Development and evaluation of in vivo tissue engineered blood vessels in a porcine model.
BACKGROUND
There's a large clinical need for novel vascular grafts. Tissue engineered blood vessels (TEBVs) have great potential to improve the outcome of vascular grafting procedures. Here, we present a novel approach to generate autologous TEBV in vivo. Polymer rods were engineered and implanted, evoking an inflammatory response that culminates in encapsulation by a fibrocellular capsule. We hypothesized that, after extrusion of the rod, the fibrocellular capsule differentiates into an adequate vascular conduit once grafted into the vasculature.


RESULTS
Rods were implanted subcutaneously in pigs. After 4 weeks, rods with tissue capsules grown around it were harvested. Tissue capsules were grafted bilaterally as carotid artery interposition. One and 4-week patency were evaluated by angiography whereupon pigs were sacrificed. Tissue capsules before and after grafting were evaluated on tissue remodeling using immunohistochemistry, RNA profiling and mechanical testing. Rods were encapsulated by thick, well-vascularized tissue capsules, composed of circumferentially aligned fibroblasts, collagen and few leukocytes, with adequate mechanical strength. Patency was 100% after 1 week and 87.5% after 4 weeks. After grafting, tissue capsules remodeled towards a vascular phenotype. Gene profiles of TEBVs gained more similarity with carotid artery. Wall thickness and αSMA-positive area significantly increased. Interestingly, a substantial portion of (myo)fibroblasts present before grafting expressed smooth muscle cell markers. While leukocytes were hardly present anymore, the lumen was largely covered with endothelial cells. Burst pressure remained stable after grafting.


CONCLUSIONS
Autologous TEBVs were created in vivo with sufficient mechanical strength enabling vascular grafting. Grafts differentiated towards a vascular phenotype upon grafting.
Department of Nephrology, Leiden University Medical Center, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, The Netherlands.
Tonia C
TC
Rothuizen
Department of Tissue Regeneration, University Twente, The Netherlands.
Febriyani F R
FFR
Damanik
Xeltis BV, Eindhoven, The Netherlands.
Tom
T
Lavrijsen
Department Surgery, Leiden University Medical Center, The Netherlands.
Michel J T
MJT
Visser
Department Surgery, Leiden University Medical Center, The Netherlands.
Jaap F
JF
Hamming
Department of Nephrology, Leiden University Medical Center, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, The Netherlands.
Reshma A
RA
Lalai
Department of Nephrology, Leiden University Medical Center, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, The Netherlands.
Jacques M G J
JMGJ
Duijs
Department of Nephrology, Leiden University Medical Center, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, The Netherlands.
Anton Jan
AJ
van Zonneveld
Laboratory of Experimental Cardiology and Dept. of Clinical Chemistry and Hematology, University Medical Center Utrecht, The Netherlands.
Imo E
IE
Hoefer
Department of Tissue Regeneration, University Twente, The Netherlands; Department of Complex Tissue Regeneration, Maastricht University, The Netherlands.
Clemens A
CA
van Blitterswijk
Department of Nephrology, Leiden University Medical Center, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, The Netherlands.
T J
TJ
Rabelink
Department of Tissue Regeneration, University Twente, The Netherlands; Department of Complex Tissue Regeneration, Maastricht University, The Netherlands.
Lorenzo
L
Moroni
Department of Nephrology, Leiden University Medical Center, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, The Netherlands. Electronic address: j.i.rotmans@lumc.nl.
Joris I
JI
Rotmans
D000818:Animals; D001696:Biomechanical Phenomena; D001807:Blood Vessel Prosthesis; D019917:Blood Vessel Prosthesis Implantation; D002339:Carotid Arteries / Q000000981:diagnostic imaging / Q000601:surgery; D002404:Catheterization; D020869:Gene Expression Profiling; D020007:Implants, Experimental; D037102:Lectins / Q000378:metabolism; D023421:Models, Animal; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011859:Radiography; D034421:Sus scrofa; D023822:Tissue Engineering / Q000379:methods*
D037102:Lectins; D012333:RNA, Messenger
Arterial bypass graft; In situ vascular tissue engineering; Porcine model; Remodeling; Tissue engineered blood vessel