JASON A. BURDICK AND SHAUNA M. DORSEY
University of Pennsylvania
Biomaterials are gaining attention in the development of biomedical therapies for treating patients after a myocardial infarction (i.e., heart attack). These materials may serve as mechanical restraints, vehicles for the delivery of therapeutics, or 3-dimensional scaffolds for tissue regeneration. This article focuses on one particular class of materials: injectable hydrogels, natural or synthetic water-swollen polymer networks that are a promising therapy to attenuate ventricular remodeling after myocardial infarction. They act both as acellular bulking agents to mechanically stabilize the myocardium and as delivery vehicles for cells and/or therapeutic molecules. Various materials, cells, and therapeutic molecules have demonstrated positive outcomes in the repair of cardiac tissue after infarction and provide insight for future material development and optimization. Further development of injectable hydrogels for cardiac repair will have considerable clinical impact by improving therapies to prevent progression to heart failure.
OVERVIEW OF HEART DISEASE
Heart failure affects almost 23 million individuals worldwide (Bui et al. 2011), and nearly 70 percent of these cases are due to coronary artery disease, which causes myocardial infarction (MI) (Go et al. 2014). MI occurs after coronary artery occlusion, resulting in depletion of nutrients and oxygen to the cardiac tissue and subsequent cell death (Cleutjens and Creemers 2002). The death of cells (i.e., cardiomyocytes) leads to the recruitment of inflammatory cells to remove the necrotic debris and the activation of bioactive molecules such as matrix metalloproteinases, which in turn cause degradation of the extracellular matrix (ECM) in cardiac tissue, weakening the myocardial wall and making it susceptible to global
geometric changes, including thinning and dilation (Buckberg 2005; Dobaczewski et al. 2010; Holmes et al. 2005; Nahrendorf 2011; Spinale 2007). Infarct expansion occurs after the initial problems and is a progressive pathologic process that causes abnormal stress distributions in the borderzone regions surrounding the infarct. The process, additional cell death, and increases in borderzone stress are termed left ventricular (LV) remodeling and can lead to altered contractile properties and heart failure (Epstein et al. 2002; Jackson et al. 2003; Pilla et al. 2005).
Building on understanding of the biological and mechanical processes after MI, many strategies now utilize biomaterials for patient treatment. Several focus on treatment after significant tissue remodeling; for example, with tissue engineering, replacement cardiac tissue is developed in the laboratory and then implanted to replace damaged tissue. Another promising approach involves treating the tissue during the acute phase to try to attenuate the remodeling response before significant damage.
One option is to limit the initial infarct expansion, which has been identified as associated with the LV remodeling that leads to heart failure. Previous strategies to limit infarct expansion involved surgical reconstruction of the dilated LV and physical restraint of the ventricle or infarct region using polymeric meshed materials to prevent dilation (Batista et al. 1997; Klodell et al. 2008; Starling et al. 2007), but these approaches are highly invasive and require open-chest surgery.
Injectable biomaterials are being developed as a minimally invasive alternative to decrease damage to surrounding tissues. Among numerous potentially injectable biomaterials (e.g., microparticles), injectable hydrogels are particularly promising; they are water-swollen networks of polymer chains that have a high degree of tunability and can be formed through numerous crosslinking mechanisms (Ruel-Gariepy and Leroux 2004). They have been shown to mechanically stabilize the myocardial wall and modulate LV remodeling either alone or through the delivery of therapies such as cells and growth factors (Figure 1) (Nelson et al. 2011; Tous et al. 2011).
Many investigators believe that post-MI regional mechanical changes and stresses in the myocardium should be addressed when designing biomaterial-based approaches for cardiac repair (Gupta et al. 1994; Holmes et al. 2005; Nelson et al. 2011). As described by the Law of Laplace (Equation 1), stress (T) is directly proportional to pressure (P) and the radius of curvature (R) and inversely proportional to the myocardial thickness (h). Therefore, the increase in R and decrease in h that occur after MI leads to an increase in T.
Injectable biomaterials can limit infarct expansion by bulking the damaged myocardial wall through mechanical stabilization (Tous et al. 2011). Infarcts naturally stiffen over time as wound healing progresses and collagen is deposited; modifying the tissue properties of the infarct region before the body compensates for the remodeling process can limit infarct expansion and post-MI remodeling (Tous et al. 2011). Injectable hydrogels act as bulking agents by increasing the myocardial wall thickness (h) to decrease LV dilation (as measured by R) and in turn decrease wall stress (T). Theoretical finite element models have confirmed this mechanism of treatment by demonstrating that hydrogels decrease both LV dilation and myofiber stresses (Wall et al. 2006).
Injectable hydrogels can be grouped into either natural or synthetic materials. Natural materials offer advantages such as inherent biological properties, including receptor-binding ligands and susceptibility to proteolytic degradation
FIGURE 1 Injectable hydrogel approaches for the treatment of MI. Hydrogels (shown in the center column) can be used as (A) acellular bulking agents or a vehicle for (B) delivery of cells, (C) therapeutic molecules, or (D) a combination of cells and molecules.
FIGURE 2 Acellular hydrogels as bulking agents for myocardial infarction repair. Injectable hyaluronic acid hydrogel distribution in cardiac tissue explant as shown by (A) magnetic resonance imaging and (B) ex vivo sectioning. Scale bar = 1 cm.
