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

Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer

Argininosuccinate lyase (ASL) belongs to the hepatic urea cycle detoxifying ammonia, and the citrulline-nitric oxide (NO) cycle producing NO. ASL-deficient patients present argini-nosuccinic aciduria characterised by hyperammonaemia, multiorgan disease and neurocognitive impairment despite treatment aiming to normalise ammonaemia without considering NO imbalance. Here we show that cerebral disease in argininosuccinic aciduria involves neuronal oxidative/nitrosative stress independent of hyperammonaemia. Intravenous injection of AAV8 vector into adult or neonatal ASL-deficient mice demonstrates long-term correction of the hepatic urea cycle and the cerebral citrulline-NO cycle, respectively. Cerebral disease persists if ammonaemia only is normalised but is dramatically reduced after correction of both ammonaemia and neuronal ASL activity. This correlates with behavioural improvement and reduced cortical cell death. Thus, neuronal oxidative/nitrosative stress is a distinct pathophysiological mechanism from hyperammonaemia. Disease amelioration by simultaneous brain and liver gene transfer with one vector, to treat both metabolic pathways, provides new hope for hepatocerebral metabolic diseases