Development of a biologically derived acellular construct for small intestine replacement.
Doctoral thesis, UCL (University College London).
Introduction: Short bowel syndrome is characterised by a severe reduction in the amount of functional intestine available as an absorptive surface. Attempts to lengthen the intestine by interposition of artificial tubular scaffolds juxtaposed between healthy tissues have shown limited success. Transplantation is limited due to organ shortage. The most promising solution may be implantation of tissue-engineered small intestine using natural scaffold. Materials and Results: Using a completely novel approach, up to 30cm lengths of ileum with the attached vasculature were harvested from porcine donors. Separate intestinal and vascular loops were identified and de-cellularised using individually tailored detergent-enzymatic protocols. The resulting scaffold was compared to native tissue in terms of retention of cellular and nuclear remnants, as well as structural and functional proteins. Its biocompatibility was assessed by subcutaneous implantation of 1cm2 pieces into rat recipients. The remodeling fate of grafts was determined by time related changes in the ratio of sub-populations of residual macrophages. Its mechanical strength and ease of handling was evaluated by performing a left-sided nephrectomy in an unrelated pig model, followed by end-to-end anastomosis of the de-cellularised scaffolds’ mesenteric vasculature to the appropriate renal artery and vein. In the last stage, porcine organoid units were isolated and their yield estimated for future in vitro studies. Conclusions: It is possible to simultaneously de-cellularise two different tissues of varying cellular configuration and composition effectively and efficiently over a relatively short period of time. The two key features of the de-cellularised scaffold are that 1) the scaffold has in place the necessary architectural topography of small intestine (including mucosal villi) and molecular cues for optimum re-cellularisation and 2) the attached vascular tree provides an ideal conduit for re-cellularisation using either vascular committed endothelial or progenitor cells. Ultimately, this scaffold can be used for constructing long segments of bio-engineered intestine with the possibility of immediate blood supply and re-vascularisation.
|Title:||Development of a biologically derived acellular construct for small intestine replacement|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Surgery and Interventional Science (Division of)|
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