Publications by authors named "James Cray"

92 Publications

Patients With a History of Oronasal Fistula Repair Exhibit Lower Oral Health Measured With Patient-Centric Outcomes Measures.

Cleft Palate Craniofac J 2020 Dec 23:1055665620981331. Epub 2020 Dec 23.

Division of Plastic and Reconstructive Surgery, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.

Introduction: Oronasal fistulae following palatoplasty may affect patients' quality of life by impacting their ability to eat, speak, and maintain oral hygiene. We aimed to quantify the impact of previous oronasal fistula repair on patients' quality of life using patient-reported outcome psychometric tools.

Methods: A cross-sectional study of 8- to 9-year-old patients with cleft palate and/or lip was completed. Patients who had a cleft team clinic between September 2018 and August 2019 were recruited. Participants were divided into 2 groups (no fistula, prior fistula repair). Differences in the individual CLEFT-Q and Child Oral Health Impact Profile-Short Form 19 (COHIP-SF 19) Oral Health scores between the 2 groups were evaluated using a multivariate analysis controlling for Veau classification and syndromic diagnosis.

Results: Sixty patients with a history of cleft palate were included. Forty-two (70%) patients had an associated cleft lip. Thirty-two (53.3%) patients had no history of fistula and 28 (46.7%) patients had undergone a fistula repair. CLEFT-Q Dental, Jaw, and Speech Function were all higher in patients without a history of a fistula repair; however, none of these differences were statistically significant. The COHIP-SF 19 Oral Health score demonstrated a significantly lower score in the fistula group, indicating poorer oral health ( = .05).

Conclusions: One would expect that successful repair of a fistula would result in improved function and patient satisfaction, but the consistent trend toward lower CLEFT-Q scores and significantly increased COHIP-SF 19 Oral Health scores in our study group suggests that residual effects linger and that the morbidity of a fistula may not be completely treated with a secondary correction.
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http://dx.doi.org/10.1177/1055665620981331DOI Listing
December 2020

Inward collapse of the nasal cavity: Perinatal consolidation of the midface and cranial base in primates.

Anat Rec (Hoboken) 2021 May 27;304(5):939-957. Epub 2020 Oct 27.

Department of Anthropology, University of Florida, Gainesville, Florida, USA.

Living primates show a complex trend in reduction of nasal cavity spaces and structures due to moderate to severe constraint on interorbital breadth. Here we describe the ontogeny of the posterior end of the primate cartilaginous nasal capsule, the thimble shaped posterior nasal cupula (PNC), which surrounds the hind end of the olfactory region. We used a histologically sectioned sample of strepsirrhine primates and two non-primates (Tupaia belangeri, Rousettus leschenaulti), and histochemical and immunohistochemical methods to study the PNC in a perinatal sample. At birth, most strepsirrhines possess only fragments of PNC, and these lack a perichondrium. Fetal specimens of several species reveal a more complete PNC, but the cartilage exhibits uneven or weak reactivity to type II collagen antibodies. Moreover, there is relatively less matrix than in the septal cartilage, resulting in clustering of chondrocytes, some of which are in direct contact with adjacent connective tissues. In one primate (Varecia spp.) and both non-primates, the PNC has a perichondrium at birth. In older, infant Varecia and Rousettus, the perichondrium of the PNC is absent, and PNC fragmentation at its posterior pole has occurred in the former. Loss of the perichondrium for the PNC appears to precede resorption of the posterior end of the nasal capsule. These results suggest that the consolidation of the basicranial and facial skeletons happens ontogenetically earlier in primates than other mammals. We hypothesize that early loss of cartilage at the sphenoethmoidal articulation limits chondral mechanisms for nasal complexity, such as interstitial expansion or endochondral ossification.
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http://dx.doi.org/10.1002/ar.24537DOI Listing
May 2021

Cranial synchondroses of primates at birth.

Anat Rec (Hoboken) 2021 May 14;304(5):1020-1053. Epub 2020 Oct 14.

Department of Public Health and Social Work, Slippery Rock University, Slippery Rock, PA.

Cranial synchondroses are cartilaginous joints between basicranial bones or between basicranial bones and septal cartilage, and have been implicated as having a potential active role in determining craniofacial form. However, few studies have examined them histologically. Using histological and immunohistochemical methods, we examined all basicranial joints in serial sagittal sections of newborn heads from nine genera of primates (five anthropoids, four strepsirrhines). Each synchondrosis was examined for characteristics of active growth centers, including a zonal distribution of proliferating and hypertrophic chondrocytes, as well as corresponding changes in matrix characteristics (i.e., density and organization of Type II collagen). Results reveal three midline and three bilateral synchondroses possess attributes of active growth centers in all species (sphenooccipital, intrasphenoidal, presphenoseptal). One midline synchondrosis (ethmoseptal) and one bilateral synchondrosis (alibasisphenoidal synchondrosis [ABS]) are active growth centers in some but not all newborn primates. ABS is oriented more anteriorly in monkeys compared to lemurs and bushbabies. The sphenoethmoidal synchondrosis (SES) varies at birth: in monkeys, it is a suture-like joint (i.e., fibrous tissue between the two bones); however, in strepsirrhines, the jugum sphenoidale is ossified while the mesethmoid remains cartilaginous. No species possesses an SES that has the organization of a growth plate. Overall, our findings demonstrate that only four midline synchondroses have the potential to actively affect basicranial angularity and facial orientation during the perinatal timeframe, while the SES of anthropoids essentially transitions toward a "suture-like" function, permitting passive growth postnatally. Loss of cartilaginous continuity at SES and reorientation of ABS distinguish monkeys from strepsirrhines.
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http://dx.doi.org/10.1002/ar.24521DOI Listing
May 2021

Degree of Asymmetry Between Patients With Complete and Incomplete Cleft Lips.

Cleft Palate Craniofac J 2021 May 30;58(5):539-545. Epub 2020 Sep 30.

Division of Plastic and Reconstructive Surgery, 7582Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.

Introduction: Surgical outcomes for patients with complete cleft lips are not as ideal as those achieved for milder phenotypes. We hypothesized that in addition to the greater width of the cleft, patients with complete cleft lip and palate exhibit a greater degree of hypoplasia and asymmetry.

Methods: Stereophotographs of 14 infants with unrepaired unilateral complete and 14 with incomplete cleft lips were measured using Vectra imaging software (Canfield Imaging). Unpaired tests were used to compare measured asymmetry between groups. Measurements included nasion to endocathion, sn-sbal, subnasale to alare (sn-al), subnasale to crista philtra, subalare to crista philtra (sbal-cphi), chelion to crista philtra, lateral lip element fullness, medial lip element fullness (mef), and non-cleft lip fullness. Duplicate measurements allowed Pearson correlation to be used to determine intra-rater reliability. Statistical significance was set at < .05.

