Flow-Induced Axial Vascularization: The Arteriovenous Loop in Angiogenesis and Tissue Engineering.
Fabrication of a viable vascular network providing oxygen supply is identified as one crucial limiting factor to generate more complex three-dimensional constructs. The arteriovenous loop model provides initial blood supply and has a high angioinductive potency, making it suitable for vascularization of larger, tissue-engineered constructs. Also because of its angiogenic capabilities the arteriovenous loop is recently also used as a model to evaluate angiogenesis in vivo. This review summarizes the history of the arteriovenous loop model in research and its technical and surgical aspects. Through modifications of the isolation chamber and its containing matrices, tissue generation can be enhanced. In addition, matrices can be used as release systems for local application of growth factors, such as vascular endothelial growth factor and basic fibroblast growth factor, to affect vascular network formation. A special focus in this review is set on the assessment of angiogenesis in the arteriovenous loop model. This model provides good conditions for assessment of angiogenesis with the initial cell-free environment of the isolation chamber, which is vascularized by the arteriovenous loop. Because of the angiogenic capabilities of the arteriovenous loop model, different attempts were performed to create functional tissue in the isolation chamber for potential clinical application. Arteriovenous loops in combination with autologous bone marrow aspirate were already used to reconstruct large bone defects in humans.
Heidelberg and Erlangen, Germany.|From the Department for Hand-, Plastic- and Reconstructive Surgery, BG Unfallklinik Ludwigshafen, Universität Heidelberg; and the Department of Plastic and Hand Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg.
Nico
N
Leibig
Heidelberg and Erlangen, Germany.|From the Department for Hand-, Plastic- and Reconstructive Surgery, BG Unfallklinik Ludwigshafen, Universität Heidelberg; and the Department of Plastic and Hand Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg.
Johanna O
JO
Wietbrock
Heidelberg and Erlangen, Germany.|From the Department for Hand-, Plastic- and Reconstructive Surgery, BG Unfallklinik Ludwigshafen, Universität Heidelberg; and the Department of Plastic and Hand Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg.
Amir K
AK
Bigdeli
Heidelberg and Erlangen, Germany.|From the Department for Hand-, Plastic- and Reconstructive Surgery, BG Unfallklinik Ludwigshafen, Universität Heidelberg; and the Department of Plastic and Hand Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg.
Raymund E
RE
Horch
Heidelberg and Erlangen, Germany.|From the Department for Hand-, Plastic- and Reconstructive Surgery, BG Unfallklinik Ludwigshafen, Universität Heidelberg; and the Department of Plastic and Hand Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg.
Thomas
T
Kremer
Heidelberg and Erlangen, Germany.|From the Department for Hand-, Plastic- and Reconstructive Surgery, BG Unfallklinik Ludwigshafen, Universität Heidelberg; and the Department of Plastic and Hand Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg.
Ulrich
U
Kneser
Heidelberg and Erlangen, Germany.|From the Department for Hand-, Plastic- and Reconstructive Surgery, BG Unfallklinik Ludwigshafen, Universität Heidelberg; and the Department of Plastic and Hand Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg.
Volker J
VJ
Schmidt
D000818:Animals; D001166:Arteriovenous Shunt, Surgical / Q000379:methods*; D006801:Humans; D008954:Models, Biological; D018919:Neovascularization, Physiologic; D023822:Tissue Engineering / Q000379:methods*
Langer R, Vacanti JP. Tissue engineering. Science 1993;260:920926.
Vacanti CA. The history of tissue engineering. J Cell Mol Med. 2006;10:569576.
Horch RE. Future perspectives in tissue engineering. J Cell Mol Med. 2006;10:46.
Horch RE, Kneser U, Polykandriotis E, Schmidt VJ, Sun J, Arkudas A. Tissue engineering and regenerative medicine: Where do we stand? J Cell Mol Med. 2012;16:11571165.
Lovett M, Lee K, Edwards A, Kaplan DL. Vascularization strategies for tissue engineering. Tissue Eng Part B Rev. 2009;15:353370.
