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Keywords:

  • tissue engineering;
  • stem cells;
  • regenerative medicine;
  • biologic scaffolds

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. CELL-THERAPY APPROACH
  5. TEMC APPROACH
  6. ACELLULAR SCAFFOLD APPROACH
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENT
  9. LITERATURE CITED

The well-recognized ability of skeletal muscle for functional and structural regeneration following injury is severely compromised in degenerative diseases and in volumetric muscle loss. Tissue engineering and regenerative medicine strategies to support muscle reconstruction have typically been cell-centric with approaches that involve the exogenous delivery of cells with myogenic potential. These strategies have been limited by poor cell viability and engraftment into host tissue. Alternative approaches have involved the use of biomaterial scaffolds as substrates or delivery vehicles for exogenous myogenic progenitor cells. Acellular biomaterial scaffolds composed of mammalian extracellular matrix (ECM) have also been used as an inductive niche to promote the recruitment and differentiation of endogenous myogenic progenitor cells. An acellular approach, which activates or utilizes endogenous cell sources, obviates the need for exogenous cell administration and provides an advantage for clinical translation. The present review examines the state of tissue engineering and regenerative medicine therapies directed at augmenting the skeletal muscle response to injury and presents the pros and cons of each with respect to clinical translation. Anat Rec, 297:51–64. 2014. © 2013 Wiley Periodicals, Inc.


INTRODUCTION

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. CELL-THERAPY APPROACH
  5. TEMC APPROACH
  6. ACELLULAR SCAFFOLD APPROACH
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENT
  9. LITERATURE CITED

The Skeletal Muscle Response to Injury

Skeletal muscle has a robust capacity for remodeling, repair, and regeneration following injury (Carlson, 1968; Carlson and Faulkner, 1983). This inherent regenerative response consists of three phases: the destruction phase, the repair phase, and the remodeling phase (Huard et al., 2002; Charge and Rudnicki, 2004; Grefte et al., 2007). The destruction phase involves necrosis of parenchymal cells, stromal disruption, hematoma formation, and the influx of inflammatory cells (Huard et al., 2002; Tidball and Villalta, 2010). The repair phase is characterized by the activation of quiescent myogenic progenitor cells that enter the cell cycle, migrate to the site of injury and become proliferative (Wozniak et al., 2005; Zammit et al., 2006). These activated progenitor cells then differentiate and fuse to form multinucleated myofibers (Hawke and Garry, 2001; Charge and Rudnicki, 2004). During the final phase of the skeletal muscle response to injury, referred to as the remodeling phase, the regenerated myofibers organize, mature, and contract. However, this response is inadequate to replace functional tissue in certain conditions such as inheritable muscle degenerative disease or volumetric muscle loss (VML).

The above phases of skeletal muscle regeneration rely heavily on a population of cells, defined anatomically, as satellite cells. Satellite cells constitute the putative muscle stem cell compartment and when quiescent, are located between the plasma and basal membrane of myofibers (Mauro, 1961; Muir et al., 1965). Satellite cells asymmetrically divide and, in response to injury, give rise to skeletal muscle myoblasts (Charge and Rudnicki, 2004). Myoblasts then proliferate, differentiate, and eventually fuse to form multinucleate and functional contractile skeletal muscle myofibers to complete the regenerative response (Charge and Rudnicki, 2004; Shi and Garry, 2006).

Myogenic Progenitor Cells

In addition to satellite cells and myoblasts, progenitor cells with high myogenic potential have been identified within adult skeletal muscle. These cell types include CD133+ progenitor cells, muscle-derived stem cells (MDSCs), multipotent perivascular progenitor cells, and muscle derived side-population (SP) cells. Multipotent cells with myogenic potential have also been isolated from tissues other than skeletal muscle such as bone marrow (BM), adipose, and umbilical cord.

The present review will examine tissue engineering and regenerative medicine approaches which utilize the above myogenic cell types through exogenous cell-therapy or endogenous cell-recruitment. The eventual goal of all therapies is the augmentation of the inherent regenerative response of injured skeletal muscle.

Tissue Engineering and Regenerative Medicine

Despite the well-accepted ability of skeletal muscle to regenerate following injury, congenital defects such as Duchenne muscular dystrophy (DMD) and massive loss of muscle tissue from trauma, tumor ablation, or prolonged denervation resulting in VML represent skeletal muscle pathologies for which the inherent repair mechanisms are inadequate. In such cases, the current standard of care includes corticosteroid therapy for DMD (Khan, 1993; Balaban et al., 2005; Manzur et al., 2008) and autologous tissue transfer for VML (Lin et al., 2004; Fan et al., 2008; Vekris et al., 2008). These treatment options show limited efficacy and are associated with severe pharmacologic side effects and donor site morbidity for DMD and VML, respectively.

Tissue engineering and regenerative medicine approaches aimed at augmenting the skeletal muscle injury response have traditionally involved the in vitro propagation and subsequent injection or implantation of myogenic progenitor cells into areas of injured muscle (Huard et al., 1994, 1991; Mendell et al., 1995; Seale and Rudnicki, 2000). More recently, myogenic cells or their precursors have been combined with biologic scaffolds in attempts to promote the muscle regenerative response. These approaches attempt to develop an implantable tissue engineered muscle construct (TEMC) and typically require a period of ex vivo culture necessary for efficient cellular-scaffold integration. Despite recent advancements, the in vitro culture and/or ex vivo engineering followed by subsequent implantation of muscle cells and/or tissue has both technical limitations and associated translational hurdles. An engineered functional skeletal muscle construct requires integration with the host tissue including functional vascularization, and neuromuscular innervation. In addition, any cell-based approach subjects the therapy to more rigorous regulatory standards that are associated with both cost and time for the manufacturer/provider.