Results: Degree of asymmetry of the nasal base, sn-al, and sn-sbal was significantly greater for patients with complete clefts ( = .0001, = .0001). Hypoplasia of the lateral lip element was seen when comparing lateral and mef ( = .04, = .004) and lateral lip height (sbal-cphi''; = .002). The degree of cupid's bow asymmetry did not differ between groups ( = .23). Intrarater reliability was high for all facial measures, ranging from 0.70 to 0.99.

Conclusions: More severe, complete cleft lips demonstrate statistically significant greater asymmetry in surgically relevant dimensions. There was greater width of the nasal base. Vertical asymmetry of cupid's bow was unaffected by cleft severity, but that asymmetry was greater in patients with complete clefts due to hypoplasia of the lateral lip element. This may contribute to the less favorable results in these patients.
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http://dx.doi.org/10.1177/1055665620962365DOI Listing
May 2021

Selective serotonin reuptake inhibitors (SSRI) affect murine bone lineage cells.

Life Sci 2020 Aug 22;255:117827. Epub 2020 May 22.

Department of Biomedical Education and Anatomy, College of Medicine, The Ohio State University, 279 Hamilton Hall, 1645 Neil Ave., Columbus, OH 43210, USA; Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH, 43210, USA. Electronic address:

Aims: Data suggest pharmacological treatment of depression with selective serotonin reuptake inhibitors (SSRI) may impair bone health. Our group has previously modeled compromised craniofacial healing after treatment with sertraline, a commonly prescribed SSRI, and hypothesized potential culprits: alterations in bone cells, collagen, and/or inflammation. Here we interrogate bone lineage cell alterations due to sertraline treatment as a potential cause of the noted compromised bone healing.

Main Methods: Murine pre-osteoblast, pre-osteoclast, osteoblast, and osteoclast cells were treated with clinically relevant concentrations of the SSRI. Studies focused on serotonin pathway targets, cell viability, apoptosis, differentiation, and the osteoblast/osteoclast feedback loop.

Key Findings: All cells studied express neurotransmitters (e.g. serotonin transporter, SLC6A4, SSRI target) and G-protein-coupled receptors associated with the serotonin pathway. Osteoclasts presented the greatest native expression of Slc6a4 with all cell types exhibiting decreases in Slc6a4 expression after SSRI treatment. Pre-osteoclasts exhibited alteration to their differentiation pathway after treatment. Pre-osteoblasts and osteoclasts showed reduced apoptosis after treatment but showed no significant differences in functional assays.

Rankl: OPG mRNA and protein ratios were decreased in the osteoblast lineage. Osteoclast lineage cells treated with sertraline demonstrated diminished TRAP positive cells when pre-exposed to sertraline prior to RANKL-induced differentiation.

Significance: These data suggest osteoclasts are a likely target of bone homeostasis disruption due to sertraline treatment, most potently through the osteoblast/clast feedback loop.
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http://dx.doi.org/10.1016/j.lfs.2020.117827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336288PMC
August 2020

Murine Aseptic Surgical Model of Femoral Atrophic Nonunion.

MethodsX 2020 21;7:100898. Epub 2020 Apr 21.

Research Services, Ralph H. Johnson VA Medical Center.

Although bone repair is typically an efficient process, an inadequate healing response can occur, with approximately 5-20% of fractures developing nonunion. Even with improved healing strategies and external fixation devices, overall rate of nonunion has not been significantly reduced, particularly for atrophic nonunion. Atrophic nonunion is characterized by sparse or no callus formation and is difficult to treat clinically, resulting in long-term pain and functional limitation. Reliable preclinical models are needed to study the pathophysiology of atrophic nonunion to create better treatment options. The MouseNail kit (RISystem, Landquart, Switzerland) provides a highly standardized approach in which stabilized segmental bone defects are achieved through interlocked intramedullary nailing. However, reliably performing this surgery is technically challenging, particularly while maintaining strict asepsis. Skilled and aseptic surgical execution is important and necessary because it ensures optimal animal welfare and reproducibility. Therefore, the aim of this paper is to describe:•Novel modifications to the MouseNail kit that allow for: 1) a completely aseptic surgical environment, including description of a hanging limb orthopedic aseptic preparation and 2) a reduction in fracture gap size necessary for induction of atrophic nonunion.•Pre- to post-operative recommendations to facilitate successful performance of murine orthopedic survival surgery.
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http://dx.doi.org/10.1016/j.mex.2020.100898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199014PMC
April 2020

rhBMP2 alone does not induce macrophage polarization towards an increased inflammatory response.

Mol Immunol 2020 01 20;117:94-100. Epub 2019 Nov 20.

Division of Anatomy, College of Medicine, The Ohio State University, 279 Hamilton Hall, 1645 Neil Ave., Columbus, OH 43210, USA; Division of Biosciences, College of Dentistry, The Ohio State University, USA. Electronic address:

Once thought to have revolutionized therapeutic intervention in surgery, Recombinant Human Bone Morphogenic Protein 2 (rhBMP2) is now in its second decade of sustained controversy over the side effects associated with its use. Side effects associated with clinical use of rhBMP2 (Infuse, Medtronic Inc) include a marked inflammatory response, pain, therapeutic failures, ectopic bone, tissue degradation, and death. What is missing, despite the depth of literature on the subject, is a direct interrogation of rhBMP2, specifically for inflammation. Here we set out to determine if rhBMP2 alters traditional macrophage markers associated with pro-inflammatory responses, and pro-reparative responses to injury. Based on our previous work, we hypothesized there would be no direct effect of the peptide on macrophage polarization. Here we utilized commercially available murine macrophages, RAW 264.7, and treated these cells with rhBMP2 in standard growth media or macrophage polarizing media (M1 and M2) at several doses of the peptide. Our readouts were cell viability, apoptosis, gene expression of M1 and M2 markers, and ELISA for M1 marker iNOS, and M2 marker Arg1. Our data give very little evidence to support an alteration in macrophage phenotype by rhBMP2 alone, or alteration of the phenotype when cultured in enriched M1 or M2 media. These results further suggest that other factors associated with the clinical use of Infuse, likely supraphysiological rhBMP2 doses and off label usage, are more likely the culprit for poor outcomes. This further reinforces the utility of rhBMP2 and other peptides in tissue engineering therapies when conditions are tightly controlled.
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http://dx.doi.org/10.1016/j.molimm.2019.10.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931256PMC
January 2020

A Novel Approach to Gross Dissection of the Human Pelvis and Perineum.