Kneser U, Schaefer DJ, Polykandriotis E, Horch RE. Tissue engineering of bone: The reconstructive surgeon’s point of view. J Cell Mol Med. 2006;10:719.
Folkman J, Hochberg M. Self-regulation of growth in three dimensions. J Exp Med. 1973;138:745753.
Bleiziffer O, Hammon M, Naschberger E, et al. Endothelial progenitor cells are integrated in newly formed capillaries and alter adjacent fibrovascular tissue after subcutaneous implantation in a fibrin matrix. J Cell Mol Med. 2011;15:24522461.
Feng L, Wu H, L E, et al. Effects of vascular endothelial growth factor 165 on bone tissue engineering. PLoS One 2013;8:e82945.
Levenberg S, Golub JS, Amit M, Itskovitz-Eldor J, Langer R. Endothelial cells derived from human embryonic stem cells. Proc Natl Acad Sci USA 2002;99:43914396.
Levenberg S, Zoldan J, Basevitch Y, Langer R. Endothelial potential of human embryonic stem cells. Blood 2007;110:806814.
Koike N, Fukumura D, Gralla O, Au P, Schechner JS, Jain RK. Tissue engineering: Creation of long-lasting blood vessels. Nature 2004;428:138139.
Arkudas A, Pryymachuk G, Beier JP, et al. Combination of extrinsic and intrinsic pathways significantly accelerates axial vascularization of bioartificial tissues. Plast Reconstr Surg. 2012;129:55e65e.
Polykandriotis E, Arkudas A, Beier JP, et al. Intrinsic axial vascularization of an osteoconductive bone matrix by means of an arteriovenous vascular bundle. Plast Reconstr Surg. 2007;120:855868.
Tanaka Y, Sung KC, Tsutsumi A, Ohba S, Ueda K, Morrison WA. Tissue engineering skin flaps: Which vascular carrier, arteriovenous shunt loop or arteriovenous bundle, has more potential for angiogenesis and tissue generation? Plast Reconstr Surg. 2003;112:16361644.
Yap KK, Dingle AM, Palmer JA, et al. Enhanced liver progenitor cell survival and differentiation in vivo by spheroid implantation in a vascularized tissue engineering chamber. Biomaterials 2013;34:39924001.
Schmidt VJ, Hilgert JG, Covi JM, et al. High flow conditions increase connexin43 expression in a rat arteriovenous and angioinductive loop model. PLoS One 2013;8:e78782.
Schmidt VJ, Hilgert JG, Covi JM, et al. Flow increase is decisive to initiate angiogenesis in veins exposed to altered hemodynamics. PLoS One 2015;10:e0117407.
Arkudas A, Tjiawi J, Bleiziffer O, et al. Fibrin gel-immobilized VEGF and bFGF efficiently stimulate angiogenesis in the AV loop model. Mol Med. 2007;13:480487.
Erol OO, Sira M. New capillary bed formation with a surgically constructed arteriovenous fistula. Plast Reconstr Surg. 1980;66:109115.
Tanaka Y, Sung KC, Fumimoto M, et al. Prefabricated engineered skin flap using an arteriovenous vascular bundle as a vascular carrier in rabbits. Plast Reconstr Surg. 2006;117:18601875.
Beier JP, Hess A, Loew J, et al. De novo generation of an axially vascularized processed bovine cancellous-bone substitute in the sheep arteriovenous-loop model. Eur Surg Res. 2011;46:148155.
Beier JP, Horch RE, Arkudas A, et al. De novo generation of axially vascularized tissue in a large animal model. Microsurgery 2009;29:4251.
Eweida AM, Nabawi AS, Marei MK, Khalil MR, Elhammady HA. Mandibular reconstruction using an axially vascularized tissue-engineered construct. Ann Surg Innov Res. 2011;5:2.
