Autologous approaches to tissue engineering

This chapter has been updated. Please click here for revised version.

  • Shaun A. Steigman1,2,
  • Dario O. Fauza1,

1Dept. of Surgery, Children's Hospital Boston and Harvard Medical School

2Dept. of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA

Stem cells have added a new thrust to tissue engineering. Their distinctive self-renewal and plasticity have not only optimized many tissue engineering developments, but also rendered feasible some applications which would otherwise be unattainable with somatic cells. This review focuses on general aspects of autologous tissue engineering based on so-called adult stem cells, which not only allow for a number of the therapeutic strategies envisioned for embryonic stem cells, but also tend to be genetically more stable than the latter, not to mention less restrained by regulatory hurdles and ethical controversy. While the breadth of stem cell-based tissue engineering has yet to be defined in various large scale clinical applications, numerous experimental reports and the early human experience underwrite its potential. Tissue engineering seems to be at the inflection point of its developmental curve. Much remains to be learned and developed, not only by scientists and clinicians, but also entrepreneurs and regulatory agencies. Nevertheless, given its scientific premises, the potential magnitude of its impact to society, and what has been achieved thus far, it should only be a matter of time until stem cell-based tissue engineering reaches the mainstream of clinical practice.

1. Introduction

The promise of tissue engineering has predictably gained renewed impetus with the addition of stem cells to its armamentarium. While the broader definition of tissue engineering includes a few non cell-based methods, the vast majority of its processes comprise different forms of cell therapies, for which stem cells, with their distinctive self-renewal and plasticity, are particularly suitable. In addition, stem cells allow for certain engineering strategies that would be impossible with other cell types. For example, the fact that it has been difficult to expand a sizeable proportion of somatic cells in sufficiently large numbers ex vivo for the engineering of many tissues or organ substitutes can, often times, be overcome by the use of stem cells. Indeed, the virtually limitless conceptual viability of autologous approaches to tissue engineering is one of the most direct consequences of this very principle.

While the breadth of stem cell-based tissue engineering has yet to be defined in different large scale clinical applications, numerous experimental reports and the initial clinical experience underwrite its potential. Still, perhaps the most compelling substantiation of this principle is nature's numerous precedents of tissue regeneration stemming from naturally-occurring (tissue-specific or not) stem cell activity. Indeed, the biomimetic stimulation of native stem cells has been an actively pursued strategy in regenerative medicine for some time now. This concept, however, is beyond the scope of this chapter. Other alternative approaches equally beyond this review include stem cell-mediated gene therapy; tolerance induction; and somatic cell nuclear transfer and/or reprogramming as autologous approaches to embryonic stem cell-based tissue engineering – the latter to be covered in the following chapter. This review focuses on general aspects of tissue engineering based on so-called adult stem cells, which not only allow for a number of the therapeutic strategies envisioned for embryonic stem cells, but also tend to be genetically more stable than the latter, as well as disconnected from their specific regulatory hurdles and ethical controversy.

