitating removal.8 Additionally, the use of alloplastic implants in the pediatric population, whose cranium is still growing, may lead to growth alteration or abnormal cranial morphology over time. Distraction osteogenesis, originally conceived and reported by Ilizarov, has been used widely to lengthen long bones and, more recently, the craniofacial skeleton.11,12 In its monofocal form, the technique slowly spreads 2 osteotomized segments of bone apart, causing the deposition of callus between them that, with time, ossifies. Bone transport osteogenesis adapts this concept with distraction of a transport segment (TS) across a defect, a process that has been utilized successfully in the mandible.13,14 The purpose of this study was to establish a sheep model for the repair of large cranial defects with bone transport osteogenesis while assessing the impact of distraction rate on bone formation. Evaluation of the outcome focused on both radiographic and histologic evidence of bone formation, as well as mechanical properties of the resultant bone.
MATERIALS AND METHODS From the Divison of Plastic Surgery, The Perelman School of Medicine at the University of Pennsylvania; Division of Plastic Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Received September 5, 2013. Accepted for publication April 4, 2014. Address correspondence and reprint requests to Dr Jesse A. Taylor, Division of Plastic Surgery, Children’s Hospital of Philadelphia, 9th Floor Colket Translational Research Building, 3501 Civic Center Blvd, Philadelphia, PA 19104; E-mail: [email protected] This work was supported by a generous grant from the Center for Human Appearance at the University of Pennsylvania. All hardware was generously donated by Synthes, CMF. Approved by the Institutional Animal Care and Use Committee (IACUC) at the Children’s Hospital of Philadelphia (Philadelphia, PA) on May 5, 2011. Protocol #2011-3-961. The authors report no conflicts of interest. Copyright © 2014 by Mutaz B. Habal, MD ISSN: 1049-2275 DOI: 10.1097/SCS.0000000000000987
Study Design and Surgical Procedure This study was reviewed and approved by the Institutional Animal Care and Use Committee at the Children’s Hospital of Philadelphia. Ten young adult, male, castrated, Dorset sheep were used for the experiment. These sheep weighed an average of 45 kg. Groups included untreated control and differential distraction rates (0.5, 1.0, and 1.5 mm/day). Sheep were pre-medicated with a fentanyl patch (Janssen Pharmaceuticals Inc., a subsidiary of Johnson & Johnson, New Brunswick, NJ) 12 hours before surgery. Immediately before surgery, they received an 11 to 15 mg/kg dose of intramuscular ketamine (Ketaset CIII, Fort Dodge, IA, USA). The sheep were intubated and maintained under general anesthesia with 2% to 5% isoflurane (IsoFlo; Abbot Animal Health CE, Abbot Park, IL, USA). Each animal also received an intraoperative 2.5 mg/kg dose of flunixin (Banamine; Schering-Plough, a subsidiary of Merck,
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Whitehouse Station, NJ, USA) and additional doses postoperatively as needed. Each animal received 1 g of cefazolin pre-incision. A mid-sagittal, “lazy-S” incision was taken down to the pericranium, and wide subgaleal undermining ensued. A Midas Rex surgical drill (Medtronic, Minneapolis, MN, USA) was used to create a 35 mm 35 mm cranial defect followed by a 20 mm 35 mm transport segment in experimental animals. A pre-cut pattern was utilized to ensure uniformity between animals (Fig. 1). A craniomaxillofacial distractor (40 mm CMF distractor; Synthes, West Chester, PA, USA) was then placed by attaching the heel and foot plates with 3-mm selfdrilling, self-tapping screws. Care was taken to avoid dural injury and maintain broad attachment of the dura to the transport segment. Twolayered closure of the scalp was undertaken, and animals were awoken from general anesthesia (Figs. 2, 3). After completion of distraction and consolidation, sheep were euthanized with a combination of ketamine and Euthasol (Pentobarbital/Phenytoin; Virbac Animal Health, Ft Worth, TX, USA). Death was confirmed with thoracotomy. The sheep were decapitated and the entire head was scanned in a high-resolution CT machine (SOMATOM Definition Flash; Siemens, Munich, Germany) under cranial bone protocol. Histologic and mechanical assessments were done on smaller harvested samples.
Distraction Protocol Distraction proceeded once daily after a 5-day latency period. The non-control animals were divided into 3 groups at different distraction rates—0.5, 1.0, or 1.5 mm per day. When distraction was complete, the animals underwent a 42-day consolidation period. The animals were euthanized at the end of this period.
Cross-Sectional Imaging and Analysis Surface models of calcified bone were created based on CT data using image analysis software (Mimics Materialise NV, Leuven, Belgium) to assess the volume of bone formed in the distracted space behind the lagging edge of the transport segment.
FIGURE 1. Defect design. The defect measures 35 35 mm with a transport segment of 20 35 mm.
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FIGURE 2. Intraoperative photograph demonstrating anterior to posterior distraction with a 40-mm CMF distractor in place. Transport segment (TS) and defect (D) labeled.
