Background: Most of the current treatment options for large-scale tissue defects represent a serious burden for the patients, are often not satisfying, and can be associated with significant side effects. Although major achievements have already been made in the field of tissue engineering, the clinical translation in case of extensive tissue defects is only in its early stages. The main challenge and reason for the failure of most tissue engineering approaches is the missing vascularization within large-scale transplants. Summary: The arteriovenous (AV) loop model is an in vivo tissue engineering strategy for generating axially vascularized tissues using the own body as a bioreactor. A superficial artery and vein are anastomosed to create an AV loop. This AV loop is placed into an implantation chamber for prevascularization of the chamber inside, e.g., a scaffold, cells, and growth factors. Subsequently, the generated tissue can be transplanted with its vascular axis into the defect site and anastomosed to the local vasculature. Since the blood supply of the growing tissue is based on the AV loop, it will be immediately perfused with blood in the recipient site leading to optimal healing conditions even in the case of poorly vascularized defects. Using this tissue engineering approach, a multitude of different axially vascularized tissues could be generated, such as bone, skeletal or heart muscle, or lymphatic tissues. Upscaling from the small animal AV loop model into a preclinical large animal model could pave the way for the first successful attempt in clinical application. Key Messages: The AV loop model is a powerful tool for the generation of different axially vascularized replacement tissues. Due to minimal donor site morbidity and the possibility to generate patient-specific tissues variable in type and size, this in vivo tissue engineering approach can be considered as a promising alternative therapy to current treatment options of large-scale defects.

Ludolph I, Lehnhardt M, Arkudas A, et al: Plastic reconstructive microsurgery in the elderly patient – consensus statement of the German Speaking Working Group for Microsurgery of the Peripheral Nerves and Vessels (in German). Handchir Mikrochir Plast Chir 2018; 50: 118–125.
Huang RL, Kobayashi E, Liu K and Li Q: Bone graft prefabrication following the in vivo bioreactor principle. E Bio Med 2016; 12: 43–54.
McMurtrey RJ: Analytic models of oxygen and nutrient diffusion, metabolism dynamics, and architecture optimization in three-dimensional tissue constructs with applications and insights in cerebral organoids. Tissue Eng Part C Methods 2016; 22: 221–249.
Zheng L, Lv X, Zhang J, Zhang Y, Cai Z, Liu S: Deep circumflex iliac artery perforator flap with iliac crest for oromandibular reconstruction. J Craniomaxillofac Surg 2018; 46: 1263–1267.
Schreiber M, Dragu A: Free temporal fascia flap to cover soft tissue defects of the foot: a case report. GMS Interdiscip Plast Reconstr Surg DGPW 2015; 4:Doc01.
Ozkan O: Single osteotomized iliac crest free flap in anterior mandible reconstruction. Microsurgery 2006; 26: 93–99.
Lakhiani C, DeFazio MV, Han K, Falola R, Evans K: Donor-site morbidity following free tissue harvest from the thigh: a systematic review and pooled analysis of complications. J Reconstr Microsurg 2016; 32: 342–357.
Wang W, Zhao M, Tang Y, et al: Long-term follow-up of flap prefabrication in facial reconstruction. Ann Plast Surg 2017; 79: 17–23.
Douglas AJ, Kyzas PA: A new autologous block-bone prefabricated flap concept based on the supraclavicular artery island flap (SCAIF) for reconstruction of a neo-mandibular osteoradionecrosis (ORN) defect, IDEAL Stage 1 report. JPRAS Open 2017; 12: 19–24.
O’brien FJ: Biomaterials and scaffolds for tissue engineering. Mater Today 2011; 14: 88–95.
Baranski JD, Chaturvedi RR, Stevens KR, et al: Geometric control of vascular networks to enhance engineered tissue integration and function. Proc Natl Acad Sci USA 2013; 110: 7586–7591.
Auger FA, Gibot L, Lacroix D: The pivotal role of vascularization in tissue engineering. Ann Rev Biomed Eng 2013; 15: 177–200.
