Cell delivery in cardiac regenerative therapy

Cell delivery in cardiac regenerative therapy

Ageing Research Reviews 11 (2012) 32–40 Contents lists available at ScienceDirect Ageing Research Reviews journal homepage: www.elsevier.com/locate/...

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Ageing Research Reviews 11 (2012) 32–40

Contents lists available at ScienceDirect

Ageing Research Reviews journal homepage: www.elsevier.com/locate/arr

Review

Cell delivery in cardiac regenerative therapy Kai Hong Wu a,b,∗ , Zhong Chao Han b,∗∗ , Xu Ming Mo a,∗∗ , Bin Zhou c,∗∗ a

Cardiovascular Center, Nanjing Children’s Hospital, Nanjing Medical University, Nanjing, China National Research Center for Stem Cell Engineering and Technology, State Key Laboratory of Experimental Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China c Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China b

a r t i c l e

i n f o

Article history: Received 10 May 2011 Received in revised form 9 June 2011 Accepted 15 June 2011 Available online 28 June 2011 Keywords: Stem cells Cell therapy Cell delivery Myocardial infarction

a b s t r a c t There is a growing interest in the clinical application of stem cells as a novel therapeutic approach for treatment of myocardial infarction and prevention of subsequent heart failure. Transplanted stem cells improve cardiac functions through multiple mechanisms, which include but are not limited to promoting angiogenesis, replacing dead cardiomyocytes, modulating cardiac remodeling. Most of the results obtained so far are exciting and very promising, spawning an increasing number of clinical trials recently. However, many problems still remain to be resolved such as the best delivery method for transplantation of cells to the injured myocardium and the issue of how to optimize the delivery of targeted cells is of exceptional clinical relevance. In this review, we focus on the different delivery strategies in cardiac regenerative therapy, as well as provide a brief overview of current clinical trials utilizing cell-based therapy in patients with ischemic heart disease. © 2011 Elsevier B.V. All rights reserved.

1. Introduction Acute myocardial infarction (AMI) is the major cause of congestive heart failure and subsequent mortality. Despite the enormous advances in the understanding pathophysiology and treatment of AMI during the past few years, it still remains an unsolved, and in fact, an increasingly serious problem worldwide (Hunt et al., 2009). The treatment options including various interventional and surgical therapeutic methods are limited in preventing ventricular remodeling because of their inability to sufficiently repair or replace the damaged myocardium. Heart transplantation is the ultimate choice for end-stage heart failure, but shortage of donor heart and immunosuppressive therapy challenge the extensive application of this treatment (Dandel et al., 2010). Thus, novel treatment methods are in urgent need to improve cardiac function and prevent heart failure. The discovery of stem cells capable of improving tissue repair through regeneration of vessel and muscle cells holds great promise for new therapeutic approach. Recent attempts based on

∗ Corresponding author at: Cardiovascular Center, Nanjing Children’s Hospital, Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, China. Tel.: +86 25 83117236, fax: +86 25 83304239. ∗∗ Co-corresponding authors. E-mail addresses: [email protected] (K.H. Wu), [email protected] (Z.C. Han), [email protected] (X.M. Mo), [email protected] (B. Zhou). 1568-1637/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.arr.2011.06.002

transplantation of stem cells to infracted areas of the heart have reached an exciting and promising result. However, a number of clinical relevant hurdles remain to be overcome such as the best method of delivering the targeted cells and surely, the issue of how to optimize delivery of targeted cells to the site. We review the different delivery strategies (Fig. 1) in recent cardiac regenerative therapy from a clinical view point, and provide a brief overview of current clinical trials utilizing cell-based therapy in patients with ischemic heart disease. 2. Overview of stem cells for cardiac regenerative therapy 2.1. Bone marrow derived stem cells While the ideal cell type for cardiac regenerative therapy remains to be determined, bone marrow is the major cell source from stem cells have been obtained for clinical trials. This is largely due to its easy accessibility, high ex vivo expansive potential, and no additional requirement of immunosuppressive treatment. Furthermore, their application does not raise the ethical controversies associated with the use of embryonic stem cells (ESCs). Phase I trials have demonstrated the safety and feasibility of unselected bone marrow cells (BMCs) in cardiac regenerative therapy. Currently, total mononuclear cells (NCT00497211, NCT01167751), mesenchymal stem cells (MSCs, NCT00587990), and enriched progenitor cells (NCT01033617, NCT01049867) from bone marrow are being employed in many Phase II and/or III trials.