An alternative approach has been investigated in which decellularized xenogeneic or allogeneic mammalian tissues have been used to create inductive bioscaffolds composed of extracellular matrix (ECM). Such scaffolds provide no external source of new cells but rather recruit endogenous progenitor cells to sites of scaffold placement/muscle injury. The relative efficacy of the cell-based versus acellular approaches has not been compared in head to head studies. Therapies which use cell-based approaches, TEMCs, and acellular scaffolds will be discussed herein (Fig. 1).

image

Figure 1. Tissue engineering and regenerative medicine approaches aimed at augmenting the skeletal response to injury. The cell-therapy approach employs the administration of exogenous myogenic progenitor cells into sites of skeletal muscle injury via intramuscular injection. The second approach seeks to develop an implantable TEMC composed of exogenous myogenic cells coupled with a biomaterial scaffold. The acellular approach employs the implantation of biologic scaffolds composed of decellularized mammalian tissue, which upon their degradation, recruit endogenous myogenic progenitor cells. These approaches share the same goal in that they seek to restore site appropriate and functional skeletal muscle tissue.

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CELL-THERAPY APPROACH

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. CELL-THERAPY APPROACH
  5. TEMC APPROACH
  6. ACELLULAR SCAFFOLD APPROACH
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENT
  9. LITERATURE CITED

Overview

The concept of a purely cell-based approach is designed to increase the local pool of cells with myogenic potential; an approach which logically augment and support the inherent regenerative response of injured skeletal muscle. A variety of stem/progenitor cells are candidates for such an approach.

Muscle-Derived Progenitor Cells

Myoblasts

Satellite cells reside beneath the basal lamina of normal adult skeletal muscle fibers and comprise only 2%–7% of muscle associated cells (Charge and Rudnicki, 2004; Zammit et al., 2006). These quiescent muscle progenitor cells become activated in response to stress from muscle overstimulation or injury and enter the cell cycle. Through asymmetric division, activated satellite cells replenish the quiescent satellite cell pool and give rise to committed myogenic precursor cells known as myoblasts (Charge and Rudnicki, 2004). Skeletal muscle myoblasts proliferate, differentiate, and fuse with other myoblasts or to existing damaged myofibers to form new skeletal muscle. Following recoverable injuries such as weight bearing or exercise, myoblasts are able to fully repair damaged muscle fibers and eventually restore normal structure–function relationships. Pathologic conditions such as DMD or irrecoverable VML involve types of muscle defects for which endogenous myoblasts are unable to fully compensate (Grady et al., 1997; Peault et al., 2007; Grogan et al., 2011).

It is now well accepted that other MDSCs or circulating progenitor cells possess myogenic potential and can contribute to new skeletal muscle formation. However, the satellite cell derived myoblast represents the primary cell type responsible for inherent skeletal muscle repair and regeneration. Transplantation of allogeneic myoblasts into injured muscle has been extensively investigated, especially as therapy for DMD. The initial preclinical demonstration that myoblast transplantation could restore dystrophin expression in animal models occurred as early as 1989 (Partridge et al., 1989). A series of clinical trials resulting in unfavorable outcomes were soon to follow (Gussoni et al., 1992; Huard et al., 1994, 1991; Karpati et al., 1993; Tremblay et al., 1993a,b; Miller et al., 1997). Although largely unsuccessful, these early clinical trials provided valuable insights surrounding the pathobiology of muscle cell implantation. The following fundamental problems with the current myoblast implantation procedures were identified: (1) At 3 days post-implantation less than 25% of the donor myoblasts remained viable (Huard et al., 1992; Guerette et al., 1994); (2) Donor myoblasts were incapable of significant migration from the injection site (Skuk et al., 2006); (3) Inadequate immunosuppressive therapy resulted in the rapid rejection of donor cells (Guerette et al., 1997); and (4) Cyclosporine mediated immunosuppression induced myoblast apoptosis (Hardiman et al., 1993; Hong et al., 2002).

There are now partial solutions for these problems. The transfer of a greater number of cells can compensate for the poor post implantation cell viability (Skuk et al., 2006). A subset of pre-myoblast satellite cells has been identified that, when injected into models of DMD, result in an efficient and functional engraftment (Cerletti et al., 2008; Sacco et al., 2008). The low migration pattern associated with injected myoblasts has been partially addressed by transplant protocols that utilize an increased number of adjacent intramuscular injections resulting in more evenly distributed cell delivery (Skuk et al., 2004). Moreover, Riederer et al. postulated that precocious differentiation of injected myoblasts prevented their post-transplantation proliferation and migration (Riederer et al., 2012). Indeed, in pre-clinical models, when myoblasts were prevented from premature cell-cycle exit by using serum prior to and during administration, these cells were able to increase in number and colonize a much larger area within the recipient's muscle (Riederer et al., 2012). As for problems associated with the prevention of graft rejection, some studies have shown that FK506 mediated immunosuppression results in favorable cell transplant outcomes when tested in mice and non-human primate models (Kinoshita et al., 1996, 1994). Although less than ideal, when some of these strategies were concurrently employed in a human patient clinical trial, they resulted in a 30% restoration of dystrophin expression (Skuk et al., 2007, 2004, 1999).