Histological Analysis After CT scans were performed, the specimens were removed from the skull to include bone anterior to the source of the transport segment, the defect, transport segment, the docking site, and posterior skull. These smaller specimens were fixed (10% neutral buffered formalin; Sigma-Aldrich, St Louis, MO, USA). Before decalcification, the samples were bisected longitudinally with a surgical saw. Half of the specimen was set aside for mechanical testing, and the other half was decalcified (Decal Solution; Sigma-Aldrich). Decalcified sections were divided sharply into sections that allowed processing and embedding. Hematoxylin/eosin and trichrome staining were performed on representative sections. Photographs of these sections were obtained using a light microscope (Olympus BH2, Center Valley, PA, USA)
FIGURE 3. Postoperative photograph of an experimental sheep with a flexible distractor arm emanating from the scalp.
© 2014 Mutaz B. Habal, MD
Copyright © 2014 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
The Journal of Craniofacial Surgery • Volume 25, Number 5, September 2014
BTO for Large Calvarial Defects
Mechanical Testing Fixed, non-decalcified portions of each sample were taken for mechanical testing. For testing, the specimens were divided with a bone saw into 10 10 mm cubic pieces. Samples were taken from native bone, newly formed bone within the defect, and the transport segment. A 3-point bending test was performed (Instron 5500, Norwood, MA, USA) to assess flexural modulus.
Statistical Analysis Mann-Whitney and Kruskal-Wallis tests were used for statistical comparisons. Significance was determined by P less than 0.05.
RESULTS The sheep in this experiment tolerated defect creation and distractor placement well. The process of activating the distractor did not produce a pain response, and the sheep were able to tolerate the device throughout consolidation. There was no statistically significant difference in the amount of distraction that occurred between experimental groups, though one of the 0.5-mm animals manifested a premature consolidation midway through the activation phase. Three minor wound infections were treated successfully with antibiotics. One major distractor failure occurred during distraction when a distractor was traumatically fractured and could no longer be turned. One animal died suddenly during distraction and was found to have ingested a foreign body. The 2 sheep that were unable to complete the treatment course were excluded from all statistical analyses; thus, 8 animals were included in the analyses, 2 in each group.
Cross-Sectional Imaging Control animals showed minor signs of bone regeneration at the edge of the defects, but otherwise developed fibrous deposition within the defects. All experimental animals demonstrated bone formation across the defect in the wake of the transport segment
FIGURE 5. Representative 3D reconstructions of control (left), 0.5 mm/day (middle), and 1.5 mm/day (right) with new bone formation and transport segment. The 0.5-mm section represents our single experimental animal that underwent premature consolidation, and thus the transport segment is halfway across the defect. The 1.5-mm section, in contrast, demonstrates bony regenerate throughout.
whereas controls were generally devoid of bone. Interestingly, the sagittal suture seemed to reform within the bone regenerate in all experimental samples (Fig. 4). 3D reconstructions demonstrate bone formation across the defect between the transport segment and its origin with consistent nonunion at the docking site (Fig. 5). The average generated bone volume per millimeter of distraction of the 3 distraction rates (0.5, 1.0, and 1.5 mm/day) were 108.71 ± 24.62 mm2, 95.42 ± 20.56 mm2, and 73.40 ± 4.00 mm2, respectively (P = 0.16). Average bone thickness was measured for each experimental group behind the transport segment and was found to be 3.11 ± 0.70 mm, 2.73 ± 0.59 mm, and 2.1 ± 0.11 mm, respectively (P = 0.10). Regardless of distraction rate, all distracted animals grew a greater quantity of bone than controls (92.51 ± 21.53 mm2 vs. 17.36 ± 11.17 mm2, P = 0.046) (Table 1). As this was uni-vector distraction in a slightly cephalad direction, the transport segment typically was located 2 to 3 mm cephalad to the native cranial docking site (Fig. 6). Experimental groups all manifested nonunion at the docking site and progressively poorer union with the side walls as the experiment progressed (Fig. 7). This was seen consistently irrespective of distraction kinetics, and seemed to be a gradual decline in union, not an abrupt stoppage. There was no indication on CT of any pleating of the dura, other signs of dural disruption, or alterations of the major venous sinuses.
Histology A comparison of the gross specimens demonstrated the formation of hard tissue in experimental animals and the formation of fibrous connective tissue in control animals. This was especially
TABLE 1. Quantification of Bone Formation Behind Transport Segment
Sheep 1
FIGURE 4. Representative coronal-section CT scans of control and experimental animals. Unrepaired defect in a control animal (top left); 0.5 mm/day distraction rate (top right); 1.0 mm/day distraction rate (bottom left); 1.5 mm/day distraction rate (bottom right).