2. Cell sources

Different putative sources of adult stem cells have been identified or suggested almost regularly over the last several years. The search for alternative sites from which to isolate these cells and/or for new means to obtain them has been one of the most prolific aspects of the whole field, with an abundance of reports to date. Adult progenitor cells have been isolated from bone marrow (Jiang et al., 2002; Pittenger et al., 1999), peripheral blood (Amos et al., 1995; Smith et al., 2000), umbilical cord blood (Amos et al., 1995; Romanov et al., 2003), placenta (Fauza, 2004; Rubinstein et al., 1998), amniotic fluid (Fauza, 2004; Kaviani et al., 2001; Prusa et al., 2002; Torricelli et al., 1993; Tsai et al., 2006), amniotic membrane (Sakuragawa et al., 2000; Takahashi et al., 2002), Wharton jelly (Wang et al., 2004), adipose tissue (Kern et al., 2006; Wagner et al., 2005; Zuk et al., 2001), dermis (Toma et al., 2001; Young et al., 2001), hair follicle (Amoh et al., 2005), synovial membrane (De Bari et al., 2001), skeletal muscle (Lee et al., 2000; Young et al., 2001), central nervous system (Snyder et al., 1992), olfactory bulb (Liu et al., 2004), retina (Coles et al., 2004), inner ear (Li et al., 2003), gastrointestinal epithelium (Bjerknes et al., 2002), fetal liver (Amos et al., 1995; Krupnick et al., 2004), and likely others by the time this goes to print. Different progenitor cell types, including mesenchymal, epithelial, hematopoietic, neural, endothelial, and trophoblastic have been identified from all these sources, some of which harbor more than one type of progenitor cell. At the same time, however, despite the apparent surplus of reports on stem cell sources, many suffer from incomplete analyses and still require further in depth validation. Most of the more widely used cell isolation methods rely on different combinations of natural selection by the culture media with some form of direct cell isolation, typically mechanical, magnetic, or immune-based. In addition, oxygen tension manipultations, multi-stage cultures, and numerous alternative media formulations have also been explored, among many other variations of this principle.

The stem cell source can impact the algorithm for eventual clinical translation of a given tissue engineering strategy. Phenotypically comparable stem cells may behave quite differently, depending on the cell source considered (Chang et al., 2006; Kern et al., 2006; Kunisaki et al., 2007; Wagner et al., 2005). Such differences can have a significant bearing not only on cell processing in vitro, but also on many relevant aspects of the engineered tissue made from comparable stem cells (Kunisaki et al., 2007). For example, mesenchymal stem cells (MSCs) procured from amniotic fluid proliferate significantly faster in vitro than immunophenotypically equivalent MSCs obtained from bone marrow or cord blood and lead to a very peculiar form of engineered cartilage, unusually rich in both glycosaminoglycans and α-elastin, when compared with constructs originated from these other MSCs, under equal bioreactor conditions (see Figure 1; Kunisaki et al., 2007).

Figure 1.
Typical gross appearance of a tubular cartilaginous construct engineered from amniotic mesenchymal stem cells.

The goal of generating clinically relevant engineered tissue places specific requirements on the cell type/source, including minimally invasive accessibility, the ability to produce an inordinately large quantity of cells in a relatively short period of time, hardiness to often prolonged in vitro processing, and reproducible differentiation pathways, among others. These parameters have favored certain stem cell types over others. Mesenchymal stem cells are among the most broadly utilized stem cells in tissue engineering due to their diverse sources, self-renewal pattern, and multilineage potential (Barrilleaux et al., 2006; Bianco et al., 2001). Indeed, most of the tissues used for structural surgical repair are mesenchymal in nature. Further, in addition to all mesenchymal lineages, certain MSCs such as those from umbilical cord blood and amniotic fluid can also differentiate into cells from different germ layers, sometimes all three of them. This broadens the appeal of these cells even further. While many sites have been shown to yield MSCs, the bone marrow remains the most studied and best characterized source, thus it is often the benchmark for comparisons involving MSCs. At the same time, nonetheless, MSC isolation and expansion from the bone marrow is more difficult than from other sources and can be significantly influenced by the donor's age (Kunisaki et al., 2007; Vaananen, 2005). Indeed, “alternative” sources of MSCs, such as the amniotic fluid and adipose tissue, have recently received increasingly more attention for tissue engineering applications, due to their better translational appeal in many clinical scenarios, when compared with bone marrow and other sources (see Figure 2; Awad et al., 2004; Dragoo et al., 2005; Fuchs et al., 2004; Kaviani et al., 2003; Kaviani et al., 2001; Kunisaki et al., 2007; Kunisaki et al., 2006; Kunisaki et al., 2006a; Kunisaki et al., 2007; Kunisaki et al., 2006b; Steigman et al., 2008; Stosich et al., 2007).

Figure 2.
Diagramatic representation of the concept of autologous amniotic mesenchymal stem cell-based fetal tissue engineering for the treatment of congenital anomalies.

3. Translational challenges

In order for novel therapeutic concepts and methodologies, such as those implicated in the development of autologous stem cell-based tissue engineering, to be brought to clinical fruition, many biological, technical, and regulatory hurdles must be overcome. While many of these hurdles are disease-specific, one can generalize certain aspects of the translational challenges involved.

3.1. Biological challenges

Timing is an intrinsic constraint in most tissue engineering concepts. Autologous construct-based approaches generally involve weeks, if not months, of processing ex vivo before final implantation. While the use of stem cells can often minimize this limitation, at least when compared with the use of most somatic cells, more often than not it remains a concern.

Even autologous cells may not be completely free of pathogens in culture, as the growth medium often requires xenogeneic products, such as fetal bovine serum. In addition, some cells can only propagate consistently on xenogeneic feeder layers, so that infectious risks cannot be completely eliminated.

The search for the ideal biocompatible scaffolding material(s) for a given clinical application is almost a never-ending pursuit. The possibility that newer components may prove better than what has been considered state of the art is an ever-present prospect. Many of the currently available synthetic scaffolds remain plagued by foreign body reaction in the setting of an immunocompetent environment, which in turn can lead to a reduction in the diffusion of nutrients and waste products, fibrosis, and other complications. Also, the cytotoxic effects of macrophage-generated nitric oxide can reach and destroy transplanted cells. Thus, it is not surprising that most of the scaffolds implanted in humans to date have been derived from natural sources. On the other hand, natural scaffolds are usually linked to unfavorable biomechanical properties and excessive heterogeneity. Not surprisingly, the search for enhanced biocompatible synthetic biomaterials, such as elastomers and others, remains a lively aspect of the development of tissue engineering, regardless of whether stem cell- or somatic cell-based. For example, scaffolds impregnated with select growth factors or specific peptide sequences may also allow for better control of the surrounding microenvironment. Undeniably, advances in synthetic materials will be instrumental in broadening the reach of tissue engineering both in the immediate and long term future.

3.2. Construct vascularization

The search for methods to establish and/or control the vascularization of engineered tissues or organs has been one of the major foci in the recent development of tissue engineering. Although the scaffold and three-dimensional milieu play a role, typically constructs greater than approximately 1cm in thickness cannot rely solely on vascular ingrowth from the host to remain viable in vivo (Davis et al., 2007). Thus, a major hurdle for clinical application of large engineered tissues and organs has been securing blood supply to the graft at the time of implantation. An appealing strategy among the many being currently explored to overcome this hindrance has been to build a microcirculation network within the engineered scaffold itself. One interesting example of such an approach has been the use of MicroElectroMechanical Systems (MEMS; Fidkowski et al., 2005). Preliminary work on MEMS has enabled the development of a robust computational model of the vascular microcirculation, including variables such as fractal network topology, blood flow rheology, and the mass transfer of oxygen and nutrients across the vascular bed. More recently, this method has allowed the etching of vascular channels onto silicon wafers, which can then be transferred onto biodegradable polymer systems by stacking multiple monolayers of this architecture so as to form three-dimensional structures. Various other approaches to establish or optimize construct vascularization, such as gene therapy, biomimetic microvascular guides, and scaffold-based delivery of angiogenic and/or growth factors, among others, have also been pursued (Brewster et al., 2007; Wong Po Foo et al., 2006). Conceivably, many of the principles established by these developments might be also be eventually applied in facilitating the formation of other complex ancillary networks within engineered grafts, such as neural, lymphatic, and biliary systems, for example (Allmeling et al., 2006).

4. Regulatory challenges

The Food and Drug Administration (FDA) has mandatory jurisdiction over cell-based therapies in The United States, including tissue engineering. An elaborate and costly infrastructure is necessary for the development and manufacture of engineered tissue amenable to FDA validation. Such regulatory clearance demands the use of so-called Good Manufacturing Practice (GMP) facilities, which not only must fulfill strict physical and operational requirements, but also be controlled by a critical mass of highly trained personnel. Another practical intricacy is the fact that certain tissues require preconditioning in complex bioreactors, which may not be readily compatible with large scaled manufacturing and shipping (Griffith et al., 2002). All of these underlying hurdles translate into chronic difficulties in establishing multicentric clinical trials, which are essential for the widespread application of technologies such as this.