Lokmic Z, Mitchell GM: Engineering the microcirculation. Tissue Eng Part B Rev 2008; 14: 87–103.
Rouwkema J, Rivron NC and van Blitterswijk CA: Vascularization in tissue engineering. Trends Biotechnol 2008; 26: 434–441.
Warnke PH, Springer IN, Wiltfang J, et al: Growth and transplantation of a custom vascularised bone graft in a man. Lancet 2004; 364: 766–770.
Erol OO, Spira M: New capillary bed formation with a surgically constructed arteriovenous fistula. Plast Reconstr Surg 1980; 66: 109–115.
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: 25–33.
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.
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: 2501–2511.
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: 1186–1194.
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: 51–57.
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: 511–522.
Yuan Q, Arkudas A, Horch RE, et al: Vascularization of the arteriovenous loop in a rat isolation chamber mod el – quantification of hypoxia and evaluation of its effects. Tissue Eng Part A 2018; 24: 719–728.
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.
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: 2062–2072.
Cassell OC, Morrison WA, Messina A, et al: The influence of extracellular matrix on the generation of vascularized, engineered, transplantable tissue. Ann NY Acad Sci 2001; 944: 429–442.
Dolderer JH, Kehrer A, Schiller SM, et al: De-novo generation of vascularized tissue using different configurations of vascular pedicles in perforated and closed chambers (in German). Wien Med Wochenschr 2010; 160: 139–146.
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: 55e–65e.
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: 1680–1694.
Arkudas A, Lipp A, Buehrer G, et al: Pedicled transplantation of axially vascularized bone constructs in a critical size femoral defect. Tissue Eng Part A 2018; 24: 479–492.
Eweida AM, Nabawi AS, Abouarab M, et al: Enhancing mandibular bone regeneration and perfusion via axial vascularization of scaffolds. Clin Oral Investig 2014; 18: 1671–1678.
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: 654–664.
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: 1503–1514.
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: 96–105.
Wu X, Wang Q, Kang N, et al: The effects of different vascular carrier patterns on the angiogenesis and osteogenesis of BMSC-TCP-based tissue-engineered bone in beagle dogs. J Tissue Eng Regen Med 2017; 11: 542–552.
Dong QS, Shang HT, Wu W, et al: Prefabrication of axial vascularized tissue engineering coral bone by an arteriovenous loop: a better model. Mater Sci Eng C Mater Biol Appl 2012; 32: 1536–1541.
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: 148–155.
Eweida A, Schulte M, Frisch O, Kneser U and Harhaus L: The impact of various scaffold components on vascularized bone constructs. J Craniomaxillofac Surg 2017; 45: 881–890.
Kim HY, Lee JH, Lee HAR, et al: Sustained release of BMP-2 from porous particles with leaf-stacked structure for bone regeneration. ACS Appl Mater Interfaces 2018; 10: 21091–21102.
Arkudas A, Beier JP, Heidner K, et al: Axial prevascularization of porous matrices using an arteriovenous loop promotes survival and differentiation of transplanted autologous osteoblasts. Tissue Eng 2007; 13: 1549–1560.
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: 1570–1572.
Bitto FF, Klumpp D, Lange C, Boos AM, Arkudas A, Bleiziffer O, Horch RE, Kneser U, Beier JP: Myogenic differentiation of mesenchymal stem cells in a newly developed neurotised AV-loop model. Biomed Res Int 2013; 2013: 935046.
Witt R, Weigand A, Boos AM, Cai A, Dippold D, Boccaccini AR, Schubert DW, Hardt M, Lange C, Arkudas A, Horch RE, Beier JP: Mesenchymal stem cells and myoblast differentiation under HGF and IGF-1 stimulation for 3D skeletal muscle tissue engineering. BMC Cell Biol 2017; 18: 15.
Dippold D, Cai A, Hardt M, Boccaccini AR, Horch R, Beier JP, Schubert DW: Novel approach towards aligned PCL-collagen nanofibrous constructs from a benign solvent system. Mater Sci Eng C Mater Biol Appl 2017; 72: 278–283.