Group
Regenerate Volume, mm3
Regenerate Volume/ Distraction Distance, mm2
Average Regenerate Thickness, mm
2 3
Control Control 0.5 mm/d
884.23 331.18 273.89
25.26 9.46 91.30
0.72 0.27 2.61
4 5 6 7 8
0.5 mm/d 1 mm/d 1 mm/d 1.5 mm/d 1.5 mm/d
3,152.99 2,529.11 2,588.22 1,199.84 2,820.50
126.12 109.96 80.88 70.58 76.23
3.60 3.14 2.31 2.01 2.18
© 2014 Mutaz B. Habal, MD
Copyright © 2014 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
Complication Infection Premature consolidation Infection Infection
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FIGURE 6. Sagittal 3D reconstruction displaying angle between sheep calvarium and vector of transport segment. Future work will concentrate on the manufacture of a curvilinear distractor to recreate the contour of the cranial defect.
evident when the samples were bisected for processing (Fig. 8). Experimental animals showed significant quantities of new bone formation within the defect. Osteogenesis appeared to occur in a membranous fashion with no sign of endochondral ossification in our representative samples. Immature bone formed in a thin trabecular pattern with a woven appearance. Osteocytes are present within the bone regenerate throughout. Neovascularization can be seen within the trabeculae. The underlying dura appears intact and not distinct from native dura.
Mechanical Testing Results of the 3-point bending test of the samples demonstrated that in experimental animals newly formed bone within the defect, the transport segment, and the native control cranial bone had flexural moduli of 4.14 ± 4.8 MPa, 6.17 ± 2.1 MPa, and
FIGURE 8. Histological sections. Control animals demonstrate fibrous nonunion (top left, 10; middle left, 40; bottom left, trichrome). Experimental animals demonstrate bony regrowth (top right, 10; middle right, 40; bottom right, trichrome).
4.50 ± 4.9 MPa, respectively. These values were not significantly different (P = 0.24).
DISCUSSION
FIGURE 7. Representative gross pathologic cross-sections demonstrating the fibrous nonunion of a control specimen (top) and the hard bony healing of a bone transport osteogenesis animal (bottom).
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Bone transport osteogenesis (BTO) utilizes the bifocal iteration of distraction osteogenesis by distracting a segment of bone across a defect. BTO has been applied most successfully to the reconstruction of long bone defects and is, in fact, practiced widely.15–19 It has been reported for mandibular segmental defects in case reports and small series in the literature but has not gained widespread popularity for various reasons,20–25 chief among them the popular use of microvascular free tissue transfer of osseous and osteocutaneous flaps with lower treatment times and high success rates.26–28 As free vascularized osseous transfer has gained utility in long bones and the mandible, the application of BTO seems most logical in calvarial reconstruction because of the large surface area that must be reconstructed. There is a limited body of literature in applying BTO to cranial defects consisting of a small number of animal studies,29–32 and one human case report.33 Cho-Lee and colleagues reported the use of BTO for a calvarial defect in 1 patient who had suffered loss of a bone flap and infection and extrusion of 2 alloplastic materials.33 Treatment with BTO was lengthy—9 months—and required multiple stages, but successfully closed nearly all of a very large and geometrically complex (85 50 mm) defect.33 The few supporting studies in small and large animal models are in animals with distinct bone physiology and healing ability that may not allow for translation of the results to humans.13,14,29–32,34–38 No experimentation of distraction kinetics have been performed for BTO in a large, highly phylogenetic animal model which will more closely reproduce human bone physiology. © 2014 Mutaz B. Habal, MD
Copyright © 2014 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
The Journal of Craniofacial Surgery • Volume 25, Number 5, September 2014
In this study, we establish a model for repair of a large calvarial defect in young adult, male, Dorset sheep. Among readily available large animal models, the sheep calvarium is most similar in physical characteristics to the human skull. The dimensions of our experimental defect and transport segment utilize virtually all of the available surface area of the skull, precluding it as a model for defects larger than 55 mm 35 mm. There are a number of advantages to using cranial BTO to repair large cranial defects. The repair is autologous and vascularized, with no required additional donor site. Successful ossification of the defect precludes the need for permanent hardware, which will prove important in patients who have recurrent problems with infection, and in the growing pediatric population. Repairing a cranial defect with vascularized bone would have the potential to grow and heal itself, if fractured. As we have shown, the bony regenerate has similar mechanical properties to native bone which conveys protection to the brain and the absence of stress shielding from surrounding areas of the cranium. These advantages will have to be weighed against the fact that the procedure requires additional cranial osteotomies and a lengthy duration of treatment. Our results did not demonstrate a significant difference in bone formation between sheep in the different distraction rate groups (0.5, 1.0, and 1.5 mm/day) though it did significantly alter length of treatment, an