Improving Senescent Wound Healing With Local and Systemic Therapies.

The population is aging, and the prevalence of chronic wounds is increasing. Because neovascularization is essential for tissue repair and both local and systemic factors affect new blood vessel formation, we hypothesize that altering either pathway would reciprocally enhance wound healing in the aged. To test this hypothesis, p53 was locally suppressed and endothelial progenitor cells (EPCs) were systemically mobilized in a murine model of senescent wound healing.Bilateral 6-mm full-thickness stented wounds were made on the dorsum of Zmpste24 mice. Animals received weekly topical p53 small interfering RNA (siRNA) (n = 25), weekly topical nonsense siRNA (n = 25), daily subcutaneous AMD3100 injections (n = 25), or daily subcutaneous saline injections (n = 25). Wounds were photographically assessed and harvested for reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and immunostaining over 40 days. Circulating EPC levels were measured using fluorescence-activated cell sorting analysis.Local p53 siRNA significantly improved Zmpste24 wound healing (18 ± 2 vs 40 ± 3 days; P ≤ 0.0001). p53 siRNA significantly increased local provasculogenic factors (hypoxia-inducible factor 1 α, stromal cell-derived factor 1 α, and vascular endothelial growth factor; P ≤ 0.05) and decreased local proapoptotic factors (p53, PUMA, and Bax; P ≤ 0.05). Local p53 siRNA also significantly increased the number of circulating EPCs (8 ± 0.2% vs 2.6 ± 0.1%; P ≤ 0.0001). AMD3100 treatment also significantly improved wound healing (20 ± 2 vs 40 ± 3 days; P ≤ 0.0001) and increased EPCs mobilization (7.8 ± 0.4% vs 2.6 ± 0.1%; P ≤ 0.0001). In addition, systemic AMD3100 increased local provasculogenic factors (hypoxia-inducible factor 1 α, stromal cell-derived factor 1 α, and vascular endothelial growth factor; P ≤ 0.05) and decreased local proapoptotic factors (p53, PUMA, and Bax; P ≤ 0.05). Both treatments significantly increased the number of blood vessels in the wound bed (P ≤ 0.0001).The marked delay in Zmpste24 wound healing is significantly improved by local (p53 siRNA) and systemic (AMD3100) treatments. The resulting decrease in proapoptotic factors and increase in provasculogenic factors in the wound bed as well as the increased level of circulating EPCs appear to reverse age-related wound healing impairment by enhancing wound neovascularization.

Acellular dermal matrix-based gene therapy augments graft incorporation.

BACKGROUND: Acellular dermal matrix (ADM) is widely used for structural or dermal replacement purposes. Given its innate biocompatibility and its potential to vascularize, we explored the possibility of ADM to function as a small interfering RNA (siRNA) delivery system. Specifically, we sought to improve ADM vascularization by siRNA-mediated inhibition of prolyl hydroxylase domain-2 (PHD2), a cytoplasmic protein that regulates hypoxia inducible factor-1α, and improve neovascularization. MATERIALS AND METHODS: Fluorescently labeled siRNA was used to rehydrate thin implantable ADM. Pharmacokinetic release of siRNA was determined. Twelve millimeter sections of ADM reconstituted with PHD2 siRNA (nonsense siRNA as control) and applied to dorsal wounds of 40 FVB mice. Grafts were sewn in, bolstered, and covered with occlusive dressings. Photographs were taken at 0, 7, and 14 d. Wounds were harvested at 7 and 14 d and analyzed (messenger RNA, protein, histology, and immunohistochemistry). RESULTS: Release kinetics was first-order with 80% release by 12 h. By day 14, PHD2-containing ADM appeared viable and adherent, whereas controls appeared nonviable and nonadherent. Real-time reverse transcription-polymerase chain reaction demonstrated near-complete knockdown of PHD2, whereas vascular endothelial growth factor and FGF-2 were increased 2.3- and 4.7-fold. On enzyme-linked immunosorbent assay, vascular endothelial growth factor was increased more than fourfold and stromal cell-derived factor doubled. Histology demonstrated improved graft incorporation in treated groups. Immunohistochemical demonstrated increased vascularity measured by CD31 staining and increased new cell proliferation by denser proliferating cell nuclear antigen staining in treated versus controls. CONCLUSIONS: We concluded that ADM is an effective matrix for local delivery of siRNA. Strategies to improve the matrix and/or genetically alter the local tissue environment can be envisioned.