Anat Sci Educ 2020 Sep 19;13(5):618-627. Epub 2019 Dec 19.

Division of Anatomy, Department of Biomedical Education and Anatomy, The Ohio State University College of Medicine, Columbus, Ohio.

Progressive curricular changes in medical education over the past two decades have resulted in the diaspora of gross anatomy content into integrated curricula while significantly reducing total contact hours. Despite the development of a wide range of alternative teaching modalities, gross dissection remains a critical component of medical education. The challenge posed to modern anatomists is how to maximize and integrate the time spent dissecting under the current curricular changes. In this study, an alternative approach to the dissection of the pelvis and perineum is presented in an effort to improve content delivery and student satisfaction. The approach involves removal of the perineum en bloc from the cadaver followed by excision of the pubic symphysis, removal and examination of the bladder and associated structures, examination and bisection of the midline pelvic organs in situ, and midsagittal hemisection of the pelvis for identification of the neurovasculature. Results indicate that this novel dissecting approach increases the number of structures identified by 46% ± 14% over current dissecting methods. Survey results indicate that students were better able to integrate lecture and laboratory concepts, understand the concepts, and successfully identify more structures using the new approach (P < 0.05). The concept of anatomic efficiency is introduced and proposed as a standard quantitative measure of gross dissection proficiency across programs and institutions. These findings provide evidence that innovative solutions to anatomy education can be found that help to maintain critical content and student satisfaction in a modern medical curriculum.
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http://dx.doi.org/10.1002/ase.1932DOI Listing
September 2020

Pharmacological exposures may precipitate craniosynostosis through targeted stem cell depletion.

Stem Cell Res 2019 10 6;40:101528. Epub 2019 Aug 6.

Department of Biomedical Education & Anatomy, The Ohio State University College of Medicine, 279 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA. Electronic address:

The Centers for Disease Control and Prevention, National Birth Defects Study suggests that environmental exposures including maternal thyroid diseases, maternal nicotine use, and use of selective serotonin reuptake inhibitors (SSRIs) may exacerbate incidence and or severity of craniofacial abnormalities including craniosynostosis. Premature fusion of a suture(s) of the skull defines the birth defect craniosynostosis which occurs in 1:1800-2500 births. A proposed mechanism of craniosynostosis is the disruption of proliferation and differentiation of cells in the perisutural area. Here, we hypothesize that pharmacological exposures including excess thyroid hormone, nicotine, and SSRIs lead to an alteration of stem cells within the sutures resulting in premature fusion. In utero exposure to nicotine and citalopram (SSRI) increased the risk of premature suture fusion in a wild-type murine model. Gli1 stem cells were reduced, stem cell populations were depleted, and homeostasis of the suture mesenchyme was altered with exposure. Thus, although these pharmacological exposures can deplete calvarial stem cell populations leading to craniosynostosis, depletion of stem cells is not a unifying mechanism for pharmacological exposure associated craniosynostosis.
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http://dx.doi.org/10.1016/j.scr.2019.101528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915957PMC
October 2019

The Use of Prophylactic Antibiotics before Primary Palatoplasty Is Not Associated with Lower Fistula Rates: An Outcome Study Using the Pediatric Health Information System Database.

Plast Reconstr Surg 2019 08;144(2):424-431

From the Division of Plastic and Reconstructive Surgery and Health Informatics, Johns Hopkins All Children's Hospital; and the Department of Oral Health Sciences, Medical University of South Carolina.

Background: Previous attempts to study the effect of prophylactic antibiotics on the outcomes of cleft palate surgery have been hampered by the need for a very large sample size to provide adequate power to discern a potentially small therapeutic effect. This limitation can be overcome by querying large databases created by health care governing bodies.

Methods: Data from the Pediatric Health Information System database were used for this analysis. Patients, aged 6 to 18 months, who had undergone primary palatoplasty (International Classification of Diseases, Ninth Revision, code 27.62) between 2004 and 2009 were included. Subsequent repair of an oronasal fistula between 2004 and 2015 was identified by International Classification of Diseases, Ninth Revision, procedure code 21.82. Pharmacy billing records were used to determine antibiotic administration. Associations between antibiotic administration and fistula repair were assessed using random-intercept logistic regression adjusting for age, sex, race, and cleft type.

Results: Seven thousand one hundred sixty patients were available for analysis; of these, 460 (6.4 percent) had a subsequent repair of an oronasal fistula. Fistula rates were 5.9, 11.4, and 5.2 percent among patients given preoperative antibiotics, only postoperative antibiotics, and no antibiotics, respectively (p < 0.001). Multivariable analysis results showed that the odds of having an oronasal fistula among patients who were administered preoperative antibiotics did not differ significantly (statistically) from patients who did not receive antibiotics (OR, 0.88; 95 percent CI, 0.59 to 1.31).

Conclusions: The treatment goal of primary palatoplasty is the successful repair of the cleft without an oronasal fistula. Administration of preoperative antibiotics did not significantly reduce the odds of subsequent fistula repair within the same Pediatric Health Information System institution following primary palatoplasty.

Clinical Question/level Of Evidence: Therapeutic, III.
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http://dx.doi.org/10.1097/PRS.0000000000005843DOI Listing
August 2019

Interleukin-10 Does Not Augment Osseous Regeneration in the Scarred Calvarial Defect Achieved with Low-Dose Biopatterned BMP2.

Plast Reconstr Surg 2019 06;143(6):1215e-1223e

From the Department of Plastic Surgery, University of Pittsburgh; Biomedical Engineering and Biological Sciences and The Robotics Institute, Carnegie Mellon University; and The Ohio State University College of Medicine.

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 débrided. 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.
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http://dx.doi.org/10.1097/PRS.0000000000005640DOI Listing
June 2019

Early Blood Profile of C57BL/6 Mice Exposed to Chronic Unpredictable Stress.

Front Psychiatry 2019 24;10:230. Epub 2019 Apr 24.

Research Services, Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, SC, United States.

