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Nonsyndromic craniosynostosis is one of the most common anomalies treated by craniofacial surgeons. Despite optimal surgical management, nearly half of affected children have subtle neurocognitive deficits. Whereas timing and type of surgical intervention have been studied, the possibility of genetic influence on neurodevelopment in nonsyndromic craniosynostosis patients remains unexplored.The authors performed whole-exome sequencing for 404 case-parent trios with sporadic nonsyndromic craniosynostosis. Statistical analyses were performed to assess the burden of de novo mutations in cases compared to both expectation and 1789 healthy control trios. Individuals with and without each mutation class were analyzed, and the presence or absence of various types of neurodevelopmental delay were recorded alongside demographic information.The authors identified a highly significant burden of damaging de novo mutations in mutation-intolerant [probability of loss of function intolerance (pLI)0.9] genes in nonsyndromic craniosynostosis probands (p = 5.9 × 10-6). Children with these mutations had a two-fold higher incidence of neurodevelopmental delay (p = 0.001) and a more than 20-fold greater incidence of intellectual disability (p = 7.2 × 10-7), and were 3.6-fold more likely to have delays that persisted past 5 years of age (p = 4.4 × 10-4) in comparison with children with nonsyndromic craniosynostosis without these mutations. Transmitted loss of function mutations in high-pLI genes also conferred a 1.9-fold greater risk of neurodevelopmental delay (p = 4.5 ×10-4).These findings implicate genetic lesions concurrently impacting neurodevelopment and cranial morphogenesis in the pathoetiology of nonsyndromic craniosynostosis and identify a strong genetic influence on neurodevelopmental outcomes in affected children. These findings may eventually prove useful in determining which children with nonsyndromic craniosynostosis are most likely to benefit from surgical intervention.Risk, III.

The middle vault plays a major aesthetic and functional role. Excessive narrowing of the middle vault can occur in the absence of appropriate middle vault reconstruction. This can result in both aesthetic flaws and functional issues. Spreader flaps combined with our hourglass shaping sutures technique yield a natural middle vault appearance and prevent unwanted functional and aesthetic complications.

A larger volume cranial vault expansion is likely facilitated by a low posterior cranial osteotomy beneath the torcula; however, this may impart an increased risk of venous bleeding. The authors compared the safety of infratorcular versus supratorcular osteotomy in patients undergoing posterior vault reconstruction or posterior vault distraction osteogenesis and analyzed volumetric changes.Patients undergoing initial posterior vault reconstruction or distraction osteogenesis between 2009 and 2021 at the authors' institution were grouped by occipital osteotomy location and analyzed retrospectively. Craniometric analysis was performed if patients had high-resolution computed tomography scans available within 180 days preoperatively and postoperatively.A total of 187 patients were included: 106 (57 percent) who underwent posterior vault distraction osteogenesis and 81 (43 percent) who underwent posterior vault reconstruction. Infratorcular osteotomy was more common in reconstruction [ n = 65 (80 percent)] than in distraction osteogenesis [ n = 61 (58 percent); p0.002]. Blood transfused was similar between low and high osteotomy cohorts in the distraction osteogenesis ( p = 0.285) and reconstruction ( p = 0.342) groups. However, median transfused blood volume per kilogram of patient weight was greater in the low versus high osteotomy distraction osteogenesis ( p = 0.010) and reconstruction ( p = 0.041) cohorts. Intraoperative venous sinus injury was rare. In the distraction osteogenesis cohort, there was increased median intracranial volumetric gain in the low (263 ml) compared with the high osteotomy cohort (127 ml; p = 0.043); however, when controlled for distraction distance, only a trend was observed ( p = 0.221). Patients undergoing distraction osteogenesis showed a larger median intracranial volume increase (168 ml) compared with those undergoing reconstruction (73 ml; p0.001).Infratorcular osteotomy can be performed safely in most patients undergoing cranial vault remodeling and does not appear to be associated with greater hemodynamic instability or sinus injury.Therapeutic, III.

There is a paucity of data on normal intracranial volumes for healthy children during the first few years of life, when cranial growth velocity is greatest. The aim of this study was to generate a normative predictive model of intracranial volumes based on brain magnetic resonance imaging from a large sample of healthy children to serve as a reference tool for future studies on craniosynostosis.Structural magnetic resonance imaging data for healthy children up to 3 years of age was acquired from the National Institutes of Health Pediatric MRI Data Repository. Intracranial volumes were calculated using T1-weighted scans with FreeSurfer (version 6.0.0). Mean intracranial volumes were calculated and best-fit logarithmic curves were generated. Results were compared to previously published intracranial volume curves.Two-hundred seventy magnetic resonance imaging scans were available: 118 were collected in the first year of life, 97 were collected between years 1 and 2, and 55 were collected between years 2 and 3. A best-fit logarithmic growth curve was generated for male and female patients. The authors' regression models showed that male patients had significantly greater intracranial volumes than female patients after 1 month of age. Predicted intracranial volumes were also greater in male and female patients in the first 6 months of life as compared to previously published intracranial volume curves.To the authors' knowledge, this is the largest series of demographically representative magnetic resonance imaging-based intracranial volumes for children aged 3 years and younger. The model generated in this study can be used by investigators as a reference for evaluating craniosynostosis patients.

Anterior cranial vault fronto-orbital distraction osteogenesis is a promising treatment modality for children with unicoronal craniosynostosis. A minimally invasive, endoscope-assisted approach offers the additional potential benefits of less scalp scarring, decreased blood loss, and decreased scalp dissection. In this article, the authors present a novel technique for minimally invasive, endoscope-assisted fronto-orbital distraction osteogenesis.

Teaching about craniofacial traumas is challenging given the complexity of the craniofacial anatomy and the necessity for good spatial representation skills. To solve these problems, three-dimensional printing seems to be an appropriate educative material. In this study, the authors conducted a randomized controlled trial. The authors' main objective was to compare the performance of the undergraduate medical students in an examination based on the teaching support: three-dimensionally printed models versus two-dimensional pictures.All participants were randomly assigned to one of two groups using a random number table: the three-dimensionally-printed support group (three-dimensional group) or the two-dimensionally-displayed support group (two-dimensional group). All participants completed a multiple-choice question evaluation questionnaire on facial traumatology (first, a zygomatic bone fracture; then, a double mandible fracture). Sex and potential confounding factors were evaluated.Four hundred thirty-two fifth-year undergraduate medical students were enrolled in this study. Two hundred six students were allocated to the three-dimensional group, and 226 were allocated to the two-dimensional group. The three-dimensionally printed model was considered to be a better teaching material compared with two-dimensional support. The global mean score was 2.36 in the three-dimensional group versus 1.99 in the two-dimensional group (p = 0.008). Regarding teaching of biomechanical aspects, three-dimensionally-printed models provide better understanding (p = 0.015). Participants in both groups exhibited similar previous student educational achievements and visuospatial skills.This prospective, randomized, controlled educational trial demonstrated that incorporation of three-dimensionally-printed models improves medical students' understanding. This trial reinforces previous studies highlighting academic benefits in using three-dimensionally-printed models mostly in the field of understanding complex structures.