Basal View Reference Photographs for Nasolabial Appearance Rating in Unilateral Cleft Lip and Palate.

The Asher-McDade system is a 5-point ordinal scale frequently used to rate the components of nasolabial appearance, including nasal form and nasal symmetry, in unilateral cleft lip and palate. Although reference photographs illustrating this scale have been identified for the frontal and right profile view, no reference photographs exist for the basal view. The aim of this study was to identify reference photographs for nasal form and nasal symmetry from the basal view to illustrate this scale and facilitate its use. Four raters assessed nasolabial appearance (form and symmetry) on basal view photographs of 50 children (average age 8 years) with a repaired cleft lip. Intraclass correlation coefficients show fair to moderate inter-rater reliability. Cronbach α indicated strong agreement between raters (0.77 nasal form; 0.78 nasal symmetry; 0.80 overall), along with low duplicate measurement error and strong internal consistency between the measures. The photographs with the highest agreement among raters were selected to illustrate each point on the 5-point scale for nasal form and for nasal symmetry, resulting in the selection of 10 reference photographs. The basal view reference photograph set developed from this study may complement existing reference photograph sets for other views and facilitate rating tasks.

Comparative Study of Early Secondary Nasal Revisions and Costs in Patients With Clefts Treated With and Without Nasoalveolar Molding.

The present study aims to determine the risk of early secondary nasal revisions in patients with complete unilateral and bilateral cleft lip and palate (U/BCLP) treated with and without nasoalveolar molding (NAM) and examine the associated costs of care. A retrospective cohort study from 1990 to 1999 was performed comparing the risk of early secondary nasal revision surgery in patients with a CLP treated with NAM and surgery (cleft lip repair and primary surgical nasal reconstruction) versus surgery alone in a private practice and tertiary level clinic. The NAM treatment group consisted of 172 patients with UCLP and 71 patients with BCLP, whereas the non-NAM-prepared group consisted of 28 patients with UCLP and 5 with BCLP. The risk of secondary nasal revision for patients with UCLP was 3% in the NAM group and 21% in the non-NAM group. The risk of secondary nasal revision for patients with BCLP was 7% in the NAM group compared with 40% in the non-NAM group. Using multicenter averages, the non-NAM revision rates were calculated at 37.8% and 48.5% for U/BCLP, respectively. Applying these risks of revision, NAM treatment led to an estimated savings of between $491 and $4893 depending on the type of cleft. In conclusion, NAM can reduce the number of early secondary nasal revision surgeries and, therefore, reduce the overall cost of care.

Unilateral Craniofacial Microsomia: Unrecognized Cause of Pediatric Obstructive Sleep Apnea.

Bilateral craniofacial microsomia causes obstructive sleep apnea (OSA). We hypothesize that unilateral craniofacial microsomia (UCFM) is an underappreciated cause of OSA. The records of all pediatric UCFM patients from 1990 to 2010 were reviewed; only complete records were included in the study. UCFM patients with OSA (apnea hypopnea index >1/hr) were compared to UCFM patients without OSA. Univariate and multivariate Fisher and χ(2) tests were performed. Of the 62 UCFM patients, 7 (11.3%) had OSA. All OSA patients had Pruzansky IIB or III mandibles. OSA patients presented with snoring (71.4%), failure to thrive (FTT) (57.1%), and chronic respiratory infections (42.8%). Snoring (P < 0.001), Goldenhar syndrome (P = 0.001), and FTT (P = 0.004) were significantly associated with OSA, but race, obesity, clefts, respiratory anomalies, adenotonsillar hypertrophy, and laterality were not. The prevalence of OSA in UCFM patients is up to 10 times greater than in the general population. Snoring, Goldenhar syndrome, and FTT are significantly associated with the presence of OSA.

Endogenous cell therapy improves bone healing.

