Antimicrobial and mechanical assessment of cellulose-based thermoformable material for invisible dental braces with natural essential oils protecting from biofilm formation.

Controlling biofilm formation in the oral cavity during orthodontic treatments is crucial. Therefore, antimicrobial surfaces for invisible dental appliances are of interest to both therapists and patients. Here we present a cellulose-based thermoformable material used for invisible braces that can be loaded with essential oils (EOs) having antibacterial and antifungal properties. We hypothesize that this material can absorb and release EOs, thus providing an antimicrobial effect without compromising the safety and mechanical properties necessary for dental invisible braces. Conventional microbiology and isothermal microcalorimetry analyses revealed that the thermoformable material loaded with essential oils significantly delayed the biofilm formation of oral streptococci (S. mutans and S. mitis) under static conditions (p < 0.05) and while simulating saliva flow (p < 0.05). In addition, cytotoxicity tests (ISO 10993-5), revealed that the loaded material is well tolerated by human gingival fibroblasts. Finally, the loading with antibacterial agents did not significantly alter the mechanical properties and stability of the material (initial force (p = 0.916); initial stress (p = 0.465)). Compared to gold-standard clear aligner materials, this material offers a reliable transmission of forces for orthodontic treatments. Moreover, this approach exhibits the potential for acting as an oral drug delivery platform for multiple compounds.

Allosteric targeting resolves limitations of earlier LFA-1 directed modalities.

Integrins are a family of cell surface receptors well-recognized for their therapeutic potential in a wide range of diseases. However, the development of integrin targeting medications has been impacted by unexpected downstream effects, reflecting originally unforeseen interference with the bidirectional signalling and cross-communication of integrins. We here selected one of the most severely affected target integrins, the integrin lymphocyte function-associated antigen-1 (LFA-1, αLß2, CD11a/CD18), as a prototypic integrin to systematically assess and overcome these known shortcomings. We employed a two-tiered ligand-based virtual screening approach to identify a novel class of allosteric small molecule inhibitors targeting this integrin's αI domain. The newly discovered chemical scaffold was derivatized, yielding potent bis-and tris-aryl-bicyclic-succinimides which inhibit LFA-1 in vitro at low nanomolar concentrations. The characterisation of these compounds in comparison to earlier LFA-1 targeting modalities established that the allosteric LFA-1 inhibitors (i) are devoid of partial agonism, (ii) selectively bind LFA-1 versus other integrins, (iii) do not trigger internalization of LFA-1 itself or other integrins and (iv) display oral availability. This profile differentiates the new generation of allosteric LFA-1 inhibitors from previous ligand mimetic-based LFA-1 inhibitors and anti-LFA-1 antibodies, and is projected to support novel immune regulatory regimens selectively targeting the integrin LFA-1. The rigorous computational and experimental assessment schedule described here is designed to be adaptable to the preclinical discovery and development of novel allosterically acting compounds targeting integrins other than LFA-1, providing an exemplary approach for the early characterisation of next generation integrin inhibitors.