Eweida AM, Nabawi AS, Marei MK, Khalil MR, Elhammady HA. Correction: Mandibular reconstruction using an axially vascularized tissue-engineered construct. Ann Surg Innov Res. 2012;6:4.
Weigand A, Beier JP, Hess A, et al. Acceleration of vascularized bone tissue-engineered constructs in a large animal model combining intrinsic and extrinsic vascularization. Tissue Eng Part A 2015;21:16801694.
Tanaka Y, Tsutsumi A, Crowe DM, Tajima S, Morrison WA. Generation of an autologous tissue (matrix) flap by combining an arteriovenous shunt loop with artificial skin in rats: Preliminary report. Br J Plast Surg. 2000;53:5157.
Watson O, Novodvorsky P, Gray C, et al. Blood flow suppresses vascular Notch signalling via dll4 and is required for angiogenesis in response to hypoxic signalling. Cardiovasc Res. 2013;100:252261.
Carmeliet P. Angiogenesis in health and disease. Nat Med. 2003;9:653660.
Kneser U, Polykandriotis E, Ohnolz J, et al. Engineering of vascularized transplantable bone tissues: Induction of axial vascularization in an osteoconductive matrix using an arteriovenous loop. Tissue Eng. 2006;12:17211731.
Lokmic Z, Thomas JL, Morrison WA, Thompson EW, Mitchell GM. An endogenously deposited fibrin scaffold determines construct size in the surgically created arteriovenous loop chamber model of tissue engineering. J Vasc Surg. 2008;48:974985.
Mian R, Morrison WA, Hurley JV, et al. Formation of new tissue from an arteriovenous loop in the absence of added extracellular matrix. Tissue Eng. 2000;6:595603.
Arkudas A, Pryymachuk G, Hoereth T, et al. Dose-finding study of fibrin gel-immobilized vascular endothelial growth factor 165 and basic fibroblast growth factor in the arteriovenous loop rat model. Tissue Eng Part A 2009;15:25012511.
Lokmic Z, Stillaert F, Morrison WA, Thompson EW, Mitchell GM. An arteriovenous loop in a protected space generates a permanent, highly vascular, tissue-engineered construct. FASEB J. 2007;21:511522.
Polykandriotis E, Drakotos D, Arkudas A, et al. Factors influencing successful outcome in the arteriovenous loop model: A retrospective study of 612 loop operations. J Reconstr Microsurg. 2011;27:1118.
Zdolsek JM, Morrison WA, Dingle AM, Palmer JA, Penington AJ, Mitchell GM. An “off the shelf” vascular allograft supports angiogenic growth in three-dimensional tissue engineering. J Vasc Surg. 2011;53:435444.
Dolderer JH, Abberton KM, Thompson EW, et al. Spontaneous large volume adipose tissue generation from a vascularized pedicled fat flap inside a chamber space. Tissue Eng. 2007;13:673681.
Manasseri B, Cuccia G, Moimas S, et al. Microsurgical arterovenous loops and biological templates: A novel in vivo chamber for tissue engineering. Microsurgery 2007;27:623629.
Asano Y, Ichioka S, Shibata M, Ando J, Nakatsuka T. Sprouting from arteriovenous shunt vessels with increased blood flow. Med Biol Eng Comput. 2005;43:126130.
Hofer SO, Mitchell GM, Penington AJ, et al. The use of pimonidazole to characterise hypoxia in the internal environment of an in vivo tissue engineering chamber. Br J Plast Surg. 2005;58:11041114.
Cassell OC, Morrison WA, Messina A, et al. The influence of extracellular matrix on the generation of vascularized, engineered, transplantable tissue. Ann N Y Acad Sci. 2001;944:429442.
Arkudas A, Pryymachuk G, Hoereth T, et al. Composition of fibrin glues significantly influences axial vascularization and degradation in isolation chamber model. Blood Coagul Fibrinolysis 2012;23:419427.