Regulatory constraints have significantly hampered the clinical translation of many tissue engineering therapies (Ahsan et al., 2005). The FDA has often been criticized for slow approval processes, which include both justifiable and debatable requirements. This predicament has been attributed, at least to some extent, to the lack of clear, predictable regulatory frameworks and to uncertainties regarding the proper classification of different tissue engineered products. This is particularly evident when stem cells are to be used, in that, besides eventual ethical concerns, they typically trigger regulatory demands for unique safety data sets, more notably on genomic stability and tumorigenesis. Fortunately, it seems that the FDA is mindful of this scenario and is working to address these concerns. Meanwhile, however, many American biotechnology companies have engaged in collecting clinical data overseas, at lower costs, as most other countries have less stringent regulatory procedures.

Regardless, these constraints, combined with strict reimbursement policies and poor business models, have typically rendered tissue engineering products commercially unsustainable in the long run (Bouchie, 2002; Fauza, 2003). Indeed, a sizeable proportion of firms with considerable interest in tissue engineering have exited the market over the last 5–10 years. On the other hand, dozens of companies still continue to invest in the development of new products (Lysaght et al., 2001; Vacanti, 2008). It seems that a healthy partnership between academia and industry should be further explored as a means to expand tissue engineering into clinical reality on a more meaningful scale, a principle which has been proven viable in a number of circumstances (Fauza, 2003; Vacanti, 2008).

5. Current clinical applications

The infancy of the field, combined with the different challenges briefly discussed above, elucidate why few controlled prospective trials have validated clinical tissue engineering applications to date. Obviously, many challenges have yet to be overcome by companies before “off-the-shelf” tissues can be offered commercially, including adequate sources of healthy expandable cells, the optimization of scaffolds, scaled-up bioreactors, the prevention of tissue rejection, and optimal product preservation ex vivo. Many of these challenges can be better tackled by the use of stem cells. Perhaps the best and most successful example is hematopoietic stem cell transplantation, which, first performed in humans during the 1950s, has long been firmly established clinically and will not be further explored here. Other, more recent examples are briefly examined below. First, however, we must consider that, although some still link the term “tissue engineering” solely to the paradigm of cell delivery within biocompatible scaffolds, the field is certainly much broader (Langer et al., 1993; Vacanti et al., 1999). In essence, tissue engineering technologies fall into one of four main strategies: delivery of isolated/expanded cells (simple cell transfers); tissue-inducing substances (not applicable to this review); extracorporeal and encapsulation techniques (closed systems); and cell transplantation within three-dimensional matrices (open systems).

5.1. Cardiac repair

Over 1 million individuals suffer a nonfatal myocardial infarction in the United States every year. The myocardium cannot repair itself after these events, seemingly at least in part because of a paucity of myocardial stem cells, not to mention the disease process and the consequential local hostile environment. The end result is fibrotic scarring, resulting in a decrease in the ventricular ejection fraction, diastolic dysfunction, and in overall myocardial performance.

Over the last several years, the local delivery of autologous skeletal muscle satellite cells or bone marrow-derived stem cells, a procedure now known as cellular cardiomyoplasty, has been evaluated as an experimental therapy in patients with ischemic myocardium. To date, hundreds of patients have received this therapy worldwide. This approach aims to minimize fibrotic remodeling of the injured myocardium by populating the damaged area with myogenic precursor cells. Support for this hypothesis has been based largely on animal data, which has shown that implanted cells can differentiate into multinucleated myocyte-like cells, resulting in improved global ventricular performance without the need for electromechanical coupling between donor cells and host cardiomyocytes (Murry et al., 2005).