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Fig. 1. Stem cell delivery strategies in cardiac regenerative therapy. A: Intravenous infusion; B: open chest direct myocardial injection or surgical injection of engineered stem cells; C: catheter based intracoronary artery infusion, intracoronary venous infusion, and catheter-based direct myocardial injection; D: engineered myocardial patch or cell sheet transplantation.

2.2. Other stem cell types Besides the bone marrow, several other sources of stem cells are also tested for their therapeutic potential. To date, circulating progenitor cells (Erbs et al., 2005), skeletal myoblasts (Gavira et al., 2006), and fetal stem cells (Benetti et al., 2010) have been transplanted into the infarcted myocardium of patients with ischemic heart disease. The results of these studies generally suggested improved systolic performance and demonstrated the feasibility and safety of cellular therapy. However, the increased number of arrhythmic events after myoblast transplantation raises serous cautions on myoblast delivery and warrants further investigation (Menasche et al., 2008). Adipose tissue is another ideal source for immediate access to a patient’s own stem cells. Two Phase I trials are now underway to explore the safety, feasibility, and efficacy of freshly isolated adipose derived stem cells (ADSCs) in both AMI (NCT00442806) and chronic myocardial ischemia patients (NCT00426868).

3. Cell delivery strategies 3.1. Intravenous infusion Stem cells can be infused intravenously post-MI due to their ability to home to injured myocardium (Boomsma et al., 2007; Min et al., 2006). This procedure is the simplest and least invasive delivery route with minimal complications and can be easily repeated if necessary. Hare et al. (Hare et al., 2009) reported the first clinical study of intravenous infusion of bone marrow MSCs after MI. Their results demonstrated the safety of intravenous infusion of MSCs during the 12 months follow-up. In addition, their results provided

provocative, preliminary indications that this therapy had clinical efficacy. A Phase II study utilizing the intravenous cell delivery route is currently underway (NCT00877903). However, the efficacy of intravenous delivery of stem cells is largely limited by entrapment of the donor cells in the lungs and other organs and eliminated by the reticulo-endothelial system (Barbash et al., 2003). The pulmonary first-pass effect with intravenous cell delivery must be considered when designing such trials. As ongoing research aims to obtain a critical cell number necessary for the repair of MI, intensive efforts should be forged to minimize the pulmonary first-pass effect: perhaps alteration of adhesion markers, rheological agent use, or optimized with enhanced cell delivery methods. 3.2. Surgical direct myocardial injection Direct myocardial injection of cells has been used, especially in the models of chronic ischemic heart disease during surgical interventions, thereby bypassing the need for mobilization and homing. The first bone marrow stem cell transplantation during coronary artery bypass surgery (CABG) was commenced in October 1999 with favorable results (Hamano et al., 2001). Thereafter, several clinical studies have suggested direct myocardial stem cell delivery be beneficial for patients with chronic ischemic heart failure. Table 1 summarizes the randomized controlled trials of cell-based therapy using direct myocardial injection in clinical settings (Akar et al., 2009; Gavira et al., 2006; Hendrikx et al., 2006; Menasche et al., 2008; Mocini et al., 2006; Patel et al., 2005; Stamm et al., 2007; Viswanathan et al., 2010; Zhao et al., 2008). The advantage of direct myocardial injection is that it provides a direct route of administration of cells to the affected

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Table 1 Randomized controlled trials of cell-based therapy by surgical direct myocardial injection. Study

Cells

Patients

Outcome

Patel et al. (2005) Hendrikx et al. (2006) Gavira et al. (2006) Mocini et al. (2006) Stamm et al. (2007) Zhao et al. (2008) Menasche et al. (2008) Akar et al. (2009) Viswanathan et al. (2010)

CD34+ BMCs BMCs Myoblasts BMCs CD133+ BMCs BMCs Myoblasts BMCs MSCs

10/10 contr 10/10 contr 12/14 contr 18/18 contr 20/20 contr 18/18 contr 33/34/30 contr 25/25 contr 15/15 contr

Improvement in LV function Better recovery of LV function No adverse events Improvement in LV function Improvement in LV function and perfusion Improvement in LV function and perfusion No positive results Improvement in myocardial perfusion Improvement in myocardial perfusion