SUMMARY Patient-reported outcomes regarding donor-site morbidity and quality of life for the fibula free flap in head and neck reconstruction patients have not been studied. The authors reviewed and identified patients who had undergone head and neck reconstruction using a fibula free flap (2011 to 2016). Patients were assessed via physical examination and two patient-reported outcomes questionnaires: the Foot and Ankle Outcome Score (score range, 0 to 100) and the Pain Disability Questionnaire (score range, 0 to 100). Quantitative data were analyzed with appropriate statistical tests. Semistructured interviews exploring donor-site challenges were performed and analyzed using thematic analysis. Seventeen patients agreed to participate. Their mean age was 62 years (range, 41 to 81 years). Mean follow-up was 38 months (range, 12 to 65 years). Mean perceived level of function compared to baseline was 67 percent. Mean scores for the Foot and Ankle Outcome Score subscales were 84.6 (pain), 80.5 (symptoms), 86.7 (activities of daily living), 67.7 (sport), and 65.6 (quality of life). The mean Pain Disability Questionnaire score was 26.3 (mild/moderate perceived disability). Higher perceived level of function was associated with higher Foot and Ankle Outcome Score values (pain, symptoms, and activities of daily living, p < 0.05). Donor limbs had decreased range of motion and manual muscle testing scores compared with their contralateral limbs (p < 0.05). Lack of ankle support and balance, resulting in limitations and aversions to daily and sporting activities, were the most common themes regarding donor-site challenges. In conclusion, patients who have undergone fibula free flap harvest struggle with ankle support and balance and face functional difficulties that have an impact on their quality of life. Multidisciplinary approaches for targeted rehabilitation after fibula free flap harvest should be explored to determine the impact on patients' quality of life.

BACKGROUND Resorbable hardware allows adequate strength for maintaining the relative position of the craniofacial skeleton during osseous healing, and allowing subsequent growth in pediatric patients. The purpose of this study was to determine the complication profile of the latest copolymer of resorbable plates for craniofacial reconstruction in pediatric patients. METHODS Retrospective query of the operative billing record was performed for use of the DePuy Synthes Rapidsorb Fixation System at the authors' tertiary children's hospital from 2015 to 2019. Three hundred twenty-five patients were randomly selected for analysis of complications within the first postoperative year. RESULTS Median age at craniofacial reconstruction was 3.0 years, with 127 procedures (39.9 percent) performed for an intracranial mass and 141 procedures (44.3 percent) performed for craniosynostosis. Overall, 7.9 percent patients had a postoperative wound complication. The most common complications were dehiscence (3.8 percent), hematoma/seroma (3.5 percent), and infection (2.5 percent). There were no instances of extrusion, plate fracture, or screw loosening. Hardware complications in the temporoparietal region were more likely to occur at incision sites (p = 0.001), whereas wound complications at the frontal region were more likely to occur away from incision sites (p < 0.001). There were no differences in complications between plates secured with resorbable screws or with the resorbable injectable polymer system (p ≥ 0.161 for all). Radiotherapy was significantly implicated in development of clinical infection (p = 0.001), culture-positive infection (p < 0.001), readmission (p = 0.007), reoperation (p = 0.003), and plate removal (p = 0.007). CONCLUSION Resorbable cranial hardware has an overall favorable complication profile for craniofacial reconstruction in pediatric patients undergoing surgical intervention for craniosynostosis or intracranial mass resection.

Background:Apert syndrome is frequently combined with respiratory insufficiency, because of the midfacial deformity which, in turn, is influenced by the malformation of the skull base. Respiratory impairment resulting from Apert syndrome is caused by multilevel limitations in airway space. Therefore

BACKGROUND Large calvarial defects represent a major reconstructive challenge, as they do not heal spontaneously. Infection causes inflammation and scarring, further reducing the healing capacity of the calvaria. Bone morphogenetic protein-2 (BMP2) has been shown to stimulate osteogenesis but has significant side effects in high doses. BMP2 has not been tested in combination with antiinflammatory cytokines such as interleukin-10. METHODS Sixteen New Zealand White rabbits underwent 15 × 15-mm flap calvarectomies. The flap was incubated in Staphylococcus aureus and replaced, and infection and scarring were allowed to develop. The flap was subsequently removed and the wound debrided. A 15 × 15-mm square of acellular dermal matrix biopatterned with low-dose BMP2, interleukin-10, or a combination was implanted. Computed tomographic scans were taken over 42 days. Rabbits were then killed and histology was performed. RESULTS Defects treated with BMP2 showed significantly (p < 0.05) greater osseous regeneration than untreated controls. Interleukin-10 did not significantly augment the healing achieved with BMP2, and interleukin-10 alone did not significantly increase healing compared with controls. Histology showed evidence of bone formation in defects treated with BMP2. Untreated controls and defects treated with interleukin-10 alone showed only fibrous tissue in the defect site. CONCLUSIONS Low-dose BMP2 delivered directly to the scarred calvarial defect augments bony healing. Interleukin-10 at the dose applied did not significantly augment healing alone or in combination with BMP2. Healing had not finished at 42 days and analysis at later time points or the use of higher doses of BMP2 may yield greater healing.

The authors' purpose was to quantify the change in unicoronal synostosis symmetry between presentation (time 0), after fronto-orbital advancement (time 1), and 2 years later (time 2).Bandeau/orbital symmetry ratios and skull base/midface twists were measured on computed tomographic scans of consecutive isolated unicoronal synostosis patients. Comparisons were made across three time points and against normal controls.Forty-three unicoronal synostosis patients and 36 controls were included. The mean bandeau ratio (symmetry = 1) changed from 0.76 (time 0), to 1.13 (time 1), and then to 1.01 (time 2). The median bandeau ratio change from time 1 to time 2 was -9.1 percent and was impacted by the degree of time 1 asymmetry. The odds of a desired symmetric or overcorrected result (bandeau ratio1.0) at time 2 were increased in patients with less severe preoperative asymmetry (OR, 4.2; p = 0.04) and in those who obtained symmetry or overcorrection at surgery (OR, 4.9; p = 0.02). Craniofacial twist did not significantly change after surgery but decreased at time 2. Orbital height ratios were 1.08, 1.00, and then 1.02 at time 2, respectively. The orbital width ratio was not significantly impacted by surgery, remaining at 0.89 at time 2.Overcorrection of the unicoronal synostosis bandeau resulted in these patients being five times more likely to have a desired result at time 2. Patients with a more severe brow presentation were four times more likely to be asymmetric at time 2. Orbital height was improved, but attention should be directed at addressing orbital width.Risk, III.

