Chronic venous insufficiency (CVI) represents a major global health problem with increasing prevalence and morbidity. CVI is due to an incompetence of the venous valves, which causes venous reflux and distal venous hypertension. Several studies have focused on the replacement of diseased venous valves using xeno- and allogenic transplants, so far with moderate success due to immunologic and thromboembolic complications. Autologous cell-derived tissue-engineered venous valves (TEVVs) based on fully biodegradable scaffolds could overcome these limitations by providing non-immunogenic, non-thrombogenic constructs with remodeling and growth potential.
Methods:
Tri- and bicuspid venous valves (n=27) based on polyglycolic acid–poly-4-hydroxybutyrate composite scaffolds, integrated into self-expandable nitinol stents, were engineered from autologous ovine bone-marrow-derived mesenchymal stem cells (BM-MSCs) and endothelialized. After in vitro conditioning in a (flow) pulse duplicator system, the TEVVs were crimped (n=18) and experimentally delivered (n=7). The effects of crimping on the tissue-engineered constructs were investigated using histology, immunohistochemistry, scanning electron microscopy, grating interferometry (GI), and planar fluorescence reflectance imaging. Results: The generated TEVVs showed layered tissue formation with increasing collagen and glycosaminoglycan levels dependent on the duration of in vitro conditioning. After crimping no effects were found on the MSC level in scanning electron microscopy analysis, GI, histology, and extracellular matrix analysis. However, substantial endothelial cell loss was detected after the crimping procedure, which could be reduced by increasing the static conditioning phase.
Conclusions:
Autologous living small-diameter TEVVs can be successfully fabricated from ovine BM-MSCs using a (flow) pulse duplicator conditioning approach. These constructs hold the potential to overcome the limitations of currently used non-autologous replacement materials and may open new therapeutic concepts for the treatment of CVI in the future.
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References
1.
EberhardtR.T., and RaffettoJ.D.Chronic venous insufficiency. Circulation, 10, 111, 2005.
2.
CasaroneM.R., BelcaroG., NicolaidesA.N., GeroulakosG., GriffinM., IncandelaL., DeS.M., SabetaiM., GeroulakosG., AgusG., BaveraP., IppolitoE., LengG., DiR.A., CazaubonM., VasdekisS., ChristopoulosD., and VellerM.Real epidemiology of varicose veins and chronic venous disease: the San Valentino Vascular Screening Project. Angiology, 53, 2002.
3.
BrandF.N., DannenbergA.L., AbbottR.D., and KannelW.B.The epidemiology of varicose veins: the Framingham Study. Am J Prev Med, 4, 96, 1988.
4.
RajuS.Venous insufficiency of the lower limb and stasis ulceration: changing concept and management. Ann Surg, 197, 688, 1983.
5.
PavcnikD., UchidaB., KaufmanJ., HindsM., KellerF.S., and RöschJ.Percutaneous management of chronic deep venous reflux: review of experimental work and early clinical experience with bioprosthetic valve. Vasc Med, 13, 1, 2008.
6.
MayberryJ.C., MonetaG.L., TaylorL.M., and PorterJ.M.Fifteen-year results of ambulatory compression therapy for chronic venous ulcers. Surgery, 109, 575, 1991.
7.
ZervidesC., and GiannoukasA.D.Historical overview of venous valve prostheses for the treatment of deep venous valve insufficiency. J Endovasc Ther, 19, 2, 2012.
8.
WeberB., EmmertM.Y., and HoerstrupS.P.Stem cells for heart valve regeneration. Swiss Med Wkly, 142, w13622, 2012.
9.
WeberB., EmmertM.Y., SchoenauerR., BrokoppC., BaumgartnerL., and HoerstrupS.P.Tissue engineering on matrix: future of autologous tissue replacement. Semin Immunopathol, 33, 3, 2011.
10.
SchmidtD., AchermannJ., OdermattB., BreymannC., MolA., GenoniM., ZundG., and HoerstrupS.P.Prenatally fabricated autologous human living heart valves based on amniotic fluid derived progenitor cells as single cell source. Circulation, 11, 116, 2007.
11.