BMCs: bone marrow cells; LV: left ventricle; MSCs: mesenchymal stem cells.

myocardium and results in higher cell engraftment in the local myocardium. The drawbacks are potential arrhythmia and its invasiveness (Menasche et al., 2008). Furthermore, left ventricular wall thickness in echocardiographic evaluation should be greater than 4 mm in order to avoid the risk of iatrogenic ventricular wall injury (Donndorf and Steinhoff, 2011). Currently, a Phase III trial (NCT00950274) is on the way, aiming to provide evidence for the effects of cardiac stem cell therapy in combination with CABG surgery on cardiac function as well as patients’ clinical outcomes and quality of life. This randomized, placebo controlled, multicentre trial is one of the first clinical trials stringently applying GMP standards for all therapeutic steps.

remains in the positive effects of intracoronary cell delivery in patients with MI (Choi et al., 2007; Wohrle et al., 2010). Moreover, Penicka et al. in a prematurely terminated stem cell trial because of a high rate of complications in the study group raises the issue of safety concerns of intracoronary stem cell delivery (Penicka et al., 2007). Another issue put forward by Kang et al. is the potential risk of increasing neointimal proliferation within a coronary stent after cell transplantation (Kang et al., 2004). Thus, several well-controlled Phase III trials (NCT00279175, NCT00747708, NCT00765453, NCT01187654) and long-term evaluation trial (NCT00962364) are currently underway to confirm the impact of intracoronary delivery of stem cells on the recovery of cardiac function and other clinical concerns.

3.3. Intracoronary artery infusion 3.4. Retrograde coronary venous infusion Intracoronary infusion is the usual method employed in the clinical studies of cardiac regenerative therapy. Cells are delivered over the lumen of an inflated over-the-wire balloon catheter placed in the re-opened coronary artery. The first clinical application of intracoronary infusion of mononuclear BMCs as an adjunct to percutaneous coronary intervention (PCI) was performed by Strauer et al. (Strauer et al., 2002). Their results demonstrated that intracoronary infusion of stem cells was safe and effective. Since then, a number of clinical trials have been conducted. Table 2 summarizes the published randomized controlled trials of cell-based therapy by intracoronary artery infusion in clinical settings (Beitnes et al., 2009; Erbs et al., 2005; Herbots et al., 2009; Kang et al., 2006; Lunde et al., 2006; Meyer et al., 2006; Plewka et al., 2009; Quyyumi et al., 2011; Schachinger et al., 2006; Strauer et al., 2010; Tendera et al., 2009; Traverse et al., 2010). Most of the studies including 3 trials in the NEJM (Assmus et al., 2006; Lunde et al., 2006; Schachinger et al., 2006) showed that intracoronary infusion was a safe delivery strategy and associated with a modest increase in cardiac function, however, controversy

Retrograde coronary venous perfusion with arterial blood or protective solutions is widely used during cardiac surgery procedures to protect against myocardial ischemia and reperfusion injury. Vicario et al. demonstrated the feasibility of cardiac regenerative therapy using retrograde coronary venous delivery method (Vicario et al., 2002). Based on the preclinical studies, the same group conducted a prospective trial in patients with chronic refractory angina. Their results showed that the procedure was technically feasible without significant changes in the tolerance parameters (Vicario et al., 2005). This method can be performed as a “stand-alone” procedure, especially to patients with occluded coronary arteries and poor collaterals who are not suitable for surgical intervention (CABG) or PCI. The retrograde infusion of stem cells via coronary vein, as indicated by Yokoyama et al., is as easy as intracoronary artery delivery. In addition, this method is considered to be more effective than intracoronary infusion because the venous system is fully open, whereas the coronary artery is obstructed in patients with coronary

Table 2 Randomized controlled trials of cell-based therapy by intracoronary artery infusion. Study

Cells

Patients

Outcome

Meyer et al. (2006) Kang et al. (2006) Erbs et al. (2005) Lunde et al. (2006) Herbots et al. (2009) Schachinger et al. (2006) Beitnes et al. (2009) Plewka et al. (2009) Tendera et al. (2009) Strauer et al. (2010) Traverse et al. (2010) Quyyumi et al. (2011)