BACKGROUND: Although bone repair is often a relatively rapid and efficient process, many bone defects do not heal. Because an adequate blood supply is essential for new bone formation, we hypothesized that augmenting new blood vessel formation by increasing the number of circulating vasculogenic progenitor cells (PCs) with AMD3100 and enhancing their trafficking to the site of injury with recombinant human parathyroid hormone (rhPTH) will improve healing. METHODS: Critical-sized 3-mm cranial defects were trephined into the right parietal bone of C57BLKS/J 6 mice (N = 120). The mice were divided into 4 equal groups (n = 30 for each). The first group received daily subcutaneous injections of AMD3100 (5 mg/kg). The second group received daily subcutaneous injections of rhPTH (5 mg/kg). The third group received both AMD3100 and rhPTH. The fourth group received subcutaneous injections of saline. Circulating vasculogenic PC numbers, new blood vessel formation, and bony regeneration were assessed. Progenitor cell adhesion, migration, and tubule formation were assessed in the presence of rhPTH and AMD3100. RESULTS: Flow cytometry demonstrated that combination therapy significantly increased the number of circulating PCs compared with all other groups. In vitro, AMD3100-treated PCs had significantly increased adhesion migration, and tubule formation was assessed in the presence of rhPTH. Combination therapy significantly improved new blood vessel formation in those with cranial defect compared with all other groups. Finally, bony regeneration was significantly increased in the combination therapy group compared with all other groups. CONCLUSIONS: The combination of a PC-mobilizing and traffic-enhancing agent improved bony regeneration of calvarial defects in mice.

Assessment of presurgical clefts and predicted surgical outcome in patients treated with and without nasoalveolar molding.

Obtaining an esthetic and functional primary surgical repair in patients with complete cleft lip and palate (CLP) can be challenging because of tissue deficiencies and alveolar ridge displacement. This study aimed to describe surgeons' assessments of presurgical deformity and predicted surgical outcomes in patients with complete unilateral and bilateral CLP (UCLP and BCLP, respectively) treated with and without nasoalveolar molding (NAM). Cleft surgeon members of the American Cleft Palate-Craniofacial Association completed online surveys to evaluate 20 presurgical photograph sets (frontal and basal views) of patients with UCLP (n = 10) and BCLP (n = 10) for severity of cleft deformity, quality of predicted surgical outcome, and likelihood of early surgical revision. Five patients in each group (UCLP and BCLP) received NAM, and 5 patients did not receive NAM. Surgeons were masked to patient group. Twenty-four percent (176/731) of surgeons with valid e-mail addresses responded to the survey. For patients with UCLP, surgeons reported that, for NAM-prepared patients, 53.3% had minimum severity clefts, 58.9% were anticipated to be among their best surgical outcomes, and 82.9% were unlikely to need revision surgery. For patients with BCLP, these percentages were 29.8%, 38.6%, and 59.9%, respectively. Comparing NAM-prepared with non-NAM-prepared patients showed statistically significant differences (P < 0.001), favoring NAM-prepared patients. This study suggests that cleft surgeons assess NAM-prepared patients as more likely to have less severe clefts, to be among the best of their surgical outcomes, and to be less likely to need revision surgery when compared with patients not prepared with NAM.

Extended Abbe flap for secondary correction of the bilateral cleft lip.

Nearly 60 years ago, Joseph Murray described several advancements to Bradford Cannon's Abbe flap reconstruction of secondary bilateral cleft lips in order to simplify the technique and improve results. Unlike their predecessors, Drs. Cannon and Murray modified the Abbe flap by splitting its apex in order to obtain a symmetrical correction of the upper lip and allow the 2 suture lines to extend vertically and laterally past the base of the columella and disappear within the floor of the nose. Eighteen years later, Dr. Murray reviewed the evolution of his own secondary cleft lip reconstruction experience to include a new approach to advance the maxilla rather than set back the mandible. In this Signature Issue, we reflect on contemporary innovations in secondary bilateral cleft lip Abbe flap reconstruction. Today, we approach the secondary reconstruction of the bilateral cleft lip in 3 stages. First, we establish normal anatomic positioning of the midface. Second, we perform secondary cleft nasal surgery as necessary. Finally, only after the midfacial skeleton and nose have been treated do we proceed with Abbe flap reconstruction of the upper lip. We inset the Abbe flap a quarter of the way out on the columella and wrap the Abbe darts around the sides of the columella. We find that designing the Abbe flap this way avoids the saber cut-like notching at the lip-columella junction, redundant vermilion, and excess flap length, and it also reduces or eliminates the need for upper or lower lip scar revision.

Maxillary mucocele with proptosis and visual impairment: a late complication of Le Fort III distraction.

Maxillary mucoceles are a relatively rare entity especially following surgical procedures involving osteotomies of the maxilla. The etiology of maxillary mucoceles has been ascribed to facial trauma (fractures), sinus surgery, and chronic inflammatory diseases or infections. Mucoceles can follow injury to the sinus mucosa and/or sinus outflow tract with a resulting expansile cystic mass. The clinical presentation ranges from swelling, pain, a palpable mass, proptosis, enophthalmos, and diplopia. The treatment involves either open or endoscopic incision and drainage of the cyst, mucosal resection, and an antrostomy for drainage.We report the case of a patient with Pfeiffer syndrome who underwent Le Fort III distraction osteogenesis and developed a symptomatic mucocele 15 years postoperatively.

Cleft palate midface is both hypoplastic and displaced.

Despite significant advances in cleft lip and palate treatment, anatomical controversies remain. Some have proposed that the width of the cleft is due to alveolar segmental displacement. Others suggest that the width is due to palatoalveolar hypoplasia. Improving our understanding of cleft anatomy may have implications for presurgical orthopedics and tissue engineering therapies. Palatoalveolar impressions of 17 noncleft children and 11 children with complete (alveolar, primary, and secondary) unilateral cleft palates were taken. Maxillary tuberosity positions and maxillary volumes were compared. Tuberosity position was determined by facebow transfer of palatoalveolar casts into geodetic datum boxes, and identification of the Cartesian coordinates (x, y, z) of the tuberosities relative to the box surfaces and Frankfurt horizontal. Maxillary volume was determined by immersing the palatoalveolar casts and measuring sand displacement. A significant difference was noted in the average tuberosity to contralateral tuberosity distance between cleft and noncleft cohorts. On average, cleft palate tuberosities were laterally displaced 8.7 mm compared with noncleft palates (P < 0.05). There was neither statistically significant alveolar segment elevation nor retroversion. A significant difference was noted in the average palatoalveolar volumes. The cleft palatoalveolar volume was 5.7 cm, and the noncleft palatoalveolar volume was 7.2 cm (P < 0.05). A palatal cleft is due to both alveolar tissue displacement and deficiency. Therefore, ideal cleft palate care should involve the correction of a displaced and deficient alveolus.

Pfeiffer syndrome: analysis of a clinical series and development of a classification system.

Among the craniosynostosis syndromes, Pfeiffer syndrome is notable because of high mortality and the need for multiple surgical interventions. However, it is variable in severity. We propose a new classification of Pfeiffer Syndrome to define pathology and function. A retrospective review was conducted of 42 patients with Pfeiffer syndrome treated from 1975 to 2010, the largest series reported to date. The classification was based on a functional assessment of patients in terms of respiratory, ocular, otological, and neurological status. This classification was tested by scoring and stratifying patients as follows: type A (mild problems), B (moderate problems), or C (severe problems). Patients were scored both at the time of presentation and after all surgical interventions to assess change in functional outcome. The functional classification system was compared to another previously reported. Type A patients did not have any change in postoperative functional outcomes (mean preoperative score 1.6, mean postoperative score 1.6); type B patients showed functional improvement (mean preoperative score 4.1, mean postoperative score 3.4) but type C patients (mean preoperative score 7.7, mean postoperative score 4.8) demonstrated the greatest improvement in functional scores after surgical intervention. Suture pathology did not indicate the clinical severity of phenotype, a variance from a previously published classification. The proposed classification is useful to assess severity of phenotype: respiratory, ocular, otologic, and neurologic problems are key indicators of the need for treatment. The classification can provide a helpful guide in multidisciplinary treatment planning, in reporting outcomes, and in the sharing of data among craniofacial anomalies centers.

Lacunocanalicular fluid flow transduces mechanical tension stress during distraction osteogenesis.