Physiological responses to psychological stressors are protective in acute fight or flight situations; however, there is increasing evidence suggesting the detrimental impact of chronic psychological stress on disease. Chronic stress has been associated with inflammation, poor prognosis, increased morbidity, and poor outcome in many diseases including atherosclerosis, cancer, and pulmonary disease. Given the systemic impact of stress, and the role of the hematopoietic system as a rapid responder to homeostatic insults, we hypothesized that early blood profile changes and biochemical alterations could be detected in a model of chronic stress. To test this hypothesis, a variation of the chronic unpredictable stress (CUS) model was employed. Following 10 days of CUS, C57BL/6 mice exhibited a chronic-stress-associated corticosterone profile. Complete blood count (CBC) revealed mild normochromic, normocytic anemia, and reduced monocyte and lymphocyte count. Serum analysis demonstrated hypoferremia with unchanged total iron binding capacity and serum ferritin levels. These findings are consistent with clinical diagnostic parameters for anemia of chronic disease and indicate that CUS results in significant changes in blood and serum biochemical profile in C57BL/6 mice. These studies identify early changes in blood parameters in response to CUS and identify hematopoietic and biochemical alterations that are often associated with increased morbidity in patients experiencing chronic-stress-associated mental health disease.
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http://dx.doi.org/10.3389/fpsyt.2019.00230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491828PMC
April 2019

Teaching Surgical Model Development in Research by Using Situated Learning and Instructional Scaffolding.

J Am Assoc Lab Anim Sci 2019 05 15;58(3):321-328. Epub 2019 Apr 15.

Research Services, Ralph H Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina; Departments of Pathology and Laboratory Medicine, Orthopedics, Medical University of South Carolina, Charleston, South Carolina; Departments of Pathology and Laboratory Medicine, Orthopedics, Medical University of South Carolina, Charleston, South Carolina;, Email:

Resources detailing the scope, details, and duration for teaching and learning surgical model development in research are poorly described. Situated learning and instructional scaffolding are useful skill-building tools. Herein, we discuss educational theory in the context of a training paradigm for surgical researchers, using our experience with a nonunion femoral fracture model as an example. Stages of learning include cognitive, associative, and autonomous stages. In surgical training, the cognitive stage involves the acquisition of basic knowledge, including anatomy, surgical approach, instrumentation, and suturing, which can be taught by using books, videos, skeletons, and cadavers. To these basic skills, the associative stage adds advanced techniques-including anesthesia, asepsis, hemostasis, and the full surgical procedure-through mentored nonsurvival surgical experiences. After a mentor has assured competence, trainees perform supervised and then independent survival surgeries to complete the autonomous stage. Through these stages, instructional scaffolding is applied in the context of a situated learning environment in which trainees learn in a layered approach through their own experiences. Thus, the proposed training paradigm is structured to teach trainees how to think and act as surgeons so they can adapt and grow, rather than only to ensure technical competency in a specific model. Development and mastery of complex surgical models may require as long as 6 mo to achieve optimal outcomes, depending on the preexisting skill of the research surgeons, technical difficulty, and the stage of model evolution.
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http://dx.doi.org/10.30802/AALAS-JAALAS-18-000090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526500PMC
May 2019

Postoperative Drain Use in Cranial Vault Remodeling: A Survey of Craniofacial Surgeon Practices and a Review of the Literature.

Cleft Palate Craniofac J 2019 09 18;56(8):1001-1007. Epub 2019 Mar 18.

1 Division of Plastic and Reconstructive Surgery, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.

Background: The use of subgaleal drains following primary cranioplasty for craniosynostosis has undergone limited investigation. Proposed benefits include prevention of seroma, detection of postoperative bleeding, and cerebrospinal fluid leak. We conducted a systematic review of the literature and surveyed craniofacial surgeons to ascertain the current evidence pertaining to drain use following primary cranioplasty for craniosynostosis and to determine surgical practice patterns.

Methods: PubMed and Embase databases were searched to identify relevant articles. Abstracts were reviewed by 2 investigators, and a Cohen κ statistic was calculated. Patient demographic and outcome data were extracted and compared. A 9-question survey was e-mailed to active and associate members of the American Society of Craniofacial Surgeons.

Results: A total of 7395 unique citations were identified. Only 2 retrospective chart reviews met inclusion criteria. All objective parameters demonstrated no difference between patients with and without drains. A subjective benefit of limiting facial swelling was proposed without objective analysis. Fifty (32.5%) of the 154 craniofacial surgeons responded to the survey. Forty-two percent used postoperative drains. A significant association ( = .01) was found between the belief that drains limited facial swelling and their use.

Conclusions: The literature examining postoperative drain use in primary cranioplasty for craniosynostosis is restricted. The current studies show no definite benefit to drain use but are limited in their assessment of key outcomes. There is wide variability among surgeons regarding drain use, and this seems to be motivated by belief and tradition.
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http://dx.doi.org/10.1177/1055665619836509DOI Listing
September 2019

Direct Effects of Nicotine Exposure on Murine Calvaria and Calvarial Cells.

Sci Rep 2019 03 7;9(1):3805. Epub 2019 Mar 7.

Department of Biomedical Education & Anatomy, The Ohio State University College of Medicine, 279 Hamilton Hall, 1645 Neil Ave, Columbus, Ohio, 43210, USA.

Despite the link between adverse birth outcomes due to pre- and peri-natal nicotine exposure, research suggests 11% of US women continue to smoke or use alternative nicotine products throughout pregnancy. Maternal smoking has been linked to incidence of craniofacial anomalies. We hypothesized that pre-natal nicotine exposure may directly alter craniofacial development independent of the other effects of cigarette smoking. To test this hypothesis, we administered pregnant C57BL6 mice drinking water supplemented with 0, 50, 100 or 200 μg/ml nicotine throughout pregnancy. On postnatal day 15 pups were sacrificed and skulls underwent micro-computed tomography (µCT) and histological analyses. Specific nicotinic acetylcholine receptors, α3, α7, β2, β4 were identified within the calvarial growth sites (sutures) and centers (synchondroses). Exposing murine calvarial suture derived cells and isotype cells to relevant circulating nicotine levels alone and in combination with nicotinic receptor agonist and antagonists resulted in cell specific effects. Most notably, nicotine exposure increased proliferation in calvarial cells, an effect that was modified by receptor agonist and antagonist treatment. Currently it is unclear what component(s) of cigarette smoke is causative in birth defects, however these data indicate that nicotine alone is capable of disrupting growth and development of murine calvaria.
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http://dx.doi.org/10.1038/s41598-019-40796-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405741PMC
March 2019

Sub-clinical dose of bone morphogenetic protein-2 does not precipitate rampant, sustained inflammatory response in bone wound healing.

Wound Repair Regen 2019 07 9;27(4):335-344. Epub 2019 Mar 9.

Division of Anatomy, College of Medicine, The Ohio State University, Columbus, Ohio.

