MMP‐2 sensitive, VEGF‐bearing bioactive hydrogels for promotion of vascular healing

Journal of Biomedical Materials Research - Part A - Tập 68A Số 4 - Trang 704-716 - 2004
Dror Seliktar1,2, Andreas H. Zisch1, Matthias P. Lütolf1, Jeffrey L. Wrana2, Jeffrey A. Hubbell1
1Institute for Biomedical Engineering, Swiss Federal Institute of Technology and University of Zurich, Moussonstrasse 18, CH-8044 Zurich, Switzerland
2Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada

Tóm tắt

Abstract

We sought to develop bioactive hydrogels to facilitate arterial healing, e.g., after balloon angioplasty. Toward this end, we developed a new class of proteolytically sensitive, biologically active polyethylene glycol (PEG)‐peptide hydrogels that can be formed in situ to temporarily protect the arterial injury from blood contact. Furthermore, we incorporated endothelial cell‐specific biological signals with the goal of enhancing arterial reendothelialization. Here we demonstrate efficient endothelial cell anchorage and activation on PEG hydrogel matrices modified by conjugation with both the cell adhesive peptide motif RGD and an engineered variant of vascular endothelial growth factor (VEGF). By crosslinking peptide sequences for cleavage by MMP‐2 into the polymer backbone, the hydrogels became sensitive to proteolytic degradation by cell‐derived matrix metalloproteinases (MMPs). Analysis of molecular hallmarks associated with endothelial cell activation by VEGF‐RGD hydrogel matrices revealed a 70% increase in production of the latent MMP‐2 zymogen compared with PEG‐peptide hydrogels lacking VEGF. By additional provision of transforming growth factor β1 (TGF‐β1) within the PEG‐peptide hydrogel, conversion of the latent MMP zymogen into its active form was demonstrated. As a result of MMP‐2 activation, strongly enhanced hydrogel degradation by activated endothelial cells was observed. Our data illustrate the critical importance of growth factor activities for remodeling of synthetic biomaterials into native tissue, as it is desired in many applications of regenerative medicine. Functionalized PEG‐peptide hydrogels could help restore the native vessel wall and improve the performance of angioplasty procedures. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 68A: 704–716, 2004

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Tài liệu tham khảo

10.1016/0735-1097(92)90389-5

10.1016/S0735-1097(10)80196-2

10.1016/0735-1097(90)92845-S

10.1073/pnas.86.21.8412

10.1056/NEJM199201233260406

10.1056/NEJM199201303260506

10.1161/hc3601.093987

10.1161/01.CIR.103.18.2289

10.1073/pnas.91.13.5967

10.1073/pnas.93.23.13188

10.1073/pnas.91.13.5967

10.1016/S0733-8651(18)30087-0

Slepian MJ, 1996, Polymeric endoluminal gel paving: therapeutic hydrogel barriers and sustained drug delivery depots for local arterial wall biomanipulation, Semin Interv Cardiol, 1, 103

10.1002/jbm.10042

10.1073/pnas.0737381100

10.1021/bc015519e

10.1021/bm025744e

10.1006/mvre.1997.2056

Eichler W, 2002, Modulation of matrix metalloproteinase and TIMP‐1 expression by cytokines in human RPE cells, Invest Ophthalmol Vis Sci, 43, 2767

10.1023/A:1012209518843

10.1093/molehr/5.10.950

Overall CM, 1991, Transcriptional and post‐transcriptional regulation of 72‐kDa gelatinase/type IV collagenase by transforming growth factor‐beta 1 in human fibroblasts. Comparisons with collagenase and tissue inhibitor of matrix metalloproteinase gene expression., J Biol Chem, 266, 14064, 10.1016/S0021-9258(18)92810-3

10.1016/S0168-3659(01)00398-4

10.1096/fj.02-1041fje

10.1016/S0168-3659(01)00266-8

10.1016/0092-8674(87)90192-9

10.1021/bm0056299

10.1021/bm015629o

10.1006/bbrc.1998.8493

10.1016/S0958-1669(99)80021-4

10.1002/(SICI)1097-4636(199802)39:2<266::AID-JBM14>3.0.CO;2-B

10.1161/res.90.3.251

Behzadian MA, 2001, TGF‐beta increases retinal endothelial cell permeability by increasing MMP‐9: possible role of glial cells in endothelial barrier function, Invest Ophthalmol Vis Sci, 42, 853

Puyraimond A, 1999, Examining the relationship between the gelatinolytic balance and the invasive capacity of endothelial cells, J Cell Sci, 112, 1283, 10.1242/jcs.112.9.1283

10.1016/S0142-9612(00)00196-4

10.1016/S0168-8278(99)80007-5

Sakurai H, 1997, Transforming growth factor‐beta selectively inhibits branching morphogenesis but not tubulogenesis, Am J Physiol, 272, F139

10.1056/NEJM199411103311907

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Thông tin xuất bản

Journal of Biomedical Materials Research - Part A

Tập 68A Số 4

704-716

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