MolA., RuttenM.C., DriessenN.J., BoutenC.V., ZündG., BaaijensF.P., and HoerstrupS.P.Autologous human tissue-engineered heart valves: prospects for systemic application. Circulation, 4, 114, 2006.
12.
SchmidtD., MolA., BreymannC., AchermannJ., OdermattB., GössiM., NeuenschwanderS., PrêtreR., GenoniM., ZundG., and HoerstrupS.P.Living autologous heart valves engineered from human prenatally harvested progenitors. Circulation, 4, 114, 2006.
13.
HoerstrupS.P., KadnerA., MelnitchoukS., TrojanA., EidK., TracyJ., SodianR., VisjagerJ.F., KolbS.A., GrunenfelderJ., ZundG., and TurinaM.I.Tissue engineering of functional trileaflet heart valves from human marrow stromal cells. Circulation, 24, 106, 2002.
14.
SchmidtD., DijkmanP.E., Driessen-MolA., StengerR., MarianiC., PuolakkaA., RissanenM., DeichmannT., OdermattB., WeberB., EmmertM.Y., ZundG., BaaijensF.P., and HoerstrupS.P.Minimally-invasive implantation of living tissue engineered heart valves: a comprehensive approach from autologous vascular cells to stem cells. J Am Coll Cardiol, 3, 56, 2010.
WeberB., SchermanJ., EmmertM.Y., GruenenfelderJ., VerbeekR., BracherM., BlackM., KortsmitJ., FranzT., SchoenauerR., BaumgartnerL., BrokoppC., AgarkovaI., WolintP., ZundG., FalkV., ZillaP., and HoerstrupS.P.Injectable living marrow stromal cell-based autologous tissue engineered heart valves: first experiences with a one-step intervention in primates. Eur Heart J, 32, 22, 2011.
17.
EmmertM.Y., WeberB., WolintP., BehrL., SammutS., FrauenfelderT., FreseL., SchermanJ., BrokoppC.E., TemplinC., GrünenfelderJ., ZündG., FalkV., and HoerstrupS.P.Stem cell-based transcatheter aortic valve implantation: first experiences in a pre-clinical model. JACC Cardiovasc Interv, 5, 8, 2012.
18.
RohJ.D., Sawh-MartinezR., BrennanM.P., JayS.M., DevineL., RaoD.A., YiT., MirenskyT.L., NalbandianA., UdelsmanB., HibinoN., ShinokaT., SaltzmanW.M., SnyderE., KyriakidesT.R., PoberJ.S., and BreuerC.K.Tissue-engineered vascular grafts transform into mature blood vessels via an inflammation-mediated process of vascular remodeling. Proc Natl Acad Sci U S A, 9, 107, 2010.
19.
WeberB., SchoenauerR., PapadopulosF., ModreggerP., PeterS., StampanoniM., MauriA., MazzaE., GorelikJ., AgarkovaI., FreseL., BreymannC., KretschmarO., and HoerstrupS.P.Engineering of living autologous human umbilical cord cell-based septal occluder membranes using composite PGA-P4HB matrices. Biomaterials, 32, 36, 2011.
20.
CesaroneC.F., BolognesiC., and SantiL.Improved microfluorometric DNA determination in biological material using 33258 Hoechst. Anal Biochem, 100, 1, 1979.
21.
FarndaleR.W., ButtleD.J., and BarrettA.J.Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethylmethylene blue. Biochim Biophys Acta, 883, 2, 1986.
22.
HuszarG., MaioccoJ., and NaftolinF.Monitoring of collagen and collagen fragments in chromatography of protein mixtures. Anal Biochem, 105, 424, 1980.
23.
DavidC., NöhammerB., SolakH.H., and ZieglerE.Differential x-ray phase contrast imaging using a shearing interferometer. Appl Phys Lett, 81, 3287, 2002.
24.
WeitkampT., DiazA., DavidC., PfeifferF., StampanoniM., and CloetensP.X-ray phase imaging with a grating interferometer, Opt Express, 13, 16, 2005.
25.
PfeifferF., BunkO., DavidC., BechM., Le DucG., BravinA., and CloetensP.High-resolution brain tumor visualization using three-dimensional x-ray phase contrast tomography. Phys Med Biol, 52, 6923, 2007.
