Rapid Prototyping of Flexible Structures for Tissue Engineered Ear Reconstruction

The tissue engineered ear has been an iconic symbol of the field since 1991, when the report of an engineered ear in a mouse model was first published A tissue engineered ear has an inherent advantage over conventional approaches because the structure is derived from the patient's own cartilage. In this approach, autologous auricular chondrocytes are harvested from the patient and grown within an ear-shaped scaffold. However, as the scaffold degrades or remodels, the ear-shaped structure undergoes significant distortion, resulting in a skewed ear shape that is smaller and often unrecognizable In order to maintain the desired ear geometry, a composite scaffold concept was developed Methods Several functional requirements for the manufacturing process were identified. First, the wire framework must be created with arbitrary three dimensional (3D) control, and with a diameter significantly smaller than the thickness of normal ear cartilage, which is about 2 mm. The bending stiffness must be sufficiently high so that shape is maintained during neocartilage maturation and sufficiently low such that flexibility of the overall structure is not impaired. The material must be approved for clinical use, and must not cause an inflammatory reaction. Finally, the manufacturing process must be capable of producing single, custom parts without significant cost burden. Plastic surgeons identified titanium and stainless steel as preferred materials due to their long history of success in medical implants Three manufacturing processes were identified that are capable of producing arbitrary shapes with the listed metals: wire bending, direct metal laser sintering (DMLS) Results Ear frameworks produced using DMLS and EBM technology are shown in Interpretation Ear frameworks produced using DMLS and EBM technology are shown i

Gene selection for the Australian Reproductive Genetic Carrier Screening Project (“Mackenzie’s Mission”)

Reproductive genetic carrier screening aims to offer couples information about their chance of having children with certain autosomal recessive and X-linked genetic conditions. We developed a gene list for use in “Mackenzie’s Mission”, a research project in which 10,000 couples will undergo screening. Criteria for selecting genes were: the condition should be life-limiting or disabling, with childhood onset, such that couples would be likely to take steps to avoid having an affected child; and/or be one for which early diagnosis and intervention would substantially change outcome. Strong evidence for gene-phenotype relationship was required. Candidate genes were identified from OMIM and via review of 23 commercial and published gene lists. Genes were reviewed by 16 clinical geneticists using a standard operating procedure, in a process overseen by a multidisciplinary committee which included clinical geneticists, genetic counselors, an ethicist, a parent of a child with a genetic condition and scientists from diagnostic and research backgrounds. 1300 genes met criteria. Genes associated with non-syndromic deafness and non-syndromic differences of sex development were not included. Our experience has highlighted that gene selection for a carrier screening panel needs to be a dynamic process with ongoing review and refinement

Expanding the spectrum of BAF-related disorders: <i>de novo</i> variants in SMARCC2 cause a syndrome with intellectual disability and developmental delay

SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.</p

Expanding the Spectrum of BAF-Related Disorders : De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay

SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits