Drosophila models of pathogenic copy-number variant genes show global and non-neuronal defects during development.

While rare pathogenic copy-number variants (CNVs) are associated with both neuronal and non-neuronal phenotypes, functional studies evaluating these regions have focused on the molecular basis of neuronal defects. We report a systematic functional analysis of non-neuronal defects for homologs of 59 genes within ten pathogenic CNVs and 20 neurodevelopmental genes in Drosophila melanogaster. Using wing-specific knockdown of 136 RNA interference lines, we identified qualitative and quantitative phenotypes in 72/79 homologs, including 21 lines with severe wing defects and six lines with lethality. In fact, we found that 10/31 homologs of CNV genes also showed complete or partial lethality at larval or pupal stages with ubiquitous knockdown. Comparisons between eye and wing-specific knockdown of 37/45 homologs showed both neuronal and non-neuronal defects, but with no correlation in the severity of defects. We further observed disruptions in cell proliferation and apoptosis in larval wing discs for 23/27 homologs, and altered Wnt, Hedgehog and Notch signaling for 9/14 homologs, including AATF/Aatf, PPP4C/Pp4-19C, and KIF11/Klp61F. These findings were further supported by tissue-specific differences in expression patterns of human CNV genes, as well as connectivity of CNV genes to signaling pathway genes in brain, heart and kidney-specific networks. Our findings suggest that multiple genes within each CNV differentially affect both global and tissue-specific developmental processes within conserved pathways, and that their roles are not restricted to neuronal functions.

Metallic additive manufacturing for bone-interfacing implants.

This review investigates the available metallic powder bed additive manufacturing technologies with respect to their basic principles and capabilities in terms of developing orthopedic implants. Detailed descriptions of commonly used metallic alloys employed for orthopedic applications are also presented. The relationship between implant surface properties and cellular attachment and the formation of bacterial colonies are also discussed. Accordingly, we show how different surface modification techniques have been applied to improve both the biointerface of metallic implants for enhanced osseointegration and to control the formation of biofilm to protect against implant infection. In addition, the future direction of metallic additive manufacturing in the case of improving bone interface has been discussed. This review aids in the design of bone-interfacing metallic implants fabricated by additive manufacturing processes, specifically accommodating enhanced biointerfaces for the next generation patient-specific orthopedic implants.

Polypropylene-nanodiamond composite for hernia mesh.

Commercial hernia mesh is commonly made from polypropylene (PP), due to its inertness, biocompatibility, physical properties, ease of processing and versatility for conversion into flexible shape. However, reportedly hernia mesh prepared from PP experienced issues such as diminished long-term strength, foreign body rejection, lack of biocompatibility and high adhesion to the abdomen wall. Infiltration of the mesh by soft tissue (called remodeling) results in an integration of mesh into the body, leading to a rapid reduction in mesh mechanical properties and potential infection. Here, this study addresses these issues through the incorporation of nanodiamond (ND) into PP filament and coating on the surface of plasma-treated PP-ND mesh. The results show that the dynamic modulus of the PP-ND mesh increased significantly, without compromising its flexibility. Coating PP-ND mesh with hydroxylated ND led to a reduction in nonspecific protein adsorption onto the surface of nanocomposite, which is an important characteristic for hernia mesh to prevent foreign body reaction, attachment of mesh to the abdominal wall and nearby organs. In-vitro study with mammalian cells shows that coated PP-ND mesh with functionalized ND exhibits a significant increase in the number of adhered cells with more elongated morphology in comparison with other PP meshes, due to the better hydrophilicity. Therefore, the ND coated nanocomposite mesh can be a promising candidate for hernia repair in the future; however, more investigation is required.

Engineering the Interface: Nanodiamond Coating on 3D-Printed Titanium Promotes Mammalian Cell Growth and Inhibits Staphylococcus aureus Colonization.

Additively manufactured selective laser melted titanium (SLM-Ti) opens the possibility of tailored medical implants for patients. Despite orthopedic implant advancements, significant problems remain with regard to suboptimal osseointegration at the interface between the implant and the surrounding tissue. Here, we show that applying a nanodiamond (ND) coating onto SLM-Ti scaffolds provides an improved surface for mammalian cell growth while inhibiting colonization of Staphylococcus aureus bacteria. Owing to the simplicity of our methodology, the approach is suitable for coating SLM-Ti geometries. The ND coating achieved 32 and 29% increases in cell density of human dermal fibroblasts and osteoblasts, respectively, after 3 days of incubation compared with the uncoated SLM-Ti substratum. This increase in cell density complements an 88% reduction in S. aureus detected on the ND-coated SLM-Ti substrata. This study paves a way to create facile antifouling SLM-Ti structures for biomedical implants.

