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Background: Assessing health-related quality of life (HRQoL) allows acquisition of the subjective perspective of patients regarding their health and functioning; however, little is known about the experiences of patients living with treated craniosynostosis (CS). Methods: School-aged children (7–16 years) treated for non-syndromic CS were assessed using the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales via both self- and proxy reports.Results: Seventy-three patients and their parents responded to the PedsQL (response rate: 80.2%). Patients generally estimated HRQoL as high, with no difference in HRQoL found between treated sagittal (SS) or metopic (MS) synostosis. In the SS group, surgical methods involving spring-assisted surgery and pi-plasty were unrelated to HRQoL outcomes. Additionally, HRQoL was highly correlated with intelligence quotient (IQ) and adaptive behavior skills (ABAS). Furthermore, we observed differences in estimated HRQoL between self- and proxy reports (i.e., parents estimated child HRQoL as higher than did the children). Conclusions: Children treated for CS have a generally high HRQoL, and neither CS type nor surgical method influenced HRQoL outcomes. Moreover, children and parents estimated HRQoL differently, suggesting the importance of using both self- and proxy reporting in patient-reported measures. We found that HRQoL was strongly related to IQ and ABAS, indicating that the PedsQL can be used as a screening instrument to identify craniofacial patients in need of further psychological assessment.

In this retrospective study, the authors determined changes in intracranial volume (ICV) and cephalic index (CI) in patients with sagittal craniosynostosis and operated with craniotomy combined with either 2 or 3 springs. The authors included patients (n = 112) with complete follow-up that had undergone surgical correction for isolated sagittal craniosynostosis with craniotomy combined with springs between 2008 and 2017. All patients underwent computed tomography examination preoperative, at the time of spring extraction, and at 3 years of age. Intracranial volume was measured using a semiautomatic MATLAB program, and CI was calculated as the width/length of the skull. The authors found that craniotomy combined with 2 springs increased the ICV from a preoperative value of 792 ± 113 mL (mean ± standard deviation) to 1298 ± 181 mL at 3 years of age and increased the CI from 72.1 ± 4.1 to 74.6 ± 4.3, whereas craniotomy combined with 3 springs increased the ICV from 779 ± 128 mL to 1283 ± 136 mL and the CI from 70.7 ± 4.3 to 74.8 ± 3.7. The relative increase in ICV was 65 ± 21% in the two-spring group and 68 ± 34% in the three-spring group (P value = 0.559), and the relative increase in CI was 3.6 ± 3.3% in the two-spring group as compared with 6.0 ± 5.0% in the three-spring group (P = 0.004). These findings demonstrated that use of 3 springs resulted in additional absolute and relative CI-specific effects as compared with 2 springs during the time when the springs were in place, with this effect maintained at 3 years of age.

Since the development of spring-assisted techniques for corrective craniofacial surgery, routine postoperative admission to intensive care units (ICUs) has been questioned. However, close monitoring is necessary if the continuous infusion of morphine is used as recommended for better pain relief. In this study, the authors evaluated a simplified postoperative protocol without continuous morphine infusion and no indwelling urinary catheter following spring-assisted surgery (SAS) for sagittal synostosis. Ten children were cared for according to a standard protocol with postoperative intravenous (i.v.) infusion of morphine and an indwelling urinary catheter, and 11 consecutive children were treated according to a simplified protocol with pain relief based on intermittent injections of morphine and clonidine [according to Face, Legs, Activity, Cry, Consolability (FLACC) scores >4] without the indwelling catheter. A Mann-Whitney U test was used for comparison of distributions between the two groups. The results revealed no differences between groups regarding the proportion of FLACC scores >4, total amount of administered i.v. morphine and clonidine, total volume of buffered glucose infused, time to first feeding on breast milk or substitute, or the length of stay. Despite the inherent limitations of our small observational study, the authors concluded that at our institution, it was possible to exclude a standard continuous i.v. infusion of morphine and an indwelling urinary catheter from our postoperative care protocol without decreasing the quality of pain relief in children submitted to SAS for sagittal synostosis. This finding supports downgrading the level of care from the ICU to a regular ward after limited immediate postoperative observation.

Objective: Descriptions of the craniofacial morphology in Saethre-Chotzen syndrome (SCS) are primarily based on case reports or visual assessments of affected families. The aim of this study was to compare cephalometric measurements of the craniofacial skeleton in a cohort of individuals with SCS and age- and sex-matched individuals without craniofacial anomalies. Design: Retrospective case series. Patients: Eight girls and 4 boys with SCS (age range, 7.0-19.2 years). Methods: Cephalometric measurements were performed using lateral and frontal cephalograms. Results: Most of the individuals with Saethre-Chotzen syndrome exhibited lower values for SNA, SNB, s-n and s-ar, while their NSL/NL, NSL/ML, NL/ML, and n-s-ba values were higher than the respective mean reference values for healthy individuals. In comparison with age- and sex-matched individuals without craniofacial anomalies, the individuals with SCS showed higher values for the maxillary and mandibular angular measurements, as well as for the menton midline angle. Conclusions: This sample of 12 unrelated individuals with SCS is the largest collected to date for cephalometric measurements. We found that the syndrome is associated with bimaxillary retrognathism, posterior maxillary and mandibular inclination, neutral sagittal relation as well as a tendency toward an open vertical skeletal relation, a short and flattened skull base, and facial asymmetry, as compared to individuals without the syndrome.