important data point for potential patients. Additionally, our single experimental animal that had premature consolidation was in the 0.5 mm group, leading us to conclude that individuals may be at higher risk for premature consolidation if the rate of activation is less than 1 mm per day; no experimental animals in our study failed to produce bone in the wake of the transport segment. Our data shows that the bony regenerate is slightly thinner than the transport segment which may translate to an alteration in aesthetic contour. Although we report no statistical difference in 3-point bending strength between native calvarium and regenerate, this feasibility study was not adequately powered to definitively conclude whether a difference exists. Given the small difference in bending strength, the number of animals required to adequately power this calculation is 45, a number not feasible due to cost. Cranial defects are often complex geometrically, and it may be difficult to design osteotomies and distraction hardware that allow for defect healing of geographically complex, large defects. There may be a theoretical maximum distance across which a transport segment of a given thickness will produce bone and a theoretical maximum distance between the transport segment and native bone beyond which bone will no longer form. While all of our experimental groups underwent fibrous union at the distal docking site, it is unclear whether this represents a problem in geometry—the segments were several millimeters higher than the native bone—or an inherent problem in bone healing given the lapse of time between defect creation and arrival of the transport segment.39 If the latter is true, it is possible that multiple bony seams would need to undergo re-grafting when the distracters are removed, making the procedure more cumbersome and introducing further complexities. We did not encounter any alterations to the underlying dura. Our hypothesis is that at these slow distraction rates, the dura may be able to remodel and expand as the transport segment moves. Besides potential dural tears, we were concerned about pleating of the dura and alterations in the venous sinuses. Although others have proposed that BTO is tantamount to distraction of a bone graft, we contend that maintenance of dural connection is important to keeping the transport segment vascularized and osteogenic.29 The risk-to-benefit ratio of cranial BTO may be particularly favorable for a challenging subset of cranial defect patients: those who have had repeated infectious complications and pediatric patients in
BTO for Large Calvarial Defects
whom further cranial growth is expected. The multiply infected cranial defect population has been studied in a limited fashion and noted anecdotally by many surgeons as being at high risk for placing further alloplast.40–42 The pediatric population in whom spontaneous regeneration is doubtful and in whom splitting the calvarium is difficult— from about 18 months to 5 years—may also be a target population. The benefits of replacing a defect that may theoretically grow, and in which cranial sutures appear to regenerate, are clear. Cranial vault distraction, especially posteriorly, has been increasingly applied to pediatric patients safely and effectively for congenital disorders, and this may be a natural extension of that.43–45 This experiment in an adult sheep model with close resemblance to human bone physiology and using clinically available distraction hardware provides more evidence that BTO is a promising technique for cranioplasty that may be readily translated. Distraction at a rate of 0.5 mm per day may place individuals at higher risk for premature consolidation, but distraction rates did not have significant effects on regenerate quantity or quality. Future work will concentrate on hardware customization for a curvilinear trajectory and growth factor delivery for improved osteogenesis.46,47
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17. Girard PJ, Kuhn KM, Bailey JR, et al. Bone transport combined with locking bridge plate fixation for the treatment of tibial segmental defects: a report of two cases. J Orthop Trauma 2013;27:E220–E226 18. Sala F, Thabet AM, Castelli F, et al. Bone transport for postinfectious segmental tibial bone defects with a combined Ilizarov/Taylor spatial frame technique. J Orthop Trauma 2011;25:162–168 19. Paley D, Maar DC. Ilizarov bone transport treatment for tibial defects. J Orthop Trauma 2000;14:76–85 20. Kuriakose MA, Shnayder Y, DeLacure MD. Reconstruction of segmental mandibular defects by distraction osteogenesis for mandibular reconstruction. Head Neck 2003;25:816–824 21. Herford AS. Use of a plate-guided distraction device for transport distraction osteogenesis of the mandible. J Oral Maxillofac Surg 2004;62:412–420 22. Fukuda M, Iino M, Yamaoka K, et al. Two-stage distraction osteogenesis for mandibular segmental defect. J Oral Maxillofac Surg 2004;62: 1164–1168 23. González-Garcia R, Rubio-Bueno P, Naval-Gías L, et al. Internal distraction osteogenesis in mandibular reconstruction: clinical experience in 10 cases. Plast Reconstr Surg 2008;121:563–575 24. Hibi H, Ueda M. Supraperiosteal transport distraction osteogenesis for reconstructing a segmental defect of the mandible. J Oral Maxillofac Surg 2011;69:742–746 25. Chanowski EJ, Sacco AG, Fung K, et al. Revascularized tissue transplant and internal transport disk distraction osteogenesis for the reconstruction of complex composite mandibular