The Development of Newborn Porcine Models for Evaluation of Tissue-Engineered Small Intestine

Abstract

Short bowel syndrome (SBS) is a major cause of morbidity and mortality in the pediatric population, for which treatment options are limited. To develop novel approaches for the treatment of SBS, we now focus on the development of a tissue-engineered intestine (also known as an "artificial intestine"), in which intestinal stem cells are cultured onto an absorbable bioscaffold, followed by implantation into the host. To enhance the translational potential of these preclinical studies, we have developed three clinically relevant models in neonatal piglets, which approximate the size of the human infant and were evaluated after implantation and establishment of intestinal continuity over the long term. The models included (1) a staged, multioperation approach; (2) a single operation with a de-functionalized loop of small intestine; and (3) a single operation with an intestinal bypass. The first model had complications related to multiple operations in a short time period, including surgical site infections and wound hernias. The second model avoided wound complications, but was associated with high ostomy output, local skin breakdown, and systemic dehydration with associated electrolyte imbalances. The third model was the most effective, although resulted in stoma prolapse. In summary, we have now developed and evaluated three operative methods for the long-term evaluation of the artificial intestine in the piglet, and conclude that a single operation with a de-functionalized loop of small intestine may be an optimal approach for evaluation over the long term.

Biomaterials and biosensors in intestinal organoid culture, a progress review

“…Their bioengineered bowel made of the tubular chitosan sheet was confirmed to have vascularization and normal cell phenotype and function after implantation in the small intestine of rats. Moreover, to obtain scaffolds with crypt‐villus architecture, Ladd et al () created a template array of 500 μm deep and ordered holes on a polymethyl‐methacrylate template. They poured either poly(ethylene‐co‐vinyl acetate) or poly(glycerol sebacate) onto the template to cast the crypt‐villus structure on the surface of scaffolds.…”

Building Scaffolds for Tubular Tissue Engineering

“…The liquid can be derived from a variety of means, including the melting and solidification of a material ( Im et al, 2019 ), the solubilization of a material in a solvent and subsequent evaporation of the solvent ( Mooney et al, 1995 ; Opitz et al, 2004 ; Nieponice et al, 2008 ; Ma et al, 2010 ; Zakhem et al, 2012 ), or the cross-linking ( Matsuda, 2004 ; Guo et al, 2017 ) or gelation of a material into a solid or semi-solid structure, such as a hydrogel ( Wang et al, 2014 ; Strobel et al, 2018b ). Casting is also applicable within the context of more complex molding techniques, such as vacuum-assisted tube formation ( Singh et al, 2017 ), and for the formation of more complex structures ( Ladd et al, 2018 ). As may be expected, the chosen material will dictate the mechanism.…”

“…The resultant mesh of nanofibers can be removed from the mandrel, producing a mesh-tube (Rocco et al, 2014), with examples producing contiguous tubular structures that are compatible with cell-seeding (Figure 4). In many cases these meshes are combined with secondary electrospinning, deposition, or casting techniques to change Seliktar et al, 2003;Matsuda, 2004;Opitz et al, 2004;Swartz et al, 2005;Liu et al, 2007;Nieponice et al, 2008;Ma et al, 2010;Wang et al, 2014;Guo et al, 2017;Atchison et al, 2017;Strobel et al, 2018b;Im et al, 2019Intestine Yu et al, 2012Zakhem et al, 2012;Chen et al, 2015;Zhou et al, 2018;Ladd et al, 2018Ladd et al, , 2019Roh et al, 2019Trachea Naito et al, 2011 • High degree of control over scaffold properties (porosity, mechanics, etc. ) • Easily applied for tube formation • Directly compatible with proteins…”

“…The permeability of the cellularized structures was gauged using electrical measurements I and permeation by two drugs, finding higher permeability coefficients in the 3D structures ( Yu et al, 2012 ). This experimental design has since been used with various other materials, mainly porous polymeric structures, to monitor the effects of bacterial culture with enterocytes ( Costello et al, 2014 ; Ladd et al, 2019 ) and has recently been formed into tubular structures for implantation ( Ladd et al, 2018 ).…”

Gut bioengineering promotes gut repair and pharmaceutical research: a review

“…91 Of note, some cases demonstrated that surgical complications such as wound infections and hernia would cause the treatment failure and even death. In an updated study, Ladd et al 92 compared the effects of intestinal organoid anastomosis using three surgical types and concluded that a single operation with a defunctionalized loop of small intestine may be an optimal approach. Undoubtedly, such efforts are important for clinical translation of intestinal organoids, and more work is needed for establishing standardized surgical methods.…”