BMCs PBSCs CPCs BMCs BMCs BMCs BMCs BMCs BMCs BMCs BMCs CD34+ BMCs

30/30 contr STEMI: (25/25 contr)OMI (16/16 contr) 13/13 contr 50/50 contr 33/34 contr 101/103 contr 50/50 contr 40/20 contr 80/40 contr 191/200 contr 30/10 contr 16/15 contr

Improvement in LV function Improvement in LV function in STEMI, not significant in OMI Reduction in infarct size Improvement in exercise time Better recovery of LV function Acceleration of LV contractile recovery Improvement in exercise tolerance Improvement in LV function Longer delay between the symptoms and revascularization Improvement in LV function Favorable effect on LV remodeling Dose dependent LV function improvement

STEMI: ST-segment elevation myocardial infarction; OMI: old myocardial infarction; BMCs: bone marrow cells; CPCs: circulating progenitor cells; PBSCs: peripheral blood stem cells.

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Table 3 Catheter based transendocardial injection of stem cells in clinical settings. Study

Cells

Patients

Outcome

Perin et al. (2004) Fuchs et al. (2006a,b) Briguori et al. (2006) de la Fuente et al. (2007) Tse et al. (2007) van Ramshorst et al. (2009)

BMCs BMCs BMCs BMCs BMCs BMCs

11 trans/9 contr 27 trans 10 trans 10 trans 19/9 contr 50 trans

Improvement in myocardial perfusion Safety and feasibility Safety and feasibility Improvement in LV function Safety and feasibility Improvement in myocardial perfusion

diseases (Yokoyama et al., 2006). However, to establish this method as the preferred route for cell delivery, greater efficacy relative to intracoronary infusion must be demonstrated first. Other considerations include the ability of this method to deliver cells to the right coronary territory, the variability of coronary venous drainage among patients, and the consistent safety of the procedure. Despite the above concerns, retrograde coronary venous infusion does appear to have the potential to become a clinically relevant method for delivery of cells and therapeutic agents to the heart. 3.5. Catheter based direct myocardial injection 3.5.1. Transcoronary venous approach Catheter-based direct myocardial delivery methods enable cells to be delivered to the close proximity of the damaged myocardium. Thompson et al. first evaluated the transcoronary venous system for direct myocardial access and cell delivery and confirmed the feasibility and safety of this approach in animal models (Thompson et al., 2003). The initial experience of catheter-based coronary venous injection on human trial has been reported by Siminiak et al. This study showed that the percutaneous approach into an injured area of myocardium using the coronary venous system is safe and feasible in most patients. Despite the high variability in the coronary venous system, it was possible to reach even remote areas of the cardiac apex (Siminiak et al., 2005, 2006). With the advancement of more delicate well-designed catheters for cardiovascular system, transcoronary venous approach has shown great potential in patients with ischemic heart disease. The limitations of this technique are similar to retrograde delivery mentioned above, including the restrictions associated with the delivery of cells to the right coronary territory, tortuosity of coronary veins and the lack of site-specific targeting. Thus, transcoronary venous approach may be one of the more technically challenging delivery methods and a better understanding of its possible benefits for the treatment of ischemic heart failure merits further investigation. 3.5.2. Transendocardial approach Transendocardial injection can be performed as a stand-alone procedure. This technique allows direct cell delivery into the targeted regions even in patients with occluded artery under the guidance of electromechanical mapping (EMM). EMM technology has been known to be accurate for delineating and identifying scarred and viable myocardium and for differentiating degrees of infarct transmurality (Kornowski et al., 1998; Perin et al., 2002). The first reported transendocardial delivery work with cells was done by Fuchs et al. in ischemic porcine models (Fuchs et al., 2001). Their results demonstrated safety and feasibility, as well as improved myocardial function and increased collateral perfusion in ischemic myocardium. Table 3 summarizes the trials of catheter based transendocardial injection of stem cells in clinical settings (Briguori et al., 2006; de la Fuente et al., 2007; Fuchs et al., 2006b; Perin et al., 2004; Tse et al., 2007; van Ramshorst et al., 2009).

Recently, a group from Hong Kong, China reported their randomized clinical results of transendocardial injection of BMCs in severe coronary artery diseases. Their findings suggest that transendocardial injection of BMCs improve myocardial perfusion reserve and reduce ischemic peri-infarct region in human ischemic myocardium, which subsequently contribute to an improvement in regional cardiac function (Chan et al., 2010). Because of the patchy nature of myocardial involvement in human ischemic heart disease, the ability of EMM to distinguish underlying tissue characteristics is important for cell delivery. In theory, transendocardial injection under the guidance of EMM offers a benefit over surgical or intracoronary delivery approaches because viability of the target site can be determined before each injection.