CD133+ progenitor cells

As mentioned earlier, attempts to transplant cells into injured muscle via intramuscular injection have been hampered by the low migratory potential of the injected cells. An alternative approach would be to deliver myogenic progenitor cells via the systemic circulation if a mechanism for homing the cells to the site of interest were available. To this end, CD133+ progenitor cells represent a promising myogenic cell type. Freshly isolated human CD133+ progenitor cells express patterns of adhesion molecules commonly associated with cells capable of extravasation through the blood vessel wall (Peault et al., 2007). When enriched CD133+ progenitor cells were injected into the systemic circulation of dystrophic mice, the CD133+ cells contributed to muscle repair, increased dystrophin expression, and were able to replenish the endogenous satellite cell pool (Torrente et al., 2007). In a head to head comparison, muscle derived CD133+ cells injected into injured mouse muscle showed a greater replenishment of the satellite cell pool and higher regenerative capacity when compared to myoblasts injected in a similar fashion (Negroni et al., 2009). To evaluate safety, Torrente et al. (2004) designed a DMD patient phase I clinical trial in which transplantation of autologous, and thus still dystrophic, muscle derived CD133+ cells was conducted. Results of this trial showed no adverse events. Future studies will attempt delivery of healthy CD133+ cells within the clinical setting.

Muscle-derived stem cells

Early myogenic progenitor cells distinct from satellite cells can be separated from other muscle cell types based on their adherence to collagen coated flasks in vitro (Lee et al., 2000). Specifically, early adhering cells express satellite cell markers, while late adhering cells express stem cell markers. These cells, isolated from muscle digests and capable of long-term proliferation and myogenic potential, have been distinctly identified as MDSCs (Qu-Petersen et al., 2002). The transplantation of enriched MDSCs into injured mouse skeletal muscle results in a more favorable outcome than the transplantation of skeletal muscle myoblasts (Qu-Petersen et al., 2002). Genetically engineered MDSCs transduced with vectors overexpressing different growth factors prior to transplantation into dystrophic mouse models have been associated with higher engraftment and better outcomes when compared to native MDSCs (Lavasani et al., 2006). One mechanism behind the improved transplantation outcomes of MDSCs over myoblasts may be the increased antioxidant levels in MDSCs which allow them to survive oxidative stress associated with the harsh injury and transplantation microenvironment (Urish et al., 2009; Drowley et al., 2010).

Multipotent perivascular progenitor cells

Perivascular cells encircle the endothelial cells that comprise capillaries and microvessels in all vascularized tissues (Andreeva et al., 1998). Perivascular cells have been traditionally associated with the control and constriction of microvasculature networks (Andreeva et al., 1998). In addition, however, perivascular cells or subsets of perivascular cells are now accepted to be multipotent (Crisan et al., 2008). It is plausible that multipotential perivascular progenitor cells represent a ubiquitous cell-type present throughout the microvasculature and represent a reserve cell population capable of responding to injury in all tissues. These perivascular stem cells are distinct from other endothelial, hematopoietic, and myogenic cells and can be isolated and enriched from human skeletal muscle according to their unique surface marker phenotype (Crisan et al., 2008). Perivascular progenitor cells have been shown to contribute to developing myofibers in postnatal skeletal muscle development and during the inherent response to injury (Dellavalle et al., 2011). Multipotent perivascular cells are myogenic in vitro, and when injected into cardiotoxin injured mouse skeletal muscle were able to induce a higher regenerative index when compared to enriched and injected myoblasts (Crisan et al., 2008).

Muscle side population cells

Muscle SP cells have been purified from mouse and human skeletal muscle using a similar approach originally optimized for the isolation of BM SP cells (Goodell et al., 1996). Muscle-derived SP cells represent a heterogeneous population of cells distinct from BM cells and other muscle-derived progenitor cells (Gussoni et al., 1999). SP cells have been shown to give rise to satellite cells and myoblasts in vivo when injected into models of skeletal muscle injury (Asakura and Rudnicki, 2002; Bachrach et al., 2004). Studies have shown that the systemic delivery of SP cells can result in engraftment within dystrophic mouse muscle (Gussoni et al., 1999).

Mesenchymal Stem Cells

Stem and progenitor cells from outside the skeletal muscle tissue compartment have been examined as potential sources of myogenic cells for skeletal muscle tissue engineering. Most of these cell populations can be generically categorized as mesenchymal stem cells (MSCs). Tissue sources of MSCs include BM (Jiang et al., 2002), adipose (Zuk et al., 2001), hair follicles (Shih et al., 2005), placenta (In 't Anker et al., 2004), umbilical cord (Erices et al., 2000), and others. MSCs give rise to tissues of mesodermal origin such as adipogenic, osteogenic, chondrogenic, and myogenic differentiation (Pittenger et al., 1999). Furthermore, MSCs are pluripotent and have been shown to differentiate into tissues of ectodermal and endodermal origin as well (Petersen et al., 1999; Woodbury et al., 2000). Following their isolation and expansion in vitro, lineage specific differentiation media is used to drive MSCs toward different phenotypes. MSCs derived from BM, adipose, and umbilical cord tissues and their use as cell therapy for augmentation of the skeletal muscle injury response are discussed herein.

Bone marrow-derived cells

Bone marrow-derived MSCs (BM-MSCs) expand rapidly in culture from BM aspirates, and like MSCs from other sources have been shown to be pluripotent (Jiang et al., 2002). It has been shown that, albeit to a small extent, endogenous circulating BM-MSCs contribute to native skeletal muscle myofiber remodeling in healthy (Brazelton et al., 2003; Dreyfus et al., 2004) and injured muscle (Ferrari et al., 1998; Bittner et al., 1999). A study by Winkler et al. (2009) showed a dose-response correlation between the number of transplanted BM-MSCs and the amount of functional recovery resulting from treatment by intramuscular injection within a skeletal muscle crush injury model. BM-MSCs delivered to injured muscle via intravenous or intra-arterial injection may contribute to host angiogenesis and myogenesis (Feng et al., 2008; Liu et al., 2009). Recently, studies have shown that many exogenous BM-MSC mediated cell-therapies have potentiated their positive effects through paracrine interactions with the host microenvironment rather than engraftment within host tissue (Gang et al., 2009; Cizkova et al., 2011).