Background Even though meshes and matrices are widely used in breast reconstruction, there is little high‐quality scientific evidence for their risks and benefits. The aim of this study was to compare first‐year surgical complication rates in implant‐based immediate breast reconstruction with a biological mesh with that of a synthetic mesh, in the same patient. Methods This study is a clinical, randomized, prospective trial. Patients operated on with bilateral mastectomy and immediate breast reconstruction were randomized to biological mesh on one side and synthetic mesh on the other side. Results A total of 48 breasts were randomized. As the synthetically and the biologically reconstructed breasts that were compared belonged to the same woman, systemic factors were exactly the same in the two groups. The most common complication was seroma formation with a frequency of 38% in the biological group and 3.8% in the synthetical group (p = .011). A higher frequency of total implant loss could be seen in the biologic mesh group (8.5% vs. 2%), albeit not statistically significant (p = .083). Conclusions In the same patient, a synthetic mesh seems to yield a lower risk for serious complications, such as implant loss, than a biological mesh.

Extracellular matrix fibril components, such as collagen, are crucial for the structural properties of several tissues and organs. Tunicate-derived cellulose nanofibrils (TNC) combined with living cells could become the next gold standard for cartilage and soft-tissue repair, as TNC fibrils present similar dimensions to collagen, feasible industrial production, and chemically straightforward and cost-efficient extraction procedures. In this study, we characterized the physical properties of TNC derived from aquaculture production in Norwegian fjords and evaluated its biocompatibility regarding induction of an inflammatory response and foreign-body reactions in a Wistar rat model. Additionally, histologic and immunohistochemical analyses were performed for comparison with expanded polytetrafluoroethylene (ePTFE) as a control. The average length of the TNC as determined by atomic force microscopy was tunable from 3 μm to 2.4 μm via selection of a various number of passages through a microfluidizer, and rheologic analysis showed that the TNC hydrogels were highly shear-thinning and with a viscosity dependent on fibril length and concentration. As a bioink, TNC exhibited excellent rheological and printability properties, with constructs capable of being printed with high resolution and fidelity. We found that post-print cross-linking with alginate stabilized the construct shape and texture, which increased its ease of handling during surgery. Moreover, after 30 days in vivo, the constructs showed a highly-preserved shape and fidelity of the grid holes, with these characteristics preserved after 90 days and with no signs of necrosis, infection, acute inflammation, invasion of neutrophil granulocytes, or extensive fibrosis. Furthermore, we observed a moderate foreign-body reaction involving macrophages, lymphocytes, and giant cells in both the TNC constructs and PTFE controls, although TNC was considered a non-irritant biomaterial according to ISO 10993-6 as compared with ePTFE. These findings represent a milestone for future clinical application of TNC scaffolds for tissue repair. One sentence summary: In this study, the mechanical properties of tunicate nanocellulose are superior to nanocellulose extracted from other sources, and the biocompatibility is comparable to that of ePTFE.

Craniosynostosis (CS), the premature closure of one or more cranial sutures, occurs both as part of a syndrome or in isolation (nonsyndromic form). Here, we have studied the prevalence and spectrum of genetic alterations associated with coronal suture closure in 100 Scandinavian patients treated at a single craniofacial unit. All patients were phenotypically assessed and analyzed with a custom-designed 63 gene NGS-panel. Most cases (78%) were syndromic forms of CS. Pathogenic and likely pathogenic variants explaining the phenotype were found in 80% of the families with syndromic CS and in 14% of those with nonsyndromic CS. Sixty-five percent of the families had mutations in the CS core genes FGFR2, TWIST1, FGFR3, TCF12, EFNB1, FGFR1, and POR. Five novel pathogenic/likely pathogenic variants in TWIST1, TCF12, and EFNB1 were identified. We also found novel variants in SPECC1L, IGF1R, and CYP26B1 with a possible modulator phenotypic effect. Our findings demonstrate that NGS targeted sequencing is a powerful tool to detect pathogenic mutations in patients with coronal CS and further emphasize the importance of thorough assessment of the patient's phenotype for reliable interpretation of the molecular findings. This is particularly important in patients with complex phenotypes and rare forms of CS.

Premature craniosynostosis is a rare condition, with a wide range of incidence estimations in the literature. The aim of this study was to establish the current incidence among the Swedish population. Since the surgical care for these children is centralized to the 2 centers of Sahlgrenska University Hospital and Uppsala University Hospital, the 2 craniofacial hospital registries were examined for surgically treated children, all having a computed tomography verified diagnosis. Results show an incidence of 7.7 cases per 10,000 live births, including 0.60/10,000 syndromic craniosynostosis. Due to information programs among health care staff and a system for early diagnosis through rapid communication, these results seem to mirror the true incidence of craniosynostosis in the Swedish population. The updated incidence data will facilitate healthcare planning and make future studies of possible changes in craniosynostosis incidence more accurate.