4. Remaining hurdles of cell delivery methods Transplanted cells must survive, and integrate into the host myocardium in order to provide beneficial effects in ischemic heart disease. An advantage of stem cells is their potential to proliferate and differentiate into multiple lineages that can be optimized so as to promote their survival and functional effects following transplantation. However, to date only limited survival of stem cells has been observed following delivery to the infarcted heart. After intracoronary delivery of autologous BMCs, only 1–2% of transplanted cells could be detected in the myocardium within 75 min after transplantation in humans (Hofmann et al., 2005). Blocklet et al. showed about 5.5% of the administered circulating CD34+ cells remained in the myocardium 1 h after intracoronary infusion and no significant activity was detected in any other areas of the myocardium (Blocklet et al., 2006). In the case of direct myocardial injection, a significant portion of the transplanted cells are also lost because of leakage from the sites of needle puncture, squeezing of cells by the contracting myocardium, and washout through the venous system (Terrovitis et al., 2009). Suzuki et al. found that about 44% of transplanted skeletal myoblasts survived only 10 min in the infracted myocardium, a figure that had steadily decreased to 15% by 24 h and to 8% by 3 days (Suzuki et al., 2004). The significant stem cell death in the ischemic myocardium is largely due to ischemia and ischemicreperfusion injury; moreover, endogenous environmental factors, such as inflammatory response can directly cause the death of grafted cells. Additionally, lack of functional coupling of transplanted cells with myocardial tissue aggravates the cell apoptosis and death. A reliable method for ensuring the survival of the desired numbers of transplanted stem cells would be of great value in developing a transplant strategy utilizing stem cells. Many strategies have been tested to promote engraftment and survival of stem cells following transplantation, including cell preconditioning (Niagara et al., 2007; Tang et al., 2009), microencapsulation (Al Kindi et al., 2010), genetic modification of donor cells (Huang et al., 2010), and myocardial tissue engineering (Fig. 2). The following section will discuss the engineered cell delivery in cardiac regenerative therapy.

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Fig. 2. Factors affecting cell engraftment and strategies to improve cell engraftment and function recovery.

5. Engineered cell delivery

The injectable matrices have been used as vehicles for cell delivery, reducing cell washout from the injection site. Matrices can also provide a scaffold for the cells to attach and prevent apoptosis triggering attributable to anoikis. In addition, embedded in bio-engineered tissues and supported by extracellular matrix, transplanted cells would have a better chance to survive and engraft in the cardiac microenvironment in comparison to direct exposure to injured tissue via injection (Kofidis et al., 2005). In a rat myocardial infarction model, Kutschka et al. (Kutschka et al., 2006) showed that injection of collagen matrices led to a significantly enhanced early survival of cardiomyoblasts and improved cardiac function. Recently, Kraehenbuehl et al. (Kraehenbuehl et al., 2011) transplanted human ESCs along with injectable bioactive hydrogel to the ischemic area of the heart. The gel was found to promote structural organization of native endothelial cells, while some of the delivered ESC-derived vascular cells formed de novo capillaries in the infarct zone. Magnetic resonance imaging (MRI) revealed that the microvascular grafts effectively preserved contractile performance, attenuated left ventricular dilation, and decreased infarct size as compared to control rats treated with PBS injection.

