**Author details**

S. L. M. van Loon, A. I. P. M. Smits, A. Driessen-Mol, F. P. T. Baaijens and C. V. C. Bouten\*

\*Address all correspondence to: C.V.C.Bouten@tue.nl

Department of Biomedical Engineering, Eindhoven University of Technology, MB, Eind‐ hoven, The Netherlands

#### **References**


[3] Bouten CV, Dankers PY, Driessen-Mol A, Pedron S, Brizard AM, Baaijens FP. Substrates for cardiovascular tissue engineering. Adv Drug Deliv Rev 2011 Apr 30;63(4-5):221-41.

**7. Conclusion**

238 Calcific Aortic Valve Disease

engineering for heart valves.

**Acknowledgements**

**Author details**

hoven, The Netherlands

**References**

The complexity of the immune response poses a challenging environment for *in situ* tissue engineering of heart valves [46]. Clearly, a better understanding of the underlying pathways appears crucial for controlling the fate of implanted biomaterial scaffolds and modulating inflammatory reactions in such a way as to induce tissue regeneration and remodeling and prevent fibrosis and/or degeneration [12]. Remaining largely unknown are the specifications of the optimal components (i.e. cells, scaffold and potentially biological modulators) and process conditions (mechanical and metabolic) that will facilitate the formation of optimal substitute heart valve tissues, whose function best emulates the structure, function, and extended durability of a natural valve in vivo [5]. However, the prosperous results of synthetic and biological scaffolds so far demonstrate the ground-breaking potential of *in situ* tissue

This work was supported by a grant from the Dutch government to the Netherlands Institute for Regenerative Medicine (NIRM, grant No. FES0908). This research forms part of the Project P1.01 iValve of the research program of the BioMedical Materials institute, co-funded by the Dutch Ministry of Economic Affairs, Agriculture and Innovation. The financial contribution

S. L. M. van Loon, A. I. P. M. Smits, A. Driessen-Mol, F. P. T. Baaijens and C. V. C. Bouten\*

Department of Biomedical Engineering, Eindhoven University of Technology, MB, Eind‐

[1] El-Hamamsy I, Eryigit Z, Stevens LM, Sarang Z, George R, Clark L, et al. Long-term outcomes after autograft versus homograft aortic root replacement in adults with aortic valve disease: a randomised controlled trial. Lancet 2010 Aug 14;376(9740):524-31.

[2] Mendelson K, Schoen FJ. Heart valve tissue engineering: concepts, approaches,

progress, and challenges. Ann Biomed Eng 2006 Dec;34(12):1799-819.

of the Nederlandse Hartstichting is gratefully acknowledged.

\*Address all correspondence to: C.V.C.Bouten@tue.nl


[18] Dijkman PE, Driessen-Mol A, Frese L, Hoerstrup SP, Baaijens FP. Decellularized homologous tissue-engineered heart valves as off-the-shelf alternatives to xeno- and homografts. Biomaterials 2012 Jun;33(18):4545-54.

[31] Anderson JM, McNally AK. Biocompatibility of implants: lymphocyte/macrophage

The Immune Response in *In Situ* Tissue Engineering of Aortic Heart Valves

http://dx.doi.org/10.5772/54354

241

[32] Ekdahl KN, Lambris JD, Elwing H, Ricklin D, Nilsson PH, Teramura Y, et al. Innate immunity activation on biomaterial surfaces: a mechanistic model and coping

[33] Mutsaers SE, Bishop JE, McGrouther G, Laurent GJ. Mechanisms of tissue repair: from

[34] Nilsson B, Ekdahl KN, Mollnes TE, Lambris JD. The role of complement in biomaterial-

[35] Eming SA, Hammerschmidt M, Krieg T, Roers A. Interrelation of immunity and tissue

[36] von Hundelshausen P, Weber C. Platelets as immune cells: bridging inflammation and

[37] Tsirogianni AK, Moutsopoulos NM, Moutsopoulos HM. Wound healing: immunolog‐

[38] Grimstad O, Sandanger O, Ryan L, Otterdal K, Damaas JK, Pukstad B, et al. Cellular sources and inducers of cytokines present in acute wound fluid. Wound Repair Regen

[39] Soehnlein O, Lindbom L. Phagocyte partnership during the onset and resolution of

[40] Harris HE, Raucci A. Alarmin(g) news about danger: workshop on innate danger

[41] Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN, et al. Nomencla‐ ture of monocytes and dendritic cells in blood. Blood 2010 Oct 21;116(16):e74-e80.