Here, we have studied the prevalence and spectrum of genetic alterations in syndromic forms of sagittal and pansynostosis. Eighteen patients with sagittal synostosis (isolated or combined with other synostoses, except coronal) or pansynostosis were phenotypically assessed by retrospective analysis of medical records, three-dimensional computed tomography skull reconstructions, and registered photos. Patient DNAs were analyzed using a targeted next-generation sequencing (NGS) panel including 63 craniosynostosis (CS) related genes. Pathogenic and likely pathogenic variants were found in 72% of the cases, mainly affecting FGFR2, TWIST1, IL11RA, and SKI. Two patients that were negative at NGS screening - one with a supernumerary marker chromosome with duplication of 15q25.2q26.3 and one with a pathogenic PHEX variant - were identified using microarray and single gene analysis, respectively. The overall diagnostic rate in the cohort was thus 83%. We identified two novel likely pathogenic variants in FGFR2 (NM_022970.3: c.811_812delGGinsCC, p.Gly271Pro) and TWIST1 (NM_000474.3: c.476TA, p.Leu159His), and a novel variant of unclear phenotypic significance in RUNX2 (NM_001024630.3: c.340G A, p.Val114Ile) which could suggest a modulatory effect. Notably, we also identified three new patients with pansynostosis and a Crouzon-like phenotype with IL11RA mutation. Targeted NGS using a broad panel of CS-related genes is a simple and powerful tool for detecting pathogenic mutations in patients with syndromic forms of CS and multiple suture involvement, in particular pansynostosis. Our results provide additional evidence of an association between pansynostosis and IL11RA, an emerging core gene for autosomal recessive CS.

The aim of this study was to carry out a retrospective multicentre study comparing the morphological outcome of 8 techniques used for the management of sagittal synostosis versus a large cohort of control patients. Computed tomographic (CT) images were obtained from children CT-scanned for non-craniosynostosis related events (n = 241) and SS patients at preoperative and postoperative follow-up stages (n = 101). No significant difference in morphological outcomes was observed between the techniques considered in this study. However, the majority of techniques showed a tendency for relapse. Further, the more invasive procedures at older ages seem to lead to larger intracranial volume compared to less invasive techniques at younger ages. This study can be a first step towards future multicentre studies, comparing surgical results and offering a possibility for objective benchmarking of outcomes between methods and centres.

Attention problems are common in patients with craniosynostosis. Craniosynostosis is a rare condition, studies face challenges of selection bias, small sample sizes, and wide age ranges. Th...

Objectives Meshes/matrices are commonly used in immediate breast reconstruction. There are few studies comparing biological and synthetic meshes and it is unknown what type of mesh gives the best long-term results. The aim of this study was to compare long-term health-related quality of life (HrQoL) and patient satisfaction in implant-based immediate breast reconstruction with a biological mesh (Surgisis®) with that of patients reconstructed with a synthetic mesh (TIGR ® Matrix Surgical Mesh). Material and methods Both cohorts were prospectively included and consecutively operated. Clinical data was collected. HrQoL was evaluated with EuroQoL-5 dimension – 3 levels questionnaire (EQ-5D-3L) and the Hospital Anxiety and Depression Scale (HADS) and the Breast-Q. Results and conclusion Seventy-one patients were operated on in the biological group and 49 in the synthetic group. The response rates were 75 and 84 per cent, respectively. Mean follow-up time was 74 months and 23 months, respectively. There were no statistical differences in satisfaction and quality of life between the two groups. Complications and radiation seem to lead to a lower satisfaction. Our findings could indicate that biological and synthetic meshes give an equal long-term result as regards patients’ perceived quality of life.

Sagittal synostosis is the most occurring form of craniosynostosis, resulting in calvarial deformation and possible long-term neurocognitive deficits. Several surgical techniques have been developed to correct these issues. Debates as to the most optimal approach are still ongoing. Finite element method is a computational tool that’s shown to assist with the management of craniosynostosis. The aim of this study was to compare and predict the outcomes of three reconstruction methods for sagittal craniosynostosis. Here, a generic finite element model was developed based on a patient at 4 months of age and was virtually reconstructed under all three different techniques. Calvarial growth was simulated to predict the skull morphology and the impact of different reconstruction techniques on the brain growth up to 60 months of age. Predicted morphology was then compared with in vivo and literature data. Our results show a promising resemblance to morphological outcomes at follow up. Morphological characteristics between considered techniques were also captured in our predictions. Pressure outcomes across the brain highlight the potential impact that different techniques have on growth. This study lays the foundation for further investigation into additional reconstructive techniques for sagittal synostosis with the long-term vision of optimizing the management of craniosynostosis.

Background Adaptive behavior skills are important when assessing cognitive functions related to daily life; however, few studies have assessed these skills in patients treated for nonsyndromic craniosynostosis. In this study, the authors assessed the adaptive behavior skills of children treated for craniosynostosis and examined whether their outcomes are related to surgical technique. Methods The Adaptive Behavior Assessment System, 2nd Edition, parent report was used for children (age, 7 to 16 years) treated for sagittal (n = 41), metopic (n = 24), and other rare synostoses (n = 8). Background data, including intelligence quotient, were controlled for confounders. Results All evaluated children treated for craniosynostosis were estimated as lower in all aspects of adaptive behavior skills (full-scale, conceptual, social, and practical composites; effect size, 0.36 to 0.44) as compared with norms. The sagittal group showed shortcomings in social composite (effect size, 0.48) and subscales measuring self-care and self-direction, although no difference was observed between spring-assisted surgery and pi-plasty regarding outcomes of adaptive behavior skills. In addition, children treated for metopic synostosis showed results indicating shortcomings with adaptive behavior according to the full-scale, conceptual, and social composites (effect size, 0.53 to 0.61) relative to norms. Furthermore, attrition analysis revealed no significant differences between responders (rate, 80.2 percent) and nonresponders. Conclusion These results found that children treated for craniosynostosis display average adaptive behavior skills, and that the two surgical techniques used to treat sagittal synostosis did not differ in their behavioral outcomes. Clinical question/level of evidence Therapeutic, III.