Learning objectives After studying this article, the participant should be able to: 1. Define and classify different types of cranial defects 2. Compare both autologous and alloplastic options for reconstruction 3. Develop an optimal approach for cranial vault reconstruction in various clinical scenarios. Summary Defects of the cranium result from various causes, including traumatic loss, neurosurgical intervention, skull tumors, and infection. Cranial vault reconstruction aims to restore both the structural integrity and surface morphology of the skull. To ensure a successful outcome, the choice of appropriate cranioplasty reconstruction will vary primarily based on the cause, location, and size of the defect. Other relevant factors that must be considered include adequacy of soft-tissue coverage, presence of infection, and previous or planned radiation therapy. This article presents an algorithm for the reconstruction of various cranial defects using both autologous and alloplastic techniques, with a comparison of their advantages and disadvantages.

SUMMARY Traditionally, surgical access for extirpation and reconstruction of midfacial tumors requires external incisions that can cause a myriad of complications, especially in irradiated patients. The modern midfacial degloving approach involves hidden, sublabial and intranasal incisions that provide reliable access for free flap reconstruction of nasal and maxillofacial tumors. Seven patients with a history of radiation therapy underwent free flap reconstruction of the midface. Five patients underwent the technique in a delayed manner, and the remaining two underwent reconstruction immediately at the time of resection. Five patients underwent free radial forearm fasciocutaneous free flaps and two underwent reconstruction with anterolateral thigh perforator flaps. Bone and/or rib cartilage grafting was used in all patients. All patients underwent successful free flap reconstruction of the midface without external incisions. The most common complication was postoperative infection requiring oral or intravenous antibiotics. No patients sustained loss of their grafts or hardware in the postoperative period. The midfacial degloving technique provides satisfactory exposure to the nasal cavity, midface, orbits, and skull base for free flap reconstruction, without disrupting the external soft tissue. The authors describe a novel use of the midfacial degloving technique to provide safe and reliable results with improved cosmetic outcome.

Background The purpose of this study was to quantify change in cranioorbital morphology from presentation, after fronto-orbital advancement, and at 2-year follow-up. Methods Volumetric, linear, and angular analyses were performed on computed tomographic scans of consecutive bilateral coronal synostosis patients. Comparisons were made across three time points, between syndromic and nonsyndromic cases, and against normal controls. Significance was set at p Results Twenty-five patients were included: 11 were nonsyndromic, eight had Saethre-Chotzen syndrome, and six had Muenke syndrome. Total cranial volume was comparable to normal, age-matched control subjects before and 2 years after surgery despite an expansion during surgery. Axial and sagittal vector analyses showed advancement and widening of the lower forehead beyond control values with surgery and comparable anterior position, but increased width compared to controls at 2 years. Frontal bossing decreased with a drop in anterior cranial height and advanced lower forehead position. Middle vault height was not normalized and turricephaly persisted at follow-up. Posterior fossa volume remained lower at all three time points compared to control subjects. Supraorbital retrusion relative to anterior corneal position was overcorrected by surgery, with values comparable to those of control subjects at 2 years because of differential growth. There was no difference at 2 years between syndromic and nonsyndromic groups. Conclusions Open fronto-orbital advancement successfully remodels the anterior forehead but requires overcorrection to be comparable to normal at 2 years. Although there are differences in syndromic cases at presentation, they do not result in significant morphometric differences on follow-up. Posterior fossa volume remains lower at all time points. Clinical question/level of evidence Therapeutic, IV.

Background: The association of isolated craniosynostosis and the influence of syndromic forms confound the understanding of craniofacial morphologic development. This study attempts to clarify the individual influences of isolated bicoronal synostosis, Apert syndrome, and Crouzon syndromes on skull base morphology. Methods:: One hundred seventeen computed tomographic scans were included (nonsyndromic bicoronal synostosis, n = 36; Apert syndrome with bicoronal synostosis, n = 25; Crouzon syndrome with bicoronal synostosis, n = 11; controls, n = 45). Cephalometric measurements were analyzed using Materialise software. Results: Nonsyndromic bicoronal synostosis patients developed a shortened cranial base length, with a significantly shortened distance between nasion and sella (p = 0.005). The cranial base angles of nonsyndromic bicoronal synostosis in both the cranial side (N-S-BA) and facial side (N-SO-BA) increased significantly, by 17.04 degrees (p < 0.001) and 11.75 degrees (p < 0.001), respectively. However, both the N-S-BA and N-SO-BA angles of Apert syndrome and Crouzon syndrome were narrowed more than that of nonsyndromic bicoronal synostosis [by 12.11 degrees (p < 0.001) and 12.44 degrees (p < 0.001), respectively, in Apert syndrome; and by 11.66 degrees (p = 0.007) and 13.71 degrees (p = 0.007), respectively, in Crouzon syndrome]. However, there is no statistically significant difference of these two angles between Apert syndrome and Crouzon syndrome, when they were only associated with bicoronal synostosis. Contrary to the relatively normal subcranial space of nonsyndromic bicoronal synostosis, both Apert and Crouzon syndromes developed a reduced subcranial space. Conclusions: Isolated bicoronal synostosis resulted in a flattened cranial base, whereas Apert syndrome and Crouzon syndrome developed a normal cranial base angle when only associated with bicoronal synostosis. The syndromic skulls had additional significantly reduced subcranial space.

BACKGROUND Spring-assisted surgery is an accepted alternative to cranial vault remodeling for treatment of sagittal craniosynostosis. The long-term safety and efficacy profiles of spring-assisted surgery have not been established. METHODS This study is a retrospective examination of all patients treated with spring-assisted surgery (n = 175) or cranial vault remodeling (n = 50) for sagittal craniosynostosis at the authors' institution from 2003 to 2017. Data collected included demographic and operative parameters, preoperative and postoperative Cephalic Indices, and complications. Whitaker grades were assigned blindly by a craniofacial surgeon not involved in patients' care. RESULTS The mean age at surgery was significantly lower for the spring-assisted surgery group compared with the cranial vault remodeling group (4.6 months versus 22.2 months; p < 0.001). Even when combining spring placement with spring removal operations, total surgical time (71.1 minutes versus 173.5 minutes), blood loss (25.0 ml versus 111.2 ml), and hospital stays (41.5 hours versus 90.0 hours) were significantly lower for the spring-assisted surgery cohort versus the cranial vault remodeling group (p < 0.001 for all). There were no differences in infection, reoperation rate, or headaches between the groups. The percentage improvement in Cephalic Index was not significantly different at 1 (p = 0.13), 2 (p = 0.99), and 6 (p = 0.86) years postoperatively. At 12 years postoperatively, the spring-assisted surgery group had persistently improved Cephalic Index (75.7 preoperatively versus 70.7 preoperatively). Those undergoing spring-assisted surgery had significantly better Whitaker scores, indicating less need for revision surgery, compared with the cranial vault remodeling group (p = 0.006). CONCLUSION Compared with the authors' cranial vault remodeling technique, spring-assisted surgery requires less operating room time and is associated with less blood loss, but it has equivalent long-term Cephalic Indices and subjectively better shape outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE Therapeutic, III.

