Ann Thorac Surg 2005;79:1831-1833
© 2005 The Society of Thoracic Surgeons
Editorial
Cardiovascular Tissue Engineering Therapy: So Near, So Far?
Gilbert H.L. Tang, MDa,
Shafie Fazel, MD, MSa,
Richard D. Weisel, MDa,
Glen S. Van Arsdell, MDb,
Ren-Ke Li, MD, PhDa,*
a Division of Cardiovascular Surgery, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
b Division of Cardiovascular Surgery, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
Accepted for publication August 13, 2004.
* Address reprint requests to Dr Li, Toronto General Hospital, NU 1–115A, 200 Elizabeth St, Toronto, Ontario M5G 2C4, Canada (E-mail: renkeli{at}uhnres.utoronto.ca).
 |
Introduction
|
|---|
In this issue of The Annals of Thoracic Surgery, Gulbins and colleagues [1] propose a novel bioreactor device for the seeding of allogenic vascular endothelial cells onto cryopreserved aortic roots and valves. Despite encouraging results, the study emphasizes the challenges in the design of a bioengineered graft: selecting the most appropriate cells, identifying the best biodegradable biomaterials, and employing a bioreactor to improve conduit engraftment.
|
Cells
|
|---|
Recent studies have emphasized the extensive remodeling that occurs after in vivo implantation of tissue-engineered constructs [2]. Biodegradable scaffolds produce excellent conduits because of the extensive in-growth of many cell types into the construct. In animal models, rapid endothelialization results in complete coverage of the luminal surface [3]. In humans, tissue in-growth is slower and endothelial coverage may be delayed [4]. Improving endothelial coverage in vitro may not alter in vivo graft endothelialization [4]. However, in vitro cell seeding of the biodegradable scaffold facilitates tissue in-growth and preseeding with fibroblasts or matrix components may reduce the time required for complete luminal coverage [5]. Seeding the biomaterial with multiple cell types results in a thicker graft with more extensive angiogenesis and a greater variety of cells within the structure [3]. Because several cell types are required for a vascular conduit, seeding with a mixture of cells may be more beneficial than seeding with a purified cell source [2]. Alternatively, stem cells, which can differentiate to a variety of phenotypes, may provide the best source for preseeding tissue-engineered conduits [6]. Bone marrow-derived stem cells offer the opportunity to develop a stable construct from a single autologous biopsy.
|
Biomaterials
|
|---|
The optimal biodegradable scaffold will improve in vitro cell seeding and in vivo tissue engraftment. We [7, 8] and the Shin’oka group [9, 10] have employed a biomaterial with a spongy inner layer, which facilitates preseeding, combined with a fibrous outer layer, which maintains the strength of the conduit during remodeling (Fig 1). Precoating synthetic scaffolds with growth factors or extracellular matrix components improves cell engraftment [11]. Synthetic biodegradable scaffolds can be designed with factors which enhance cell attachment and proliferation. The time required for the scaffold to completely degrade after implantation varies with different polymers. Delayed or prolonged resorption may prevent the creation of a stable tissue-engineered conduit. Premature resorption may provide insufficient biomechanical strength of the scaffold and predispose the graft to aneurysm formation and early structural failure.
View larger version (107K):
[in this window]
[in a new window]
|
Fig 1. The electron micrograph depicts the structure of the composite biodegradable biomaterial. (A) The fibrous outer layer (knitted poly-L-lactide fabric) provides support for the construct and persists for nearly 2 years. (B) The spongy inner core ( -caprolactone-co-L-lactide) facilitates in vitro cell seeding. (C) The composite graft material supports cell engraftment and maintains the structure of the vascular or cardiac tissue-engineered graft even after the disappearance of the inner core.
|
|
Naturally derived scaffolds consisting of matrix components provide a more physiologic substrate for cell attachment, but retained cells or proteins may limit engraftment. Decellularized small intestinal submucosal matrix has been isolated as a resorbable scaffold for tissue engineering [12]. Other decellularized tissue such as heart valves, arterial walls, or pericardium may provide a physiologic template for cell attachment and remodeling, giving rise to a construct functionally similar to that of the native tissue. Currently, the most widely used method to preserve natural tissue for clinical use is glutaraldehyde fixation. While the process minimizes graft antigenicity and stabilizes the tissue against host-induced degradation, it results in cytotoxicity, calcification, and structural deterioration. Gulbins and colleagues [1] reported a small number of residual donor cells despite cryopreservation of the aortic roots. Inadequate removal of cellular remnants predisposes the graft to immune rejection and subsequent calcification [13]. To remove the donor cells without injury to the scaffold, alternate novel techniques have been evaluated including photooxidation, detergent extraction, and enzymatic digestion. The ideal biomaterial may be a stabilized but decellularized matrix, or a synthetic material with matrix components or cytokines, or both, attached to enhance in vitro cell seeding and in vivo tissue in-growth.
|
Bioreactors
|
|---|
Exposing bioengineered tissue to a simulated physiologic environment (a bioreactor) before implantation improves cell seeding and in vitro biomechanical performance [6, 14]. The bioreactor enhances culture media delivery to the interstices, which permits the creation of thicker vascular grafts. After in vivo implantation, engrafted cells induce angiogenesis, but the process may not occur rapidly enough to salvage the implanted cells and the thicker grafts may have greater cell loss. By providing a mechanical stress in vitro, the bioreactor induces cell differentiation and tissue formation and increases the strength of the construct [14]. However, improved biomechanical performance in vitro may not persist after in vivo implantation because of extensive remodeling. Further studies are required to improve bioreactor design and tissue construction.