defects. J Otolaryngol Head Neck Surg 2011;40:330–336 26. Hidalgo DA. Fibula free flap: a new method of mandible reconstruction. Plast Reconstr Surg 1989;84:71–79 27. Disa JJ, Winters RM, Hidalgo DA. Long-term evaluation of bone mass in free fibula flap mandible reconstruction. Am J Surg 1997;174:503–506 28. Hidalgo DA, Pusic AL. Free-flap mandibular reconstruction: a 10-year follow-up study. Plast Reconstr Surg 2002;110:438–449 29. Müller MC, Kramer FJ, Swennen GRJ, et al. A comparison of two types of free bone grafts as transport disks in segmental distraction for reconstruction of calvarial bone defects: an experimental study. Arch Orthop Trauma Surg 2004;124:665–674 30. Hirano N, Tanabe M, Watanabe T, et al. Novel approach to calvarial bone transport using a rabbit model. Neurol Med Chir 2006;46:69–74 31. Fukuta K, Saito K, Potparib Z. A comparison of single-stage versus gradual fronto-parietal advancement in terms of extradural dead space and bone deposition. Br J Plast Surg 1998;51:169–175 32. Pautke C, Vogt S, Tischer T, et al. Polychrome labeling of bone with seven different fluorochromes: enhancing fluorochrome discrimination by spectral image analysis. Bone 2005;37:441–445
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Copyright © 2014 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
Treatment of Large Calvarial Defects With Bone Transport Osteogenesis: A Preclinical Sheep Model Patrick A. Gerety, MD, Jason D. Wink, MD, MTR, Rami D. Sherif, BA, Nadya Clarke, MD, Hyun-Duck Nah, DMD, PhD, and Jesse A. Taylor, MD Background: Bone transport osteogenesis (BTO), distraction of a free portion of bone across a defect, offers an autologous solution to large cranial defects that may allow treatment without permanent hardware implantation. This study establishes a sheep model to evaluate the feasibility and distraction kinetics of BTO. Methods: Subtotal cranial defects (3.5 3.5 cm) were created in 10 young adult sheep and a transport segment (3.5 2 cm) traversed the defect at varying distraction rates (0, 0.5, 1.0, and 1.5 mm/ day) using semi-buried cranial distractors. After a 6-week consolidation period, sheep were euthanized and the resultant bone was analyzed by CT, histology, and mechanical testing. Results: Gross examination, histology, and 3D CT revealed that control animals had fibrous nonunion whereas distraction animals had ossified defects with fibrous nonunion at the distal docking site. There was one premature consolidation in the 0.5 mm/day group. The volume of bony regenerate in the 0.5, 1.0, and 1.5 mm/day distraction rate groups was statistically indistinct (P = 0.16). The mean flexural moduli (MPa) of non-decalcified samples from the control cranium, transport segment, and bone regenerate were found to be 4.50 ± 4.9, 6.17 ± 2.1, and 4.14 ± 4.8, respectively (P = 0.24). Conclusions: This experiment provides proof of concept for BTO for large calvarial defects in a sheep model. Distraction at a rate of 0.5 mm per day may place individuals at higher risk for premature consolidation, but distraction rates did not have significant effects on regenerate quantity or quality. Future work will include the use of curvilinear distraction devices for 3-dimensional contour. Key Words: Calvarial defect, bone transport osteogenesis, sheep model, critical-sized defect, osteodistraction (J Craniofac Surg 2014;25: 1917–1922)
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arge cranial defects place patients at risk for cerebral injury, acute and chronic neurologic symptoms related to perturbed intracranial pressure (“Syndrome of the Trephined”), and contour irregularities.1–3 Cranioplasty aims to restore contour and mechanical protection. Physical properties of an ideal cranioplasty are biocompatibility, infection resistance, and biomechanical properties similar to bone. If available, such as in the trauma setting, the replacement of a banked cranial bone flap is an option.4 When the native cranial bone flap is unavailable, many have advocated for the use of autologous bone graft despite numerous reports of significant resorption and contour irregularities.5 For most surgeons, alloplastic materials including methylmethacrylate, PEEK, titanium mesh, and hydroxyapatite cement are the next line of treatment for patients failing bone grafting.6–10 Alloplasts have the advantage of no additional donor site, but their use may be complicated by erosion, mechanical failure, migration, and infection necessitating removal.8 Additionally, the use of alloplastic implants in the pediatric population, whose cranium is still growing, may lead to growth alteration or abnormal cranial morphology over time. Distraction osteogenesis, originally conceived and reported by Ilizarov, has been used widely to lengthen long bones and, more recently, the craniofacial skeleton.11,12 In its monofocal form, the technique slowly spreads 2 osteotomized segments of bone apart, causing the deposition of callus between them that, with time, ossifies. Bone transport osteogenesis adapts this concept with distraction of a transport segment (TS) across a defect, a process that has been utilized successfully in the mandible.13,14 The purpose of this study was to establish a sheep model for the repair of large cranial defects with bone transport osteogenesis while assessing the impact of distraction rate on bone formation. Evaluation of the outcome focused on both radiographic and histologic evidence of bone formation, as well as mechanical properties of the resultant bone.