Bacterial nanocellulose (BNC) is a 3D network of nanofibrils exhibiting excellent biocompatibility. Here, we present the aqueous counter collision (ACC) method of BNC disassembly to create bioink with suitable properties for cartilage-specific 3D-bioprinting. BNC was disentangled by ACC, and fibril characteristics were analyzed. Bioink printing fidelity and shear-thinning properties were evaluated. Cell-laden bioprinted grid constructs (5 × 5 × 1 mm3) containing human nasal chondrocytes (10 M mL-1) were implanted in nude mice and explanted after 30 and 60 days. Both ACC and hydrolysis resulted in significantly reduced fiber lengths, with ACC resulting in longer fibrils and fewer negative charges relative to hydrolysis. Moreover, ACC-BNC bioink showed outstanding printability, postprinting mechanical stability, and structural integrity. In vivo, cell-laden structures were rapidly integrated, maintained structural integrity, and showed chondrocyte proliferation, with 32.8 ± 13.8 cells per mm2 observed after 30 days and 85.6 ± 30.0 cells per mm2 at day 60 (p = 0.002). Furthermore, a full-thickness skin graft was attached and integrated completely on top of the 3D-bioprinted construct. The novel ACC disentanglement technique makes BNC biomaterial highly suitable for 3D-bioprinting and clinical translation, suggesting cell-laden 3D-bioprinted ACC-BNC as a promising solution for cartilage repair.

Summary Background The FACE-Q Craniofacial Module is a patient-reported outcome measure designed for patients aged 8 to 29 years with conditions associated with a facial difference. In part 1, we describe the psychometric findings for the original CLEFT-Q scales tested in patients with cleft and noncleft facial conditions. The aim of this study was to examine psychometric performance of new FACE-Q Craniofacial Module scales. Methods Data were collected between December 2016 and December 2019 from patients aged 8 to 29 years with conditions associated with a visible or functional facial difference. Rasch measurement theory (RMT) analysis was used to examine psychometric properties of each scale. Scores were transformed from 0 (worst) to 100 (best) for tests of construct validity. Results 1495 participants were recruited with a broad range of conditions (e.g., birthmarks, facial paralysis, craniosynostosis, craniofacial microsomia, etc.) RMT analysis resulted in the refinement of 7 appearance scales (Birthmark, Cheeks, Chin, Eyes, Forehead, Head Shape, Smile), two function scales (Breathing, Facial), and an Appearance Distress scale. Person separation index and Cronbach alpha values met criteria. Three checklists were also formed (Eye Function, and Eye and Face Adverse Effects). Significantly lower scores on eight of nine scales were reported by participants whose appearance or functional difference was rated as a major rather than minor or no difference. Higher appearance distress correlated with lower appearance scale scores. Conclusion The FACE-Q Craniofacial Module scales can be used to collect and compare patient reported outcomes data in children and young adults with a facial condition.

BACKGROUND: Acute normovolemic hemodilution (ANH) has been proposed as a microsurgical technique to improve blood flow in free flaps. OBJECTIVE: Here, we present the first systematic review of clinical and experimental studies on the effect of ANH. METHODS: We performed a systematic literature search of PubMed, Medline, the Cochrane Library, Google Scholar, and ClinicalTrials.gov using search strategies and a review process in agreement with the PRISMA statement and the Cochrane Handbook for systematic reviews of interventions. PICO criteria were defined before bibliometric processing of the retrieved articles, which were analyzed with the SYRCLE RoB tool for risk of bias and the GRADE scale for level of evidence. RESULTS: We retrieved 74 articles from the literature search, and after processing according to PICO criteria, only four articles remained, all of which were experimental. The rating for risk of bias was uncertain according to SYRCLE RoB results, and the level of evidence was low according to GRADE evaluation. CONCLUSIONS: There is no clinical evidence for the effect of ANH on microcirculation in free flaps, and experimental studies provide weak evidence supporting the use of hemodilution in reconstructive microsurgery.

Background There is little high-quality scientific evidence identifying the best and safest methods for delayed breast reconstruction, with most previous studies retrospective in nature. The primary aim was to compare early complication rates for two different breast-reconstructive methods in radiated and non-radiated patients, using a validated scale. The secondary aim was to identify predictors for complications. Materials and methods This study represents a clinical, randomized, prospective trial ( ClinicalTrials.Gov identifier: NCT03963427), where the patients were divided into two study arms: non-radiated and radiated. In the non-radiated arm, patients were randomized to a one-stage lateral thoracodorsal flap with an implant or two-stage expander reconstruction. In the radiated arm, patients were randomized to a latissimus dorsi reconstruction combined with an implant or deep inferior epigastric artery perforator (DIEP) reconstruction. All adverse events were classified according to Clavien–Dindo and summarization of overall morbidity was performed by calculating the Comprehensive Complication Index score. The study was conducted from 2008 to 2020. Results The complication frequencies were similar for the two surgical methods within each arm. In the non-radiated arm, risk factors for any complication were any comorbidities, and in the radiated arm, factors were a high body mass index and a contralateral operation. Conclusions The usage of the Clavien-Dindo scale in reconstructive surgery is feasible, but further validation is needed. In non-radiated patients, the frequencies of short-term complications were similar for lateral thoracodorsal flap and expander reconstruction, whereas in radiated patients, they were similar for DIEP and latissimus dorsi. The complication profile of the methods varied.

