Darren M. Smith

Bone morphogenetic protein 2 therapy for craniofacial surgery.

Between 2 and 10 years of age, the developing craniofacial skeleton poses a significant reconstructive challenge. Local autogenous bone is largely unavailable, distant bone grafts are fraught with significant morbidity and limited yield, and alloplastic materials are incompatible with the growing calvarium and facial skeleton. Bone morphogenetic protein (BMP) 2, a member of a class of proteins first noticed in the 1960s to promote bone deposition in soft tissues, offers a potential solution to the bone shortage historically faced by the pediatric craniofacial surgeon. A review of English language literature was conducted from the 1960s to the present. Attention was focused on BMP-2s osteoinductive mechanism, basic science and translational laboratory findings, and multidisciplinary clinical experiences. Bone morphogenetic protein 2 has been embraced by spine surgeons, is gaining in popularity for long-bone repair, and is making its way into the plastic surgery literature. Bone morphogenetic protein 2 may provide a basis for an off-the-shelf tissue-engineered bone construct that is compatible with the growing craniofacial skeleton while free from the morbidities of distant graft harvest. Questions remain, however, regarding the safety and efficacy of this compound in the context of pediatric craniofacial surgery. In an effort to facilitate the clinicians risk-benefit analysis of this emerging technology, we present a primer on the basic science of BMP-2, a discussion of possible morbidities associated with its use, a review of laboratory and clinical trials with this substance to date, and an analysis of strategies to maximize its efficacy in craniofacial surgery.

The Pittsburgh Fistula Classification System: A Standardized Scheme for the Description of Palatal Fistulas

Objective: Vague terminology is a problem in cleft palate research. No classification scheme for palatal fistulas has been proposed to date. Although a well-healed velum is a significant outcome of palatoplasty, it is nearly impossible to compare fistula-related palatoplasty results in the literature or in medical records without a standardized vocabulary. We endeavor to devise a palatal fistula classification system that may have clinical and research applicability. Design: PubMed was searched for definitions and classifications of palatal fistula as well as incidence and recurrence rates of this outcome. Next, a 25-year retrospective review of our Cleft Centers records was performed, and fistulas were identified (n = 641 charts reviewed). The fistula descriptions yielded by this chart review were evaluated in the context of anatomical descriptions in the literature, and a clinician-friendly classification scheme was designed. Results: A literature review failed to reveal a standardized fistula classification system. An anatomically based numerical fistula classification system was devised: type I, bifid uvula; type II, soft palate; type III, junction of the soft and hard palate; type IV, hard palate; type V, junction of the primary and secondary palates (for Veau IV clefts); type VI, lingual alveolar; and type VII, labial alveolar. Conclusions: We propose a standardized numerical classification system for palatal fistulas. Its clinical adoption may prospectively clarify ambiguities in the literature and facilitate future cleft palate research and clinical practice.

Characterization of Transplanted Green Fluorescent Protein+ Bone Marrow Cells into Adipose Tissue

Following transplantation of green fluorescent protein (GFP)‐labeled bone marrow (BM) into irradiated, wild‐type Sprague‐Dawley rats, propagated GFP+ cells migrate to adipose tissue compartments. To determine the relationship between GFP+ BM‐derived cells and tissue‐resident GFP− cells on the stem cell population of adipose tissue, we conducted detailed immunohistochemical analysis of chimeric whole fat compartments and subsequently isolated and characterized adipose‐derived stem cells (ASCs) from GFP+ BM chimeras. In immunohistochemistry, a large fraction of GFP+ cells in adipose tissue were strongly positive for CD45 and smooth muscle actin and were evenly scattered around the adipocytes and blood vessels, whereas all CD45+ cells within the blood vessels were GFP+. A small fraction of GFP+ cells with the mesenchymal marker CD90 also existed in the perivascular area. Flow cytometric and immunocytochemical analyses showed that cultured ASCs were CD45−/CD90+/CD29+. There was a significant difference in both the cell number and phenotype of the GFP+ ASCs in two different adipose compartments, the omental (abdominal) and the inguinal (subcutaneous) fat pads; a significantly higher number of GFP−/CD90+ cells were isolated from the subcutaneous depot as compared with the abdominal depot. The in vitro adipogenic differentiation of the ASCs was achieved; however, all cells that had differentiated were GFP−. Based on phenotypical analysis, GFP+ cells in adipose tissue in this rat model appear to be of both hematopoietic and mesenchymal origin; however, infrequent isolation of GFP+ ASCs and their lack of adipogenic differentiation suggest that the contribution of BM to ASC generation might be minor.