MATERIALS AND METHODS From the Divison of Plastic Surgery, The Perelman School of Medicine at the University of Pennsylvania; Division of Plastic Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Received September 5, 2013. Accepted for publication April 4, 2014. Address correspondence and reprint requests to Dr Jesse A. Taylor, Division of Plastic Surgery, Children’s Hospital of Philadelphia, 9th Floor Colket Translational Research Building, 3501 Civic Center Blvd, Philadelphia, PA 19104; E-mail: [email protected] This work was supported by a generous grant from the Center for Human Appearance at the University of Pennsylvania. All hardware was generously donated by Synthes, CMF. Approved by the Institutional Animal Care and Use Committee (IACUC) at the Children’s Hospital of Philadelphia (Philadelphia, PA) on May 5, 2011. Protocol #2011-3-961. The authors report no conflicts of interest. Copyright © 2014 by Mutaz B. Habal, MD ISSN: 1049-2275 DOI: 10.1097/SCS.0000000000000987
Study Design and Surgical Procedure This study was reviewed and approved by the Institutional Animal Care and Use Committee at the Children’s Hospital of Philadelphia. Ten young adult, male, castrated, Dorset sheep were used for the experiment. These sheep weighed an average of 45 kg. Groups included untreated control and differential distraction rates (0.5, 1.0, and 1.5 mm/day). Sheep were pre-medicated with a fentanyl patch (Janssen Pharmaceuticals Inc., a subsidiary of Johnson & Johnson, New Brunswick, NJ) 12 hours before surgery. Immediately before surgery, they received an 11 to 15 mg/kg dose of intramuscular ketamine (Ketaset CIII, Fort Dodge, IA, USA). The sheep were intubated and maintained under general anesthesia with 2% to 5% isoflurane (IsoFlo; Abbot Animal Health CE, Abbot Park, IL, USA). Each animal also received an intraoperative 2.5 mg/kg dose of flunixin (Banamine; Schering-Plough, a subsidiary of Merck,
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Whitehouse Station, NJ, USA) and additional doses postoperatively as needed. Each animal received 1 g of cefazolin pre-incision. A mid-sagittal, “lazy-S” incision was taken down to the pericranium, and wide subgaleal undermining ensued. A Midas Rex surgical drill (Medtronic, Minneapolis, MN, USA) was used to create a 35 mm 35 mm cranial defect followed by a 20 mm 35 mm transport segment in experimental animals. A pre-cut pattern was utilized to ensure uniformity between animals (Fig. 1). A craniomaxillofacial distractor (40 mm CMF distractor; Synthes, West Chester, PA, USA) was then placed by attaching the heel and foot plates with 3-mm selfdrilling, self-tapping screws. Care was taken to avoid dural injury and maintain broad attachment of the dura to the transport segment. Twolayered closure of the scalp was undertaken, and animals were awoken from general anesthesia (Figs. 2, 3). After completion of distraction and consolidation, sheep were euthanized with a combination of ketamine and Euthasol (Pentobarbital/Phenytoin; Virbac Animal Health, Ft Worth, TX, USA). Death was confirmed with thoracotomy. The sheep were decapitated and the entire head was scanned in a high-resolution CT machine (SOMATOM Definition Flash; Siemens, Munich, Germany) under cranial bone protocol. Histologic and mechanical assessments were done on smaller harvested samples.
Distraction Protocol Distraction proceeded once daily after a 5-day latency period. The non-control animals were divided into 3 groups at different distraction rates—0.5, 1.0, or 1.5 mm per day. When distraction was complete, the animals underwent a 42-day consolidation period. The animals were euthanized at the end of this period.
Cross-Sectional Imaging and Analysis Surface models of calcified bone were created based on CT data using image analysis software (Mimics Materialise NV, Leuven, Belgium) to assess the volume of bone formed in the distracted space behind the lagging edge of the transport segment.
FIGURE 1. Defect design. The defect measures 35 35 mm with a transport segment of 20 35 mm.
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FIGURE 2. Intraoperative photograph demonstrating anterior to posterior distraction with a 40-mm CMF distractor in place. Transport segment (TS) and defect (D) labeled.
Histological Analysis After CT scans were performed, the specimens were removed from the skull to include bone anterior to the source of the transport segment, the defect, transport segment, the docking site, and posterior skull. These smaller specimens were fixed (10% neutral buffered formalin; Sigma-Aldrich, St Louis, MO, USA). Before decalcification, the samples were bisected longitudinally with a surgical saw. Half of the specimen was set aside for mechanical testing, and the other half was decalcified (Decal Solution; Sigma-Aldrich). Decalcified sections were divided sharply into sections that allowed processing and embedding. Hematoxylin/eosin and trichrome staining were performed on representative sections. Photographs of these sections were obtained using a light microscope (Olympus BH2, Center Valley, PA, USA)
FIGURE 3. Postoperative photograph of an experimental sheep with a flexible distractor arm emanating from the scalp.
© 2014 Mutaz B. Habal, MD
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The Journal of Craniofacial Surgery • Volume 25, Number 5, September 2014
BTO for Large Calvarial Defects
Mechanical Testing Fixed, non-decalcified portions of each sample were taken for mechanical testing. For testing, the specimens were divided with a bone saw into 10 10 mm cubic pieces. Samples were taken from native bone, newly formed bone within the defect, and the transport segment. A 3-point bending test was performed (Instron 5500, Norwood, MA, USA) to assess flexural modulus.
Statistical Analysis Mann-Whitney and Kruskal-Wallis tests were used for statistical comparisons. Significance was determined by P less than 0.05.
RESULTS The sheep in this experiment tolerated defect creation and distractor placement well. The process of activating the distractor did not produce a pain response, and the sheep were able to tolerate the device throughout consolidation. There was no statistically significant difference in the amount of distraction that occurred between experimental groups, though one of the 0.5-mm animals manifested a premature consolidation midway through the activation phase. Three minor wound infections were treated successfully with antibiotics. One major distractor failure occurred during distraction when a distractor was traumatically fractured and could no longer be turned. One animal died suddenly during distraction and was found to have ingested a foreign body. The 2 sheep that were unable to complete the treatment course were excluded from all statistical analyses; thus, 8 animals were included in the analyses, 2 in each group.
