Silsesquioxane polymer as a potential scaffold for laryngeal reconstruction

Cancer, disease and trauma to the larynx and their treatment can lead to permanent loss of structures critical to voice, breathing and swallowing. Engineered partial or total laryngeal replacements would need to match the ambitious specifications of replicating functionality, outer biocompatibility, and permissiveness for an inner mucosal lining. Here we present porous polyhedral oligomeric silsesquioxane-poly(carbonate urea) urethane (POSS-PCUU) as a potential scaffold for engineering laryngeal tissue. Specifically, we employ a precipitation and porogen leaching technique for manufacturing the polymer. The polymer is chemically consistent across all sample types and produces a foam-like scaffold with two distinct topographies and an internal structure composed of nano- and micro-pores. Whilst the highly porous internal structure of the scaffold contributes to the complex tensile behaviour of the polymer, the surface of the scaffold remains largely non-porous. The low number of pores minimise access for cells, although primary fibroblasts and epithelial cells do attach and proliferate on the polymer surface. Our data show that with a change in manufacturing protocol to produce porous polymer surfaces, POSS-PCUU may be a potential candidate for overcoming some of the limitations associated with laryngeal reconstruction and regeneration

Host macrophage response to injectable hydrogels derived from ECM and α-helical peptides

Tissue engineering materials play a key role in how closely the complex architectural and functional characteristics of native healthy tissue can be replicated. Traditional natural and synthetic materials are superseded by bespoke materials that cross the boundary between these two categories. Here we present hydrogels that are derived from decellularised extracellular matrix and those that are synthesised from de novo α-helical peptides. We assess in vitro activation of murine macrophages to our hydrogels and whether these gels induce an M1-like or M2-like phenotype. This was followed by the in vivo immune macrophage response to hydrogels injected into rat partial-thickness abdominal wall defects. Over 28 days we observe an increase in mononuclear cell infiltration at the hydrogel-tissue interface without promoting a foreign body reaction and see no evidence of hydrogel encapsulation or formation of multinucleate giant cells. We also note an upregulation of myogenic differentiation markers and the expression of anti-inflammatory markers Arginase1, IL-10, and CD206, indicating pro-remodelling for all injected hydrogels. Furthermore, all hydrogels promote an anti-inflammatory environment after an initial spike in the pro-inflammatory phenotype. No difference between the injected site and the healthy tissue is seen after 28 days, indicating full integration. These materials offer great potential for future applications in regenerative medicine and towards unmet clinical needs

Surface modification of a POSS-nanocomposite material to enhance cellular integration of a synthetic bioscaffold

AbstractPolyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane (POSS-PCU) is a versatile nanocomposite biomaterial with growing applications as a bioscaffold for tissue engineering. Integration of synthetic implants with host tissue can be problematic but could be improved by topographical modifications. We describe optimization of POSS-PCU by dispersion of porogens (sodium bicarbonate (NaHCO3), sodium chloride (NaCl) and sucrose) onto the material surface, with the principle aim of increasing surface porosity, thus providing additional opportunities for improved cellular and vascular ingrowth. We assess the effect of the porogens on the material's mechanical strength, surface chemistry, wettability and cytocompatibilty. Surface porosity was characterized by scanning electron microscopy (SEM). There was no alteration in surface chemistry and wettability and only modest changes in mechanical properties were detected. The size of porogens correlated well with the porosity of the construct produced and larger porogens improved interconnectivity of spaces within constructs. Using primary human bronchial epithelial cells (HBECs) we demonstrate moderate in vitro cytocompatibility for all surface modifications; however, larger pores resulted in cellular aggregation. These cells were able to differentiate on POSS-PCU scaffolds. Implantation of the scaffold in vivo demonstrated that larger pore sizes favor cellular integration and vascular ingrowth. These experiments demonstrate that surface modification with large porogens can improve POSS-PCU nanocomposite scaffold integration and suggest the need to strike a balance between the non-porous surfaces required for epithelial coverage and the porous structure required for integration and vascularization of synthetic scaffolds in future construct design

Strange Quark Contributions to Parity-Violating Asymmetries in the Backward Angle G0 Electron Scattering Experiment

We have measured parity-violating asymmetries in elastic electron-proton and quasi-elastic electron-deuteron scattering at Q^2 = 0.22 and 0.63 GeV^2. They are sensitive to strange quark contributions to currents in the nucleon, and to the nucleon axial current. The results indicate strange quark contributions of < 10% of the charge and magnetic nucleon form factors at these four-momentum transfers. We also present the first measurement of anapole moment effects in the axial current at these four-momentum transfers.Comment: 5 pages, 2 figures, changed references, typo, and conten

Transverse Beam Spin Asymmetries at Backward Angles in Elastic Electron-Proton and Quasi-elastic Electron-Deuteron Scattering

We have measured the beam-normal single-spin asymmetries in elastic scattering of transversely polarized electrons from the proton, and performed the first measurement in quasi-elastic scattering on the deuteron, at backward angles (lab scattering angle of 108 degrees) for Q2 = 0.22 GeV^2/c^2 and 0.63 GeV^2/c^2 at beam energies of 362 MeV and 687 MeV, respectively. The asymmetry arises due to the imaginary part of the interference of the two-photon exchange amplitude with that of single photon exchange. Results for the proton are consistent with a model calculation which includes inelastic intermediate hadronic (piN) states. An estimate of the beam-normal single-spin asymmetry for the scattering from the neutron is made using a quasi-static deuterium approximation, and is also in agreement with theory

SOX9 predicts progression towards cirrhosis in patients while its loss protects against liver fibrosis

Fibrosis and organ failure is a common endpoint for many chronic liver diseases. Much is known about the upstream inflammatory mechanisms provoking fibrosis and downstream potential for tissue remodeling. However, less is known about the transcriptional regulation in vivo governing fibrotic matrix deposition by liver myofibroblasts. This gap in understanding has hampered molecular predictions of disease severity and clinical progression and restricted targets for antifibrotic drug development. In this study we show the prevalence of SOX9 in biopsies from patients with chronic liver disease correlated with fibrosis severity and accurately predicted disease progression towards cirrhosis. Inactivation of Sox9 in mice protected against both parenchymal and biliary fibrosis, improved liver function and ameliorated chronic inflammation. SOX9 was downstream of mechanosignaling factor, YAP1. These data demonstrate a role for SOX9 in liver fibrosis and open the way for the transcription factor and its dependent pathways as new diagnostic, prognostic and therapeutic targets in patients with liver fibrosis

Transverse Beam Spin Asymmetries in Forward-Angle Elastic Electron-Proton Scattering

We have measured the beam-normal single-spin asymmetry in elastic scattering of transversely-polarized 3 GeV electrons from unpolarized protons at Q^2 = 0.15, 0.25 (GeV/c)^2. The results are inconsistent with calculations solely using the elastic nucleon intermediate state, and generally agree with calculations with significant inelastic hadronic intermediate state contributions. A_n provides a direct probe of the imaginary component of the 2-gamma exchange amplitude, the complete description of which is important in the interpretation of data from precision electron-scattering experiments.Comment: 5 pages, 3 figures, submitted to Physical Review Letters; shortened to meet PRL length limit, clarified some text after referee's comment