Cao Y, Mitchell G, Messina A, et al. The influence of architecture on degradation and tissue ingrowth into three-dimensional poly(lactic-co-glycolic acid) scaffolds in vitro and in vivo. Biomaterials 2006;27:28542864.
Bouhadir KH, Mooney DJ. Promoting angiogenesis in engineered tissues. J Drug Target. 2001;9:397406.
Kohane DS, Langer R. Polymeric biomaterials in tissue engineering. Pediatr Res. 2008;63:487491.
Morin KT, Tranquillo RT. In vitro models of angiogenesis and vasculogenesis in fibrin gel. Exp Cell Res. 2013;319:24092417.
Ceccarelli J, Putnam AJ. Sculpting the blank slate: How fibrin’s support of vascularization can inspire biomaterial design. Acta Biomater. 2014;10:15151523.
Fiegel HC, Pryymachuk G, Rath S, et al. Foetal hepatocyte transplantation in a vascularized AV-loop transplantation model in the rat. J Cell Mol Med. 2010;14:267274.
Polykandriotis E, Arkudas A, Horch RE, Kneser U. To matrigel or not to matrigel. Am J Pathol. 2008;172:1441; author reply 1441–1442.
Polykandriotis E, Arkudas A, Beier JP, et al. The impact of VEGF and bFGF on vascular stereomorphology in the context of angiogenic neo-arborisation after vascular induction. J Electron Microsc (Tokyo) 2011;60:267274.
Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993;362:841844.
Hofer SO, Knight KM, Cooper-White JJ, et al. Increasing the volume of vascularized tissue formation in engineered constructs: An experimental study in rats. Plast Reconstr Surg. 2003;111:11861192; discussion 1193–1194.
Bitto FF, Klumpp D, Lange C, et al. Myogenic differentiation of mesenchymal stem cells in a newly developed neurotised AV-loop model. Biomed Res Int. 2013;2013:935046.
Weis C, Covi JM, Hilgert JG, et al. Automatic quantification of angiogenesis in 2D sections: A precise and timesaving approach. J Microsc. 2015;259:185196.
Morritt AN, Bortolotto SK, Dilley RJ, et al. Cardiac tissue engineering in an in vivo vascularized chamber. Circulation 2007;115:353360.
Polykandriotis E, Euler S, Arkudas A, et al. Regression and persistence: Remodelling in a tissue engineered axial vascular assembly. J Cell Mol Med. 2009;13:41664175.
Polykandriotis E, Tjiawi J, Euler S, et al. The venous graft as an effector of early angiogenesis in a fibrin matrix. Microvasc Res. 2008;75:2533.
Arkudas A, Beier JP, Pryymachuk G, et al. Automatic quantitative micro-computed tomography evaluation of angiogenesis in an axially vascularized tissue-engineered bone construct. Tissue Eng Part C Methods 2010;16:15031514.
Beier JP, Horch RE, Hess A, et al. Axial vascularization of a large volume calcium phosphate ceramic bone substitute in the sheep AV loop model. J Tissue Eng Regen Med. 2010;4:216223.
Laws MJ, Taylor RN, Sidell N, et al. Gap junction communication between uterine stromal cells plays a critical role in pregnancy-associated neovascularization and embryo survival. Development 2008;135:26592668.
Wang HH, Kung CI, Tseng YY, et al. Activation of endothelial cells to pathological status by down-regulation of connexin43. Cardiovasc Res. 2008;79:509518.
Yuan Q, Bleiziffer O, Boos AM, et al. PHDs inhibitor DMOG promotes the vascularization process in the AV loop by HIF-1a up-regulation and the preliminary discussion on its kinetics in rat. BMC Biotechnol. 2014;14:112.
Ding Z, Wan W, Zheng J, Deng C, Mao G, Yang S. Flap prefabrication using arterialized vein ring as implanted vascular pedicle. J Plast Reconstr Aesthet Surg. 2012;65:17541756.
Boos AM, Loew JS, Weigand A, et al. Engineering axially vascularized bone in the sheep arteriovenous-loop model. J Tissue Eng Regen Med. 2013;7:654664.