Cross-Sectional Imaging Control animals showed minor signs of bone regeneration at the edge of the defects, but otherwise developed fibrous deposition within the defects. All experimental animals demonstrated bone formation across the defect in the wake of the transport segment
FIGURE 5. Representative 3D reconstructions of control (left), 0.5 mm/day (middle), and 1.5 mm/day (right) with new bone formation and transport segment. The 0.5-mm section represents our single experimental animal that underwent premature consolidation, and thus the transport segment is halfway across the defect. The 1.5-mm section, in contrast, demonstrates bony regenerate throughout.
whereas controls were generally devoid of bone. Interestingly, the sagittal suture seemed to reform within the bone regenerate in all experimental samples (Fig. 4). 3D reconstructions demonstrate bone formation across the defect between the transport segment and its origin with consistent nonunion at the docking site (Fig. 5). The average generated bone volume per millimeter of distraction of the 3 distraction rates (0.5, 1.0, and 1.5 mm/day) were 108.71 ± 24.62 mm2, 95.42 ± 20.56 mm2, and 73.40 ± 4.00 mm2, respectively (P = 0.16). Average bone thickness was measured for each experimental group behind the transport segment and was found to be 3.11 ± 0.70 mm, 2.73 ± 0.59 mm, and 2.1 ± 0.11 mm, respectively (P = 0.10). Regardless of distraction rate, all distracted animals grew a greater quantity of bone than controls (92.51 ± 21.53 mm2 vs. 17.36 ± 11.17 mm2, P = 0.046) (Table 1). As this was uni-vector distraction in a slightly cephalad direction, the transport segment typically was located 2 to 3 mm cephalad to the native cranial docking site (Fig. 6). Experimental groups all manifested nonunion at the docking site and progressively poorer union with the side walls as the experiment progressed (Fig. 7). This was seen consistently irrespective of distraction kinetics, and seemed to be a gradual decline in union, not an abrupt stoppage. There was no indication on CT of any pleating of the dura, other signs of dural disruption, or alterations of the major venous sinuses.
Histology A comparison of the gross specimens demonstrated the formation of hard tissue in experimental animals and the formation of fibrous connective tissue in control animals. This was especially
TABLE 1. Quantification of Bone Formation Behind Transport Segment
Sheep 1
FIGURE 4. Representative coronal-section CT scans of control and experimental animals. Unrepaired defect in a control animal (top left); 0.5 mm/day distraction rate (top right); 1.0 mm/day distraction rate (bottom left); 1.5 mm/day distraction rate (bottom right).
Group
Regenerate Volume, mm3
Regenerate Volume/ Distraction Distance, mm2
Average Regenerate Thickness, mm
2 3
Control Control 0.5 mm/d
884.23 331.18 273.89
25.26 9.46 91.30
0.72 0.27 2.61
4 5 6 7 8
0.5 mm/d 1 mm/d 1 mm/d 1.5 mm/d 1.5 mm/d
3,152.99 2,529.11 2,588.22 1,199.84 2,820.50
126.12 109.96 80.88 70.58 76.23
3.60 3.14 2.31 2.01 2.18
© 2014 Mutaz B. Habal, MD
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Complication Infection Premature consolidation Infection Infection
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FIGURE 6. Sagittal 3D reconstruction displaying angle between sheep calvarium and vector of transport segment. Future work will concentrate on the manufacture of a curvilinear distractor to recreate the contour of the cranial defect.
evident when the samples were bisected for processing (Fig. 8). Experimental animals showed significant quantities of new bone formation within the defect. Osteogenesis appeared to occur in a membranous fashion with no sign of endochondral ossification in our representative samples. Immature bone formed in a thin trabecular pattern with a woven appearance. Osteocytes are present within the bone regenerate throughout. Neovascularization can be seen within the trabeculae. The underlying dura appears intact and not distinct from native dura.
Mechanical Testing Results of the 3-point bending test of the samples demonstrated that in experimental animals newly formed bone within the defect, the transport segment, and the native control cranial bone had flexural moduli of 4.14 ± 4.8 MPa, 6.17 ± 2.1 MPa, and
FIGURE 8. Histological sections. Control animals demonstrate fibrous nonunion (top left, 10; middle left, 40; bottom left, trichrome). Experimental animals demonstrate bony regrowth (top right, 10; middle right, 40; bottom right, trichrome).
4.50 ± 4.9 MPa, respectively. These values were not significantly different (P = 0.24).
DISCUSSION
FIGURE 7. Representative gross pathologic cross-sections demonstrating the fibrous nonunion of a control specimen (top) and the hard bony healing of a bone transport osteogenesis animal (bottom).
