Tracheal Replacement Therapy with a Stem Cell-Seeded Graft: Lessons from Compassionate Use Application of a GMP-Compliant Tissue-Engineered Medicine

Tracheal replacement for the treatment of end-stage airway disease remains an elusive goal. The use of tissue-engineered tracheae in compassionate use cases suggests that such an approach is a viable option. Here, a stem cell-seeded, decellularized tissue-engineered tracheal graft was used on a compassionate basis for a girl with critical tracheal stenosis after conventional reconstructive techniques failed. The graft represents the first cell-seeded tracheal graft manufactured to full good manufacturing practice (GMP) standards. We report important preclinical and clinical data from the case, which ended in the death of the recipient. Early results were encouraging, but an acute event, hypothesized to be an intrathoracic bleed, caused sudden airway obstruction 3 weeks post-transplantation, resulting in her death. We detail the clinical events and identify areas of priority to improve future grafts. In particular, we advocate the use of stents during the first few months post-implantation. The negative outcome of this case highlights the inherent difficulties in clinical translation where preclinical in vivo models cannot replicate complex clinical scenarios that are encountered. The practical difficulties in delivering GMP grafts underscore the need to refine protocols for phase I clinical trials

ASKAP and MeerKAT surveys of the magellanic clouds

The Magellanic Clouds are a stepping stone from the overwhelming detail of the Milky Way in which we are immersed, to the global characteristics of galaxies both in the nearby and distant universe. They are interacting, gas-rich dwarf galaxies of sub-solar metallicity, not unlike the building blocks that assembled the large galaxies that dominate groups and clusters, and representative of the conditions at the height of cosmic star formation. The Square Kilometre Array (SKA) can make huge strides in understanding galactic metabolism and the ecological processes that govern star formation, by observations of the Magellanic Clouds and other, nearby Magellanic-type irregular galaxies. Two programmes with SKA Pathfinders attempt to pave the way: the approved Galactic ASKAP Spectral Line Survey (GASKAP) includes a deep survey in H I and OH of the Magellanic Clouds, whilst MagiKAT is proposed to perform more detailed studies of selected regions within the Magellanic Clouds - also including Faraday rotation measurements and observations at higher frequencies. These surveys also close the gap with the revolutionizing surveys at far-IR wavelengths with the Spitzer Space Telescope and Herschel Space Observatory

A pilot study investigating a novel subcutaneously implanted pre-cellularised scaffold for tissue engineering of intestinal mucosa

Tissue engineering of the small intestine offers an alternative to long-term intravenous nutrition and transplantation in patients with intestinal failure. Initial work, although encouraging, is limited by the volume of neonatal tissue required to produce a small neomucosal cyst. Our novel approach is to implant tubular poly-lactide-co-glycolide (PGLA) foam scaffolds subcutaneously. The aim of this study was to investigate whether these scaffolds would support growth of intestinal neomucosa. PGLA scaffolds were implanted subcutaneously into 8 Lewis rats; after 5 weeks, 'organoid units' were injected into the lumens. Tissue was assessed histologically after harvesting and quantitative immunohistochemistry was performed using antibodies against vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGF-R2), fibroblast growth factor basic (bFGF) and fibroblast growth factor receptor 2 (FGF-R2). At 4 weeks post organoid unit implantation, clearly recognisable mucosa and submucosa was present on the luminal surface of the scaffold. Densities of VEGF and VEGF-R2 positive cells increased with time post organoid unit implantation. This pilot study demonstrates that it is possible to tissue engineer small intestinal neomucosa using subcutaneously implanted PLGA scaffolds. The yield of the process compares favourably to the published literature. Further work is required to optimise the technique