Scaffolding for challenging environments: materials selection for tissue engineered intestine.

Novel therapies are crucially needed for short bowel syndrome. One potential therapy is the production of tissue engineered intestine (TEI). The intestinal environment presents significant challenges to the selection of appropriate material for tissue engineering scaffolds. Our goal was to characterize different scaffold materials to downselect to that best suited for TEI production. To investigate this, various tubular scaffolds were implanted into the peritoneal cavity of adult rats and harvested at multiple time-points. Harvested scaffolds were examined histologically and subjected to degradation studies and mechanical evaluation. We found that poly(glycolic acid) (PGA)-nanofiber and PGA-macrofiber scaffolds exhibited early robust tissue infiltration. Poly(ɛ-caprolactone) (PCL)-nanofiber, poly(l-lactic acid) (PLLA)-nanofiber, poly(d-lactic acid-co-glycolic acid) (PDLGA)-nanofiber and polyurethane (PU)-nanofiber experienced slower tissue infiltration. Poly(ɛ-caprolactone-co-lactic acid) (PLC) nanofiber had poor tissue infiltration. Significant weight loss was observed in PGA-nanofiber (92.2%), PGA-macrofiber (67.6%), and PDLGA-nanofiber (76.9%) scaffolds. Individual fibers were no longer seen by scanning electron microscopy in PLC-nanofiber and PGA-nanofiber scaffolds after 1 week, PGA-macrofiber scaffolds after 2 weeks, and PDLGA-nanofiber scaffolds after 4 weeks. In conclusion, PGA-macrofiber and PDLGA appear to be the most appropriate materials choices as TEI scaffolds due to their biocompatibility and degradation. Future experiments will confirm these results by analyzing cell-seeded scaffolds in vitro and in vivo.

p53 regulates renal expression of HIF-1{alpha} and pVHL under physiological conditions and after ischemia-reperfusion injury.

Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI) and is characterized by widespread tubular and microvascular damage. The tumor suppressor p53 is upregulated after IRI and contributes to renal injury in part by promoting apoptosis. Acute, short-term inhibition of p53 with pifithrin-alpha conveys significant protection after IRI. The hypoxia-inducible factor-1 (HIF-1) pathway is also activated after IRI and has opposing effects to those promoted by p53. The balance between the HIF-1 and p53 responses can determine the outcome of IRI. In this manuscript, we investigate whether p53 regulates the HIF-1 pathway in a rodent model of IRI. HIF-1alpha is principally expressed in the collecting tubules (CT) and thick ascending limbs (TAL) under physiological conditions. However, inhibition of p53 with pifithrin-alpha increases the faint expression of HIF-1alpha in proximal tubules (PT) under physiological conditions. Twenty-four hours after IRI, HIF-1alpha expression is decreased in both CT and TAL. HIF-1alpha expression in the PT is not significantly altered after IRI. Acute inhibition of p53 significantly increases HIF-1alpha expression in the PT after IRI. Additionally, pifithrin-alpha prevents the IRI-induced decrease in HIF-1alpha in the CT and TAL. Parallel changes are observed in the HIF-1alpha transcriptive target, carbonic anhydrase-9. Finally, inhibition of p53 prevents the dramatic changes in Von Hippel-Lindau protein morphology and expression after IRI. We conclude that activation of p53 after IRI mitigates the concomitant activation of the protective HIF-1 pathway. Modulating the interactions between the p53 and HIF-1 pathway can provide novel options in the treatment of AKI.