Background Facial allotransplantation including the temporomandibular joints may improve the functional outcomes in face transplant candidates who have lost or damaged this joint. Methods Linear and angular measurements were taken in 100 dry skulls and mandibles and in 100 three-dimensionally-reconstructed facial computed tomographic scans to determine the variability of the temporomandibular joint, glenoid fossa, and mandible. A vascular study was performed in six fresh cadaveric heads, followed by harvest of the face allograft in three heads. Next, four heads were used for mock transplantation (two donors and two recipients). The full facial allograft included four different segments: a Le Fort III, a mandibular tooth-bearing, and two condyle and temporomandibular joint-bearing segments. Statistical analysis was performed using SAS software. Results In only one-third of the skulls, the condylar shape was symmetric between right and left sides. There was a wide variability in the condylar coronal (range, 14.3 to 23.62 mm) and sagittal dimensions (range, 5.64 to 10.96 mm), medial intercondylar distance (range, 66.55 to 89.91 mm), and intercondylar angles (range, 85.27 to 166.94 degrees). This high variability persisted after stratification by sex, ethnicity, and age. The temporomandibular joint was harvested based on the branches of the superficial temporal and maxillary arteries. The design of the allograft allowed fixation of the two condyle and temporomandibular joint-bearing segments to the recipient skull base, preserving the articular disk-condyle-fossa relationship, and differences were adjusted at the bilateral sagittal split osteotomy sites. Conclusion Procurement and transplantation of a temporomandibular joint-containing total face allograft is technically feasible in a cadaveric model.

BACKGROUND Current methods to analyze three-dimensional photography do not quantify intracranial volume, an important metric of development. This study presents the first noninvasive, radiation-free, accurate, and reproducible method to quantify intracranial volume from three-dimensional photography. METHODS In this retrospective study, cranial bones and head skin were automatically segmented from computed tomographic images of 575 subjects without cranial abnormality (average age, 5 ± 5 years; range, 0 to 16 years). The intracranial volume and the head volume were measured at the cranial vault region, and their relation was modeled by polynomial regression, also accounting for age and sex. Then, the regression model was used to estimate the intracranial volume of 30 independent pediatric patients from their head volume measured using three-dimensional photography. Evaluation was performed by comparing the estimated intracranial volume with the true intracranial volume of these patients computed from paired computed tomographic images; two growth models were used to compensate for the time gap between computed tomographic and three-dimensional photography. RESULTS The regression model estimated the intracranial volume of the normative population from the head volume calculated from computed tomographic images with an average error of 3.81 ± 3.15 percent (p = 0.93) and a correlation (R) of 0.96. The authors obtained an average error of 4.07 ± 3.01 percent (p = 0.57) in estimating the intracranial volume of the patients from three-dimensional photography using the regression model. CONCLUSION Three-dimensional photography with image analysis provides measurement of intracranial volume with clinically acceptable accuracy, thus offering a noninvasive, precise, and reproducible method to evaluate normal and abnormal brain development in young children. CLINICAL QUESTION/LEVEL OF EVIDENCE Diagnostic, V.

BACKGROUND: Dermoid cysts are benign lesions lined by keratinizing squamous epithelium that also contain epidermal adnexa (hair follicles, hair shafts, sebaceous glands, and both apocrine and eccrine sweat glands) and mesodermal derivatives (smooth muscle fibers, vascular stroma, nerves, and collagen fibers). Craniofacial dermoid cysts represent approximately 7 percent of all dermoids and have an incidence ranging between 0.03 and 0.14 percent. METHODS: The authors conducted a single-center, consecutive, nonrandomized comparative case series over a 20-year period of all patients treated surgically for craniofacial dermoid at the Royal Children's Hospital in Melbourne, Australia. Six hundred forty-seven patients had craniofacial dermoids and adequate information to be included in the study. The authors also conducted a thorough review of the literature using the MEDLINE and Embase databases. RESULTS: Six hundred forty-seven patients amounted to 655 lesions in our case series. The age at surgery ranged from 2 months to 18 years, with an average age of 25.65 months. The depth of the lesions was stratified using a classification system, and the risk of intracranial extension was assessed using these data. Midline nasal lesions are established as high risk by other studies, but frontal, temporal, and occipital lesions were found to be as risky if not more risky for intracranial extension. CONCLUSIONS: Several classification systems for craniofacial dermoid cysts have used both broader anatomical locations and physical characteristics to group these lesions and identify those warranting preoperative imaging. The authors propose a system using more specific classification of anatomical location to assist in the prompt identification of high-risk lesions and facilitate sound preoperative planning. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Background Large decompressive craniectomies may be life-saving; however, they may also result in syndrome of the trephined. This postrecovery sequela is characterized by dizziness, fatigue, depression, weakness, speech slowing, gait disturbance, and impaired mentation. Because this entity is poorly understood, the authors attempted to quantify the functional improvement in patients with syndrome of the trephined after cranial vault reconstruction. Methods Patients with cranial vault defects (>50 cm) from trauma, meningioma, and hemorrhage were studied preoperatively and postoperatively (6 months) after cranial vault reconstruction using (1) the Cognistat Active Form and (2) the Functional Independence Measure instrument (n = 40). Cranial vault reconstructive techniques varied from split cranial bone to alloplastic implants (polyetheretherketone or titanium mesh). Results Of the 143 patients treated with decompressive craniectomies, 28 percent (n = 40) developed symptoms of syndrome of the trephined. A larger craniectomy defect size correlated with development of syndrome of the trephined. Time from craniectomy to presentation of symptoms was 4.5 months. Time from craniectomy to cranial vault reconstruction was 6.1 months. Time from cranial vault reconstruction to symptom improvement was 4.3 days. Complete functional recovery of syndrome of the trephined was seen in 70 percent. Type of cranial vault reconstruction included polyetheretherketone implant (57.5 percent), split calvarial graft (22.5 percent), and titanium mesh (20 percent), and was not a determinant of functional improvement. Cognistat assessment score noted improvement (from 38 to 69); likewise, the Functional Independence Measure measurement tool showed improvement (from 38 to 98). Conclusions Syndrome of the trephined occurs more frequently than previously described in posttraumatic patients with large cranial vault defects. Cranial vault reconstruction leads to significant, quantifiable functional improvement in a large number of patients. Clinical question/level of evidence Therapeutic, IV.