regenerating myocardial tissue to repair the injured heart. Hopefully, the engineered myocardial patch would consist of viable and autologous tissue, which could eventually function like a native biological structure with the potential to grow, to repair, and to remodel, and thus it could significantly improve the function of injured heart (Wu et al., 2007). Fuchs et al. isolated myoblasts from skeletal muscle of fetal lambs, expanded in vitro, and then seeded onto collagen hydrogels. After birth, animals underwent autologous implantation of the engineered constructs onto the myocardium. Their results indicated that skeletal myoblasts engraft in native myocardium up to 30 weeks after postnatal implantation as components of engineered patches (Fuchs et al., 2006a). Siepe et al. provided further evidence that myoblast-seeded polyurethane scaffolds prevent postmyocardial infarction progression toward heart failure in a rat MI model (Siepe et al., 2006). Caspi et al. seeded scaffolds using Matrigel with ESC-derived cardiomyocytes alone, in biculture with endothelial cells or a triculture with ECs and mouse embryonic fibroblasts. Histologic assessment of the in vitro constructs suggested that triculture tissues support the highest cardiomyocyte and EC proliferation rates as well as the greatest formation of vessel-like structures. Confocal line scanning suggested electrical coupling between transplanted cardiomyocytes and neighboring host cardiomyocytes (Caspi et al., 2007). Furthermore, the same group assessed the ability of the 3D engineered myocardial patch to engraft in a rat MI model and showed the presence of transplanted cardiomyocytes in the host myocardium 2 weeks after transplantation. In addition, the preexisting human vessels became functional and contributed to tissue perfusion (Lesman et al., 2010). Although the model appears to hold great potential, the viability of core tissue is low, thus an improved version of the myocardial patch remains to be developed.

5.2. Myocardial patch

5.3. Cell sheet transplantation

The field of myocardial tissue engineering has been working toward the development of biologic, cell-based therapies using knowledge from basic science research with the ultimate aim of

Shimizu et al. first proposed the concept of cell sheet engineering for myocardial tissue reconstruction using temperatureresponsive culture dishes. The cell sheets allow for cell-to-cell

As discussed above, conventional cell delivery strategies are blemished by poor cell engraftment. Moreover, isolated stem cell transplantation is not enough for treatment of large injured areas and congenital heart defects. The advent of tissue engineering provides an enticing alternative for clinical therapeutics. 5.1. Injectable tissue engineering

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connections and maintain the presence of adhesion proteins because enzymatic digestion is not needed. Therefore, cell sheet transplantation may be a promising cell delivery strategy for cardiac regenerative therapy (Shimizu et al., 2002). Miyahara et al. transplanted the monolayered MSCs onto the scarred myocardium 4 weeks after coronary ligation and showed the engrafted sheet gradually grew to form a thick stratum that included newly formed vessels, undifferentiated cells and few cardiomyocytes after transplantation. The MSC sheet also acted through paracrine pathways to trigger angiogenesis. In addition to the isolated stem cell delivery, transplantation of monolayered MSCs may become a new therapeutic strategy for cardiac tissue regeneration (Miyahara et al., 2006). Memon et al. compared the therapeutic effects of myoblast transplantation and myoblast sheet implantation. Echocardiographic results indicated higher improvement of cardiac performance in the myoblast sheet group until 8 weeks after transplantation. Histologic comparison revealed greater cellularity and abundant widespread neocapillaries within the noticeable uniform thickened wall in myoblast sheet group hearts (Memon et al., 2005). Bel et al. developed a composite construct made of a sheet of ADSCs and ESC-derived cardiac progenitors. Two weeks after MI model was created, the composite cell sheet was delivered to the infarcted area of the experimental monkey. The results indicated a robust engraftment of transplanted ADSCs and increased angiogenesis compared with the sham group. The advantages of the composite cell sheets are the absence of any foreign material, the preservation of cell cohesiveness and the possibility to incorporate different cell populations, such as cardiac progenitors and ADSCs (Bel et al., 2010). The results are in line with the studies that have reported successful outcomes after the epicardial delivery of composite cell sheets harboring cardiomyocytes, endothelial cells, and fibroblasts (Sekine et al., 2008; Stevens et al., 2009).

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the intravenous route (Freyman et al., 2006). In an experimental swine model where the direct myocardial, intracoronary, and retrograde coronary venous routes for cell delivery were compared using 111 Indium-labeled peripheral mononuclear cells, direct myocardial cell delivery resulted in the higher engraftment, whereas the retrograde approach was proven feasible and superior to the intracoronary route. However, the majority of delivered cells are not retained in the heart for each delivery modality (Hou et al., 2005). Silva et al. compared intracoronary artery delivery with retrograde coronary venous approach in patients with ischemic heart disease and demonstrated higher cell retention in ischemic myocardium when the intracoronary approach was used (Silva et al., 2009). This study was designed to answer the questions of delivery technique and the consequent distribution of cells. However, its small sample size and open label characteristic prevent the trial from conclusions regarding efficacy of the delivery route. Indeed, the author concluded that injection procedures through both approaches were feasible and safe in patients, indicating further studies were required to verify the initial data. Pioneering work from Siepe et al. demonstrated that myoblast patch transplantation could prevent post-myocardial infarction progression toward heart failure as efficiently as direct intramyocardial injection (Siepe et al., 2006). Hamdi et al. used skeletal myoblasts to perform a head-to-head comparison of direct myocardial injection with epicardial deposition of engineered myocardial patch. The results indicated that delivery of myoblasts in a construct overlaying the infarcted area was associated with better graft functionality compared with direct injection (Hamdi et al., 2009). Engineered cell delivery makes cell therapy more effective in that myocardial patch made of a clinically usable material can be reproducibly deposited onto the surface of the heart during a surgical procedure. However, the field of cardiac tissue engineering is still in its infancy and there is a long way to go before its clinical application.