Adipose-derived cells

Adipose tissue is now recognized as an abundant and readily accessible source of adult pluripotent cells. In adult mammals, adipose tissue is composed of mesodermally derived adipocytes associated within a network of loose, areolar collagenous connective tissue. In addition to parenchymal tissue and in similar fashion to BM, adipose tissue contains a stromal vascular cell population. Adipose tissues' stromal vascular compartment is comprised of endothelial, smooth muscle, and progenitor cell populations (Zuk et al., 2001). Following enzymatic digestion, the stromal cellular fraction can be separated from adipocytes and connective tissue and the resulting cell populations can be cultured in vitro. Tissue culture plastic adhering cells comprise the progenitor cell compartment and are commonly referred to as adipose derived stem cells (ADSCs). In the presence of lineage specific inductive culture media, ADSCs can differentiate into adipogenic, chondrogenic, osteogenic, and myogenic cells (Strem et al., 2005). ADSCs have been shown to spontaneously display myogenic potential in vitro and have been examined as potential donor cells aimed at augmenting skeletal muscle regeneration in vivo (Di Rocco et al., 2006). For example, following injection into injured skeletal muscle, ADSCs modulate inflammation, increase angiogenesis, and restore dystrophin expression in mouse models of muscular dystrophy (Pinheiro et al., 2012). Kang et al. (2010) investigated the ability of ADSCs to repair tissue damage in a murine ischemic hindlimb model. At four weeks post injury and implantation, ADSC-transplanted limbs showed increased vascular density and reduced muscle atrophy. Treated limb musculature was comprised of donor derived differentiated myocytes (Kang et al., 2010).

Umbilical cord blood-derived cells

As an alternative to BM, human umbilical cord blood (UCB) has been explored as a source of MSCs (Erices et al., 2000). Some data suggest UCB derived MSCs posses a higher proliferative capacity when compared to BM-MSCs or ADSCs (Kern et al., 2006). Unlike BM aspiration, human UCB is obtained by a simple and painless procedure after birth, ameliorating any ethical concerns. UCB derived MSCs are pluripotent and some studies have shown that subpopulations of UCB cells display high myogenic potential (Pesce et al., 2003). Injections of myogenic human UCB derived MSCs have promoted myogenesis in mouse models of muscular dystrophy and hindlimb ischemia (Kong et al., 2004; Koponen et al., 2007).

Limitations Associated With Cell-Therapy

One limitation of cell-based therapies lies in the potential routes of administration. Typically, injected cells display an impaired ability to redistribute and do not migrate more than 200 μm from the intramuscular injection site (Skuk et al., 2006). The systemic delivery of cells via intravenous injection has resulted in unintentional cell engraftment at sites such as the liver and spleen (Peault et al., 2007). Another limitation to cell-therapy-based strategies is the inadequate supply of fresh donor cells. Regardless of the auto- or allogeneic progenitor cell source (muscle derived, MSC, or others), cells typically must be expanded in culture to obtain an adequate cell number. Most cell therapy trials in skeletal muscle have utilized ex vivo expanded myoblasts, which most likely undergo culture-induced changes with associated deleterious effects upon the differentiation potential of the pre-transplanted cells. Consistent with this notion, a study by Montarras et al. (2005) reported that an ex vivo culture period of as little as three days, of satellite cells or myoblasts, negatively impacts their ability to contribute to skeletal muscle repair upon transplantation in vivo. Clonal assays comparing freshly isolated cells versus culture-expanded cells indicated that short-term culture decreases proliferative and differentiation potentials (Montarras et al., 2005). A potential safety concern associated with the use of pluripotent MSCs mediated cell therapy is the risk of transdifferentiation (Song and Tuan, 2004). It is now well accepted that some genes that confer pluripotency also confer oncogenicity. Studies determining the risk:benefit ratio associated with these cell-types are still in their infancy and need to be further studied prior to FDA consideration. These perspectives provide an overview of the significant hurdles to clinical translation. Perhaps the most significant limitation associated with cell-therapy approaches is the general poor engraftment of donor cells into host tissue (Huard et al., 1992; Fan et al., 1996; Guerette et al., 1994; Glimm et al., 2000; Camargo et al., 2006).

After over 3 decades of study, it is widely accepted that myogenic progenitor cell transplantation and stem cell transplantation typically does not result in a significant engraftment of donor cells into host tissue. It has also been demonstrated that the low number of viable engrafted cells are not typically correlated with the levels of functional improvement in host tissue. For these reasons, it is now widely accepted that favorable outcomes resulting from stem and progenitor cell transplantation, whether alone or in the context of a TEMC, are most likely associated with a paracrine effect of the donor cells upon the host injured microenvironment (Gnecchi et al., 2005, 2008; Murry et al., 2006; Perez-Ilzarbe et al., 2008; Arthur et al., 2009; Gharaibeh et al., 2011). The release of cytokines or other signaling molecules by donor cells most likely play a role in the recruitment of host cells and/or the modulation of the host innate immune response. For example, many of the above myogenic cell types have been shown to secrete growth factors which, through their paracrine effects, have the potential to stimulate angiogenesis and modulate the host pro-inflammatory response (Springer et al., 1998, 2003; Deasy et al., 2009; Ota et al., 2011).