A Successful Algorithm for Limiting Postoperative Fistulae following Palatal Procedures in the Patient with Orofacial Clefting

Background: Palatal procedures include (1) primary palatoplasty, (2) oronasal fistulas repair, and (3) secondary palatoplasty for velopharyngeal insufficiency. Any time a palatal procedure is performed, postoperative fistulas remain potential consequences. Presented here is a successful algorithm for performing palatal procedures and decreasing the rate of postoperative fistulas in a large, single-surgeon, consecutive series. Methods: A retrospective review of all consecutive palatal procedures performed between 2002 and 2006 including (1) primary palatoplasty, (2) oronasal fistulas repair, and (3) secondary palatoplasty for velopharyngeal insufficiency was performed. Cleft Veau type, surgical technique, and outcomes are reviewed. The algorithm included (1) relaxing incisions, (2) complete intravelar veloplasty, (3) total release of the tensor tendon, (4) dissection of the neurovascular bundle with optional osteotomy of the foramen, and (5) incorporation of acellular dermal matrix to achieve complete nasal lining reconstruction. Results: Two hundred sixty-eight palatal procedures were performed: (1) 132 primary Furlow palatoplasties yielding one symptomatic post–Furlow palatoplasty fistula (0.76 percent) (acellular dermal matrix was used in 39.4 percent of primary palatoplasties); (2) 55 oronasal fistula repairs yielding two symptomatic postoperative fistulas (3.6 percent) (acellular dermal matrix was used in 90.9 percent of fistula repairs); and (3) 81 secondary palatoplasties for velopharyngeal insufficiency resulting in no postoperative fistulas. Acellular dermal matrix was used in 14.8 percent of secondary palatoplasties for velopharyngeal insufficiency. No recommendations for speech surgery followed palatoplasty. Conclusions: Using the proposed algorithm in this single-surgeon consecutive series of 268 cases, the authors achieved the lowest reported incidence of postoperative fistulas in all forms of palatal procedures, including the lowest incidence (0.76 percent) of symptomatic palatal fistulas following primary Furlow palatoplasty.

BMP-2-based repair of large-scale calvarial defects in an experimental model: regenerative surgery in cranioplasty.

Pediatric craniofacial surgery is complicated by a shortage of autologous bone. Children between 2 and 10 years of age are especially problematic, as the dura has lost its potential to spontaneously heal large calvarial defects by approximately 2 years of age, and split calvarial grafts are often unavailable because of the underdeveloped diploic space until later childhood. We demonstrate the efficacy of a BMP-2-based system in repairing large-scale cranial defects in a rabbit model. Calvarial defects, 15 mm2, were created in 18 adult New Zealand white rabbits, treated as follows: group 1, no repair (n = 6); group 2, absorbable collagen sponge (ACS) (n = 4); and group 3, recombinant human bone morphogenetic protein 2 delivered on ACS (rhBMP-2/ACS) (n = 8). Bone regeneration 6 weeks postoperatively was evaluated by 2- and 3-dimensional standard computed tomography, micro-computed tomography. Analysis of variance was performed using SPSS. The generated bone was also evaluated histologically. After 6 weeks, group 1 defects were on average 32.8% (SD, 8.8%) ossified. Group 2 defects were on average 34.4% (SD, 17.1%) ossified. Defects in group 3 were on average 96.9% (SD, 3.7%) ossified, significantly (P < 0.005) more than the defects in groups 1 and 2. rhBMP-2-induced bone was histologically and radiographically consistent with native bone. This study demonstrates the efficacy of rhBMP-2/ACS for the repair of calvarial defects in the rabbit model. rhBMP-2/ACS may offer a viable treatment option for craniofacial surgeons facing a shortage of bone, with the potential to replace autologous bone grafts and render their attendant morbidities obsolete.

Pediatric facial fractures: demographics, injury patterns, and associated injuries in 772 consecutive patients.

Background: Pediatric craniofacial fractures are anatomically distinct from their adult counterparts and must be managed with respect for future growth and development. These injuries must be approached as entities fundamentally different from adult craniofacial fractures. Here, the authors aim to provide context for practitioners managing pediatric facial fractures by augmenting presently available demographic, diagnostic, and treatment data. Methods: This is a retrospective review of demographics, diagnosis, and treatment of patients under 18 years of age presenting to the emergency department of a pediatric level I trauma center between 2000 and 2005 with facial fractures. Patients were included regardless of treating specialty, treatment modality, or inpatient status. Results: A total of 772 consecutive patients met inclusion criteria. A significant majority (p < 0.001) of patients (68.9 percent) were male; older children were significantly more likely to sustain a facial fracture (p < 0.001). Fracture pattern, level of care, and cause of injury varied by age; 55.6 percent of patients had severe associated injuries. Male subjects, older patients, and patients of lower socioeconomic status were significantly more likely to sustain facial fractures secondary to violence (p ⩽ 0.001). Conclusions: Pediatric facial fractures may be associated with severe concomitant injuries. Injury patterns are significantly correlated with socioeconomic metrics. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, IV.

Cleft Palate Repair

The authors begin with a discussion of the anatomy relevant to palatoplasty. Perioperative considerations are then addressed. A broad range of surgical options has evolved over time; these are discussed in their historical context. The authors present a detailed description of their preferred surgical approach. Postoperative care is then described. An examination of recent trends and controversies in the field is then offered. Finally, an approach to outcomes assessment is discussed. It is hoped that this monograph will be of use in guiding others as they embark on the highly challenging, but equally rewarding, task of perfecting the palatoplasty.

Custom porous polyethylene implants for large-scale pediatric skull reconstruction: early outcomes.