Polycrystalline Diamond Coating of Additively Manufactured Titanium for Biomedical Applications.

Additive manufacturing using selective laser melted titanium (SLM-Ti) is used to create bespoke items across many diverse fields such as medicine, defense, and aerospace. Despite great progress in orthopedic implant applications, such as for "just in time" implants, significant challenges remain with regards to material osseointegration and the susceptibility to bacterial colonization on the implant. Here, we show that polycrystalline diamond coatings on these titanium samples can enhance biological scaffold interaction improving medical implant applicability. The highly conformable coating exhibited excellent bonding to the substrate. Relative to uncoated SLM-Ti, the diamond coated samples showed enhanced mammalian cell growth, enriched apatite deposition, and reduced microbial S. aureus activity. These results open new opportunities for novel coatings on SLM-Ti devices in general and especially show promise for improved biomedical implants.

Brushite-based calcium phosphate cement with multichannel hydroxyapatite granule loading for improved bone regeneration.

In this work, we report brushite-based calcium phosphate cement (CPC) system to enhance the in vivo biodegradation and tissue in-growth by incorporation of micro-channeled hydroxyapatite (HAp) granule and silicon and sodium addition in calcium phosphate precursor powder. Sodium- and silicon-rich calcium phosphate powder with predominantly tri calcium phosphate (TCP) phase was synthesized by an inexpensive wet chemical route to react with mono calcium phosphate monohydrate (MCPM) for making the CPC. TCP nanopowder also served as a packing filler and moderator of the reaction kinetics of the setting mechanism. Strong sintered cylindrical HAp granules were prepared by fibrous monolithic (FM) process, which is 800 µm in diameter and have seven micro-channels. Acid sodium pyrophosphate and sodium citrate solution was used as the liquid component which acted as a homogenizer and setting time retarder. The granules accelerated the degradation of the brushite cement matrix as well as improved the bone tissue in-growth by permitting an easy access to the interior of the CPC through the micro-channels. The addition of micro-channeled granule in the CPC introduced porosity without sacrificing much of its compressive strength. In vivo investigation by creating a critical size defect in the femur head of a rabbit model for 1 and 2 months showed excellent bone in-growth through the micro-channels. The granules enhanced the implant degradation behavior and bone regeneration in the implanted area was significantly improved after two months of implantation.

HAp granules encapsulated oxidized alginate-gelatin-biphasic calcium phosphate hydrogel for bone regeneration.

Bone repair in the critical size defect zone using 3D hydrogel scaffold is still a challenge in tissue engineering field. A novel type of hydrogel scaffold combining ceramic and polymer materials, therefore, was fabricated to meet this challenge. In this study, oxidized alginate-gelatin-biphasic calcium phosphate (OxAlg-Gel-BCP) and spherical hydroxyapatite (HAp) granules encapsulated OxAlg-Gel-BCP hydrogel complex were fabricated using freeze-drying method. Detailed morphological and material characterizations of OxAlg-Gel-BCP hydrogel (OGB00), 25wt% and 35wt% granules encapsulated hydrogel (OGB25 and OGB35) were carried out for micro-structure, porosity, chemical constituents, and compressive stress analysis. Cell viability, cell attachment, proliferation and differentiation behavior of rat bone marrow-derived stem cell (BMSC) on OGB00, OGB25 and OGB35 scaffolds were confirmed by MTT assay, Live-Dead assay, and confocal imaging in vitro experiments. Finally, OGB00 and OGB25 hydrogel scaffolds were implanted in the critical size defect of rabbit femoral chondyle for 4 and 8 weeks. The micro-CT analysis and histological studies conducted by H&E and Masson's trichrome demonstrated that a significantly higher (***p<0.001) and earlier bone formation happened in case of 25% HAp granules encapsulated OxAlg-Gel-BCP hydrogel than in OxAlg-Gel-BCP complex alone. All results taken together, HAp granules encapsulated OxAlg-Gel-BCP system can be a promising 3D hydrogel scaffold for the healing of a critical bone defect.