Long-term stability and biological safety are crucial for translation of 3D-bioprinting technology into clinical applications. Here, we addressed the long-term safety and stability issues associated with 3D-bioprinted constructs comprising a cellulose scaffold and human cells (chondrocytes and stem cells) over a period of 10 months in nude mice. Our findings showed that increasing unconfined compression strength over time significantly improved the mechanical stability of the cell-containing constructs relative to cell-free scaffolds. Additionally, the cell-free constructs exhibited a mean compressive stress and stiffness (compressive modulus) of 0.04 +/- 0.05 MPa and 0.14 +/- 0.18 MPa, respectively, whereas these values for the cell-containing constructs were 0.11 +/- 0.08 MPa (p= .019) and 0.53 +/- 0.59 MPa (p= .012), respectively. Moreover, histomorphologic analysis revealed that cartilage formed from the cell-containing constructs harbored an abundance of proliferating chondrocytes in clusters, and after 10 months, resembled native cartilage. Furthermore, extension of the experiment over the complete lifecycle of the animal model revealed no signs of ossification, fibrosis, necrosis, or implant-related tumor development in the 3D-bioprinted constructs. These findings confirm the in vivo biological safety and mechanical stability of 3D-bioprinted cartilaginous tissues and support their potential translation into clinical applications.

Background ERF-related craniosynostosis are a rare, complex, premature trisutural fusion associated with a broad spectrum of clinical features and heterogeneous aetiology. Here we describe two cases with the same pathogenic variant and a detailed description of their clinical course. Case presentation Two subjects; a boy with a BLSS requiring repeated skull expansions and his mother who had been operated once for sagittal synostosis. Both developed intracranial hypertension at some point during the course, which was for both verified by formal invasive intracranial pressure monitoring. Exome sequencing revealed a pathogenic truncating frame shift variant in the ERF gene. Conclusions Here we describe a boy and his mother with different craniosynostosis patterns, but both with verified intracranial hypertension and heterozygosity for a truncating variant of ERF c.1201_1202delAA (p.Lys401Glufs*10). Our work provides supplementary evidence in support of previous phenotypic descriptions of ERF-related craniosynostosis, particularly late presentation, an evolving synostotic pattern and variable expressivity even among affected family members.

The formation of the cranial sutures, in utero, occurs when the ossification of the skull bones reaches predestined positions around gestational week 15 to 20. Craniosynostosis, and the consequent skull shape deformities, is treated with surgery including osteotomies of the fused sutures. The occasional appearance of a new suture in the osteotomy lines has previously been described as sporadic events. In this retrospective study, a 4-year consecutive series of osteotomies combined with springs for craniosynostosis were systematically analysed regarding the appearance of neosutures. In total, 84 patients were included and in 16 patients (19%) a new radiologically normal suture appeared in a part of the suture that was completely closed preoperatively. Additionally, in 7 patients (8%) a new suture appeared in a part of the suture that had a discernible suture prior to surgery.In conclusion, in this consecutive and well-defined patient cohort operated for craniosynostosis, the formation of a neosuture is not a rare, and speculatively not a random, event. The appearance of a new suture long after the normal time period for suture formation in utero indicates that the craniosynostosis may just as well be caused by disturbed formation of the suture as actual premature closure.

Establishing functional circulation in bioengineered tissue after implantation is vital for the delivery of oxygen and nutrients to the cells. Native cartilage is avascular and thrives on diffusion, which in turn depends on proximity to circulation. Here, we investigate whether a gridded three-dimensional (3D) bioprinted construct would allow ingrowth of blood vessels and thus prove a functional concept for vascularization of bioengineered tissue. Twenty 10 × 10 × 3-mm 3Dbioprinted nanocellulose constructs containing human nasal chondrocytes or cell-free controls were subcutaneously implanted in 20 nude mice. Over the next 3 months, the mice were sequentially imaged with a 7 T small-animal MRI system, and the diffusion and perfusion parameters were analyzed. The chondrocytes survived and proliferated, and the shape of the constructs was well preserved. The diffusion coefficient was high and well preserved over time. The perfusion and diffusion patterns shown by MRI suggested that blood vessels develop over time in the 3D bioprinted constructs; the vessels were confirmed by histology and immunohistochemistry. We conclude that 3D bioprinted tissue with a gridded structure allows ingrowth of blood vessels and has the potential to be vascularized from the host. This is an essential step to take bioengineered tissue from the bench to clinical practice.

Three-dimensional (3D) bioprinting offers the ability to design and biofabricate 3D structures based on autologous fat; however, the lack of vascularization in larger 3D-bioprinted constructs represents a limiting factor that hampers translation of this technology from bench to bedside. 3D bioprinting using microfractured fat mixed with nanocellulose–alginate hydrogel can promote vascularization through connections of fragments of vessels included in the fat. In this study, we determined the perfusion and diffusion characteristics of 3D-bioprinted fat constructs using magnetic resonance imaging (MRI) and assessed correlations between perfusion and angiogenesis within the printed constructs. Microfractured human fat from liposuction was printed with tunicate nanocellulose–alginate hydrogel, followed by transplantation of the constructs (10 × 10 × 3 mm) into nude mice that underwent longitudinal MRI for up to 99 days. Confirmation of vascularization was undertaken using immunohistochemical and histologic analyses. Before implantation, the constructs contained abundant fat tissue and fragments of human blood vessels (CD31+ and Ku80+), with subsequent in vivo MRI analysis following transplantation indicating low perfusion and suggesting their continued survival mainly by diffusion. Additionally, we observed a high diffusion coefficient (~2 × 10−3 mm2/s) that was preserved throughout the observation period. Following explantation, evaluation revealed that the constructs displayed preserved histology along with a mixture of human (Ku80+) and murine (Ku80−) erythrocyte-containing vessels. These results demonstrated successful interconnection of blood-vessel fragments from microfractured human fat via angiogenesis to form a vascular network with the host circulation, thereby confirming vascularization of the 3D-bioprinted fat constructs.