When analyzing intracranial volume gain resulting from operative intervention in craniosynostosis, it is necessary to understand the underlying growth. The authors sought to create comprehensive intracranial volume and occipitofrontal circumference growth charts, as measured on unoperated craniosynostotic children, and aimed to investigate whether intracranial volume and occipitofrontal circumference could act as proxy measures for each other.All preoperative Great Ormond Street Hospital patients with a diagnosis of Apert, Crouzon-Pfeiffer, or Saethre-Chotzen syndrome from the year 2004 onward were considered for this study. A control group of unaffected Great Ormond Street Hospital patients were also measured. Intracranial volume and occipitofrontal circumference were measured on the same scans. To study correlation between intracranial volume and occipitofrontal circumference, logarithmic fits were assessed.One hundred forty-seven craniosynostotic children with 221 preoperative scans were included (81 Apert, 81 Crouzon, 31 Pfeiffer, and 28 Saethre-Chotzen). The control group comprised 56 patients with 58 scans. Apert intracranial volume curves were significantly larger than those of other syndromes from 206 days onward; occipitofrontal circumference curves were not significantly different. The correlation coefficient between intracranial volume and occipitofrontal circumference was R = 0.87 for all syndromes combined and R = 0.91 for the control group.Apert syndrome children have a larger intracranial volume than children with other syndromic craniosynostotic conditions and unaffected children but maintain a similar occipitofrontal circumference. This study demonstrates high correlation between intracranial volume and occipitofrontal circumference with clinical care implications. The authors' reference growth curves can be used to monitor intracranial volume change over time and correct operative change for underlying growth.

BACKGROUND Sphenoid wing dysplasia in patients with neurofibromatosis type 1 may result in challenging and significant changes, including ultimately vision loss. The authors describe the radiographic patterns of sphenoid dysmorphology with time and age, and the impact of surgical intervention on preservation of vision. METHODS A retrospective study was performed at a single pediatric hospital, identifying subjects with neurofibromatosis type 1. Records were reviewed in their entirety for each subject, with attention to ophthalmologic evaluation. Radiographic images were digitally analyzed and scored for sphenoid transformations on a grade of 0 to 3. RESULTS Fifty-two subjects were identified. On initial imaging, 42.31 percent had a normal sphenoid (grade 0), 32.69 percent had an abnormal contour (grade 1), 11.54 percent had thinning (grade 2), and 13.46 percent had a gross defect (grade 3). Among the 45 subjects with serial imaging, 55.56 percent demonstrated progression of the deformity of at least one grade. Deformity progression correlated with length of imaging interval. Enucleation was noted to occur more often in subjects with a gross sphenoid defect (p < 0.0001). Of subjects identified as having a gross sphenoid defect, 26.7 percent were managed using orbitosphenoid reconstruction with titanium mesh and cranial bone graft, and 33.3 percent were managed with soft-tissue debulking and canthopexy only. Vision was more likely to be preserved with early orbitosphenoid reconstruction (p < 0.05). CONCLUSIONS Sphenoid dysplasia is a progressive disease. Loss of vision is associated with a gross defect, and appears to be better preserved with early orbitosphenoid reconstruction with titanium mesh and cranial bone graft.

Background The use of magnetic resonance imaging (MRI) for virtual surgical planning has not yet been described. In the United States, over 600,000 computed tomographic (CT) scans are performed annually on children, who are at higher risk than adults of developing cancer caused by ionizing radiation. The aim of this study was to demonstrate whether three-dimensionally-printed craniofacial surgical guides created from "black bone" MRI are comparable in accuracy to those created from CT scans. Methods A mock craniosynostosis surgery translocating four calvarial segments was virtually planned and performed in 10 cadavers. For five specimens, planning was performed and three-dimensionally-printed guides were created using black bone MRI scans. Five specimens underwent standard planning using CT scans. Reconstructed skulls underwent CT scans and three-dimensional reconstruction. Accuracy was compared to that of virtually planned surgeries. Results The preoperative black bone MRI scan had an average deviation from the preoperative CT scan of 1.37 mm. There was no statistically significant difference in the fit accuracy of MRI versus CT-created guides. Average deviation of postoperative anatomy from preoperative plan was within 1.5 mm for guides created from either scanning modality, with no statistically significant difference in accuracy between the two methods. Planned versus postoperative skull volume was not statistically significantly different when MRI versus CT was used. Conclusions This study demonstrates that virtual surgical planning and three-dimensional craniofacial surgical guide creation can be performed using black bone MRI with accuracy comparable to that of CT. This could dramatically reduce radiation exposure of craniofacial reconstruction patients.

Background Restoring craniofacial symmetry is an important objective in the treatment of many craniofacial conditions. Normal form has been measured using anthropometry, cephalometry, and photography, yet all of these modalities have drawbacks. In this study, the authors define normal pediatric craniofacial form and craniofacial asymmetry using stereophotogrammetric images, which capture a densely sampled set of points on the form. Methods After institutional review board approval, normal, healthy children (n = 533) with no known craniofacial abnormalities were recruited at well-child visits to undergo full head stereophotogrammetric imaging. The children's ages ranged from 0 to 18 years. A symmetric three-dimensional template was registered and scaled to each individual scan using 25 manually placed landmarks. The template was deformed to each subject's three-dimensional scan using a thin-plate spline algorithm and closest point matching. Age-based normal facial models were derived. Mean facial asymmetry and statistical characteristics of the population were calculated. Results The mean head asymmetry across all pediatric subjects was 1.5 ± 0.5 mm (range, 0.46 to 4.78 mm), and the mean facial asymmetry was 1.2 ± 0.6 mm (range, 0.4 to 5.4 mm). There were no significant differences in the mean head or facial asymmetry with age, sex, or race. Conclusions Understanding the "normal" form and baseline distribution of asymmetry is an important anthropomorphic foundation. The authors present a method to quantify normal craniofacial form and baseline asymmetry in a large pediatric sample. The authors found that the normal pediatric craniofacial form is asymmetric, and does not change in magnitude with age, sex, or race.