Tee R, Morrison WA, Dusting GJ, et al: Transplantation of engineered cardiac muscle flaps in syngeneic rats. Tissue Eng Part A 2012; 18: 1992–1999.
Tee R, Morrison WA, Dilley RJ: A novel microsurgical rodent model for the transplantation of engineered cardiac muscle flap. Microsurgery 2018; 38: 544–552.
Schmidt VJ, Wietbrock JO, Leibig N, et al: Collagen-elastin and collagen-glycosaminoglycan scaffolds promote distinct patterns of matrix maturation and axial vascularization in arteriovenous loop-based soft tissue flaps. Ann Plast Surg 2017; 79: 92–100.
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 1. Cell Transplant 2006; 15: 319–324.
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: 267–274.
Kanapathy M, Patel NM, Kalaskar DM, Mosahebi A, Mehrara BJ, Seifalian AM: Tissue-engineered lymphatic graft for the treatment of lymphedema. J Surg Res 2014; 192: 544–554.
Schaupper M, Jeltsch M, Rohringer S, Redl H, Holnthoner W: Lymphatic vessels in regenerative medicine and tissue engineering. Tissue Eng Part B Rev 2016; 22: 395–407.
Robering JW, Weigand A, Pfuhlmann R, Horch RE, Beier JP, Boos AM: Mesenchymal stem cells promote lymphangiogenic properties of lymphatic endothelial cells. J Cell Mol Med 2018; 22: 3740–3750.
Eweida A, Fathi I, Eltawila AM, et al: Pattern of bone generation after irradiation in vascularized tissue engineered constructs. J Reconstr Microsurg 2018; 34: 130–137.
Beier JP, Horch RE, Arkudas A, et al: De novo generation of axially vascularized tissue in a large animal model. Microsurgery 2009; 29: 42–51.
Schmidt VJ, Wietbrock JO, Leibig N, et al: Haemodynamically stimulated and in vivo generated axially vascularized soft-tissue free flaps for closure of complex defects: evaluation in a small animal model. J Tissue Eng Regen Med 2018; 12: 622–632.
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: 1478–1485.
Zhan W, Marre D, Mitchell GM, Morrison WA, Lim SY: Tissue engineering by intrinsic vascularization in an in vivo tissue engineering chamber. J Vis Exp 2016; 111:e54099.
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: 11–18.
Weigand A, Boos AM, Ringwald J, et al: New aspects on efficient anticoagulation and antiplatelet strategies in sheep. BMC Vet Res 2013; 9: 192.
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: 1636–1644.
Polykandriotis E, Arkudas A, Euler S, Beier JP, Horch RE, Kneser U: Prevascularisation strategies in tissue engineering (in German). Handchir Mikrochir Plast Chir 2006; 38: 217–223.
Polykandriotis E, Schmidt VJ, Kneser U, Jianming S, Boccaccini AR, Horch RE: Bioreactors in regenerative medicine–from a technical device to a reconstructive alternative? (in German). Handchir Mikrochir Plast Chir 2012; 44: 198–203.
Schmidt VJ, Covi JM, Koepple C, et al: Flow induced microvascular network formation of therapeutic relevant arteriovenous (AV) loop-based constructs in response to ionizing radiation. Med Sci Monit 2017; 23: 834–842.
Horch RE, Weigand A, Wajant H, Groll J, Boccaccini AR, Arkudas A: Biofabrication: new approaches for tissue regeneration (in German). Handchir Mikrochir Plast Chir 2018; 50: 93–100.
Hutmacher DW, Horch RE, Loessner D, et al: Translating tissue engineering technology platforms into cancer research. J Cell Mol Med 2009; 13: 1417–1427.
Weigand A, Tasbihi K, Strissel PL, Strick R, Horch RE, Boos AM: Development of an innovative cell isolation method for the investigation of breast cancer pathogenesis and angiogenesis for experimental in vitro and in vivo assays (in German). Handchir Mikrochir Plast Chir 2017; 49: 111–122.
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