Large bone injuries, defects, and chronic wounds present a major problem for medicine. Several therapeutic strategies are used clinically to precipitate bone including a combination therapy delivering osteoinductive bone morphogenetic protein 2 (rhBMP-2) via an osteoconductive scaffold (absorbable collagen sponge [ACS], i.e., INFUSE). Adverse side effects reportedly associated with rhBMP2 administration include rampant inflammation and clinical failures. Although acute inflammation is necessary for proper healing in bone, inflammatory cascade dysregulation can result in sustained tissue damage and poor healing. We hypothesized that a subclinical dose of rhBMP2 modeled in the murine calvarial defect would not precipitate alterations to inflammatory markers during acute phases of bone wound healing. We utilized the 5 mm critical size calvarial defect in C57BL6 wild-type mice which were subsequently treated with ACS and a subclinical dose of rhBMP2 shown to be optimal for healing. Three and 7-day postoperative time points were used to assess the role that rhBMP-2 plays in modulating inflammation vs. ACS alone by cytokine array and histological interrogation. Data revealed that rhBMP-2 delivery resulted in substantial modulation of several markers associated with inflammation, most of which decreased to levels similar to control by the 7-day time point. Additionally, while rhBMP-2 administration increased macrophage response, this peptide had a little noticeable effect on traditional markers of macrophage polarization (M1-iNOS, M2-Arg1). These results suggest that rhBMP-2 delivered at a lower dose does not precipitate rampant inflammation. Thus, an assessment of dosing for rhBMP-2 therapies may lead to better healing outcomes and less surgical failure.
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http://dx.doi.org/10.1111/wrr.12710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602834PMC
July 2019

Optimizing bone wound healing using BMP2 with absorbable collagen sponge and Talymed nanofiber scaffold.

J Transl Med 2018 11 21;16(1):321. Epub 2018 Nov 21.

Division of Anatomy, Department of Biomedical Education & Anatomy, The Ohio State University College of Medicine, 279 Hamilton Hall, 1645 Neil Ave., Columbus, OH, 43210, USA.

Background: Bone is a highly vascularized and resilient organ with innate healing abilities, however some bone injuries overwhelm these attributes and require intervention, such as bone tissue engineering strategies. Combining biomaterials and growth factors, such as bone morphogenetic protein 2 (BMP2), is one of the most commonly used tissue engineering strategies. However, use of BMP2 has been correlated with negative clinical outcomes including aberrant inflammatory response, poor quality bone, and ectopic bone.

Methods: In the present study, a novel poly-n-acetyl glucosamine (pGlcNAc, trade name Talymed) scaffold was utilized in addition to the commonly used acellular collagen sponge (ACS) BMP2 delivery system in a murine calvarial defect model to investigate whether the innate properties of Talymed can reduce the noted negative bone phenotypes associated with BMP2 treatment.

Results: Comparison of murine calvarial defect healing between ACS with and without Talymed revealed that there was no measurable healing benefit for the combined treatment. Healing was most effective utilizing the traditional acellular collagen sponge with a reduced dose of BMP2.

Conclusions: The results of this investigation lead to the conclusion that excessive dosing of BMP2 may be responsible for the negative clinical side effects observed with this bone tissue engineering strategy. Rather than augmenting the currently used ACS BMP2 bone wound healing strategy with an additional anti-inflammatory scaffold, reducing the dose of BMP2 used in the traditional delivery system results in optimal healing without the published negative side effects of BMP2 treatment.
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http://dx.doi.org/10.1186/s12967-018-1697-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249740PMC
November 2018

Identification of circulating murine CD34OCN cells.

Cytotherapy 2018 11 16;20(11):1371-1380. Epub 2018 Oct 16.

Research Services, Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, SC, USA; Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA. Electronic address:

Background Aims: Previous studies identified a circulating human osteoblastic population that expressed osteocalcin (OCN), increased following fracture and pubertal growth, and formed mineralized colonies in vitro and bone in vivo. A subpopulation expressed CD34, a hematopoietic/endothelial marker. These findings led to our hypothesis that hematopoietic-derived CD34OCN cells exist in the circulation of mice and are modulated after fracture.

Methods: Flow cytometry was used to identify CD34OCN cells in male B6.SJL-PtprcPepc/BoyJ and Vav-Cre/mTmG (VavR) mice. Non-stabilized tibial fractures were created by three-point bend. Fractures were longitudinally imaged by micro-computed tomography, and immunofluorescent staining was used to evaluate CD34OCN cells within fracture callus. AMD3100 (10 mg/kg) was injected subcutaneously for 3 days and the CD34OCN population was evaluated by flow cytometry.

Results: Circulating CD34OCN cells were identified in mice and confirmed to be of hematopoietic origin (CD45; Vav1) using two mouse models. Both circulating and bone marrow-derived CD34OCN cells peaked three weeks post-non-stabilized tibial fracture, suggesting association with cartilage callus transition to bone and early mineralization. Co-expression of CD34 and OCN in the fracture callus at two weeks post-fracture was observed. By three weeks, there was 2.1-fold increase in number of CD34OCN cells, and these were observed throughout the fracture callus. AMD3100 altered CD34OCN cell levels in peripheral blood and bone marrow.

Discussion: Together, these data demonstrate a murine CD34OCN circulating population that may be directly involved in fracture repair. Future studies will molecularly characterize CD34OCN cells, determine mechanisms regulating their contribution, and examine if their number correlates with improved fracture healing outcomes.
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http://dx.doi.org/10.1016/j.jcyt.2018.07.004DOI Listing
November 2018

Reconstruction of a Calvarial Wound Complicated by Infection: Comparing the Effects of Biopatterned Bone Morphogenetic Protein 2 and Vascular Endothelial Growth Factor.

J Craniofac Surg 2019 Jan;30(1):260-264

Department of Plastic Surgery, University of Pittsburgh.

Bone morphogenetic protein 2 (BMP2) bioprinted on biological matrix induces osseous regeneration in large calvarial defects in rabbits, both uncomplicated and scarred. Healing in unfavorable defects scarred from previous infection is decreased due in part to the lack of vascularity. This impedes the access of mesenchymal stem cells, key to osseous regeneration and the efficacy of BMP2, to the wound bed. The authors hypothesized that bioprinted vascular endothelial growth factor (VEGF) would augment the osseous regeneration achieved with low dose biopatterned BMP2 alone. Thirteen New Zealand white rabbits underwent subtotal calvariectomy using a dental cutting burr. Care was taken to preserve the underlying dura. A 15 mm × 15 mm flap of bone was cut away and incubated in a 1 × 108 cfu/mL planktonic solution of S aureus before reimplantation. After 2 weeks of subsequent infection the flap was removed and the surgical wound debrided followed by 10 days of antibiotic treatment. On postoperative day 42 the calvarial defects were treated with acellular dermal matrix bioprinted with nothing (control), VEGF, BMP2, BMP2/VEGF combined. Bone growth was analyzed with serial CT and postmortem histology. Defects treated with BMP2 (BMP2 alone and BMP2/VEGF combination) showed significantly greater healing than control and VEGF treated defect (P < 0.5). Vascular endothelial growth factor treated defect demonstrated less healing than control and VEGF/BMP2 combination treatments achieved less healing than BMP2 alone though these differences were nonsignificant. Low dose BMP2-patterned acellular dermal matrix improves healing of scarred calvarial defects. Vascular endothelial growth factor at the doses applied in this study failed to increase healing.
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http://dx.doi.org/10.1097/SCS.0000000000004779DOI Listing
January 2019

Anthropometric Evaluation of Periorbital Region and Facial Projection Using Three-Dimensional Photogrammetry.