BACKGROUND: This series describes the results of minimally invasive strip craniotomy with additional spring distraction.METHODS: Included are the first 83 consecutive patients who underwent this procedure (January 1, 2010, to January 1, 2014). Outcome parameters were collected prospectively and included surgical parameters and complications, the occurrence of papilledema, skull growth, cephalic index, and photographic scores.RESULTS: Duration of surgery was 63 minutes, 19 percent required blood transfusion, and complications were minor. Postoperative papilledema occurred in two patients (2.4 percent). Head growth increased after insertion of the springs and declined afterward to 0.7 SD, comparable to earlier cohorts in the authors' center. The cephalic index increased from 67 before surgery to 74 after surgery and showed a small decrease during the 4-year follow-up. Photographic scores confirmed the initial improvement and showed a trend to further improvement during follow-up.CONCLUSIONS: In this cohort, spring-assisted, minimally invasive strip craniotomy was safe and effective. Results were similar to those from other techniques but with smaller incisions, shorter interventions, reduced blood loss, and a lower incidence of postoperative papilledema.CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Supplemental Digital Content is available in the text., Background: Toll-like receptor 4 (TLR4) has been implicated in inflammation-induced bone destruction in various chronic bone diseases; however, its direct influence on bone healing is not well understood. The authors’ previous study showed accelerated bone healing with higher osteoclastogenesis gene expression in toll-like receptor 4 knockout mice (TLR4-/-). This study aimed to further elucidate the underlying cellular mechanisms during fracture healing by generating a myeloid cell-specific toll-like receptor 4 knockout model (Lyz-TLR4-/- mice). Methods: Calvarial defects, 1.8 mm in diameter, were created in wild-type, TLR4-/-, and Lyz-TLR4-/- mice. Bone healing was investigated using micro–computed tomography and histologic, histomorphometric, and immunohistochemistry analyses. Primary bone marrow–derived cells were also isolated from wild-type, TLR4-/-, and Lyz-TLR4-/- mice to measure their osteoclast differentiation and resorption properties. Results: A similar faster bone healing response, with active intramembranous bone formation, intense osteopontin staining, and more osteoblast infiltration, was observed in TLR4-/- and Lyz-TLR4-/- mice. Tartrate-resistant acid phosphatase staining showed more osteoclast infiltration in Lyz-TLR4-/- mice than in wild-type mice at day 7. Primary bone marrow–derived cells isolated from TLR4-/- and Lyz-TLR4-/- mice presented enhanced osteoclastogenesis and resorption activity compared with those from wild-type mice. Comparable M0, M1, and M2 macrophage infiltration was found among all groups at days 1, 4, and 7. Conclusions: This study revealed that inactivation of toll-like receptor 4 in myeloid cells enhanced osteoclastogenesis and accelerated healing response during skull repair. Together with the role of toll-like receptor 4 in inflammation-mediated bone destruction, it suggests that toll-like receptor 4 might regulate inflammation-induced osteoclastogenesis under different clinical settings.

Background: The relationship between trigonocephaly and cognitive problems might be explained by: secondary mechanical factors related to growth restriction of the skull, and primary structural defects caused by a shared mechanism related to brain developmental disorder(s) and skull malformation. However, because the exact pathophysiology remains unknown, we examined the pathophysiologic mechanisms behind cognitive dysfunction in patients with trigonocephaly, with an aim of providing a model for cognitive dysfunction based on routinely available variables. Methods: Included were 72 patients with trigonocephaly who were operated on. Postoperatively, intelligence was assessed prospectively. The two independent variables, secondary mechanical and primary brain developmental mechanisms, were evaluated retrospectively. Computed tomographic imaging was used to assess skull volume and severity of the frontal stenosis (secondary mechanical factors), width of the central part of the lateral ventricles, and other structural brain anomalies (primary brain developmental factors). Extracranial congenital anomalies were also taken into account. Results: No association was found between secondary mechanical factors and postoperative IQ score. Width of the central part of the lateral ventricles, and an interaction effect between this width and additional extracranial anomalies, showed a significant negative association with postoperative IQ. Conclusions: Primary brain developmental disorders seem to play an important role in the development of cognitive problems in trigonocephaly. Assessment of width of the central part of the lateral ventricle scores and additional extracranial congenital anomalies for the early prediction of cognitive problems in patients with trigonocephaly could be clinically valuable and can be performed using routinely available tools.

Supplemental Digital Content is available in the text., Background: Inflammation is integral to the injury response. The inflammatory response is essential to the host defense against infection and also to tissue regeneration and repair. Toll-like receptors (TLRs) are critical activators of the innate immune response and present attractive therapeutic targets for inflammation-modulated tissue regeneration. The authors’ previous study showed that depletion of TLR4 resulted in accelerated skull bone healing concurrent with increased expression of osteoclastogenic genes. As such, in the present study, the authors used various knockout mouse models for TLR4 and its associated signaling mediators as tools to further understand the role of Toll-like receptor–mediated inflammation in calvarial bone healing. Methods: Calvarial defects (1.8-mm diameter) were created in wild-type, TLR4 knockout (TLR4−/−), TLR2−/−, MyD88−/−, TRIF−/−, TLR4 knockout in myeloid cell (Lyz-TLR4−/−), and TLR4 knockout in dendritic-lineage cell (CD11c-TLR4−/−) mice. Bone healing was examined using micro–computed tomographic, histologic, and histomorphometric analyses. Results: Micro–computed tomographic and histomorphometric analyses revealed that TLR4-deficient mice (TLR4−/−, Lyz-TLR4−/−, and CD11c-TLR4−/−) exhibited a faster intramembraneous healing response at postoperative day 7, whereas MyD88−/− and CD11c-TLR4−/− mice showed enhanced bone healing at day 28. Conclusions: The authors’ data suggest a detrimental role for TLR4 in CD11c+ cells, mediated by Myd88 signaling, during calvarial bone healing. The authors have demonstrated that Toll-like receptor signaling components affect calvarial bone healing, establishing a link between the skeletal and immune systems during craniofacial bone healing. Toll-like receptor signaling components might be used to initiate enhanced healing in bone defects to improve clinical outcomes.