The mechanotransduction mechanisms linking distraction device activation to new bone formation remain unknown. We hypothesize that the tension stress of activation during distraction osteogenesis is transmitted through lacunocanalicular fluid flow to initiate the osteogenic signaling cascade. Adult Sprague-Dawley rats (N = 24) were subjected to mandibular osteotomy and application of an external distraction device. After a 3-day latency period, half the animals (n = 12) underwent device activation at 0.25 mm twice daily for 6 days (total activation, 3 mm), and the other half (n = 12) had no activation. On day 10, the animals were injected with fluorescent reactive red lacunocanalicular tracer before killing. Mandibles were harvested, embedded, and sectioned, and reactive red epifluorescence lacunocanalicular flow was measured. Protein was harvested for focal adhesion kinase 1 (FAK1), NESPRIN1, SUN1, LAMIN A/C, and SMAD1 Western blotting as well as for bone morphogenetic protein (BMP)-2 enzyme-linked immunosorbent assay and alkaline phosphatase assay. Lacunocanalicular fluid flow was significantly greater in the distracted samples (60.5 ± 14 vs 10.3 ± 4 molecules of equivalent soluble fluorochrome per megapixel, P = 0.01). Flow distribution demonstrated the highest lacunocanalicular flow near the center of the distraction gap. Increased lacunocanalicular flow resulted in increased FAK1 (P = 0.009), NESPRIN1 (P = 0.01), SUN1 (P = 0.01), and LAMIN A/C (P = 0.008) expression. Focal adhesion kinase 1 activation in the presence of BMP-2 protein expression (P = 0.001) resulted in increased intranuclear SMAD1 phosphorylation (P = 0.04) and alkaline phosphatase activity (P < 0.0001). These findings suggest that activation of the distraction osteogenesis device affects cellular response through changes in lacunocanalicular fluid flow.

Incidence of oronasal fistula formation after nasoalveolar molding and primary cleft repair.

The incidence of postoperative complications in cleft care is low. In this 19-year retrospective analysis of cleft lip and palate patients treated with preoperative nasoalveolar molding, we examine the incidence of postoperative oronasal fistulae. The charts of 178 patients who underwent preoperative nasoalveolar molding by the same orthodontist/prosthodontist team and primary cleft lip/palate repair by the same surgeon over a 19-year period were reviewed. Millard, Mohler, Cutting, or Mulliken-type techniques were used for cleft lip repairs. Oxford-, Bardach-, or von Langenbeck-type techniques were used for cleft palate repairs. One nasolabial fistula occurred after primary cleft lip repair (0.56% incidence) and was repaired surgically. Four palatal fistulae (3 at the junction between soft and hard palate and 1 at the right anterior palate near the incisive foramen) occurred, but 3 healed spontaneously. Only 1 palatal fistula (0.71%) required surgical repair. All 5 fistulae occurred within the first 8 years of the study period, with 4 (80%) of 5 occurring within the first 3 years. Although fistula rate may be related to surgeon experience and the evolution of presurgical techniques, nasoalveolar molding in conjunction with nasal floor closure contributes to a low incidence of oronasal fistulae.

Presurgical nasoalveolar molding and primary gingivoperiosteoplasty reduce the need for bone grafting in patients with bilateral clefts.

Preoperative nasoalveolar molding (NAM) in combination with primary gingivoperiosteoplasty (GPP) reduces the need for secondary alveolar bone grafting by 60% in patients with unilateral cleft lip and palate (CL/P). Herein, we investigate the efficacy of NAM and primary GPP in patients with bilateral CL/P. All patients (n = 38) with bilateral CL/P who underwent NAM and primary GPP from 1988 to 1998 with at least 14 years of follow-up were included in this study. Panoramic and periapical radiographs were used to assess dentoalveolar bone formation. A total of 38 patients were identified with median follow-up of 18 years (range 14-26 years). Of the 27 patients who underwent bilateral GPP, 14 (51%) patients had successful dentoalveolar bone formation bilaterally and 13 (49%) had unilateral bone formation. No patient had a bilateral failure. Of the 11 patients who underwent unilateral GPP, 7 (63%) patients had successful dentoalveolar bone formation. Bilateral successful dentoalveolar bone formation following primary bilateral GPP has a dependent probability of 52% and a conditional probability of 82%.

Obesity impairs wound closure through a vasculogenic mechanism.