[42] Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev

[43] Shantsila E, Wrigley B, Tapp L, Apostolakis S, Montoro-Garcia S, Drayson MT, et al. Immunophenotypic characterization of human monocyte subsets: possible implica‐ tions for cardiovascular disease pathophysiology. J Thromb Haemost 2011 May;9(5):

[44] Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat

[45] Kou PM, Babensee JE. Macrophage and dendritic cell phenotypic diversity in the

[46] Beghdadi W, Madjene LC, Benhamou M, Charles N, Gautier G, Launay P, et al. Mast cells as cellular sensors in inflammation and immunity. Front Immunol 2011;2:37.

context of biomaterials. J Biomed Mater Res A 2011 Jan;96(1):239-60.

wound healing to fibrosis. Int J Biochem Cell Biol 1997 Jan;29(1):5-17.

interactions. Semin Immunopathol 2011 May;33(3):221-33.

strategies. Adv Drug Deliv Rev 2011 Sep 16;63(12):1042-50.

induced inflammation. Mol Immunol 2007 Jan;44(1-3):82-94.

cardiovascular disease. Circ Res 2007 Jan 5;100(1):27-40.

inflammation. Nat Rev Immunol 2010 Jun;10(6):427-39.

signals and HMGB1. EMBO Rep 2006 Aug;7(8):774-8.

ical aspects. Injury 2006 Apr;37 Suppl 1:S5-12.

2011 May;19(3):337-47.

Immunol 2011 Nov;11(11):762-74.

Rev Immunol 2008 Dec;8(12):958-69.

1056-66.

repair or regeneration. Semin Cell Dev Biol 2009 Jul;20(5):517-27.


[31] Anderson JM, McNally AK. Biocompatibility of implants: lymphocyte/macrophage interactions. Semin Immunopathol 2011 May;33(3):221-33.

[18] Dijkman PE, Driessen-Mol A, Frese L, Hoerstrup SP, Baaijens FP. Decellularized homologous tissue-engineered heart valves as off-the-shelf alternatives to xeno- and

[19] White JK, Agnihotri AK, Titus JS, Torchiana DF. A stentless trileaflet valve from a sheet of decellularized porcine small intestinal submucosa. Ann Thorac Surg 2005 Aug;80(2):

[20] Hoerstrup SP, Sodian R, Daebritz S, Wang J, Bacha EA, Martin DP, et al. Functional living trileaflet heart valves grown in vitro. Circulation 2000 Nov 7;102(19 Suppl

[21] Schmidt D, Dijkman PE, Driessen-Mol A, Stenger R, Mariani C, Puolakka A, et al. Minimally-invasive implantation of living tissue engineered heart valves: a comprehensive approach from autologous vascular cells to stem cells. J Am Coll

[22] Pektok E, Nottelet B, Tille JC, Gurny R, Kalangos A, Moeller M, et al. Degradation and healing characteristics of small-diameter poly(epsilon-caprolactone) vascular grafts in

[23] Roh JD, Sawh-Martinez R, Brennan MP, Jay SM, Devine L, Rao DA, et al. Tissueengineered vascular grafts transform into mature blood vessels via an inflammationmediated process of vascular remodeling. Proc Natl Acad Sci U S A 2010 Mar 9;107(10):

[24] Hibino N, McGillicuddy E, Matsumura G, Ichihara Y, Naito Y, Breuer C, et al. Lateterm results of tissue-engineered vascular grafts in humans. J Thorac Cardiovasc Surg

[25] Wu W, Allen RA, Wang Y. Fast-degrading elastomer enables rapid remodeling of a

[26] Yokota T, Ichikawa H, Matsumiya G, Kuratani T, Sakaguchi T, Iwai S, et al. In situ tissue regeneration using a novel tissue-engineered, small-caliber vascular graft without cell

[27] Gonzales-Simon A, Eniola-Adefeso O. Host Response to Biomaterials. In: Bhatia S, editor. Engineering Biomaterials for Regenerative Medicine. 1 ed. Cambridge: Springer

[28] Barton GM. A calculated response: control of inflammation by the innate immune

[29] Norton LW, Babensee JE. Innate and Adaptive Immune Responses in Tissue Engineering. In: Meyer U, Handschel J, Wiesmann HP, Meyer T, editors. Fundamentals of Tissue Engineering and Regenerative Medicine. Springer Berlin Heidelberg; 2009. p.

cell-free synthetic graft into a neoartery. Nat Med 2012 Jul;18(7):1148-53.

seeding. J Thorac Cardiovasc Surg 2008 Oct;136(4):900-7.