At this time, the clinical feasibility of this form of cell transfer in the management of ischemic heart disease has mostly been reported in multiple descriptive, pilot studies (Murry et al., 2005). It has been shown that hundreds of millions of myoblasts can be grown from a small muscle biopsy under GMP conditions. Several uncontrolled studies have demonstrated modest improvements in ejection fraction and regional wall activity after skeletal myoblast transplantation (Herreros et al., 2003; Menasche et al., 2003; Siminiak et al., 2004). At least two small randomized trials using autologous bone marrow mesenchymal cells have also demonstrated improvements in cardiac performance, including increased myocardial fluorodeoxyglucose uptake, enhanced wall motion, a reduction in ventricular end-systolic and end-diastolic volumes, and a 14% net increase in ejection fraction, when compared with a saline-infused control group (Chen et al., 2004; Murry et al., 2005).

The mechanisms for the observed clinical benefits of cellular cardiomyoplasty remain unknown. Because cell survival after the procedure appears to be quite low, proponents have speculated that the improved myocardial indices may be secondary to other factors, such as increased angiogenesis, minimization of deleterious ventricular remodeling, and/or enhanced cytokine-mediated resident cell survival. Further studies are certainly needed in order to adequately assess the risks and benefits of cellular cardiomyoplasty. Also, whether or not the direct myocardial injection of donor cells may also be associated with an increased risk for malignant arrhythmias warrants further scrutiny.

Several products based on the principle of cellular cardiomyoplasty have been, or are currently being tested in controlled clinical trials, both in the United States and in Europe. One such therapy, marketed as MyoCellTM (Bioheart, Inc.) involves a collaboration of over 30 centers in Europe and has enrolled several dozen patients to date. In this approach, autologous skeletal myoblasts are expanded ex vivo and supplied as a cell suspension to be delivered directly into the epicardium during coronary artery bypass grafting surgery. In the United States, a donor-derived bone marrow preparation, marketed as ProvacelTM (Osiris Therapeutics) is being evaluated, with preliminary data suggesting that the product is safe when injected intravenously within 7 days of a myocardial infarction.

Anecdotal clinical experience with heart valves engineered from autologous endothelial progenitor cells has also started to be reported, with encouraging results (Cebotari et al., 2006). This methodology benefited from the presence of a small population of CD34 positive mononuclear hematopoietic progenitor cells in human peripheral blood capable of differentiating into the endothelial lineage in culture (Asahara et al., 1997; Assmus et al., 2002), as this obviates the need for vascular procurement. Nevertheless, in addition to the endothelial lining, a mesenchymal population is typically needed to maintain the extracellular matrix and overall integrity of the valvular construct, for which MSCs have been explored. The optimum cell sources and scaffold–cell interactions remain to be established. Yet another significant and somewhat unique limitation of heart valve engineering stems from the complex and dynamic demands of the constantly moving three-dimensional environment, as well as its long term stability, particularly in pediatric applications. Protein precoating of elastomeric scaffolds as a means to overcome at least some of these limitations has led to some encouraging, albeit still preliminary results (Sales et al., 2007). Certainly, much more data is needed before this concept can be widely recommended.

5.2. Neural repair

Parkinson's disease is a prevalent and debilitating neurodegenerative disorder caused by a selective loss of mesencephalic dopaminergic neurons within the substantia nigra. Affected patients have characteristic symptoms, including bradykinesia, resting tremors, muscle rigidity, and gait disturbance. Current medical therapy, including the exogenous administration of dopamine (levodopa), can be effective in many patients but in some is associated with numerous secondary motor complications.

Another type of simple cell transfer, namely the transplantation of human fetal dopaminergic cells, has been studied for many years as a potential treatment for Parkinson's disease. Initial observational studies suggested prolonged survival of the transplanted cells, as well as substantial clinical neurological improvements in the absence of medication. Nevertheless, at least two randomized controlled trials comparing the effectiveness of human fetal cell transplantation with sham surgery demonstrated no significant differences between the two groups, except for some modest gains in a cohort of younger patients (Freed et al., 2001; Olanow et al., 2003). Furthermore, both the practical and regulatory limitations of human fetal cell transplantation have precluded its widespread clinical application. Porcine fetal nigral cell transplantation has been reported to provide some benefit for Parkinson's disease in a phase I study (Fink et al., 2000). However, this procedure ultimately proved no better than placebo in a subsequent, as yet unpublished controlled trial.