TEMC APPROACH

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. CELL-THERAPY APPROACH
  5. TEMC APPROACH
  6. ACELLULAR SCAFFOLD APPROACH
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENT
  9. LITERATURE CITED

Limitations associated with cell-based therapies provide the impetus for innovative tissue engineering approaches, which can augment the innate skeletal muscle response to injury. Since in vivo myogenic cells differentiate within a three-dimensional environment, one approach involves the incorporation of myogenic cells or precursor cells within an appropriate three-dimensional biomaterial scaffold; that is, a microenvironmental niche. A biomaterial scaffold in conjunction with a myogenic cell component is referred to as a TEMC. Ideal biomaterials for skeletal muscle engineering should be able to support the propagation and expansion of myogenic progenitor cells in vitro and also, for in vivo implantation purposes, be able to integrate into host tissue. Scaffolds with a variety of compositional and biological features have been developed. Although several studies have examined the efficacy of non-biodegradable scaffolds, such as phosphate-based glass (Shah et al., 2005), biodegradable scaffolds are preferred (Koning et al., 2009). Following in vivo implantation, biodegradable scaffolds promote host tissue integration, and have the potential to be replaced with host skeletal muscle tissue (Rossi et al., 2010). Both synthetic and natural biodegradable scaffolds have been examined as described below.

Synthetic Scaffold Based TEMC

The copolymer poly-lactide-co-glycolide (PLG) is FDA approved and has been used clinically as a source material for biodegradable sutures for more than 30 years (Athanasiou et al., 1996). Biodegradable PLG has also been described as a suitable scaffold material that promotes cell adherence, proliferation, and formation of new three-dimensional tissues (Harris et al., 1998; Smith et al., 2004). Porous PLG scaffolds have also been shown to promote host mediated vascularization and cell infiltration upon their in vivo implantation (Peters et al., 2002). These characteristics suggest that PLG may hold potential as a biomaterial for TEMCs. In a study by Thorrez et al. (2008), human skeletal muscle myoblasts were cultured within collagen coated porous PLG scaffolds and showed significant myogenic differentiation in vitro. However, when implanted subcutaneously in a mouse model after 4 weeks, these PLG based TEMCs resulted in only 22% donor cell viability (Thorrez et al., 2008). Results showed that despite their incorporation within the scaffold, implanted cells were depleted due to host derived NK cells.

Polymers composed of poly(ε-caprolactone) (PCL) and polylactic-co-glycolic acid (PGA) have also been examined as synthetic biodegradable three-dimensional scaffolds for skeletal muscle tissue engineering (Saxena et al., 1999; Choi et al., 2008). PCL-based scaffolds with uni-directionally oriented nanofibers were able to promote muscle cell alignment and myotube formation (Choi et al., 2008). Following the implantation of neonatal rat myoblasts seeded onto PGA scaffolds, viable skeletal muscle and neo-vascularization could be identified within the TEMC at 45 days (Saxena et al., 1999).

Naturally Occurring Scaffold Based TEMC

TEMCs have been created from naturally occurring scaffolds as an alternative to the above mentioned synthetic polymers. The ECM consists of structural and functional molecules which support cell–cell interactions (Badylak et al., 2005). For these reasons, most TEMCs with a naturally occurring scaffold component are composed of ECM materials.

Native ECM is composed of the secreted products of the resident cells of each tissue and organ within the body. Furthermore, each tissue's ECM contains a distinct structural and compositional blueprint of proteins, proteoglycans, glycosaminoglycans (GAG), and growth factors that are in a continuous state of dynamic reciprocity with the resident cells as microenvironmental conditions change (Bissell and Aggeler, 1987). The conventional role of ECM has been to provide mechanical support; however, the tissue specific composition and architecture of the ECM also plays a central role in directing cell communication and behavior by providing an instructive ligand landscape (Kleinman et al., 2003; Rosso et al., 2004). A preferred tissue engineered biomaterial would preserve these characteristics to effectively promote tissue remodeling. Most naturally occurring scaffolds used in TEMC design consist of components of ECM or whole mammalian ECM itself.

Collagen I based TEMCs

Type I collagen is the predominant component of the ECM and represents the most abundant protein within mammalian tissue (Di Lullo et al., 2002). As a substrate in vitro, collagen I can enhance the viability and proliferation of myogenic progenitor cells (Shih et al., 2006; Heckmann et al., 2008). TEMCs collagen I based scaffolds have been injected as hydrogels and as implanted as three-dimensional scaffolds (Zhang et al., 2008; Dai et al., 2009). In several studies, the implantation of a myoblast-collagen I based TEMC within a VML injury model was associated with a minimal inflammatory response and a donor cell contribution that enhanced host-mediated myogenesis (Kroehne et al., 2008; Ma et al., 2011). In a head-to-head comparison, when implemented within a DMD mouse model, a collagen I TEMC seeded with myogenic precursor cells restored dystrophin more efficiently when compared to cell-therapy-alone based injections of the same cells (Carnio et al., 2011).

Hyaluronic acid based TEMCs

Hyaluronic acid (HA) is a major component of the ECM and has been shown to have biologic activity including the ability to promote angiogenesis and prevent apoptosis (Stern et al., 2006). Myoblasts seeded within a three-dimensional HA based culture system were able to proliferate and fuse (Wang et al., 2009). In a study by Rossi et al. (2011), satellite cells and myoblasts were incorporated into a photo-crosslinked HA-based hydrogel and delivered to injured skeletal muscle in a pre-clinical model of VML. This HA-based TEMC resulted in functional recovery as assessed by contractile force measurements and was associated with the formation of new neural and vascular networks.