The temporal contour deformity typical of metopic synostosis is often referred to as temporal hollowing, but has not been quantitatively defined. This deformity is present before surgery and remains to a varying extent at long-term follow-up. The present study aimed to objectively evaluate the degree of this contour deformity in metopic synostosis before and after surgical correction.All children surgically treated for metopic synostosis at Sahlgrenska University Hospital between 2002 and 2014 (n = 120) with appropriate computed tomography scans (n = 160) performed preoperatively and/or at follow-up at 3 years of age were included. Depending on age, 1 of 2 surgical techniques was used. Children presenting before the age of 6 months were treated with frontal remodeling in combination with a spring (S group), whereas children older than 6 months were treated with a bone transplant (BT group). The bony temporal deformity was measured with a semiautomatic MATLAB program and patients were compared to sex- and age-matched controls.The deformity was significantly reduced in both groups (P < 0.001). In the S group, it was reduced from a mean ± standard deviation of 3.6 ± 1.9% to 1.0 ± 1.2% and in the BT group, it was reduced from 3.3% ± 1.4% to 1.1% ± 0.8%.The contour deformity in metopic synostosis is present both before and after surgery and should therefore be termed temporal retrusion (TR). This assessment method enables objective comparison of TR before and after surgical correction and is a potential tool to evaluate TR in metopic synostosis.

INTRODUCTION Spring-assisted cranioplasty to correct sagittal synostosis is based on midline craniotomy through the closed sagittal suture, over the superior sagittal sinus (SSS). The aim of the present study was to evaluate the perioperative safety of this technique. MATERIALS AND METHODS This is a retrospective study of all patients operated with median craniotomy and springs from 1998 to the end of 2015. For comparison, all Pi-plasties performed during the same time interval were also evaluated. The safety measures were evaluated based on incidence of damage to SSS, incidence of dural tears, perioperative blood loss, operative time, and hospital stay. RESULTS In the group that had undergone midline craniotomy combined with springs (n = 225), 4 perioperative damages to SSS and 1 dural tear were seen. The perioperative blood loss was 62.8 ± 65.3 mL (mean ± standard deviation). The operative time was 67.9 ± 21.5 minutes and the hospital stay was 4.8 ± 1.1 days. In the group that had undergone pi-plasty (n = 105), no damages to SSS but 3 dural tears were seen. The perioperative blood loss was 352.8 ± 174.4 mL. The operative time was 126.0 ± 31.7 minutes and the hospital stay was 7.1 ± 1.4 days. CONCLUSION Craniotomy SSS in sagittal synostosis is a safe procedure with low morbidity in terms of damage to the SSS. Midline craniotomy combined with springs has significantly lower preoperative blood loss, operative time, and hospital stay (P

Introduction Infantile myofibroma (IM) is a benign mesenchymal disorder. Although it is the most common tumor of infancy, it is a relatively rare pathological entity. IM occurs predominantly before the age of two. It is characterized by tumor formation in skin, muscle, viscera, bone and subcutaneous tissues. The tumor can occur in either solitary or multicentric forms. The solitary form without visceral involvement usually has a benign course. Male gender predominates in the solitary form. Case presentation We report a clinical case of an osseous infantile myofibroma of the zygomatico-maxillo-orbital complex in a 4 months old male. We also show the radiological spontaneous regression without surgical intervention. Clinical, radiological, and histopathological examinations established the diagnosis. Our treatment was conservative with clinical follow-up. No surgical intervention was carried out during the course of the disease. Significant spontaneous regression occurred after a year and was confirmed by CT scan. Conclusion Radiologically aggressive infantile myofibroma has been previously treated by surgical intervention. In this case report there was a significant spontaneous regression. Conservative treatment and follow-up may be an appropriate alternative.

Attention problems are common in patients with craniosynostosis. Craniosynostosis is a rare condition, studies face challenges of selection bias, small sample sizes, and wide age ranges. The aim of the study was to assess the sustained attention and vigilance of children treated for sagittal and metopic craniosynostosis. To reduce selection bias, we included children that had previously undergone surgery for craniosynostosis, were between 8 and 16 years, and lived close to the craniofacial centre. The Connors Continuous Performance Test (3

Comparing complication rates between centres is difficult due to the lack of unanimous criteria regarding what adverse events should be defined as complications and how these events should be compiled. This study analysed all adverse events in a cohort of craniofacial (CF) operations over a 10-year period and applied three different scales (Clavien-Dindo, Leeds and Oxford) for systematic comparison. A total of 1023 consecutive CF procedures in 641 patients was identified. The Clavien-Dindo scale captured 74 complications in 74 procedures (7.2%), whereas the Leeds and Oxford scales captured 163 complications in 134 procedures (13.1%) and 85 complications in 83 procedures (8.1%), respectively. The Clavien-Dindo scale appeared less suitable for CF surgery, because it is predominantly adapted to severe complications and also regards blood transfusion as a complication. The Leeds scale provided a detailed picture of all complications, as well as minor events, whereas the Oxford scale captured all major complications well but applied less accurate definitions for the minor events. Our findings contribute to the benchmarking of complications between CF centres and suggest that both the Leeds and the Oxford scale appear relevant, depending on the emphasis required for major and minor complications and inter-centre audits, respectively.