26.
McDonaldS.A., MaroneF., HintermüllerC., MikuljanG., DavidC., and PfeifferF.Advanced phase-contrast imaging using a grating interferometer. J Synchrotron Radiat, 16, 4, 2009.
27.
ModreggerP., PinzerB.R., ThüringT., RutishauserS., DavidC., and StampanoniM.Sensitivity of X-ray grating interferometry. Opt Express, 19, 18324, 2011.
28.
CriquiM.H., JamosmosM., FronekA., DenenbergJ.O., LangerR.D., BerganJ., and GolombB.A.Chronic venous disease in an ethnically diverse population: the San Diego Population Study. Am J Epidemiol, 158, 5, 2003.
KayaM., GroganJ.B., LentzD., TewW., and RajuS.Glutaraldehyde-preserved venous valve transplantation in the dog. J Surg Res, 45, 3, 1988.
32.
NeglénP., and RajuS.Venous reflux repair with cryopreserved vein valves. J Vasc Surg, 37, 3, 2003.
33.
RosenbloomM.S., SchulerJ.J., BisharaR.A., RonanS.G., and FlaniganD.P.Early experimental experience with a surgically created, totally autogenous venous valve: a preliminary report. J Vasc Surg, 7, 5, 1988.
34.
DalsingM.C., LalkaS.G., UnthankJ.L., GrieshopR.J., NixonC., and DavisT.Venous valvular insufficiency: influence of a single venous valve (native and experimental). J Vasc Surg, 14, 5, 1991.
35.
PlagnolP., CiostekP., GrimaudJ.P., and ProkopowiczS.C.Autogenous valve reconstruction technique for post-thrombotic reflux. Ann Vasc Surg, 13, 3, 1999.
36.
OpieJ.C., IzdebskiT., PayneD.N., and OpieS.R.Monocusp—novel common femoral vein monocusp surgery uncorrectable chronic venous insufficiency with aplastic/dysplastic valves. Phlebology, 23, 4, 2008.
37.
TeebkenO.E., PuschmannC., AperT., HaverichA., and MertschingH.Tissue-engineered bioprosthetic venous valve: a long-term study in sheep. Eur J Vasc Endovasc Surg, 25, 4, 2003.
38.
LlamesS., GarcíaE., Otero, HernándezJ., and MeanaA.Tissue bioengineering and artificial organs. Adv Exp Med Biol, 741, 314, 2012.
39.
Rodés-CabauJ.Transcatheter aortic valve implantation: current and future approaches. Nat Rev Cardiol, 15, 9, 2011.
40.
de BorstG.J., TeijinkJ.A., and PattersonM.A percutaneous approach to deep venous valve insufficiency with a new self-expanding venous frame valve. J Endovasc Ther, 10, 341, 2003.
41.
MollF.Venous valves for chronic venous insufficiency. Presented at the Inaugural Global Endovascular Forum, London, United Kingdom, 2003.
PavcnikD., KaufmanJ., and UchidaB.Second-generation percutaneous bioprosthetic valve: a short-term study in sheep. J Vasc Surg, 40, 1223, 2004.
44.
PavcnikD., KaufmanJ.A., and UchidaB.T.Significance of spatial orientation of percutaneously placed bioprosthetic venous valves in an ovine model. J Vasc Interv Radiol, 16, 1511, 2005.
45.
PavcnikD., YinQ., and UchidaB.Percutaneous autologous venous valve transplantation: short-term feasibility study in an ovine model. J Vasc Surg, 46, 338, 2007.
46.
KieferP., GruenwaldF., KempfertJ., AupperleH., SeeburgerJ., MohrF.W., and WaltherT.Crimping may affect the durability of transcatheter valves: an experimental analysis. Ann Thorac Surg, 92, 1, 2011.
47.
DijkmanP.E., Driessen-MolA., FreseL., HoerstrupS.P., and BaaijensF.P.Decellularized homologous tissue-engineered heart valves as off-the-shelf alternatives to xeno- and homografts. Biomaterials, 33, 18, 2012.