Decellularized mammalian whole-ECM based TEMCs

While individual purified components of the ECM such as collagen I and HA have been used as substrates or vehicles for cell delivery, the most extensively investigated naturally occurring scaffold in TEMC design is decellularized native mammalian tissue, that is, ECM. Acellular ECM scaffolds are essentially free from DNA and xenogeneic and antigenic epitopes when manufactured by methods that meet stringent criteria (Crapo et al., 2011), and therefore will not elicit an adverse immune response. A three-dimensional matrix derived by decellularization of skeletal muscle or other native mammalian tissue may be advantageous because the differentiation of myogenic progenitor cells can be influenced by natural tissue specific factors including the three-dimensional ultrastructure, surface ligands, and chemical and mechanical microenvironment (Engler et al., 2004, 2006). Myoblasts cultured on ECM derived from skeletal muscle showed enhanced growth rates and differentiation potentials compared to myoblasts on tissue culture plastic (Stern et al., 2009). These data support the use of intact ECM scaffolds as a suitable substrate for TEMCs. In a study by Merritt et al., a rat model of VML injury was repaired with a TEMC composed of BM-MSCs seeded onto an acellular muscle ECM scaffold. The construct was implanted into injured gastrocnemius muscles and showed the presence of vascularized regenerating skeletal muscle after 42 days. In addition, the TEMC repaired muscle was associated with a partial functional recovery (Merritt et al., 2010).

Studies have shown that a conditioning period of in vitro mechanical loading upon whole ECM TEMCs can affect the biologic properties of the scaffold and influence myogenesis and improve cell-scaffold integration prior to transplantation (Corona et al., 2012; Machingal et al., 2011; Moon du et al., 2008). Vandenburgh et al. (2002) conducted pioneering work in which a mechanical cell stimulator device applied mechanical stimulation to a TEMC composed of skeletal muscle myoblasts incorporated into a Matrigel:collagen scaffold. This approach resulted in improved myofiber diameter and alignment, increased elasticity of the muscle fibers, and improved cell-generated passive force compared to static cultures. A study by Borschel et al. (2004) showed that TEMCs composed of skeletal muscle myoblasts seeded onto decellularized muscle scaffolds produced specific forces that were approximately 5% of that observed for the native muscle after 3 weeks of culture. In a similar fashion, Christ and coworkers seeded primary human muscle precursor cells onto acellular bladder submucosa and subjected the constructs to cyclic strain for up to 4 weeks, followed by subcutaneous implantation of the cell-seeded construct within the latissimus dorsi muscle of mice. This study showed that specific forces of 1% of that observed for native latissimus dorsi were produced when the constructs were preconditioned in an in vitro bioreactor (Machingal et al., 2011). Although the observed maximal contractility was only 1% of that of native muscle, this result was still 75-fold greater than in previous reports (Machingal et al., 2011).

Limitations associated with TEMCs

The formation of TEMCs through the incorporation of myogenic cells into biomaterial scaffolds has, as discussed above, been occasionally able to enhance donor cell viability and myogenicity. Many limitations associated with TEMC cell-scaffold integration have been at least partially resolved by the practice of ex vivo mechanical loading prior to implantation. However, the practical and regulatory hurdles associated with the TEMC approach will limit clinical translation in the near term. Because TEMCs involve the use of a cellular component, the same challenges associated with pure cell-based therapies apply.

ACELLULAR SCAFFOLD APPROACH

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. CELL-THERAPY APPROACH
  5. TEMC APPROACH
  6. ACELLULAR SCAFFOLD APPROACH
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENT
  9. LITERATURE CITED

Limitations associated with the use of a cell-based therapy, including the TEMC approach, provide the stimulus for alternative cell-free approaches. The use of decellularized tissues as (acellular) ECM bioscaffolds has been explored as a therapeutic approach for functional skeletal muscle reconstruction. The approach is based upon the concept of the ECM providing an instructive and conducive microenvironment that can modulate the default scar tissue response to injury toward a constructive regenerative response. Obviously for such a cell-free based approach to be viable, endogenous cells must serve as the source of myogenic precursors.

Implanted Acellular ECM Scaffolds Influence the Host Tissue Microenvironment

The in vivo placement of an ECM bioscaffold affects the injured tissue response by several mechanisms including: (1) provision of an ultrastructure environment that is cell-friendly (Badylak et al., 2009; Zantop et al., 2006; Crisan et al., 2008; Reing et al., 2009), (2) release of bound growth factors, chemokines, and cytokines during the process of degradation (Hodde et al., 2001; Wang et al., 2009), (3) release of bioactive cryptic peptides generated by the degradation of matrix parent molecules (Voytik-Harbin et al., 1998; Davis et al., 2000; Hodde et al., 2001; Record et al., 2001; Sarikaya et al., 2002; Li et al., 2004; Brennan et al., 2006, 2008; Gilbert et al., 2007a,b; Beattie et al., 2009; Reing et al., 2009; Agrawal et al., 2012), and (4) modulation of the host innate immune response toward a regulatory and constructive phenotype (Allman et al., 2001; Badylak et al., 2001; Brown et al., 2009).

Preclinical and clinical examples of these processes have been shown in a number of tissues including esophagus (Badylak et al., 2011, 2008), lower urinary tract (Sutherland et al., 1996; Wood et al., 2005), myocardium (Robinson et al., 2005; Ota et al., 2008), and skeletal muscle (Clarke et al., 1996; Badylak et al., 2002; Iannotti et al., 2006; Zantop et al., 2006; Agrawal et al., 2009; Mase et al., 2010; Turner et al., 2010a; Valentin et al., 2010; Daly et al., 2011) among others. The natural tendency of skeletal muscle to regenerate following mild injury involves a temporally orchestrated series of similar events that have been recently reviewed by Tidball and Villalta (2010). Stated differently, the use of acellular matrix scaffolds appears to provide an environment that augments the natural response of skeletal muscle to injury including activation, recruitment, and differentiation of endogenous stem/progenitor cells and minimization of a prolonged pro-inflammatory reaction.