BACKGROUND Long-term neuropsychological and cognitive outcomes in patients with nonsyndromic craniosynostosis have proven difficult to evaluate objectively because of methodologic problems with published studies based on their small and biased samples of patients, wide age ranges, and testing with unacceptable psychometric properties. This study evaluated the Full-Scale Intelligence Quotient and its subscales in a cohort with a small selection bias. METHODS Patients aged 7 to 16 years, born with nonsyndromic craniosynostosis and surgically treated, were tested using the Wechsler Intelligence Scale for Children, Fourth Edition. Ninety-one patients were invited, and 73 patients were tested. RESULTS There was no difference in Full-Scale Intelligence Quotient score between patients who had undergone operations for sagittal synostosis or metopic synostosis and norms provided by the test. Patients operated on for sagittal synostosis showed a significantly higher perceptual reasoning intelligence quotient, but also significantly lower working-memory intelligence quotient and processing-speed intelligence quotient compared with the norms. Patients operated on for metopic synostosis showed no differences in any intelligence quotient index compared with the norm. In addition, attrition analysis showed no differences in background factors between responders and nonresponders. CONCLUSIONS These results derived from a group of patients with uniform age range, and tested using an established tool, revealed that nonsyndromic children having undergone surgery for craniosynostosis exhibited average intellectual ability. However, the analysis indicated possible issues with working memory and processing speed in patients operated on for sagittal synostosis, highlighting impairments potentially associated with neuropsychological problems and that might contribute to learning disabilities.

Spring-assisted cranioplasty (SAC) was recently introduced in Moscow. This study provides a detailed analysis of the results of the first 14 SAC cases in Russia. The patients underwent a computed tomography scan before surgery and prior to spring removal 3 months later. Fourteen cases (10 males and 4 females) were operated on, with a mean surgery time of 56 ± 14 min. All operations were uneventful, with a mean hospital stay of 4.2 days. Detailed craniometry of the 10 male patients and their matched controls revealed that SAC induced changes in the shape of the entire skull. The cranial index of the male patients increased from 68.2 to 72.3, whereas it remained stable at ∼80 for the controls. The anterior and middle skull heights were significantly larger in cases as compared with controls but shifted toward normal levels following SAC. Additionally, SAC increased parietal bone curvature, and principal component analysis showed that post-SAC morphological changes in patients were comparable to normal growth changes in the skull morphology of the controls. However, several months after the operation, patients continued to display a clearly distinct cranial morphology as compared with that of controls. These results indicated that SAC is a safe technique that showed good surgical results immediately after introduction.

Brooke-Spiegler syndrome (BSS; a.k.a. tuban tumor syndrome) is an autosomal dominant inherited skin disorder caused by germline mutations in the CYLD tumor suppressor gene. BSS is characterized by multiple skin adnexal tumors, mainly cylindromas and spiradenomas on the head and neck. The tumors are often severely disfiguring and require repeated surgical interventions. Here, we describe a four-generation BSS-family with a novel germline c.1613_1614delGC CYLD mutation that introduces a premature STOP codon predicted to result in a truncated, inactivated CYLD protein. In addition, we present a pilot study describing establishment of the first patient-derived xenografts (PDXs) from cutaneous CYLD-defective cylindromas. Fresh tumor tissues from cylindromas were transplanted into immunocompromised mice to generate PDXs. One xenograft showed progressive tumor growth after 3 months whereas the others remained unchanged in size during the 6 months study period. Histopathological and immunohistochemical analyses of the PDXs revealed that they recapitulate the histological and molecular features of their respective primary tumors, including expression of NTRK3 and the oncogenic driver MYB. In summary, we present the first preclinical BSS-model that morphologically and genetically recapitulates human CYLD-defective cylindromas. This model will be useful for preclinical therapeutic drug testing and for further studies of the molecular pathogenesis of inherited cylindromas.

INTRODUCTION Craniosynostosis is a premature closure of a cranial suture. Cranioplasty is indicated to correct skull deformity, relieve increased intracranial pressure, and promote homogenous cranial growth. Different techniques have been adopted to achieve optimal outcomes. Although surgical benefits are widely accepted, this intervention might also affect cranial skeletal growth. METHODS The authors conducted a retrospective case-control study including patients operated for isolated metopic or sagittal synostosis. These patients had undergone a computed tomography (CT) scan before surgery and/or at 3 years of age postoperatively. These were operated between 2002 and 2012. Intracranial volume was measured using a MATLAB application. The control group was age and sex-matched individuals who had CT scans for trauma or neurological indications. All results with P value

Background The aim of the current study was to determine the intracranial volume (ICV) and cephalic index (CI) in patients operated for sagittal synostosis, and to compare the outcome of 2 different surgical techniques: craniotomy combined with springs and modified pi-plasty. Methods The authors studied all patients who had been operated for isolated sagittal synostosis and registered in the Gothenburg Craniofacial Registry until the end of 2012 and who had undergone a preoperative and/or postoperative (at 3 years of age) computed tomography examination. Sex- and age-matched controls were identified from children who had undergone computed tomography for other reasons. Results Craniotomy combined with springs increased the ICV and CI from 802 ± 127 mL (mean ± SD) and 70.1 ± 4.0 to 1300 ± 158 mL and 73.1 ± 3.3, respectively. The corresponding values for controls were 796 ± 136 mL and 83.6 ± 7.3 preoperatively and 1334 ± 136 mL and 80.0 ± 4.5 at 3 years of age. Pi-plasty increased the ICV and CI from 1014 ± 115 mL and 69.7 ± 3.3 to 1286 ± 122 mL and 74.1 ± 2.6, respectively. Corresponding values for controls were 1043 ± 153 mL and 83.4 ± 7.0 preoperatively and 1362 ± 122 mL and 79.6 ± 3.9 at 3 years of age. Conclusions There was no significant difference between craniotomy combined with springs in children younger than 6 months and pi-plasty in older children regarding the efficacy of improving ICV and CI. Neither of the techniques fully normalized the head shape.