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Bone transport osteogenesis (BTO) utilizes the bifocal iteration of distraction osteogenesis by distracting a segment of bone across a defect. BTO has been applied most successfully to the reconstruction of long bone defects and is, in fact, practiced widely.15–19 It has been reported for mandibular segmental defects in case reports and small series in the literature but has not gained widespread popularity for various reasons,20–25 chief among them the popular use of microvascular free tissue transfer of osseous and osteocutaneous flaps with lower treatment times and high success rates.26–28 As free vascularized osseous transfer has gained utility in long bones and the mandible, the application of BTO seems most logical in calvarial reconstruction because of the large surface area that must be reconstructed. There is a limited body of literature in applying BTO to cranial defects consisting of a small number of animal studies,29–32 and one human case report.33 Cho-Lee and colleagues reported the use of BTO for a calvarial defect in 1 patient who had suffered loss of a bone flap and infection and extrusion of 2 alloplastic materials.33 Treatment with BTO was lengthy—9 months—and required multiple stages, but successfully closed nearly all of a very large and geometrically complex (85 50 mm) defect.33 The few supporting studies in small and large animal models are in animals with distinct bone physiology and healing ability that may not allow for translation of the results to humans.13,14,29–32,34–38 No experimentation of distraction kinetics have been performed for BTO in a large, highly phylogenetic animal model which will more closely reproduce human bone physiology. © 2014 Mutaz B. Habal, MD
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The Journal of Craniofacial Surgery • Volume 25, Number 5, September 2014
In this study, we establish a model for repair of a large calvarial defect in young adult, male, Dorset sheep. Among readily available large animal models, the sheep calvarium is most similar in physical characteristics to the human skull. The dimensions of our experimental defect and transport segment utilize virtually all of the available surface area of the skull, precluding it as a model for defects larger than 55 mm 35 mm. There are a number of advantages to using cranial BTO to repair large cranial defects. The repair is autologous and vascularized, with no required additional donor site. Successful ossification of the defect precludes the need for permanent hardware, which will prove important in patients who have recurrent problems with infection, and in the growing pediatric population. Repairing a cranial defect with vascularized bone would have the potential to grow and heal itself, if fractured. As we have shown, the bony regenerate has similar mechanical properties to native bone which conveys protection to the brain and the absence of stress shielding from surrounding areas of the cranium. These advantages will have to be weighed against the fact that the procedure requires additional cranial osteotomies and a lengthy duration of treatment. Our results did not demonstrate a significant difference in bone formation between sheep in the different distraction rate groups (0.5, 1.0, and 1.5 mm/day) though it did significantly alter length of treatment, an important data point for potential patients. Additionally, our single experimental animal that had premature consolidation was in the 0.5 mm group, leading us to conclude that individuals may be at higher risk for premature consolidation if the rate of activation is less than 1 mm per day; no experimental animals in our study failed to produce bone in the wake of the transport segment. Our data shows that the bony regenerate is slightly thinner than the transport segment which may translate to an alteration in aesthetic contour. Although we report no statistical difference in 3-point bending strength between native calvarium and regenerate, this feasibility study was not adequately powered to definitively conclude whether a difference exists. Given the small difference in bending strength, the number of animals required to adequately power this calculation is 45, a number not feasible due to cost. Cranial defects are often complex geometrically, and it may be difficult to design osteotomies and distraction hardware that allow for defect healing of geographically complex, large defects. There may be a theoretical maximum distance across which a transport segment of a given thickness will produce bone and a theoretical maximum distance between the transport segment and native bone beyond which bone will no longer form. While all of our experimental groups underwent fibrous union at the distal docking site, it is unclear whether this represents a problem in geometry—the segments were several millimeters higher than the native bone—or an inherent problem in bone healing given the lapse of time between defect creation and arrival of the transport segment.39 If the latter is true, it is possible that multiple bony seams would need to undergo re-grafting when the distracters are removed, making the procedure more cumbersome and introducing further complexities. We did not encounter any alterations to the underlying dura. Our hypothesis is that at these slow distraction rates, the dura may be able to remodel and expand as the transport segment moves. Besides potential dural tears, we were concerned about pleating of the dura and alterations in the venous sinuses. Although others have proposed that BTO is tantamount to distraction of a bone graft, we contend that maintenance of dural connection is important to keeping the transport segment vascularized and osteogenic.29 The risk-to-benefit ratio of cranial BTO may be particularly favorable for a challenging subset of cranial defect patients: those who have had repeated infectious complications and pediatric patients in
BTO for Large Calvarial Defects
whom further cranial growth is expected. The multiply infected cranial defect population has been studied in a limited fashion and noted anecdotally by many surgeons as being at high risk for placing further alloplast.40–42 The pediatric population in whom spontaneous regeneration is doubtful and in whom splitting the calvarium is difficult— from about 18 months to 5 years—may also be a target population. The benefits of replacing a defect that may theoretically grow, and in which cranial sutures appear to regenerate, are clear. Cranial vault distraction, especially posteriorly, has been increasingly applied to pediatric patients safely and effectively for congenital disorders, and this may be a natural extension of that.43–45 This experiment in an adult sheep model with close resemblance to human bone physiology and using clinically available distraction hardware provides more evidence that BTO is a promising technique for cranioplasty that may be readily translated. Distraction at a rate of 0.5 mm per day may place individuals at higher risk for premature consolidation, but distraction rates did not have significant effects on regenerate quantity or quality. Future work will concentrate on hardware customization for a curvilinear trajectory and growth factor delivery for improved osteogenesis.46,47
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