Abstract
Clinical applications of tissue engineering are constrained by the ability of the implanted construct to invoke vascularization in adequate extent and velocity. To overcome the current limitations presented by local delivery of single angiogenic factors, we explored the incorporation of prolyl hydroxylase inhibitors (PHIs) into scaffolds as an alternative vascularization strategy. PHIs are small molecule drugs that can stabilize the alpha subunit of hypoxia-inducible factor-1 (HIF-1), a key transcription factor that regulates a variety of angiogenic mechanisms. In this study, we conjugated the PHI pyridine-2,4-dicarboxylic acid (PDCA) through amide bonds to a gelatin sponge (Gelfoam®). Fibroblasts cultured on PDCA-Gelfoam were able to infiltrate and proliferate in these scaffolds while secreting significantly more vascular endothelial growth factor than cells grown on Gelfoam without PDCA. Reporter cells expressing green fluorescent protein-tagged HIF-1α exhibited dose-dependent stabilization of this angiogenic transcription factor when growing within PDCA-Gelfoam constructs. Subsequently, we implanted PDCA-Gelfoam scaffolds into the perirenal fat tissue of Sprague Dawley rats for 8 days. Immunostaining of explants revealed that the PDCA-Gelfoam scaffolds were amply infiltrated by cells and promoted vascular ingrowth in a dose-dependent manner. Thus, the incorporation of PHIs into scaffolds appears to be a feasible strategy for improving vascularization in regenerative medicine applications.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1106-1115 |
| Number of pages | 10 |
| Journal | Tissue Engineering - Part A |
| Volume | 21 |
| Issue number | 5-6 |
| DOIs | |
| State | Published - Mar 1 2015 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Bioengineering
- Biochemistry
- Biomedical Engineering
- Biomaterials
Cite this
Incorporation of a prolyl hydroxylase inhibitor into scaffolds : A strategy for stimulating vascularization. / Sham, Adeline; Martinez Valencia, Eliana Cecilia; Beyer, Sebastian; Trau, Dieter W.; Raghunath, Michael.
In: Tissue Engineering - Part A, Vol. 21, No. 5-6, 01.03.2015, p. 1106-1115.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Incorporation of a prolyl hydroxylase inhibitor into scaffolds
T2 - A strategy for stimulating vascularization
AU - Sham, Adeline
AU - Martinez Valencia, Eliana Cecilia
AU - Beyer, Sebastian
AU - Trau, Dieter W.
AU - Raghunath, Michael
PY - 2015/3/1
Y1 - 2015/3/1
N2 - Clinical applications of tissue engineering are constrained by the ability of the implanted construct to invoke vascularization in adequate extent and velocity. To overcome the current limitations presented by local delivery of single angiogenic factors, we explored the incorporation of prolyl hydroxylase inhibitors (PHIs) into scaffolds as an alternative vascularization strategy. PHIs are small molecule drugs that can stabilize the alpha subunit of hypoxia-inducible factor-1 (HIF-1), a key transcription factor that regulates a variety of angiogenic mechanisms. In this study, we conjugated the PHI pyridine-2,4-dicarboxylic acid (PDCA) through amide bonds to a gelatin sponge (Gelfoam®). Fibroblasts cultured on PDCA-Gelfoam were able to infiltrate and proliferate in these scaffolds while secreting significantly more vascular endothelial growth factor than cells grown on Gelfoam without PDCA. Reporter cells expressing green fluorescent protein-tagged HIF-1α exhibited dose-dependent stabilization of this angiogenic transcription factor when growing within PDCA-Gelfoam constructs. Subsequently, we implanted PDCA-Gelfoam scaffolds into the perirenal fat tissue of Sprague Dawley rats for 8 days. Immunostaining of explants revealed that the PDCA-Gelfoam scaffolds were amply infiltrated by cells and promoted vascular ingrowth in a dose-dependent manner. Thus, the incorporation of PHIs into scaffolds appears to be a feasible strategy for improving vascularization in regenerative medicine applications.
AB - Clinical applications of tissue engineering are constrained by the ability of the implanted construct to invoke vascularization in adequate extent and velocity. To overcome the current limitations presented by local delivery of single angiogenic factors, we explored the incorporation of prolyl hydroxylase inhibitors (PHIs) into scaffolds as an alternative vascularization strategy. PHIs are small molecule drugs that can stabilize the alpha subunit of hypoxia-inducible factor-1 (HIF-1), a key transcription factor that regulates a variety of angiogenic mechanisms. In this study, we conjugated the PHI pyridine-2,4-dicarboxylic acid (PDCA) through amide bonds to a gelatin sponge (Gelfoam®). Fibroblasts cultured on PDCA-Gelfoam were able to infiltrate and proliferate in these scaffolds while secreting significantly more vascular endothelial growth factor than cells grown on Gelfoam without PDCA. Reporter cells expressing green fluorescent protein-tagged HIF-1α exhibited dose-dependent stabilization of this angiogenic transcription factor when growing within PDCA-Gelfoam constructs. Subsequently, we implanted PDCA-Gelfoam scaffolds into the perirenal fat tissue of Sprague Dawley rats for 8 days. Immunostaining of explants revealed that the PDCA-Gelfoam scaffolds were amply infiltrated by cells and promoted vascular ingrowth in a dose-dependent manner. Thus, the incorporation of PHIs into scaffolds appears to be a feasible strategy for improving vascularization in regenerative medicine applications.
UR - http://www.scopus.com/inward/record.url?scp=84924387946&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84924387946&partnerID=8YFLogxK
U2 - 10.1089/ten.tea.2014.0077
DO - 10.1089/ten.tea.2014.0077
M3 - Article
C2 - 25370818
AN - SCOPUS:84924387946
VL - 21
SP - 1106
EP - 1115
JO - Tissue Engineering - Part A
JF - Tissue Engineering - Part A
SN - 1937-3341
IS - 5-6
ER -