|
Clinical Application: Too Soon for Prime Time?
|
|---|
The initial results of implantation of tissue-engineered constructs in patients has had mixed results. Shin’oka and colleagues [9, 10] reported excellent outcomes in children who received a cell-seeded biodegradable conduit implanted in the pulmonary outflow tract. Implantation of porcine heart valves treated with Synergraft decellularization technology had evidence of early calcification resulting in significant morbidity and mortality [13]. Cell engraftment was limited in the explanted valves. The mixed results emphasize the need for continuing investigations to define the best cell source, the optimal biomaterials, and the most appropriate bioreactor.
The studies by Shin’oka and colleagues demonstrate the evolution of our approach to tissue engineering. In 1998 they reported excellent results with a pulmonary conduit seeded with multiple differentiated cells in a lamb model [2]. They subsequently employed a composite biodegradable biomaterial, which permitted better in vitro engraftment of vascular smooth muscle cells and in infants with favorable results [9]. Recently, they reported their results with bone marrow cell-seeded vascular autografts for repair of congenital heart defects with no complications and no mechanical failures at 2 years [10]. Some of the conduits increased their diameter with time, suggesting that the bioengineered constructs may be growing as the infants become children. This experience emphasizes the evolution of tissue engineering from the insertion of preformed conduits to the implantation of materials that will encourage the development of a stable tissue after in vivo remodeling. Although tissue-engineered conduits are not ready for prime time, continued clinical investigations will be required to define the response of the biological construct to engraftment in humans.
|
References
|
|---|
- Gulbins H, Pritisanac A, Uhlig A, et al. Seeding of human endothelial cells on valve containing aortic mini-rootsdevelopment of a seeding device and procedure. Ann Thorac Surg 2005;79:2119-2126.[Abstract/Free Full Text]
- Shin’oka T, Shum-Tim D, Ma PX, et al. Creation of viable pulmonary artery autografts through tissue engineering J Thorac Cardiovasc Surg 1998;115:536-545.[Abstract/Free Full Text]
- Ozawa T, Mickle DA, Weisel RD, et al. Histologic changes of nonbiodegradable and biodegradable biomaterials used to repair right ventricular heart defects in rats J Thorac Cardiovasc Surg 2002;124:1157-1164.[Abstract/Free Full Text]
- Zilla P, Fasol R, Deutsch M, et al. Endothelial cell seeding of polytetrafluoroethylene vascular grafts in humansa preliminary report. J Vasc Surg 1987;6:535-541.[Medline]
- Zhang JC, Wojta J, Binder BR. Growth and fibrinolytic parameters of human umbilical vein endothelial cells seeded onto cardiovascular grafts J Thorac Cardiovasc Surg 1995;109:1059-1065.[Abstract/Free Full Text]
- Hoerstrup SP, Kadner A, Melnitchouk S, et al. Tissue engineering of functional trileaflet heart valves from human marrow stromal cells Circulation 2002;106(Suppl 1):143-150.[Free Full Text]
- Ozawa T, Mickle DA, Weisel RD, et al. Optimal biomaterial for creation of autologous cardiac grafts Circulation 2002;106(Suppl 1):176-182.[Free Full Text]
- Matsubayashi K, Fedak PW, Mickle DA, et al. Improved left ventricular aneurysm repair with bioengineered vascular smooth muscle grafts Circulation 2003;108(Suppl 1):219-225.
- Shin’oka T, Imai Y, Ikada Y. Transplantation of a tissue-engineered pulmonary artery N Engl J Med 2001;344:532-533.[Free Full Text]
- Shin’oka T. Mid-term clinical results of tissue-engineered vascular autografts seeded with autologous bone marrow cells Yonsei Med J 2004;45(Suppl):73-74.[Medline]
- Ye Q, Zund G, Jockenhoevel S, et al. Scaffold precoating with human autologous extracellular matrix for improved cell attachment in cardiovascular tissue engineering ASAIO J 2000;46:730-733.[Medline]
- Matheny RG, Hutchison ML, Dryden PE, et al. Porcine small intestine submucosa as a pulmonary valve leaflet substitute J Heart Valve Dis 2000;9:769-774.[Medline]
- Simon P, Kasimir MT, Seebacher G, et al. Early failure of the tissue engineered porcine heart valve Synergraft in pediatric patients Eur J Cardiothorac Surg 2003;23:1002-1006.[Abstract/Free Full Text]
- Akhyari P, Fedak PW, Weisel RD, et al. Mechanical stretch regimen enhances the formation of bioengineered autologous cardiac muscle grafts Circulation 2002;106(Suppl 1):137-142.
This article has been cited by other articles:
|
|
|
|
 
K. L. Fujimoto, J. Guan, H. Oshima, T. Sakai, and W. R. Wagner
In Vivo Evaluation of a Porous, Elastic, Biodegradable Patch for Reconstructive Cardiac Procedures
Ann. Thorac. Surg.,
February 1, 2007;
83(2):
648 - 654.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Introduction
Cells