Background The authors sought to ascertain the upper limits of secondary skull defect size amenable to autogenous reconstructions and to examine outcomes of a surgical series. Published data for autogenous and alloplastic skull reconstructions were also examined to explore associations that might guide treatment. Methods A retrospective review of autogenously reconstructed secondary skull defects was undertaken. A structured literature review was also performed to assess potential differences in reported outcomes between autogenous bone and synthetic alloplastic skull reconstructions. Weighted risks were calculated for statistical testing. Results Ninety-six patients underwent autogenous skull reconstruction for an average defect size of 93 cm (range, 4 to 506 cm) at a mean age of 12.9 years. The mean operative time was 3.4 hours, 2 percent required allogeneic blood transfusions, and the average length of stay was less than 3 days. The mean length of follow-up was 28 months. There were no postoperative infections requiring surgery, but one patient underwent secondary grafting for partial bone resorption. An analysis of 34 studies revealed that complications, infections, and reoperations were more commonly reported with alloplastic than with autogenous reconstructions (relative risk, 1.57, 4.8, and 1.48, respectively). Conclusions Autogenous reconstructions are feasible, with minimal associated morbidity, for patients with skull defect sizes as large as 500 cm. A structured literature review suggests that autogenous bone reconstructions are associated with lower reported infection, complication, and reoperation rates compared with synthetic alloplasts. Based on these findings, surgeons might consider using autogenous reconstructions even for larger skull defects. Clinical question/level of evidence Therapeutic, IV.

Background Surgical repair for craniosynostosis varies depending on the infant's age, location of suture fusion, and approach (e.g., open versus endoscopic). Existing data suggest possible racial and ethnic disparities in timely access to surgical care for craniosynostosis that may, in turn, be associated with surgical approach and perioperative outcomes. This study examined racial and ethnic variation in craniosynostosis operations by surgical approach and perioperative outcomes. Methods Data were collected by the 2013 to 2015 Pediatric National Surgical Quality Improvement Program. Patients aged younger than 24 months with diagnoses and procedure codes consistent with surgery for craniosynostosis were identified. Periprocedural characteristics and surgical approach (open, endoscopic/minimally invasive, or both) were examined descriptively, overall, and separately by race and ethnicity. Results The authors identified 1982 admissions. Mean age at surgery was 7.8 ± 4.7 months. Ninety-one percent of procedures were classified as open operations, 5.8 percent were endoscopic, and 3.4 percent were both open and endoscopic. Relative to white/non-Hispanic patients, Hispanic and nonwhite patients underwent surgery at older ages, experienced longer operative and anesthesia times, and were hospitalized longer. Hispanic patients had the highest rates of open operations. Conclusions These data suggest that Hispanic and nonwhite patients tend to undergo craniosynostosis repair at older ages and to have lengthier operations than white/non-Hispanic patients. Although we were unable to examine the root cause(s) of these differences, delayed diagnosis is one factor that might result in surgery at an older age and more complex operations requiring open surgery. Prospective studies examining racial/ethnic disparities are needed to inform a comparison of outcomes associated with surgical approach.

Evaluation of surgical treatment for craniosynostosis is typically based on subjective visual assessment or simple clinical metrics of cranial shape that are prone to interobserver variability. Three-dimensional photography provides cheap and noninvasive information to assess surgical outcomes, but there are no clinical tools to analyze it. The authors aim to objectively and automatically quantify head shape from three-dimensional photography.The authors present an automatic method to quantify intuitive metrics of local head shape from three-dimensional photography using a normative statistical head shape model built from 201 subjects. The authors use these metrics together with a machine learning classifier to distinguish between patients with (n = 266) and without (n = 201) craniosynostosis (aged 0 to 6 years). The authors also use their algorithms to quantify objectively local surgical head shape improvements on 18 patients with presurgical and postsurgical three-dimensional photographs.The authors' methods detected craniosynostosis automatically with 94.74 percent sensitivity and 96.02 percent specificity. Within the data set of patients with craniosynostosis, the authors identified correctly the fused sutures with 99.51 percent sensitivity and 99.13 percent specificity. When the authors compared quantitatively the presurgical and postsurgical head shapes of patients with craniosynostosis, they obtained a significant reduction of head shape abnormalities (p0.05), in agreement with the treatment approach and the clinical observations.Quantitative head shape analysis and three-dimensional photography provide an accurate and objective tool to screen for head shape abnormalities at low cost and avoiding imaging with radiation and/or sedation. The authors' automatic quantitative framework allows for the evaluation of surgical outcomes and has the potential to detect relapses.Diagnostic, I.

BACKGROUND Patients with syndromic craniosynostosis have an increased incidence of progressive hydrocephalus and Chiari malformations, with few data on the relative benefit of various surgical interventions. The authors compare the incidence and resolution of Chiari malformations and hydrocephalus between patients undergoing posterior vault distraction osteogenesis (PVDO) and patients undergoing conventional cranial vault remodeling. METHODS Patients with syndromic craniosynostosis who underwent cranial vault surgery from 2004 to 2016 at a single academic hospital, with adequate radiographic assessments, were reviewed. Demographics, interventions, the presence of a Chiari malformation on radiographic studies and hydrocephalus requiring shunt placement were recorded. Mann-Whitney U and Fisher's exact tests were used as appropriate. RESULTS Forty-nine patients underwent PVDO, and 23 patients underwent cranial vault remodeling during the study period. Median age at surgery (p = 0.880), sex (p = 0.123), and types of syndrome (p = 0.583) were well matched. Patients who underwent PVDO had a decreased incidence of developing Chiari malformations postoperatively compared with the cranial vault remodeling cohort (2.0 percent versus 17.4 percent; p = 0.033). Not surprisingly, no significant difference was found between the groups with regard to the incidence of postoperative hydrocephalus requiring shunt placement (PVDO, 4.1 percent; cranial vault remodeling, 4.3 percent; p = 0.999). CONCLUSIONS As expected, PVDO did not significantly affect intracranial hydrodynamics to the extent that hydrocephalus shunting rates were different for patients with syndromic craniosynostosis. However, PVDO was associated with a reduced risk of developing a Chiari malformation; however, prospective evaluation is needed to determine causality. CLINICAL QUESTION/LEVEL OF EVIDENCE Therapeutic, III.

Orthognathic surgery is a powerful tool for correction of facial asymmetry and malocclusion. The goal is to achieve good dental function and facial aesthetics. Three-dimensional simulation is used for surgical planning, and bone gaps could be created to achieve facial balance. In this study, customized "spacers" were made using computer-aided design and three-dimensional printing for guides for use during surgery. With the final three-dimensional plan, the skull images were exported to 3-Matic software, where spacers were designed according to the bone gaps. Three-dimensionally-printed spacers were made and used to facilitate positioning and fixation. Consecutive patients with facial asymmetry were recruited in this prospective study. The postoperative outcome was assessed using a visual analogue scale and the three-dimensional facial surface area discrepancy index for subjective and objective evaluation. There were 12 patients and a total of 19 spacers for the Le Fort I and mandibular ramus segments. The spacers worked nicely during the bone fixation process. Mean preoperative and postoperative visual analogue scale scores were 4.83 and 7.14, with a statistically significant improvement for facial symmetry (p = 0.018). Mean preoperative and postoperative facial surface area discrepancy index was 0.95 and 0.98, and the correction of asymmetry was significant (p = 0.009). There were no related surgical complications. All patients were satisfied with the correction of facial asymmetry and malocclusion. The custom-made, three-dimensionally-printed spacers help to achieve surgical precision to correct and prevent facial asymmetry in orthognathic surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE:: Therapeutic, IV.