6. Comparison of delivery techniques The delivery techniques each has their own distinct advantages and limitations as outlined in Table 4 and no singular approach has gained favor as the optimal technique. Intravenous delivery has been asserted to be advantageous because of its ability to handle a large-volume infusion and ease of access. Nonetheless, questions have been raised regarding its ability to transport a critical number of cells to the injured heart. Freyman et al. have compared intravenous with intracoronary or transendocardial MSC delivery in a porcine MI model. They noted increased myocardial engraftment with the intracoronary and transendocardial route, as opposed to Table 4 Advantages and limitations of stem cell delivery methods. Delivery method

Advantages

Limitations

Transvenous

Simple Non-invasive

Surgical delivery

Direct inspection Higher cell engraftment Direct infusion infarct related coronary artery

Microembolism Homing to non-cardiac organs Arrhythmia potential

Intracoronary delivery

Retrograde delivery Transendocardial

Engineering delivery

Applicable to occluded artery Higher cell engraftment Repair of large scar areas

Microembolism No applicable to occluded artery Risk of vein perforation Arrhythmia potential Risk of myocardial perforation Still in experimental phase

7. Conclusions Stem cell therapy for ischemic heart disease has tremendous therapeutic potential. Direct myocardial injection combined with CABG and catheter based intracoronary artery infusion are two mostly used delivery methods in clinical trials. Phase I and/or II trials of both methods have demonstrated the safety and efficacy of stem cells in cardiac regenerative therapy. However, the function improvement is far from satisfactory and controversy still remains in cell dose, timing and which method is best for the patient. Several ongoing Phase III efficacy trials are now being initiated, aiming to address these issues. Retrograde delivery and catheter based direct myocardial injection have shown their own benefits in both experimental and human trials, and will be expected to play an increasingly important role in future cardiac regenerative therapy. Despite major advances made in delivering cells to the ischemic heart, suboptimal cell engraftment and survival remains as one of the major hurdles of current cell delivery methods. In order to achieve actual cardiac regeneration, it is necessary to improve cell engraftment and survival. For these purposes, engineered cell delivery together with cell preconditioning and genetic modification of donor cells are new ways of tuning stem cells to boost their regeneration capacity. Although initial encouraging results have been achieved, most of the experiments are limited to studies performed in small rodents. Therefore, further validation in large animal models is needed. We expect that the increasing knowledge in these novel fields would provide the next generation of tools and bioproducts necessary to overcome the current limitations of cell delivery in cardiac regenerative therapy. We also believe significant

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advances in the efficacy of cell delivery will be achieved in the coming years. Acknowledgments The ongoing clinical trials with only an identifier number were found in the website: http://www.clinicaltrials.gov. This work was supported by the Natural Science Foundation of Jiangsu Province, China (BK2008076), and BaiRen Program Grant of Chinese Academy of Sciences (B.Z.). References Akar, A.R., Durdu, S., Arat, M., Kilickap, M., Kucuk, N.O., Arslan, O., Kuzu, I., Ozyurda, U., 2009. Five-year follow-up after transepicardial implantation of autologous bone marrow mononuclear cells to ungraftable coronary territories for patients with ischaemic cardiomyopathy. Eur. J. Cardiothorac. Surg. 36 (4), 633–643. Al Kindi, A.H., Asenjo, J.F., Ge, Y., Chen, G.Y., Bhathena, J., Chiu, R.C., Prakash, S., Shum-Tim, D., 2010. Microencapsulation to reduce mechanical loss of microspheres: implications in myocardial cell therapy. Eur. J. Cardiothorac. Surg. 39 (2), 241–247. 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