Since obesity impairs wound healing and bone marrow (BM)-derived vasculogenic progenitor cells (PCs) are important for tissue repair, we hypothesize that obesity-impaired wound healing is due, in part, to impaired PC mobilization, trafficking, and function. Peripheral blood was obtained from nondiabetic, obese (BMI > 30, n = 25), and nonobese (BMI < 30, n = 17) subjects. Peripheral blood human (h)PCs were isolated, quantified, and functionally assessed. To corroborate the human experiments, 6-mm stented wounds were created on nondiabetic obese mice (TALLYHO/JngJ, n = 15) and nonobese mice (SWR/J, n = 15). Peripheral blood mouse (m)PCs were quantified and wounds were analyzed. There was no difference in the number of baseline circulating hPCs in nondiabetic, obese (hPC-ob), and nonobese (hPC-nl) subjects, but hPC-ob had impaired adhesion (p < 0.05), migration (p < 0.01), and proliferation (p < 0.001). Nondiabetic obese mice had a significant decrease in the number of circulating PCs (mPC-ob) at 7 (p = 0.008) and 14 days (p = 0.003) after wounding. The impaired circulating mPC-ob response correlated with significantly impaired wound closure at days 14 (p < 0.001) and 21 (p < 0.001) as well as significantly fewer new blood vessels in the wounds (p < 0.001). Our results suggest that obesity impairs the BM-derived vasculogenic PC response to peripheral injury and this, in turn, impairs wound closure.

Exogenous calreticulin improves diabetic wound healing.

A serious consequence of diabetes mellitus is impaired wound healing, which largely resists treatment. We previously reported that topical application of calreticulin (CRT), an endoplasmic reticulum chaperone protein, markedly enhanced the rate and quality of wound healing in an experimental porcine model of cutaneous repair. Consistent with these in vivo effects, in vitro CRT induced the migration and proliferation of normal human cells critical to the wound healing process. These functions are particularly deficient in poor healing diabetic wounds. Using a genetically engineered diabetic mouse (db/db) in a full-thickness excisional wound healing model, we now show that topical application of CRT induces a statistically significant decrease in the time to complete wound closure compared with untreated wounds by 5.6 days (17.6 vs. 23.2). Quantitative analysis of the wounds shows that CRT increases the rate of reepithelialization at days 7 and 10 and increases the amount of granulation tissue at day 7 persisting to day 14. Furthermore, CRT treatment induces the regrowth of pigmented hair follicles observed on day 28. In vitro, fibroblasts isolated from diabetic compared with wild-type mouse skin and human fibroblasts cultured under hyperglycemic compared with normal glucose conditions proliferate and strongly migrate in response to CRT compared with untreated controls. The in vitro effects of CRT on these functions are consistent with CRT's potent effects on wound healing in the diabetic mouse. These studies implicate CRT as a potential powerful topical therapeutic agent for the treatment of diabetic and other chronic wounds.

Autologous fat grafting and facial reconstruction.

There is tremendous interest in autologous fat grafting for the management of soft tissue volume deficiencies, treatment of cutaneous injuries, and regeneration of missing parts. Given its relative abundance and proximity to the surface of the skin, adipose tissue seems an excellent choice for the treatment of both congenital and acquired soft tissue defects, but the mesenchymal stem cells contained within the fat may provide unexpected opportunities for tissue replacement and repair. Although adipose transfer has been successfully used for reconstructive purposes since the end of the 19th century, numerous controversies about adipose harvesting, processing, delivery, survival, and efficacy still persist today. The purpose of this article was to highlight current practices, areas of controversy, and near-term future applications of fat grafting for reconstruction of the face.

Bony engineering using time-release porous scaffolds to provide sustained growth factor delivery.