Process of Acellular ECM Scaffold Remodeling

Biologic scaffolds composed of ECM are rapidly infiltrated by host polymorphonuclear and mononuclear cells in vivo, which initiate the scaffold degradation process. Macrophages, in particular, are key facilitators of this degradation, as their depletion prevents the degradation of ECM scaffolds (Valentin et al., 2009). Quantitative studies of 14C-labeled ECM scaffolds show that approximately 50% of the ECM scaffold is degraded after 28 days and virtually all of the ECM is replaced with host tissue by 60–90 days post-implantation (Record et al., 2001; Gilbert et al., 2007a,b); a process partially dependent upon the anatomic site of placement. The degradation of ECM scaffolds in vivo is critical to the constructive remodeling process (Beattie et al., 2009; Reing et al., 2009; Agrawal et al. 2010, 2011a,b). Degradation of ECM generates cryptic oligopeptides with potent in vitro and in vivo bioactivity not present in the parent ECM molecules. These “matri-cryptic” peptides have shown chemotactic activity for a number of stem/progenitor cells in vitro and have been shown to induce the endogenous recruitment of host progenitor cells in vivo (Reing et al., 2009; Turner et al., 2010a,b; Agrawal et al., 2010, 2011b; Tottey et al., 2011a,b; Wolf et al. 2012). A large number of these multipotential cell-types influenced by the degradation products of ECM scaffold, both in vitro and in vivo, have myogenic potential (Fig. 2).

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Figure 2. The implantation of an acellular ECM scaffold promotes the recruitment of host cells. Upon their implantation into areas of skeletal muscle injury (A), ECM scaffolds are subjected to rapid host-mediated proteolytic degradation (B). The degradation process releases cryptic peptides, which influence the local tissue microenvironment, including the recruitment of distinct populations of myogenic cells (C). The implantation of acellular ECM scaffolds ultimately results in constructive tissue remodeling, characterized by the formation of site-appropriate and functional tissue (D).

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Acellular ECM Scaffolds Recruit Progenitor Cells

The accumulation of potentially therapeutic progenitor cells into sites of injury, whether administrated via direct injection (cell based approach) or implanted in context with a TEMC, is associated with several limitations including the poor engraftment of donor cells into host tissue. However, the in vivo recruitment of endogenous stem/progenitor cells may partially obviate this limitation, either because of the selection of appropriate precursor cells and/or the lack of external manipulation of the cells. Matrix generated chemotactic peptides have been shown to be chemotactic for several distinct populations of myogenic stem and progenitor cells in vitro including: multipotential progenitor cells (Reing et al., 2009); Sox2+ cells (Agrawal et al., 2011b); skeletal muscle myoblasts (Wolf et al., 2012); and multipotent perivascular progenitor cells (Crisan et al., 2008; Agrawal et al., 2010; Tottey et al., 2011a,b). Endogenous cells with myogenic potential have been recruited to sites of ECM scaffold implantation and degradation in vivo. For example, endogenous CD133+ progenitor cells (Turner et al., 2010a,b), multipotent perivascular progenitor cells (Sicari et al., 2011), and BM-MSCs (Badylak et al., 2009; Zantop et al., 2006; Nieponice et al., 2012) have been recruited to sites of ECM implantation within pre-clinical models of skeletal muscle VML. These same cells have previously been used, with limited success, as cell sources for exogenous cell-therapy and in the context with scaffolds as TEMCs (Fig. 3). ECM scaffolds have also been shown to recruit CD34+ progenitor cells (Turner et al., 2010b), Sox2+, Sca1+, Rex1+ progenitor cells (Agrawal et al., 2010), and cardiomyocytes (Kochupura et al., 2005; Badylak et al., 2006) upon their implantation in vivo. These results show the ability of acellular ECM scaffolds to induce endogenous cell-therapy and recruit progenitor cells to sites of injury.

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Figure 3. Common populations of cells with myogenic potential employed in exogenous cell-therapy, exogenous TEMC therapy, and acellular ecm scaffold mediated endogenous cell recruitment. Several ideal cell-types investigated for exogenous cell-therapy are recruited endogenously by ECM scaffolds.

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Acellular ECM Scaffolds Influence the Host Innate Immune Response

The innate immune system has recently been shown to play a pivotal role in both the activation and propagation of the inherent regenerative response of skeletal muscle (Tidball and Villalta, 2010). Following injury, a heterogeneous population of responding macrophages is necessary for muscle's regenerative plasticity (Tidball and Villalta, 2010). Specifically, after injury a population of cells consisting primarily of pro-inflammatory (M1) macrophages not only facilitates pathogen control and debris clearance, but also stimulates the activation of quiescent muscle satellite cells (Li, 2003; Tidball and Villalta, 2010). For efficient regeneration and restoration of function, at 48 hr after injury, the primary cell population responding to skeletal muscle injury must be composed of constructive (M2) macrophages (Ruffell et al., 2009). M2 macrophages are essential in propagating the inherent regenerative response of skeletal muscle by promoting myogenesis (Arnold et al., 2007; Tidball and Wehling-Henricks, 2007).