(Karam et al. 2012; Lutolf and Hubbell 2005). For cardiac applications where the goal is to replace or repair the damaged ECM, natural biomaterials more closely mimic features of the native ECM and can also be therapeutic in their degradation products through the recruitment of cells (Sui et al. 2011). Commonly used natural injectable materials for cardiac repair are fibrin, alginate, collagen, Matrigel, chitosan, hyaluronic acid, keratin, and decellularized matrices (Tous et al. 2011). But natural materials have limited tunability in properties.
Synthetic materials have defined material properties such as molecular weight, gelation, hydrophilic/hydrophobic properties, degradation, and mechanics, without batch-to-batch variations (Lutolf and Hubbell 2005). They can also be modified with cell binding sites or adhesive ligands to encourage cell interaction (Davis et al. 2005). Various synthetic materials have been explored for cardiac repair therapy, including poly(N-isopropylacrylamide) (PNIPAm)- and poly(ethylene glycol) (PEG)-based hydrogels (Tous et al. 2011). An example of an injected hydrogel based on hyaluronic acid is shown in Figure 2.
Myocardial infarction results in the loss of over 1 billion cardiomyocytes in the infarct region, and cell delivery is one strategy used for tissue repair (Beltrami et al. 1994). A variety of cell types have been delivered—fetal or neonatal cardiomyocytes, embryonic stem cells (ESCs), skeletal myoblasts, bone marrow–derived stem cells (BSCs), adipose-derived stem cells, and cardiac stem cells (Menasche 2005; Segers and Lee 2008). Each has advantages and disadvantages for use in therapies. For example, ESCs offer the advantage of differentiating into both
cardiomyocyte and vascular lineages, but their efficacy is limited because of their immunogenicity, risk of tumor development, and ethical concerns (Zimmermann 2011). BSCs are an autologous option that can be readily isolated and delivered to cardiac tissue, but their fate is not clear (Le Blanc and Pittenger 2005).
Although both animal models (Segers and Lee 2008) and clinical studies (Menasche 2005) have demonstrated some enhancement in cardiac function with cell delivery, these improvements are often insufficient and transient, which is believed to result from unsatisfactory cell retention, survival, and engraftment (D’Alessandro and Michler 2010). For example, less than 10 percent of BSCs delivered have been detected two hours after injection (Hofmann et al. 2005; Hou et al. 2005), and of those that stay at the injury site approximately 90 percent die within the first week because of physical stress, ischemia (due to microvasculature obstruction), inflammation, and release of cytokines and reactive oxygen species (Robey et al. 2008).
Injectable hydrogels have been explored to enhance cell retention and engraftment for cardiac repair by improving cell attachment, migration, and survival upon delivery (Huang et al. 2005). They permit both high encapsulation efficiency (cells are entrapped during gelation) and precise control over the biophysical and biochemical microenvironment surrounding cells after delivery (Bian et al. 2009).
As with acellular hydrogels, both synthetic and natural polymers have been investigated. Natural materials, such as fibrin, alginate, collagen, and Matrigel, are a popular choice for cell delivery because their inherent biological activity initiates cell-biomaterial interactions (Tous et al. 2011). Synthetic hydrogels can also be used to deliver cells for cardiac repair. With their tunability, synthetic materials can be modified to control both adhesion for cell retention and degradation for desired timing of cell release into the tissue environment. As with the acellular hydrogels, the primary synthetic materials used for cell delivery are PNIPAm and PEG (Tous et al. 2011).
INJECTABLE HYDROGELS FOR MOLECULE DELIVERY
In addition to the approaches described above to alter local mechanical stabilization and serve as a cell delivery vehicle, injectable hydrogels can deliver therapeutic molecules to address post-MI LV remodeling.
Tissue repair is a complex process controlled in part by numerous molecules, such as growth factors and cytokines, and the delivery of such molecules can modulate post-MI endogenous biological responses (Segers and Lee 2010). Delivery of therapeutic molecules alone, by either direct myocardial injection or systemic intravenous circulation, has helped restore cardiac function in some animal models, but the short half-life of the molecules and off-target complications limit clinical application (Urbanek et al. 2005).
Because of these limitations, injectable hydrogels have been used as delivery vehicles to localize molecules and tailor release kinetics through changes in
polymer-molecule interactions, polymer hydrophobicity, and hydrogel degradation (Chen and Mooney 2003; Kretlow et al. 2007). Hydrogels can both sustain local molecule release and prolong molecule bioactivity (Langer and Folkman 1976). For cardiac applications, injectable hydrogels are useful to deliver antiapoptotic molecules (which limit cell death after injury), angiogenic factors to promote vessel formation, or chemoattractants to recruit cells for repair and attenuation of post-MI remodeling (Tous et al. 2011).
As discussed here, a range of injectable hydrogels, cell types, and molecules have been delivered with the intent of attenuating LV remodeling after myocardial infarction. Although many hydrogels have shown positive outcomes in animal models, only one (alginate) has progressed to clinical trials.1 Research is needed to elucidate the effects of hydrogel properties, mode of delivery (e.g., direction injection vs. catheter delivery), and timing of delivery (e.g., acute vs. chronic MI) on LV remodeling. Future studies should further investigate the mechanisms by which hydrogels act on the heart, including both biological and mechanical effects, and focus on clinically relevant parameters to optimize repair outcomes.
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1 Information about the trials is available at http://clinicaltrials.gov/ct2/show/NCT01226563 (“IK-5001 for the Prevention of Remodeling of the Ventricle and Congestive Heart Failure after Acute Myocardial Infarction”) and at http://clinicaltrials.gov/ct2/results?term=Safety+and+Feasibility+of+the+Injectable+BL-1040+Implant&Search=Search.
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