More recently, a number of investigators have shifted their focus from fetal cell transplantation to approaches that employ either embryonic or neural stem cells. Both these cells have a high capacity for self-renewal, which could conceivably supply an abundant number of neurons for the treatment of Parkinson's disease. One biotechnology company, NeuroGeneration, has engaged in clinical trials using autologous neural stem cells. In their approach, a needle biopsy of the brain is performed to harvest neural cells. Neural stem cells are then isolated from the sample, cultured, and differentiated into dopaminergic neurons over a 6 to 9 month period prior to injection into the putamen. Based on as yet unpublished studies, this technique has been associated with a significant increase in clinical scores after mid-term follow-up. The use of neural and other stem cells in spinal cord repair is of course another area of even greater experimental activity, not within the scope of this review.

5.3. Bone repair

Different forms of bone loss can occur in a variety of pathological entities. Fairly established bone replacement methodologies include autologous and allogeneic bone grafts, demineralized bone, and numerous natural or synthetic bone substitutes, all still fraught with substantial limitations. Thus, more recently, in addition to growth factors and cytokines such as Bone Morphogenic Proteins (BMPs), the use of cell-based methods has been explored. Mesenchymal stem cells are natural candidates for bone replacement and indeed a number of anecdotal cases and small series of MSC-based tissue engineering to that end have been reported to date. Injectable suspensions of bone marrow MSCs have been used as a means to enhance bone healing in the treatment of congenital and acquired bone defects for decades (Healey et al., 1990; Hibi et al., 2006a; Hibi et al., 2006b; Jackson et al., 1981; Kitoh et al., 2004; Salama et al., 1978). However, the first instance of bone repair using a three-dimensional cell-seeded construct, by Vacanti et al., took place only in the late 1990’s, on a patient with traumatic avulsion of a distal phalanx, in whom partial local bone formation was documented post-operatively (Vacanti et al., 2001). In this case, no stem cells were used, but rather osteoblasts obtained from a periosteal biopsy. Reports of different forms of bone repair with bone marrow MSC-seeded three-dimensional constructs have followed, typically in very small series or case reports (Marcacci et al., 2007; Ohgushi et al., 1989; Quarto et al., 2001; Warnke et al., 2004). Although variable degrees of osteoregeneration have been documented in these studies, the role of stem cell-based tissue engineering in bone repair remains to be properly defined. One additional interesting development, also still in its infancy, is the use of MSCs, for example procured from fetal liver, delivered prenatally to ameliorate genetic bone disorders, such as osteogenesis imperfecta (Guillot et al., 2008; Horwitz et al., 1999; Horwitz et al., 2001). Also here, while the results of the first clinical applications have been encouraging, much remains to be achieved before this principle, as all as the other MSC-based therapies discussed above, can be fully validated and broadly recommended.

5.4. Skeletal muscle repair

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder caused by a defect in the encoding for dystrophin, a muscle fiber stabilizing protein. The disease results in chronic injury to skeletal myocytes, leading to a vicious cycle of myocyte degradation and fibrosis. Most affected children are wheelchair-bound by early adolescence and, by early adulthood, most patients develop severe respiratory failure and cardiomyopathy. Despite significant advances in the understanding of the pathophysiology of DMD, its management continues to be largely supportive as no effective therapy yet exists for this disease.

One experimental approach to the treatment of DMD has been to enable relocalization and expression of normal functional dystrophin transcripts within the muscle through the transplantation of muscle precursor cells from normal donors, a procedure known as myoblast transfer therapy (MTT). This approach was originally shown to have promising results in animal models using mdx mice. Initial clinical experience showed evidence of dystrophin transcript expression in DMD patients by reverse-transcriptase polymerase chain reaction (Law et al., 1992). However, multiple clinical trials to date have not shown any objective benefit in DMD patients injected with donor myoblasts. In one of the earlier human studies, dystrophin-positive fibers comprised up to 36 percent of the injected muscles after 1 month (Gussoni et al., 1992). Nonetheless, such expression has generally been undetectable by 6 months post-injection. A subsequent study employing serial injections of normal myoblasts procured from unaffected relatives over a 6 month time period also did not show any clinical benefit (Mendell et al., 1995).

