Safety and Efficacy Results of BonoFill First-in-Human, Phase I/IIa Clinical Trial for the Maxillofacial Indication of Sinus Augmentation and Mandibular Bone Void Filling.

PURPOSE: The gold standard for bone regeneration of bone deficiencies is still an autologous bone graft, which has considerable disadvantages; namely, the need for a second major surgery and the limited volume of bone available for harvesting. BonoFill (BF) is a novel, tissue-engineered, bone graft with intrinsic osteoinductive, osteoconductive, and osteogenic properties, consisting of the patient's own adipose tissue-derived mesenchymal stem cells, attached to hydroxyapatite particles. Here, we present the safety and efficacy results of BF first-in-human clinical study for maxillofacial bone tissue regeneration. MATERIALS AND METHODS: Eleven eligible male and female subjects, aged 49-65 years, were enrolled into the clinical study in 2 clinical indications: Bone augmentation and bone void grafting in the jaws. Clinical follow-up was performed throughout a period of 6 months after BF treatment and included clinical examination, blood tests, CT scans, and biopsies collected from the transplantation site to assess chronic bone infection, changes in complete blood count, and adequate bone augmentation for implant placement. RESULTS: The study results demonstrated that BF promoted adequate bone tissue regeneration without complications. Per our evaluation, there were no incidents of chronic bone infection, or significant changes in complete blood count, and the patients reported overall good health for the duration of the study. At trial end, in the sinus augmentation indication, the BF treated sites residual bone was augmented at an average of 6.36 mm (Δ new bone, n = 10) and the total bone height at the treated area was on average 11.44 mm (n = 10). In the indication of filling of bone voids, the patient's average residual bone height of 2.91 mm was 15.76 mm (n = 1) at trial end. CONCLUSIONS: BF treatment was shown to be safe and resulted in newly generated bone, which provided adequate bone height for placement of dental implants. Thus, BF is a promising novel autologous bone graft for bone tissue repair.

The specificity of Av3 sea anemone toxin for arthropods is determined at linker DI/SS2-S6 in the pore module of target sodium channels.

Av3 is a peptide neurotoxin from the sea anemone Anemonia viridis that shows specificity for arthropod voltage-gated sodium channels (Navs). Interestingly, Av3 competes with a scorpion α-toxin on binding to insect Navs and similarly inhibits the inactivation process, and thus has been classified as 'receptor site-3 toxin', although the two peptides are structurally unrelated. This raises questions as to commonalities and differences in the way both toxins interact with Navs. Recently, site-3 was partly resolved for scorpion α-toxins highlighting S1-S2 and S3-S4 external linkers at the DIV voltage-sensor module and the juxtaposed external linkers at the DI pore module. To uncover channel determinants involved in Av3 specificity for arthropods, the toxin was examined on channel chimaeras constructed with the external linkers of the mammalian brain Nav1.2a, which is insensitive to Av3, in the background of the Drosophila DmNav1. This approach highlighted the role of linker DI/SS2-S6, adjacent to the channel pore, in determining Av3 specificity. Point mutagenesis at DI/SS2-S6 accompanied by functional assays highlighted Trp404 and His405 as a putative point of Av3 interaction with DmNav1. His405 conservation in arthropod Navs compared with tyrosine in vertebrate Navs may represent an ancient substitution that explains the contemporary selectivity of Av3. Trp404 and His405 localization near the membrane surface and the hydrophobic bioactive surface of Av3 suggest that the toxin possibly binds at a cleft by DI/S6. A partial overlap in receptor site-3 of both toxins nearby DI/S6 may explain their binding competition capabilities.

Convergent evolution of sodium ion selectivity in metazoan neuronal signaling.

Ion selectivity of metazoan voltage-gated Na(+) channels is critical for neuronal signaling and has long been attributed to a ring of four conserved amino acids that constitute the ion selectivity filter (SF) at the channel pore. Yet, in addition to channels with a preference for Ca(2+) ions, the expression and characterization of Na(+) channel homologs from the sea anemone Nematostella vectensis, a member of the early-branching metazoan phylum Cnidaria, revealed a sodium-selective channel bearing a noncanonical SF. Mutagenesis and physiological assays suggest that pore elements additional to the SF determine the preference for Na(+) in this channel. Phylogenetic analysis assigns the Nematostella Na(+)-selective channel to a channel group unique to Cnidaria, which diverged >540 million years ago from Ca(2+)-conducting Na(+) channel homologs. The identification of Cnidarian Na(+)-selective ion channels distinct from the channels of bilaterian animals indicates that selectivity for Na(+) in neuronal signaling emerged independently in these two animal lineages.