J Craniofac Surg 2018 Nov;29(8):2017-2020

Division of Plastic and Reconstructive Surgery, Johns Hopkins All Children's Hospital, St. Petersburg.

Introduction: Direct anthropometric and three-dimensional (3D) photogrammetry measurements have been used extensively in cleft/craniofacial surgery to assess morphological changes and surgical outcomes. Craniofacial procedures alter the sagittal projection of periorbital bony prominences. Mulliken described a method of measuring their projection relative to the corneal plane but is impractical in clinical practice. Three-dimensional photogrammetry may offer a solution; however, the cornea is not visualized on this. The authors propose to develop new normative measurements of facial projection relative to the pupil.

Methods: Five 3D photographs were taken of 5 individuals using Vectra M5 camera. Facial projection measurements were taken of the sagittal projection of the bilateral periorbital landmarks and nasal radix relative to the pupil using Mirror 3D analysis. Standard deviations (SD) were determined for each subject and laterality. Chi-square tests confirmed all SD <1 mm. Intra and inter-rater reliability were confirmed with an intraclass correlation coefficient assessment.

Results: Three male and 2 female subjects were photographed with 5 unique images. Standard deviations of repeat measures of all landmarks were <0.5 mm. Chi-square tests confirmed with statistical significance that SD for all values except for the radix was <1 mm (P<0.05). Intrarater reliability was high for all landmarks (intraclass correlation coefficient coefficients 0.93-0.99). Inter-rater reliability was good for the lateral canthi and excellent for all others.

Conclusion: This technique demonstrates repeatability with high reliability on serial photographs and is applicable to measuring surgery effects and growth on facial projection. Establishment of age-specific normative values for landmark projection will refine usage applicability in operative planning.
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http://dx.doi.org/10.1097/SCS.0000000000004761DOI Listing
November 2018

Genetic associations and phenotypic heterogeneity in the craniosynostotic rabbit.

PLoS One 2018 20;13(9):e0204086. Epub 2018 Sep 20.

Department of Plastic Surgery, University of Pittsburgh/Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

Craniosynostosis (CS) is a disorder that involves the premature ossification of one or more cranial sutures. Our research team has described a naturally occurring rabbit model of CS with a variable phenotype and unknown etiology. Restriction-site associated DNA (RAD) sequencing is a genomic sampling method for identifying genetic variants in species with little or no existing sequence data. RAD sequencing data was analyzed using a mixed linear model to identify single nucleotide polymorphisms (SNPs) associated with disease occurrence and onset in the rabbit model of CS. SNPs achieving a genome-wide significance of p ≤ 5 x 10-8 were identified on chromosome 2 in association with disease occurrence and on chromosomes 14 and 19 in association with disease onset. Genotyping identified a coding variant in fibroblast growth factor binding protein 1 (FGFBP-1) on chromosome 2 and a non-coding variant upstream of integrin alpha 3 (ITGA3) on chromosome 19 that associated with disease occurrence and onset, respectively. Retrospective analysis of patient data revealed a significant inverse correlation between FGFBP-1 and ITGA3 transcript levels in patients with coronal CS. FGFBP-1 and ITGA3 are genes with roles in early development that warrant functional study to further understand suture biology.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0204086PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147457PMC
March 2019

Selective serotonin re-uptake inhibitor sertraline inhibits bone healing in a calvarial defect model.

Int J Oral Sci 2018 09 3;10(3):25. Epub 2018 Sep 3.

Oral Health Sciences, Medical University of South Carolina, Charleston, SC, USA.

Bone wound healing is a highly dynamic and precisely controlled process through which damaged bone undergoes repair and complete regeneration. External factors can alter this process, leading to delayed or failed bone wound healing. The findings of recent studies suggest that the use of selective serotonin reuptake inhibitors (SSRIs) can reduce bone mass, precipitate osteoporotic fractures and increase the rate of dental implant failure. With 10% of Americans prescribed antidepressants, the potential of SSRIs to impair bone healing may adversely affect millions of patients' ability to heal after sustaining trauma. Here, we investigate the effect of the SSRI sertraline on bone healing through pre-treatment with (10 mg·kg sertraline in drinking water, n = 26) or without (control, n = 30) SSRI followed by the creation of a 5-mm calvarial defect. Animals were randomized into three surgical groups: (a) empty/sham, (b) implanted with a DermaMatrix scaffold soak-loaded with sterile PBS or (c) DermaMatrix soak-loaded with 542.5 ng BMP2. SSRI exposure continued until sacrifice in the exposed groups at 4 weeks after surgery. Sertraline exposure resulted in decreased bone healing with significant decreases in trabecular thickness, trabecular number and osteoclast dysfunction while significantly increasing mature collagen fiber formation. These findings indicate that sertraline exposure can impair bone wound healing through disruption of bone repair and regeneration while promoting or defaulting to scar formation within the defect site.
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http://dx.doi.org/10.1038/s41368-018-0026-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119683PMC
September 2018

Testing a novel nanofibre scaffold for utility in bone tissue regeneration.

J Tissue Eng Regen Med 2018 10 29;12(10):2055-2066. Epub 2018 Aug 29.

Division of Anatomy, College of Medicine, The Ohio State University, Columbus, Ohio.

Many variables serve to alter the process of bone remodelling and diminish regeneration including the size and nature of the wound bed and health status of the individual. To overcome these inhibitory factors, tissue-engineered osteoconductive scaffolds paired with various growth factors have been utilized clinically. However, many limitations still remain, for example, bone morphogenetic protein 2 (BMP2) can lead to rampant inflammation, ectopic bone formation, and graft failure. Here, we studied the ability for a nanofiber scaffold (Talymed) to accelerate BMP2 growth factor-induced bone healing compared with the traditional absorbable collagen sponge (ACS) delivery system. One hundred fifty-five adult wild type mice were arranged in 16 groups by time, 4 and 8 weeks, and treatment, ACS or Talymed, loaded with control, low, medium, or high dosages of BMP2. Skulls were subjected to microCT, biomechanical, and histological analysis to assess bone regeneration. The use of Talymed within the defect site was found to decrease the bone volume, bone formation rate, and alkaline phosphatase activity compared with ACS/BMP2 combinations. Interestingly, though Talymed regenerated less bone, the regenerate was found to have a greater hardness value than that of bone within the ACS groups. However, the difference in bone hardness between scaffolds was not detectable by 8 weeks. Based on these results, we found that the nanofiber scaffold generated a better quality of bone regenerate at 4 weeks but, due to the lack of overall bone formation and the inhibition of normal remodelling processes, was not as efficacious as the current clinical standard ACS/BMP2 therapy.
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http://dx.doi.org/10.1002/term.2740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175654PMC
October 2018

Involvement of calvarial stem cells in healing: A regional analysis of large cranial defects.