These disappointing clinical results to date have likely been due to multiple factors, including poor cell survival, immune rejection, and limited cell distribution after injection. To our knowledge, there are no clinical trials of MTT currently ongoing. Still, the past few years have witnessed a renaissance in preclinical efforts to hopefully enable MTT eventually. These studies are attempting to address some of the shortcomings of the previous human trials, using enhanced immunosuppressive regimens and alternative stem/progenitor cell sources such as muscle-derived stem cells, among other approaches (Urish et al., 2005).

5.5. Pediatric vascular conduits

The surgical treatment of infants and children with different forms of severe congenital cardiovascular anomalies with the currently available homografts and synthetic prostheses has been hampered by numerous complications, including thrombosis, limited durability, susceptibility to infection, and calcification. Besides, as these conduits essentially cannot grow, the need for one or more re-operations later in life is the rule.

In recent years, a Japanese group has accumulated considerable clinical experience with the use of conduits engineered from endothelial cells obtained from a peripheral vein as vascular replacements in low-pressure systems. Their first case, a 4-year old girl who developed total occlusion of the right intermediate pulmonary artery after a local angioplasty and a Fontan procedure, was reported in 2001 (Shin’oka et al., 2001). That group has since reported their experience using a similar approach in over 40 children with varying forms of complex congenital cardiovascular anomalies (Matsumura et al., 2003). Current methods are focusing on the use of autologous bone marrow progenitor cells for seeding scaffold tubes based on a copolymer of polylactic–polycaprolactone reinforced with woven polyglycolic acid (Hibino et al., 2005; Shin’oka et al., 2005).

Thus far, the mid-term outcome of engineered vascular grafts in children have shown no significant complications, as well as continued patency. However, balloon angioplasty has been required in some cases as a means to manage tissue overgrowth at anastomotic sites. The long-term growth, remodeling, and biomechanical profile of these grafts remain unknown. Most importantly, there have been no well-controlled prospective human trials comparing tissue engineered conduits to those consisted solely of synthetic materials. Without these data, the ultimate role of tissue engineering in this setting will continue to be understandably questioned.

6. Future perspectives

Tissue engineering seems to be at the inflection point of a sharp upward slope on its developmental curve. As evidenced in many examples discussed in this chapter and others, concrete clinical benefits from this technology have accrued in the past several years, albeit still at a much slower pace than what we can expect for the future, particularly as stem/progenitor cells become increasingly explored for these applications. In addition to the therapeutic implications of the use of stem cells in tissue engineering, related studies can also lead to unique insights into more basic aspects of stem cell biology, which in turn may bring further, as yet unsuspected therapeutic developments. Although the widespread availability of “custom-made” tissues and organs has yet to become a reality, the field is both very young and very vibrant. Much remains to be learned and developed, not only by scientists and clinicians, but also entrepreneurs and regulatory agencies. Nevertheless, given its scientific premises, the potential magnitude of its impact to society, and what has been achieved thus far, it should only be a matter of time until stem cell-based tissue engineering reaches the mainstream of clinical practice, from fetal medicine to geriatrics and the entire gamut in between.


S.A.S. was supported by the Joshua Ryan Rappaport Fellowship, at the Dept. of Surgery, Children's Hospital Boston.


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*Edited by: Sangeeta Bhatia and Julia Polak. Last revised June 27, 2008. Published August 31, 2008. This chapter should be cited as: Steigman, S.A. and Fauza, D.O., Autologous approaches to tissue engineering (August 31, 2008), StemBook, ed. The Stem Cell Research Community, StemBook, doi/10.3824/stembook.1.13.1,