As stated above, interventions with a cellular component plagued by the lack of donor cell engraftment are typically associated with less than favorable outcomes. However, limited positive results of cell-based interventions have been associated with donor cell-mediated production of soluble factors capable of affecting the host innate immune system (Caplan and Dennis, 2006; Le Blanc and Ringden, 2007; Burchfield et al., 2008). Similar to these paracrine effects, acellular ECM scaffolds, upon their implantation in vivo, have been shown to influence the local host innate immune response. Specifically, correctly prepared ECM scaffolds promote the constructive M2 macrophage phenotype (Badylak et al., 2001; Brown et al., 2009). The ECM scaffold-mediated predominant M2 macrophage response is associated with constructive remodeling outcomes downstream of the initial participation of the innate immune system (Wang et al., 2009; Sicari et al., 2012). Stated differently, ECM scaffolds induce host constructive macrophages and result in favorable remodeling outcomes.

Limitations Associated with Acellular ECM Scaffolds

Outcomes resulting from preclinical and clinical applications of acellular ECM scaffolds have varied considerably and have ranged from poor to excellent (Zheng et al., 2005; Adams et al., 2006; Zalavras et al., 2006; Walton et al., 2007; Ayyildiz et al., 2008; Doede et al., 2009; Badylak et al., 2008). A potential explanation for these discrepancies may lie within the preparation methods for such materials. For example, numerous decellularization strategies exist for each source tissue; all varying in their effectiveness of removing cellular material as well as altering the ECM structure and composition. Effective decellularization with preservation of native structure–function relationships of the component ECM molecules has been shown to be critical for in vivo constructive remodeling outcomes (Keane et al., 2012). For example, in vivo implantation of biologic scaffold materials with notable residual DNA amounts was directly correlated to a negative host response (Keane et al., 2012). Thus, the clinical performance of biologic scaffolds is largely dependent on the preparation and processing techniques.

Clinical Translation of ECM Scaffolds

Biologic scaffolds are commonly used as an alternative to synthetic scaffolds in tissue engineering and regenerative medicine applications (Clarke et al., 1996; Badylak et al., 2002, 2008; Pu, 2005; Ansaloni et al., 2007; Agrawal et al., 2009; Turner et al., 2010a; Valentin et al., 2010; Daly et al., 2011). There exist numerous commercially available ECM based products which are derived from a variety of species including human, porcine, and bovine; as well as an array of tissue sources such as small intestinal submucosa (SIS), urinary bladder, dermis, pericardium, heart valves, and peritoneum, among others.

More than 4 million patients have been implanted with an ECM scaffold for a variety of conditions including: hernia repair (Hope et al., 2012; Kissane and Itani, 2012), diabetic ulcers (Niezgoda et al., 2005; Lullove, 2012), rotator cuff repair (Badhe et al., 2008; Derwin et al., 2010; Wong et al., 2010), breast reconstruction (Cheng and Saint-Cyr, 2012; Mofid et al., 2012), musculotendinous reinforcement (Mase et al., 2010), pelvic floor reconstruction (Han et al., 2010; Momoh et al., 2010), and urologic defects (Weiser et al., 2003; Carpenter et al., 2012), among others.

A recent clinical case study highlighted the ability of an acellular ECM scaffold to promote skeletal muscle constructive remodeling within a wounded soldier suffering from VML of the quadriceps femoris muscle (Mase et al., 2010). At 16 weeks post-implantation, the patient showed a 30% increase in muscle function that was concomitant with the presence of soft tissue resembling skeletal muscle on CT.

A clinical study is in progress which evaluates the effect of ECM implantation at the site of VML in 80 patients. The outcome measures of this trial include mechanical strength and function, the cell populations involved in the process, quality of life in these patients, as well as to examine the cellular composition of the remodeled tissue. Preliminary results show the presence of multipotent perivascular cells, desmin+ skeletal muscle cells, neovascularization, and regenerating skeletal muscle tissue (centrally located nuclei) widely distributed throughout the remodeling ECM (Sicari et al., 2011). Furthermore, at 16 weeks post-operatively these patients have exhibited at least a 20% increase in strength compared to pre-ECM implantation values (Unpublished data). Taken together, these results demonstrate the potential clinical efficacy of ECM scaffolds in promoting the recruitment of perivascular progenitor cells and facilitating restoration of structure and function in volumetric skeletal muscle defects.

CONCLUSIONS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. CELL-THERAPY APPROACH
  5. TEMC APPROACH
  6. ACELLULAR SCAFFOLD APPROACH
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENT
  9. LITERATURE CITED

Tissue engineering and regenerative medicine approaches aimed at augmenting the regenerative response of skeletal muscle to injury have included both cell-based and acellular strategies. The cell-based interventions face significant hurdles to clinical translation including poor donor cell viability and engraftment, and regulatory challenges. Acellular strategies include the use of ECM scaffolds, which constructively influence the host injured skeletal muscle microenvironment. ECM scaffolds are presently FDA approved for many clinical applications and have been shown to recruit endogenous myogenic progenitor cells to sites of injury and implantation. Although cell based and acellular approaches have not been compared in head to head studies, it is clear that each approach has pros and cons that are worthy of consideration. In the near term, acellular approaches may be preferable because of their existing regulatory approval.

ACKNOWLEDGEMENT

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. CELL-THERAPY APPROACH
  5. TEMC APPROACH
  6. ACELLULAR SCAFFOLD APPROACH
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENT
  9. LITERATURE CITED

Authors apologize to those colleagues whose work could not be cited due to space limitations.

LITERATURE CITED

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. CELL-THERAPY APPROACH
  5. TEMC APPROACH
  6. ACELLULAR SCAFFOLD APPROACH
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENT
  9. LITERATURE CITED
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