Wound Repair Regen 2018 09 8;26(5):359-365. Epub 2018 Nov 8.

Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina.

Large craniofacial defects present a substantial clinical challenge that often requires the use of osteoconductive matrices and osteoinductive cues (i.e., bone morphogenetic proteins [BMP2]) to augment healing. While these methods have improved clinical outcomes, a better understanding of how the osteogenic fronts surrounding the defect, the underlying dura mater, and the cranial suture area contribute to healing may lead to more targeted therapies to enhance bone regeneration. We hypothesized that healing within a large bone defect will be precipitated from cells within the remaining or available suture mesenchyme abutting the edges of a murine critical sized defect. To investigate this hypothesis, 39 adult, wild-type mice were randomly arranged into groups (9 or 10 per group) by time (4 and 8 weeks) and treatment (control, acellular collagen sponge alone, or acellular collagen sponge loaded with a clinically relevant scaled dosage of BMP2). The skulls were then subjected to microcomputed tomography and histological analysis to assess bone regeneration in regions of interest within the defect area. A regional assessment of healing indicated that BMP2 drives greater healing than control and that healing emanates from the surgical margin, particularly from the margin associated with undisrupted suture mesenchyme. Though BMP2 treatment drove an increase in cell presence within the healing defect, there was no regional orientation of craniofacial stem cells or vascularity. Overall, these data reinforce that osteoconductive matrices in conjunction with osteoinductive peptides result in better healing of large calvarial defects. This healing is characterized as emanating from the surgical margin where there is an abundant supply of vasculature and progenitor cells.
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http://dx.doi.org/10.1111/wrr.12658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398939PMC
September 2018

Maternal environment and craniofacial growth: geometric morphometric analysis of mandibular shape changes with in utero thyroxine overexposure in mice.

J Anat 2018 07 2;233(1):46-54. Epub 2018 Apr 2.

Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA.

An estimated 3% of US pregnancies are affected by maternal thyroid dysfunction, with between one and three of every 1000 pregnancies being complicated by overactive maternal thyroid levels. Excess thyroid hormones are linked to neurological impairment and excessive craniofacial variation, affecting both endochondral and intramembranous bone. Using a geometric morphometric approach, this study evaluates the role of in utero thyroxine overexposure on the growth of offspring mandibles in a sample of 241 mice. Canonical variate analysis utilized 16 unilateral mandibular landmarks obtained from 3D micro-computed tomography to assess shape changes between unexposed controls (n = 63) and exposed mice (n = 178). By evaluating shape changes in the mandible among three age groups (15, 20 and 25 days postnatal) and different dosage levels (low, medium and high), this study found that excess maternal thyroxine alters offspring mandibular shape in both age- and dosage-dependent manners. Group differences in overall shape were significant (P < 0.001), and showed major changes in regions of the mandible associated with muscle attachment (coronoid process, gonial angle) and regions of growth largely governed by articulation with the cranial base (condyle) and occlusion (alveolus). These results compliment recent studies demonstrating that maternal thyroxine levels can alter the cranial base and cranial vault of offspring, contributing to a better understanding of both normal and abnormal mandibular development, as well as the medical implications of craniofacial growth and development.
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http://dx.doi.org/10.1111/joa.12810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987819PMC
July 2018

Marginal discrepancy of noble metal-ceramic fixed dental prosthesis frameworks fabricated by conventional and digital technologies.

J Prosthet Dent 2018 Feb 15;119(2):307.e1-307.e7. Epub 2017 Nov 15.

Private practice, Seattle, Wash.

Statement Of Problem: Studies evaluating the marginal adaptation of available computer-aided design and computer-aided manufacturing (CAD-CAM) noble alloys for metal-ceramic prostheses are lacking.

Purpose: The purpose of this in vitro study was to evaluate the vertical marginal adaptation of cast, milled, and direct metal laser sintered (DMLS) noble metal-ceramic 3-unit fixed partial denture (FDP) frameworks before and after fit adjustments.

Material And Methods: Two typodont teeth were prepared for metal-ceramic FDP abutments. An acrylic resin pattern of the prepared teeth was fabricated and cast in nickel-chromium (Ni-Cr) alloy. Each specimen group (cast, milled, DMLS) was composed of 12 casts made from 12 impressions (n=12). A single design for the FDP substructure was created on a laboratory scanner and used for designing the specimens in the 3 groups. Each specimen was fitted to its corresponding cast by using up to 5 adjustment cycles, and marginal discrepancies were measured on the master Ni-Cr model before and after laboratory fit adjustments.

Results: The milled and DMLS groups had smaller marginal discrepancy measurements than those of the cast group (P<.001). Significant differences were found in the number of adjustments among the groups, with the milled group requiring the minimum number of adjustments, followed by the DMLS and cast groups (F=30.643, P<.001).

Conclusions: Metal-ceramic noble alloy frameworks fabricated by using a CAD-CAM workflow had significantly smaller marginal discrepancies compared with those with a traditional cast workflow, with the milled group demonstrating the best marginal fit among the 3 test groups. Manual refining significantly enhanced the marginal fit of all groups. All 3 groups demonstrated marginal discrepancies within the range of clinical acceptability.
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http://dx.doi.org/10.1016/j.prosdent.2017.08.012DOI Listing
February 2018

Biomechanical Integrity in Craniofacial Surgery: Calvarial Reconstruction in Favorable and Infected Defects with Bone Morphogenetic Protein 2.

Plast Reconstr Surg 2017 May;139(5):1141-1150

Pittsburgh, Pa.; and Augusta, Ga.

Background: The limitations of autologous and alloplastic reconstruction for craniofacial bone defects have created a clinical need for viable tissue-engineering strategies. Recombinant human bone morphogenetic protein-2 (rhBMP-2) has shown promise in this setting. The aim of this study was to determine the long-term biomechanical properties of rhBMP-2-mediated calvarial reconstruction.