BACKGROUND Considerable craniofacial features of Crouzon syndrome are attributed to the dysmorphology of the cranial base. As cephalometric studies have focused mainly on the facial deformity, rather than the cranial base, the underlying cause of deformity is not as well understood. Therefore, the authors compared the cranial base development of Crouzon syndrome to controls to trace the timing of deformity in the cranial base and face, to analyze their temporal correlation. METHODS Ninety computed tomographic scans were included (Crouzon, n = 36; controls, n = 54) and divided into five age subgroups. Craniofacial cephalometric measurements were analyzed by Materialise software. RESULTS The overall cranial base length in Crouzon syndrome compared with controls decreased 8 percent (p = 0.014) on average. The posterior cranial fossa shortening accounted for most of this reduction. The cranial base displaced with the distances from basion, sella, and ethmosphenoid to posterior nasal spine shortened by 21%, 18%, and 16%, respectively (all p < 0.01) during life. Although the cranial base angle on intracranial surface remains normal, the angles on facial surface narrowed were reduced. CONCLUSIONS The cranial base deformity of Crouzon syndrome consists of the whole skull base and particularly anterior skull base shortening early, leading to a compensatory widened anterior skull base. However, when this widening did not compensate fully for the rapid enlargement of the brain, the posterior skull base displaced inferiorly and became kyphotic. The cranial base deformity develops sequentially anterior to posterior in a probable cascade of influence pattern. CLINICAL QUESTION/LEVEL OF EVIDENCE Risk, II.

Background Autogenous bone is frequently espoused as the gold standard material for cranioplasty procedures, yet alloplastic cranioplasty continues to persist in the search, presumably, for a simpler technique. Although short-term outcomes can be successful using foreign materials, long-term follow-up in these patients often demonstrates increased rates of failure because of exposure or late infection. Autogenous bone grafts, however, integrate and revascularize, and are thus more resistant to infection than alloplastic materials. Methods This is a retrospective review of all patients that underwent reconstructive cranioplasty for full-thickness defects, as performed by the senior author (S.A.W.) between 1975 and 2018. All procedures were performed with autogenous bone. Results One hundred fifty-four patients met criteria for inclusion in the report. Cranioplasties were performed for both congenital and secondary indications. Split calvaria was used in 115 patients (74.7 percent), rib graft was used in 12 patients (7.8 percent), iliac crest graft was used in 10 patients (6.5 percent), and combinations of donor-site grafts were used in 17 patients (11.0 percent). In the entire series, none of the patients suffered from complications related to infection of either the donor site or transferred bone graft. None of the patients required secondary operations to fill in defects created by the postoperative resorption. Conclusions Although autologous bone is widely considered the gold standard material for cranioplasty procedures, some argue against its use, mainly citing unpredictable resorption as the purported disadvantage. However, it is less susceptible to infection, and results in fewer long-term complications than alloplastic materials. There is no alloplastic material that has matched these outcomes, and thus autogenous bone should be considered as the primary option for cranioplasty procedures. Clinical question/level of evidence Therapeutic, IV.

Autologous bone grafts remain the gold standard for craniofacial reconstruction despite limitations of donor-site availability and morbidity. A myriad of commercial bone substitutes and allografts are available, yet no product has gained widespread use because of inferior clinical outcomes. The ideal bone substitute is both osteoconductive and osteoinductive. Craniofacial reconstruction often involves irregular three-dimensional defects, which may benefit from malleable or customizable substrates. "Hyperelastic Bone" is a three-dimensionally printed synthetic scaffold, composed of 90% by weight hydroxyapatite and 10% by weight poly(lactic-co-glycolic acid), with inherent bioactivity and porosity to allow for tissue integration. This study examines the capacity of Hyperelastic Bone for bone regeneration in a critical-size calvarial defect.Eight-millimeter calvarial defects in adult male Sprague-Dawley rats were treated with three-dimensionally printed Hyperelastic Bone, three-dimensionally printed Fluffy-poly(lactic-co-glycolic acid) without hydroxyapatite, autologous bone (positive control), or left untreated (negative control). Animals were euthanized at 8 or 12 weeks postoperatively and specimens were analyzed for new bone formation by cone beam computed tomography, micro-computed tomography, and histology.The mineralized bone volume-to-total tissue volume fractions for the Hyperelastic Bone cohort at 8 and 12 weeks were 74.2 percent and 64.5 percent of positive control bone volume/total tissue, respectively (p = 0.04). Fluffy-poly(lactic-co-glycolic acid) demonstrated little bone formation, similar to the negative control. Histologic analysis of Hyperelastic Bone scaffolds revealed fibrous tissue at 8 weeks, and new bone formation surrounding the scaffold struts by 12 weeks.Findings from our study suggest that Hyperelastic Bone grafts are effective for bone regeneration, with significant potential for clinical translation.

Background Cell-seeded biomaterial scaffolds have been proposed as a future option for reconstruction of bone tissue. The ability to generate larger, functional volumes of bone has been a challenge that may be addressed through the use of perfusion bioreactors. In this study, the authors investigated use of a tubular perfusion bioreactor system for the growth and differentiation of bone marrow stromal (mesenchymal stem) cells seeded onto fibrin, a highly angiogenic biomaterial. Methods Cells were encapsulated within fibrin beads and cultured either within a tubular perfusion bioreactor system or statically for up to 14 days. Scaffolds were analyzed for osteogenic differentiation. A rodent cranial defect model (8-mm diameter) was used to assess the bone regeneration of scaffolds cultured in the bioreactor, statically, or used immediately after formation. Immunohistochemistry was used to visualize CD31 vessel density. Micro-computed tomographic imaging was used to visualize mineral formation within the defect volume. Results Tubular perfusion bioreactor system-cultured samples showed significantly greater osteodifferentiation, indicated by an increase in VEGF expression and mineral deposition, compared with statically cultured samples. Increased expression of OPN, RUNX2, VEGF, and CD90 was seen over time in both culture methods. After implantation, bioreactor samples exhibited greater bone formation and vessel density compared with all other groups. Analysis of micro-computed tomographic images showed full union formation through the greatest diameter of the defect in all bioreactor samples and the highest levels of mineralized volume after 8 weeks. Conclusion Mesenchymal stem cells encapsulated in fibrin beads and cultured in the tubular perfusion bioreactor system resulted in increased vascularization and mineralized tissue formation in vivo relative to static culture.