Local fistula injection of mesenchymal stromal/stem cells (MSC) is effective for complex perianal Crohn's fistulas but is also expensive and requires specialised facilities for cell revival before administration. Human amnion epithelial cells (hAEC) are non-MSC cells with therapeutic properties. The primary aim of this study was safety of hAEC therapy. Secondary aims included hAEC efficacy, feasibility of the protocol and impact on quality of life. A phase I open label study of ten adults with active complex Crohn's perianal fistulas refractory to conventional treatment, including anti-tumour necrosis factor alpha therapy, was undertaken. A single dose of hAEC was injected into the fistula tract(s) after surgical closure of the internal opening(s). Study outcomes were assessed at week 24 with follow up for at least 52 weeks. Local injection of hAEC was safe, well tolerated and the injection procedure was feasible. Complete response occurred in 4 patients, and a partial response in an additional 4 patients. There was a mean reduction in the Perianal Disease Activity Index of 6.5 points (95% CI -9.0 to -4.0, p = 0.0002, paired t-test), modified Van Assche MRI Index of 2.3 points (95% CI -3.9 to -0.6, p = 0.012, paired t-test) and a mean improvement of 15.8 points (95% CI 4.9 to 26.8, p = 0.010, paired t-test) in quality of life using the Short IBD-Questionnaire in complete responders. Local injection of hAEC therapy for refractory complex perianal fistulising Crohn's disease appears safe, well-tolerated, feasible and demonstrated improvement. Quality of life is improved in those who achieve complete fistula healing. This study was funded by competitive research grant funding from the Gastroenterological Society of Australia Seed Grant 2018.

Survival outcomes and predictors of mortality, re-bleeding and complications for acute severe variceal bleeding requiring balloon tamponade

The diagnosis and management of inflammatory bowel disease relies on histological assessment, which is costly, subjective, and lacks utility for point-of-care diagnosis. Fourier-transform infra-red spectroscopy provides rapid, non-destructive, reproducible, and automatable label-free biochemical imaging of tissue for diagnostic purposes. This study characterises colitis using spectroscopy, discriminates colitis from healthy tissue, and classifies inflammation severity. Hyperspectral images were obtained from fixed intestinal sections of a murine colitis model treated with cell therapy to improve inflammation. Multivariate analyses and classification modelling were performed using supervised and unsupervised machine-learning algorithms. Quantitative analysis of severe colitis showed increased protein, collagen, and nucleic acids, but reduced glycogen when compared with normal tissue. A partial least squares discriminant analysis model, including spectra from all intestinal layers, classified normal colon and severe colitis with a sensitivity of 91.4% and a specificity of 93.3%. Colitis severity was classified by a stacked ensemble model yielding an average area under the receiver operating characteristic curve of 0.95, 0.88, 0.79, and 0.85 for controls, mild, moderate, and severe colitis, respectively. Infra-red spectroscopy can detect unique biochemical features of intestinal inflammation and accurately classify normal and inflamed tissue and quantify the severity of inflammation. This is a promising alternative to histological assessment.

Regenerative medicine, and in particular cell-based therapies, are under investigation as therapeutics in the management of inflammatory bowel disease, where despite significant advancements in management, prolonged remission is achieved in less than half of patients experiencing these disorders. In contrast to conventional immunomodulatory medications, these therapies are hypothesised to act through multiple pathways including via regenerative mechanisms, which may enable them to break through the current therapeutic ceiling. Potential therapy candidates include mesenchymal stem cells, human amnion epithelial cells, and regulatory T-cells, as well as their derivatives including extracellular vesicles. Extensive preclinical studies have demonstrated the multi-modal nature of these therapies as well as shared and unique properties. Controversy remains regarding contradictory study outcomes and the efficacy of regenerative therapies in human trials. In this narrative review, we first examine the mechanisms of these candidate cell therapies, including signalling via cytokines and extracellular vesicles, and interactions with immune cells, stromal cells, and the microbiome to determine differences and similarities between them. The second part delves into the current state of regenerative and cell-based therapy, focusing on mesenchymal stem cell, human amnion epithelial cell, T regulatory cells, and their respective extracellular vesicles in IBD treatment. Finally, we close by identifying the major literature gaps and barriers to bringing regenerative medicines to clinical use, resulting in recommendations for future research.