Microporous scaffolds designed to improve bony repair have had limited success; therefore, we sought to evaluate whether time-released porous scaffolds with or without recombinant bone morphogenetic protein 2 (rhBMP-2) could enhance stem cell osteoinduction. Custom-made 15/85 hydroxyapatite/ß-tricalcium phosphate scaffolds were left empty (E) or filled with rhBMP-2 (E+), calcium sulfate (CS), or CS and rhBMP-2 (CS+). All scaffolds were placed in media and weighed daily. Conditioned supernatant was analyzed for rhBMP-2 and then used to feed human adipose-derived mesenchymal stem cells (ASCs). Adipose-derived mesenchymal stem cell ALP activity, OSTERIX expression, and bone nodule formation were determined. E scaffolds retained 97% (SD, 2%) of the initial weight, whereas CS scaffolds had a near-linear 30% (SD, 3%) decrease over 60 days. E+ scaffolds released 155 (SD, 5) ng of rhBMP-2 (77%) by day 2. In contrast, CS+ scaffolds released only 30 (SD, 2) ng (10%) by day 2, and the remaining rhBMP-2 was released over 20 days. Conditioned media from E+ scaffolds stimulated the highest ALP activity and OSTERIX expression in ACSs on day 2. However, after day 6, media from CS+ scaffolds stimulated the highest ALP activity and OSTERIX expression in ASCs. Adipose-derived mesenchymal stem cells exposed to day 8 CS+-conditioned media produced significantly more bone nodules (10.1 [SD, 1.7] nodules per high-power field) than all other scaffolds. Interestingly, day 8 conditioned media from CS scaffolds simulated significantly more bone nodules than either E or E+ scaffold (P < 0.05 for both). Time-released hydroxyapatite/ß-tricalcium phosphate porosity provides sustained growth factor release, enhances ASC osteoinduction, and may result in better in vivo bone formation.

Parameters of care for craniosynostosis.

BACKGROUND: A multidisciplinary meeting was held from March 4 to 6, 2010, in Atlanta, Georgia, entitled "Craniosynostosis: Developing Parameters for Diagnosis, Treatment, and Management." The goal of this meeting was to create parameters of care for individuals with craniosynostosis. METHODS: Fifty-two conference attendees represented a broad range of expertise, including anesthesiology, craniofacial surgery, dentistry, genetics, hand surgery, neurosurgery, nursing, ophthalmology, oral and maxillofacial surgery, orthodontics, otolaryngology, pediatrics, psychology, public health, radiology, and speech-language pathology. These attendees also represented 16 professional societies and peer-reviewed journals. The current state of knowledge related to each discipline was reviewed. Based on areas of expertise, four breakout groups were created to reach a consensus and draft specialty-specific parameters of care based on the literature or, in the absence of literature, broad clinical experience. In an iterative manner, the specialty-specific draft recommendations were presented to all conference attendees. Participants discussed the recommendations in multidisciplinary groups to facilitate exchange and consensus across disciplines. After the conference, a pediatric intensivist and social worker reviewed the recommendations. RESULTS: Consensus was reached among the 52 conference attendees and two post hoc reviewers. Longitudinal parameters of care were developed for the diagnosis, treatment, and management of craniosynostosis in each of the 18 specialty areas of care from prenatal evaluation to adulthood. CONCLUSIONS: To our knowledge, this is the first multidisciplinary effort to develop parameters of care for craniosynostosis. These parameters were designed to help facilitate the development of educational programs for the patient, families, and health-care professionals; stimulate the creation of a national database and registry to promote research, especially in the area of outcome studies; improve credentialing of interdisciplinary craniofacial clinical teams; and improve the availability of health insurance coverage for all individuals with craniosynostosis.

Parameters of care for craniosynostosis: dental and orthodontic perspectives.

INTRODUCTION: A multidisciplinary conference was convened in March 2010 with the charge to develop parameters of care for patients with craniosynostosis. The 52 participants represented 16 medical specialties and 16 professional societies. Herein, we present the dental, orthodontic, and surgical care recommendations for those with craniosynostosis, with special emphasis on craniosynostosis syndromes. METHODS: Plenary and small-group iterative discussions were held to draft specialty-specific parameters of care. All participants reviewed and discussed each specialty-specific document. Special care was taken to ensure cross-discipline interactions, recognizing the importance of interdisciplinary team care. RESULTS: A unified document was produced delineating longitudinal care parameters from prenatal assessment and consultation to adulthood in all the represented specialty areas. The dental and orthodontic care parameters from infancy to adulthood are explained in terms of stages of development and coordinated with interdisciplinary assessments and interventions. CONCLUSIONS: The consensus document provides a detailed description of physical, functional, and cognitive development in persons with craniosynostosis and recommends staged team observations and interventions. The expectation is that the document will help to ensure state-of-the-art care for patients with craniosynostosis and provide a generally acceptable framework for collaborative studies.