Lokmic Z, Mitchell GM. The source and commencement of angiogenesis from the arterio-venous loop model. Microvasc Res. 2008;75:142143.
Tee R, Morrison WA, Dusting GJ, et al. Transplantation of engineered cardiac muscle flaps in syngeneic rats. Tissue Eng Part A 2012;18:19921999.
Mian RA, Knight KR, Penington AJ, et al. Stimulating effect of an arteriovenous shunt on the in vivo growth of isografted fibroblasts: A preliminary report. Tissue Eng. 2001;7:7380.
Matsuda K, Falkenberg KJ, Woods AA, Choi YS, Morrison WA, Dilley RJ. Adipose-derived stem cells promote angiogenesis and tissue formation for in vivo tissue engineering. Tissue Eng Part A 2013;19:13271335.
Brown DL, Meagher PJ, Knight KR, et al. Survival and function of transplanted islet cells on an in vivo, vascularized tissue engineering platform in the rat: A pilot study. Cell Transplant. 2006;15:319324.
Messina A, Bortolotto SK, Cassell OC, Kelly J, Abberton KM, Morrison WA. Generation of a vascularized organoid using skeletal muscle as the inductive source. FASEB J. 2005;19:15701572.
Bach AD, Arkudas A, Tjiawi J, et al. A new approach to tissue engineering of vascularized skeletal muscle. J Cell Mol Med. 2006;10:716726.
Rophael JA, Craft RO, Palmer JA, et al. Angiogenic growth factor synergism in a murine tissue engineering model of angiogenesis and adipogenesis. Am J Pathol. 2007;171:20482057.
Findlay MW, Dolderer JH, Trost N, et al. Tissue-engineered breast reconstruction: Bridging the gap toward large-volume tissue engineering in humans. Plast Reconstr Surg. 2011;128:12061215.
Buehrer G, Balzer A, Arnold I, et al. Combination of BMP2 and MSCs significantly increases bone formation in the rat arterio-venous loop model. Tissue Eng Part A 2015;21:96105.
Hoang NT, Staudenmaier R, Hai LH, Hai le H, Doan le V, Hoehnke C. Successful re-construction of a large tissue defect using a free pre-fabricated flap with purely implanted arterialised venous loop. J Plast Reconstr Aesthet Surg. 2009;62:e225e228.
Hoang NT, Kloeppel M, Werner J, Staudenmaier R, Biemer E. Proposed new method for angiographically quantifying neovascularization in prefabricated flaps. Microsurgery 2005;25:220226.
Vranckx JJ, Den Hondt M, Delaere P. Prefabrication and prelamination strategies for the reconstruction of complex defects of trachea and larynx. J Reconstr Microsurg. 2014;30:145152.
Vranckx JJ, Den Hondt M, Delaere P. Prefabrication and prelamination strategies for the reconstruction of complex defects of trachea and larynx. J Reconstr Microsurg. 2014;30:145152.
Tamai S, Yajima H, Ono H. Revascularization procedures in the treatment of Kienböck’s disease. Hand Clin. 1993;9:455466.
Fukui A, Maeda M, Inada Y, Tamai S, Sempuku T. Arteriovenous shunt in digit replantation. J Hand Surg Am. 1990;15:160165.
Horch RE, Beier JP, Kneser U, Arkudas A. Successful human long-term application of in situ bone tissue engineering. J Cell Mol Med. 2014;18:14781485.
Bleiziffer O, Hammon M, Arkudas A, et al. Guanylate-binding protein 1 expression from embryonal endothelial progenitor cells reduces blood vessel density and cellular apoptosis in an axially vascularised tissue-engineered construct. BMC Biotechnol. 2012;12:94.
Jiang F, Zhang G, Hashimoto I, et al. Neovascularization in an arterio-venous loop-containing tissue engineering chamber: Role of NADPH oxidase. J Cell Mol Med. 2008;12:20622072.