[30] Parham P. The Immune System. 2 ed. Garland Science; 2005.

system. J Clin Invest 2008 Feb;118(2):413-20.

the rat systemic arterial circulation. Circulation 2008 Dec 9;118(24):2563-70.

homografts. Biomaterials 2012 Jun;33(18):4545-54.

704-7.

240 Calcific Aortic Valve Disease

3):III44-III49.

4669-74.

721-47.

Cardiol 2010 Aug 3;56(6):510-20.

2010 Feb;139(2):431-6, 436.

New York; 2012. p. 143-59.


[47] Badylak SF, Valentin JE, Ravindra AK, McCabe GP, Stewart-Akers AM. Macrophage phenotype as a determinant of biologic scaffold remodeling. Tissue Eng Part A 2008 Nov;14(11):1835-42.

[61] Lowery JL, Datta N, Rutledge GC. Effect of fiber diameter, pore size and seeding method on growth of human dermal fibroblasts in electrospun poly(epsilon-

The Immune Response in *In Situ* Tissue Engineering of Aortic Heart Valves

http://dx.doi.org/10.5772/54354

243

[62] Kurpinski KT, Stephenson JT, Janairo RR, Lee H, Li S. The effect of fiber alignment and heparin coating on cell infiltration into nanofibrous PLLA scaffolds. Biomaterials 2010

[63] Simonet M, Driessen-Mol A, Baaijens FP, Bouten CV. Heart valve tissue regeneration. In: Bosworth L, Downes S, editors. Electrospinning for tissue regeneration.Cambridge:

[64] Pham QP, Sharma U, Mikos AG. Electrospun poly(epsilon-caprolactone) microfiber and multilayer nanofiber/microfiber scaffolds: characterization of scaffolds and measurement of cellular infiltration. Biomacromolecules 2006 Oct;7(10):2796-805.

[65] Chiu LL, Radisic M. Scaffolds with covalently immobilized VEGF and Angiopoietin-1 for vascularization of engineered tissues. Biomaterials 2010 Jan;31(2):226-41.

[66] Jay SM, Shepherd BR, Andrejecsk JW, Kyriakides TR, Pober JS, Saltzman WM. Dual delivery of VEGF and MCP-1 to support endothelial cell transplantation for therapeutic

[67] Thevenot PT, Nair AM, Shen J, Lotfi P, Ko CY, Tang L. The effect of incorporation of SDF-1alpha into PLGA scaffolds on stem cell recruitment and the inflammatory

[68] De Visscher G, Lebacq A, Mesure L, Blockx H, Vranken I, Plusquin R, et al. The remodeling of cardiovascular bioprostheses under influence of stem cell homing signal

[69] Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Jung S, et al. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 2006

[70] Silva EA, Mooney DJ. Spatiotemporal control of vascular endothelial growth factor delivery from injectable hydrogels enhances angiogenesis. J Thromb Haemost 2007

[71] Sun Q, Silva EA, Wang A, Fritton JC, Mooney DJ, Schaffler MB, et al. Sustained release of multiple growth factors from injectable polymeric system as a novel therapeutic

[72] Ota T, Sawa Y, Iwai S, Kitajima T, Ueda Y, Coppin C, et al. Fibronectin-hepatocyte growth factor enhances reendothelialization in tissue-engineered heart valve. Ann

[73] Weber B, Scherman J, Emmert MY, Gruenenfelder J, Verbeek R, Bracher M, et al. Injectable living marrow stromal cell-based autologous tissue engineered heart valves:

approach towards angiogenesis. Pharm Res 2010 Feb;27(2):264-71.

caprolactone) fibrous mats. Biomaterials 2010 Jan;31(3):491-504.

Woodhead Publishing Limited; 2011. p. 202-24.

vascularization. Biomaterials 2010 Apr;31(11):3054-62.

response. Biomaterials 2010 May;31(14):3997-4008.

pathways. Biomaterials 2010 Jan;31(1):20-8.

Thorac Surg 2005 Nov;80(5):1794-801.

Jan 13;124(1):175-89.

Mar;5(3):590-8.

May;31(13):3536-42.


[61] Lowery JL, Datta N, Rutledge GC. Effect of fiber diameter, pore size and seeding method on growth of human dermal fibroblasts in electrospun poly(epsiloncaprolactone) fibrous mats. Biomaterials 2010 Jan;31(3):491-504.