Background and Purpose Some of the most problematic craniofacial injuries in pediatric plastic surgery are large calvarial defects in children who have passed the age of maximal dural osteogenic potential and yet are too young to yield split calvarial grafts. Porous polyethylene (Medpor; Porex) is an alloplastic material that can be customized to precisely match a cranial defect. We present a clinical series that demonstrates successful use of porous polyethylene cranioplasties in large pediatric cranial defects. Methods From 2007 to 2009, 9 pediatric patients underwent custom-made porous polyethylene cranioplasties for large calvarial defects. Descriptive statistical analyses were performed on the cause of the defects, time to cranioplasty, size of defect, reconstruction technique, and postoperative healing. Results A total of 5 boys and 4 girls, with a mean age of 6.8 years, underwent 9 cranioplasties incorporating custom porous polyethylene implants. Initial pathologic findings included 7 patients with traumatic brain injuries, 1 patient with intractable seizures, and 1 patient with brain cancer. Initially, each patient had a craniectomy followed by replacement of the frozen bone “flap.” All patients experienced either infection or resorption of the bone leading to a permanent defect. The mean defect size was 152 cm2. The mean delay between the removal of failed bone “flap” and the final implant cranioplasty was 6.8 months. At the last follow-up, which averaged 3.6 months, all patients had stable wounds with acceptable cranial contour. Conclusions For pediatric large-scale calvarial defects, custom-made porous polyethylene implants can be safely used for cranioplasty. Tissue expansion and acellular dermal matrix were useful tools to help augment the soft tissues of the scalp before cranioplasty to prevent complications of implant extrusion and wound breakdown.

Demineralized bone matrix and resorbable mesh bilaminate cranioplasty: a novel method for reconstruction of large-scale defects in the pediatric calvaria.

Background: Pediatric patients with large-scale calvarial defects often lose the osteogenic potential of their dura before developing a diploic space sufficient to facilitate harvest of split-thickness calvarial grafts. The authors present their experience using demineralized bone matrix and resorbable mesh bilaminate for the repair of large-scale cranial defects in pediatric patients. Methods: A retrospective review of the Cleft-Craniofacial Center database at Children’s Hospital of Pittsburgh was performed from 2003 through 2007. Patients who underwent cranioplasties using demineralized bone matrix and resorbable mesh bilaminate were identified. Indications, defect size, quantity of demineralized bone matrix used, complications, follow-up, and computed tomographic scans were reviewed. Results: Eleven patients underwent 13 skull reconstructions using demineralized bone matrix and resorbable mesh bilaminate cranioplasty. Mean age was 3.6 years (range, 2.1 to 4.9 years); average defect size was 30.8 cm2 (range, 6.6 to 80.0 cm2). Mean clinical follow-up was 29.3 months (range, 13.4 to 41.8 months). All patients had follow-up computed tomographic scans. The average time of follow-up scan was 18.7 months postoperatively (range, 6.9 to 32.6 months). Seven patients had immediate postoperative scans in addition to long-term follow-up scans, facilitating the calculation of a 98 percent average defect healing (range, 95 to 100 percent). All patients had clinically stable cranial reconstructions at follow-up. Conclusions: When autogenous bone is not available, demineralized bone matrix and resorbable mesh bilaminate cranioplasty is an alternative method of calvarial reconstruction when used in a healthy site free of scarring or infection. This cranioplasty technique has provided consistent bony regeneration, with no donor-site morbidity.

Regenerative surgery in cranioplasty revisited: the role of adipose-derived stem cells and BMP-2.

Background: Reconstruction of the pediatric calvaria is frequently complicated by a shortage of bone. This problem is most apparent between 2 and 10 years of age, when the osteogenic potential of the dura is diminished and the diploic space has not matured to the point that split-thickness calvarial grafting is practical. In this article, the authors evaluate and compare the relative efficacy of adipose-derived stem cells, bone morphogenetic protein (BMP)-2, and adipose-derived stem cells osteoinduced with BMP-2 in addressing these defects. Methods: Cranial defects measuring 15 × 15 mm were created in New Zealand White rabbits. Five treatment modalities were compared: no repair (surgical control); untreated acellular collagen sponge (vehicle control); BMP-2 on acellular collagen sponge; adipose-derived stem cells on acellular collagen sponge; and osteoinduced adipose-derived stem cells on acellular collagen sponge. Osteogenesis was assessed with radiology and histology. Statistical significance was determined by analysis of variance. Results: No significant difference in osseous healing was observed among empty controls (32.8 percent), acellular collagen sponge alone (34.4 percent), adipose-derived stem cells on acellular collagen sponge (33.9 percent), and osteoinduced adipose-derived stem cells on acellular collagen sponge (40.2 percent). Defects reconstructed with recombinant human BMP-2/acellular collagen sponge were on average 96.9 percent ossified, significantly (p < 0.05) more than the defects in all other groups. Conclusions: BMP-2–based tissue engineering is a viable approach to craniofacial reconstruction. Adipose-derived stem cells did not significantly augment this process as modeled here. Advances in the understanding of craniofacial biology, and of protein- and cell-based therapies, will enhance the efficacy of tissue-engineering strategies for this problem in the future.