Methods: Twelve-week-old New Zealand White rabbits underwent subtotal calvarectomy. Defects were repaired in one of several groups: immediate reconstruction with autologous graft, immediate reconstruction with cryopreserved bone graft, immediate reconstruction with rhBMP-2 (favorable), and delayed reconstruction with rhBMP-2 following infection and subsequent débridement (unfavorable). Cryopreserved reconstructions were measured at 6 weeks; autologous reconstructions were measured at 6 weeks and 6 months; and both favorable and unfavorable rhBMP-2 reconstructions were assessed at 6 weeks, 6 months, and 1 year after reconstruction. Healing was assessed with computed tomography. An unconfined compression test was performed for biomechanical analysis. Stress at 20 percent strain, percentage relaxation, tangent modulus, and final strain at 1800 N were compared between groups.

Results: Nearly complete radiographic coverage was achieved by 6 months for autologous reconstruction and by 6 weeks for rhBMP-2 reconstruction. Favorable rhBMP-2 reconstruction demonstrated a larger final strain at 1800 N through 1 year compared with native bone. Bone in unfavorable rhBMP-2 reconstruction was more compressible than native bone, with a larger final strain at 1800 N at 1 year. There were no significant differences between favorable and unfavorable groups.

Conclusions: Despite providing radiographic coverage, the biomechanical properties of rhBMP-2 bone differ from those of native bone. Further studies are warranted to determine how these properties affect overall strength and structural integrity.
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http://dx.doi.org/10.1097/PRS.0000000000003261DOI Listing
May 2017

Thyroxine Exposure Effects on the Cranial Base.

Calcif Tissue Int 2017 09 8;101(3):300-311. Epub 2017 Apr 8.

Department of Oral Health Sciences, Medical University of South Carolina, 173 Ashley Avenue, BS 230B, Charleston, SC, 29425, USA.

Thyroid hormone is important for skull bone growth, which primarily occurs at the cranial sutures and synchondroses. Thyroid hormones regulate metabolism and act in all stages of cartilage and bone development and maintenance by interacting with growth hormone and regulating insulin-like growth factor. Aberrant thyroid hormone levels and exposure during development are exogenous factors that may exacerbate susceptibility to craniofacial abnormalities potentially through changes in growth at the synchondroses of the cranial base. To elucidate the direct effect of in utero therapeutic thyroxine exposure on the synchondroses in developing mice, we provided scaled doses of the thyroid replacement drug, levothyroxine, in drinking water to pregnant C57BL6 wild-type dams. The skulls of resulting pups were subjected to micro-computed tomography analysis revealing less bone volume relative to tissue volume in the synchondroses of mouse pups exposed in utero to levothyroxine. Histological assessment of the cranial base area indicated more active synchondroses as measured by metabolic factors including Igf1. The cranial base of the pups exposed to high levels of levothyroxine also contained more collagen fiber matrix and an increase in markers of bone formation. Such changes due to exposure to exogenous thyroid hormone may drive overall morphological changes. Thus, excess thyroid hormone exposure to the fetus during pregnancy may lead to altered craniofacial growth and increased risk of anomalies in offspring.
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http://dx.doi.org/10.1007/s00223-017-0278-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545063PMC
September 2017

Effects of In Utero Thyroxine Exposure on Murine Cranial Suture Growth.

PLoS One 2016 13;11(12):e0167805. Epub 2016 Dec 13.

Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America.

Large scale surveillance studies, case studies, as well as cohort studies have identified the influence of thyroid hormones on calvarial growth and development. Surveillance data suggests maternal thyroid disorders (hyperthyroidism, hypothyroidism with pharmacological replacement, and Maternal Graves Disease) are linked to as much as a 2.5 fold increased risk for craniosynostosis. Craniosynostosis is the premature fusion of one or more calvarial growth sites (sutures) prior to the completion of brain expansion. Thyroid hormones maintain proper bone mineral densities by interacting with growth hormone and aiding in the regulation of insulin like growth factors (IGFs). Disruption of this hormonal control of bone physiology may lead to altered bone dynamics thereby increasing the risk for craniosynostosis. In order to elucidate the effect of exogenous thyroxine exposure on cranial suture growth and morphology, wild type C57BL6 mouse litters were exposed to thyroxine in utero (control = no treatment; low ~167 ng per day; high ~667 ng per day). Thyroxine exposed mice demonstrated craniofacial dysmorphology (brachycranic). High dose exposed mice showed diminished area of the coronal and widening of the sagittal sutures indicative of premature fusion and compensatory growth. Presence of thyroid receptors was confirmed for the murine cranial suture and markers of proliferation and osteogenesis were increased in sutures from exposed mice. Increased Htra1 and Igf1 gene expression were found in sutures from high dose exposed individuals. Pathways related to the HTRA1/IGF axis, specifically Akt and Wnt, demonstrated evidence of increased activity. Overall our data suggest that maternal exogenous thyroxine exposure can drive calvarial growth alterations and altered suture morphology.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167805PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154521PMC
June 2017

Effects of thyroxine exposure on the Twist 1 +/- phenotype: A test of gene-environment interaction modeling for craniosynostosis.

Birth Defects Res A Clin Mol Teratol 2016 Oct 20;106(10):803-813. Epub 2016 Jul 20.

Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina.

Background: Craniosynostosis, the premature fusion of one or more of the cranial sutures, is estimated to occur in 1:1800 to 2500 births. Genetic murine models of craniosynostosis exist, but often imperfectly model human patients. Case, cohort, and surveillance studies have identified excess thyroid hormone as an agent that can either cause or exacerbate human cases of craniosynostosis.

Methods: Here we investigate the influence of in utero and in vitro exogenous thyroid hormone exposure on a murine model of craniosynostosis, Twist 1 +/-.

Results: By 15 days post-natal, there was evidence of coronal suture fusion in the Twist 1 +/- model, regardless of exposure. With the exception of craniofacial width, there were no significant effects of exposure; however, the Twist 1 +/- phenotype was significantly different from the wild-type control. Twist 1 +/- cranial suture cells did not respond to thyroxine treatment as measured by proliferation, osteogenic differentiation, and gene expression of osteogenic markers. However, treatment of these cells did result in modulation of thyroid associated gene expression.

Conclusion: Our findings suggest the phenotypic effects of the genetic mutation largely outweighed the effects of thyroxine exposure in the Twist 1 +/- model. These results highlight difficultly in experimentally modeling gene-environment interactions for craniosynostotic phenotypes. Birth Defects Research (Part A) 106:803-813, 2016. © 2016 Wiley Periodicals, Inc.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088492PMC
http://dx.doi.org/10.1002/bdra.23543DOI Listing
October 2016