[47] Badylak SF, Valentin JE, Ravindra AK, McCabe GP, Stewart-Akers AM. Macrophage phenotype as a determinant of biologic scaffold remodeling. Tissue Eng Part A 2008

[48] Biswas SK, Chittezhath M, Shalova IN, Lim JY. Macrophage polarization and plasticity

[49] Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat

[50] Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and

[51] Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling

[52] Brown BN, Ratner BD, Goodman SB, Amar S, Badylak SF. Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine.

[53] Yu Q, Zhang Y, Wang H, Brash J, Chen H. Anti-fouling bioactive surfaces. Acta

[54] Rolfe B, Mooney J, Zhang B, Jahnke S, Le S, Chau Y, et al. The Fibrotic Response to Implanted Biomaterials: Implications for Tissue Engineering. In: Eberli D, editor. Regenerative Medicine and Tissue Engineering - Cells and Biomaterials. InTech; 2011.

[55] Milleret V, Hefti T, Hall H, Vogel V, Eberli D. Influence of the fiber diameter and surface roughness of electrospun vascular grafts on blood activation. Acta Biomater 2012 Jul

[56] Hibino N, Yi T, Duncan DR, Rathore A, Dean E, Naito Y, et al. A critical role for macrophages in neovessel formation and the development of stenosis in tissue-

[57] Dijkman PE. Tissue-engineered heart valves for minimally invasive surgery. PhD

[58] Balguid A, Mol A, van Marion MH, Bank RA, Bouten CV, Baaijens FP. Tailoring fiber diameter in electrospun poly(epsilon-caprolactone) scaffolds for optimal cellular infiltration in cardiovascular tissue engineering. Tissue Eng Part A 2009 Feb;15(2):

[59] Szentivanyi A, Chakradeo T, Zernetsch H, Glasmacher B. Electrospun cellular microenvironments: Understanding controlled release and scaffold structure. Adv

[60] Li WJ, Cooper JA, Jr., Mauck RL, Tuan RS. Fabrication and characterization of six electrospun poly(alpha-hydroxy ester)-based fibrous scaffolds for tissue engineering

engineered vascular grafts. FASEB J 2011 Dec;25(12):4253-63.

Drug Deliv Rev 2011 Apr 30;63(4-5):209-20.

applications. Acta Biomater 2006 Jul;2(4):377-85.

thesis. Eindhoven University of Technology, The Netherlands; 2012.

diversity with identity. Nat Rev Immunol 2011 Nov;11(11):750-61.

in health and disease. Immunol Res 2012 Sep;53(1-3):11-24.

Rev Immunol 2011 Nov;11(11):723-37.

Biomaterials 2012 May;33(15):3792-802.

Biomater 2011 Apr;7(4):1550-7.

p. 551-68.

27.

437-44.

functions. Immunity 2010 May 28;32(5):593-604.

Nov;14(11):1835-42.

242 Calcific Aortic Valve Disease


first experiences with a one-step intervention in primates. Eur Heart J 2011 Nov;32(22): 2830-40.

[87] Hibino N, Villalona G, Pietris N, Duncan DR, Schoffner A, Roh JD, et al. Tissueengineered vascular grafts form neovessels that arise from regeneration of the adjacent

The Immune Response in *In Situ* Tissue Engineering of Aortic Heart Valves

http://dx.doi.org/10.5772/54354

245

[88] Zilla P, Bezuidenhout D, Human P. Prosthetic vascular grafts: wrong models, wrong

[89] Smits AI, Driessen-Mol A, Bouten CV, Baaijens FP. A mesofluidics-based test platform for systematic development of scaffolds for in situ cardiovascular tissue engineering.

[90] Young A, McNaught CE. The physiology of wound healing. Surgery (Oxford) 2011 Oct;

questions and no healing. Biomaterials 2007 Dec;28(34):5009-27.

blood vessel. FASEB J 2011 Aug;25(8):2731-9.

Tissue Eng Part C Methods 2012 Jun;18(6):475-85.

29(10):475-9.


[87] Hibino N, Villalona G, Pietris N, Duncan DR, Schoffner A, Roh JD, et al. Tissueengineered vascular grafts form neovessels that arise from regeneration of the adjacent blood vessel. FASEB J 2011 Aug;25(8):2731-9.

first experiences with a one-step intervention in primates. Eur Heart J 2011 Nov;32(22):

[74] Mammadov R, Mammadov B, Guler MO, Tekinay AB. Growth factor binding on

[75] Zhao X, Kim J, Cezar CA, Huebsch N, Lee K, Bouhadir K, et al. Active scaffolds for ondemand drug and cell delivery. Proc Natl Acad Sci U S A 2011 Jan 4;108(1):67-72.