Metopic synostosis results in a keel-shaped forehead, reduced frontal intracranial volume (ICV), and lower frontal to total volume ratio. The ratio improves with cranioplasty, but at 3 years of age, the ratio is still not normalized when compared to that in normal children. The aim of the present study was to investigate whether a low frontal to total ICV ratio at 3 years of age was due to relapse or insufficient correction.All children surgically treated for metopic synostosis in combination with a spring at Sahlgrenska University Hospital with subsequent spring extraction between 2002 and 2008 (n = 20) were included. A MATLAB program was used to measure frontal and total ICV.Preoperatively, the frontal to total ICV ratio was 9.8 ± 1.3% (mean ± standard deviation). At spring removal, 6 months after cranioplasty, the ratio had increased to 11.8 ± 2.4%. At 3 years of age, the ratio was 11.6 ± 1.9%. In age-matched normal children, the ratio was 14.4 ± 1.9% preoperatively, 15.3 ± 2.2% at time of spring extraction, and 13.4 ± 1.4% at 3 years of age.Cranioplasty thus improved the frontal to total ICV ratio, but did not normalize it. The ratio did not change from 6 months after the cranioplasty to 3 years of age. These results indicate that a more pronounced frontal volume correction during cranioplasty is necessary to achieve a normalized distribution of ICV in metopic synostosis.

Autologous fat grafting is commonly used for correction of soft-tissue deformities, despite a high rate of graft resorption and nutrition-supply challenges. Three-dimensional (3D)-bioprinting techniques enable tailor-made architecture of grafts and promote vascularization. In recent years, the importance of adipose tissue-derived stromal/stem cells (ASCs) for graft survival has become evident. This study investigated the printability of mechanically processed lipoaspirate containing ASCs, as well as in vivo survival and neovascularisation of the 3D-bioprinted grafts. Human lipoaspirate-derived adipose tissue was 3D bioprinted in alginate/nanocellulose bioink, implanted into nude mice, and harvested at days 3, 7, and 30, respectively. The processed lipoaspirate showed high viability and good printability when combined with alginate/nanocellulose, and the 3D-bioprinted grafts contained intact vascular structures and a high density of mature adipocytes before and after engraftment. After 30 days in vivo, novel blood vessels were present on the graft surface, showing signs of angiogenesis into the graft, as well as vascularization in the centre of the tissue. Moreover, histologic and immunohistochemical characterisation confirmed the presence of potential ASCs during the first week in vivo. These results demonstrated that human lipoaspirate-derived adipose tissue showed high printability, survived 3D bioprinting and engraftment in vivo, and displayed macroscopic and microscopic evidence of vascularization.

Background:. Three-dimensional (3D) bioprinting of cartilage is a promising new technique. To produce, for example, an auricle with good shape, the printed cartilage needs to be covered with skin that can grow on the surface of the construct. Our primary question was to analyze if an integrated 3D bioprinted cartilage structure is a tissue that can serve as a bed for a full-thickness skin graft. Methods:. 3D bioprinted constructs (10 × 10 × 1.2 mm) were printed using nanofibrillated cellulose/alginate bioink mixed with mesenchymal stem cells and adult chondrocytes and implanted subcutaneously in 21 nude mice. Results:. After 45 days, a full-thickness skin allograft was transplanted onto the constructs and the grafted construct again enclosed subcutaneously. Group 1 was sacrificed on day 60, whereas group 2, instead, had their skin-bearing construct uncovered on day 60 and were sacrificed on day 75 and the explants were analyzed morphologically. The skin transplants integrated well with the 3D bioprinted constructs. A tight connection between the fibrous, vascularized capsule surrounding the 3D bioprinted constructs and the skin graft were observed. The skin grafts survived the uncovering and exposure to the environment. Conclusions:. A 3D bioprinted cartilage that has been allowed to integrate in vivo is a sufficient base for a full-thickness skin graft. This finding accentuates the clinical potential of 3D bioprinting for reconstructive purposes.

Multisutural nonsyndromic craniosynostosis is a rare group of malformations, whose frequency has been reported between 3% and 7% of all craniosynostosis. The clinical diagnosis can be difficult and computed tomography is usually required. Surgical treatment is challenging and staged procedures are performed in up to 80% of patients. The aim of the present study was to determine the reoperation rate and to evaluate the surgical outcomes by measuring intracranial volume (ICV) preoperatively and at follow-up, and comparing it to a control group. Perioperative variables and reoperation rate were recorded. Fifty-one patients presented with a complex pattern of synostosis without a recognizable syndrome (5% of cases of total patients evaluated). Fifteen patients have been treated with spring-assisted surgery, either alone or in combination with a foreheadplasty. The mean follow-up was 6.2 years. The mean preoperative ICV of the patients was smaller, but not significantly, than in the normal population (P = 0.13). Postoperatively, the mean ICV was similar to that of the control group at 1 year (P = 0.92), while at 3 years it was appreciably smaller, although not significantly different (P = 0.06). Five patients (33%) went through a secondary skull expansion for either raised intracranial pressure or cosmetic reasons. Spring-assisted surgery seems to temporarily expand ICV in children with complex synostosis and lower the reoperation rate, thus reducing the need for a second procedure. A longer follow-up would be necessary to further investigate the effects of springs over time.