[76] Dankers PY, Harmsen MC, Brouwer LA, van Luyn MJ, Meijer EW. A modular and supramolecular approach to bioactive scaffolds for tissue engineering. Nat Mater 2005

[77] Koh TJ, DiPietro LA. Inflammation and wound healing: the role of the macrophage.

[78] Brown BN, Londono R, Tottey S, Zhang L, Kukla KA, Wolf MT, et al. Macrophage phenotype as a predictor of constructive remodeling following the implantation of biologically derived surgical mesh materials. Acta Biomater 2012 Mar;8(3):978-87.

[79] Fioretta ES, Fledderus JO, Burakowska-Meise EA, Baaijens FP, Verhaar MC, Bouten CV. Polymer-based scaffold designs for in situ vascular tissue engineering: controlling recruitment and differentiation behavior of endothelial colony forming cells. Macromol

[80] Lutter G, Ardehali R, Cremer J, Bonhoeffer P. Percutaneous valve replacement: current

[81] Walther T, Dewey T, Borger MA, Kempfert J, Linke A, Becht R, et al. Transapical aortic

[82] Emmert MY, Weber B, Behr L, Frauenfelder T, Brokopp CE, Grunenfelder J, et al. Transapical aortic implantation of autologous marrow stromal cell-based tissueengineered heart valves: first experiences in the systemic circulation. JACC Cardiovasc

[83] Emmert MY, Weber B, Wolint P, Behr L, Sammut S, Frauenfelder T, et al. Stem cellbased transcatheter aortic valve implantation: first experiences in a pre-clinical model.

[84] Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol 2008 Jan;214(2):

[85] Sun L, Louie MC, Vannella KM, Wilke CA, LeVine AM, Moore BB, et al. New concepts of IL-10-induced lung fibrosis: fibrocyte recruitment and M2 activation in a CCL2/

[86] Low QE, Drugea IA, Duffner LA, Quinn DG, Cook DN, Rollins BJ, et al. Wound healing in MIP-1alpha(-/-) and MCP-1(-/-) mice. Am J Pathol 2001 Aug;159(2):457-63.

CCR2 axis. Am J Physiol Lung Cell Mol Physiol 2011 Mar;300(3):L341-L353.

state and future prospects. Ann Thorac Surg 2004 Dec;78(6):2199-206.

valve implantation: step by step. Ann Thorac Surg 2009 Jan;87(1):276-83.

heparin mimetic peptide nanofibers. Biomacromolecules 2012 Sep 10.

2830-40.

244 Calcific Aortic Valve Disease

Jul;4(7):568-74.

Expert Rev Mol Med 2011;13:e23.

Biosci 2012 May;12(5):577-90.

Interv 2011 Jul;4(7):822-3.

199-210.

JACC Cardiovasc Interv 2012 Aug;5(8):874-83.


**Chapter 9**

**Cutting-Edge Regenerative Medicine Technologies for**

An early attempt of designing a valvular device was made already in 1513 by Leonardo da Vinci, who depicted the appearance of a prosthetic aortic valve to be reproduced in glass

The first real manufacture of valve substitutes goes back to the '50s of the previous century, when the application in heterotopic position of an aortic mechanical valve by Hufnagel and colleagues triggered the beginning of the surgical therapeutic era of valvulopathies [2]. It was however the contribution of Harken, Starr and Edwards to demonstrate the feasibility of orthotopic valve replacement with these early devices [3]. Since then, several mechanical and bioprosthetic replacements have been proposed as valve substitutes. Still, these solutions are

Heart valve tissue engineering and, later, tissue-guided regeneration have been proposed to overcome the limitations associated to current valve substitutes. Principles, preclinical and clinical models of each approach are discussed in this chapter, together to the diverse improv‐ ing strategies for the final achievement of viable and functional aortic valve substitutes.

The different drawbacks related to commercial replacement devices compromise their durability once in the patient and have shift the attention of cardiac surgeons and biomedical engineers towards a new therapeutic concept: heart valve tissue engineering. The first general definition of this approach has been proposed by Langer and Vacanti, as the *in vitro* creation

and reproduction in any medium, provided the original work is properly cited.

© 2013 Iop and Gerosa; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**the Treatment of Heart Valve Calcification**

Laura Iop and Gino Gerosa

http://dx.doi.org/10.5772/55327

not meeting important prerequisites.

**2. Tissue engineering**

**1. Introduction**

material [1].

Additional information is available at the end of the chapter
