Madalina Elena Grigore*
Department of Biomaterials and Medical Devices, Faculty of Medical Engineering, University Politehnica of Bucharest, Bucharest 060042, Romania
Received: 26 December, 2016; Accepted: 27 July, 2017; Published: 28 July, 2017
*Corresponding author:
Madalina Elena Grigore, Department of Biomaterials and Medical Devices, Faculty of Medical Engineering, University Politehnica of Bucharest, Bucharest 060042, Romania, E-mail: @
Grigore ME (2017) Hydrogels for Cardiac Tissue Repair and Regeneration. J Cardiovasc Med Cardiol 4(3): 049-057. 10.17352/2455-2976.000049
© 2017 Grigore ME. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Myocardial infarction; Tissue engineering; Hydrogels; Stem cells

The main cause of death in the world continues to be cardiovascular disease, which affects annually over 900,000 people and in the entire word approximately 50% of the people suffering myocardial infarction (MI) die within 5 years. MI causes a number of cardiac pathologies like hypertension, blocked coronary arteries and valvular heart diseases resulting ischemic cardiac injury. In the last years, cardiac tissue engineering has made considerable progress, because this progress have been made towards developing injectable hydrogels for the purpose of cardiac repair and/or regeneration. This study aims to provide an updated survey of the major progress in the flied of injectable cardiac tissue engineering, including biomaterials (natural, synthetic or hybrid hydrogels), their advantages or disadvantages and the main seeding cell sources. Also, this review focuses on the progress made in the field of hydrogels for cardiac tissue repair and/or regeneration for MI over the last years.


The heart is a fibromuscular organ situated in the middle of thoracic mediastinum, the heart wall consists of three layers (myocardium, endocardium and epicardium) and four chambers (the right and left atrium; the right and left ventricle) [1].

One of the main causes of death in the world is represented by cardiovascular disease. It was reported that in USA, the myocardial infarction affects annually over 900,000 people and in the entire word approximately 50% of the people suffering myocardial infarction (MI) die within 5 years [2,3]. The main causes leading to congestive heart failure are represented by adverse remodeling of the left ventricle, loss of non-regenerative cardiomyocytes and myocardial infarction [3].

In the last years, cardiac tissue engineering has made considerable progress. To solve these problems, biomaterials are increasingly investigated as potential scaffolds for cardiac tissue repair and/or regeneration. It was discovered that injectable hydrogels offers several advantages such as: ability to self-assemble in situ, minimally invasive delivery capacity (in comparison with other methods like in vitro engineered tissue or epicardial patch implantation) and capacity to encourage host tissue regeneration [2,4]. Also, these hydrogels possess the ability to mechanically stabilize the myocardial wall and modulate left ventricular remodeling alone or through delivery of therapies, like cells and growth factors and they can deliver cells directly into the infarcted wall (Figure 1) [4,5]. When the hydrogel is ready (gel formation) is injected at the site of interest and besides the mechanically supporting of the injured myocardium, the hydrogel present also a water-swollen matrix to encapsulate therapeutic molecules for targeted molecule delivery to the interest zone. Molecules (with repair and/or regeneration capacities of the damaged tissue) are encapsulated in the hydrogel and released locally over time (the hydrazone bond is then broken and occurs the molecules release from nanoparticles). In several studies it was reported that polymer matrices can be used to sustain the release of encapsulated molecules for up to 100 days and the release profile initially showed a quick release followed by a slower release rate [6-10].


- Myocardial infarction causes a number of cardiac pathologies like hypertension, blocked coronary arteries and valvular heart diseases resulting ischemic cardiac injury [11]. In the last decade, this subject has been deeply studied and it was reported that most important criteria for these types of biomaterials are:Biocompatibility (the used materials has to cause minimal responses in vivo, non-toxicity and has to support cell culture in vitro);

- Biodegradability (the material must degrade within a given time - frame and its degradation products must also be biocompatible);

- Provide adequate mechanical support;

- Must be readily injectable.

Also, a biomaterial must offer adequate mechanical support requires to the specific application. For example, in the case of human myocardium the stiffness varies between 20 kPa (at the end of diastole) to 500 kPa (at the end of systole), in comparison with the case of rat myocardium were the stiffness varies between 0.1 and 140 kPa [12]. Another feature very important in the design of these hydrogels refers to the composition of materials, so there can exist three cases (natural hydrogels, synthetic hydrogels and hybrid hydrogels).

In the first case, the materials are natural (collagen, gelatin, hyaluronic acid, fibrin, alginate, chitosan, etc), but their mechanical properties are week and their physical properties can vary from source to source [13]. In the second case, the materials are synthetic (poly (acrylic acid) derivatives, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, polypeptides, etc) and these materials present the advantages that provide consistent, controllable and precise mechanical properties like stiffness, porosity and elasticity, but present the disadvantages that some of these materials can induce cytotoxicity. Only polyethylene glycol (PEG), polylactide (PLA) and polylactide - glycolic acid (PLGA) have been approved by the FDA for clinical applications [7,14,15]. The last case is represented by natural and synthetic polymer - based hydrogels (ECM - fibrin hydrogels, ECM - polyethylene glycol hydrogels, fibrin - polyethylene glycol hydrogels, alginate – polypirrole, etc) to combine the advantages of both natural and synthetic materials [7,16]. The key steps involved in the preparation of an injectable hydrogel for cardiac tissue repair and/or regeneration are presented in Figure 2.

Natural hydrogels

The injectable hydrogels are superior to other forms of biomaterials beside their properties like cell/drug delivery vehicle or because it provides a platform for elucidating cardiogenic stem cell biology, the most important thing is due to the property that these hydrogels can be injected. Injectable hydrogels act as bulking agents by increasing the myocardial wall thickness, decreasing the left ventricle dilatation and then occurred the reduction of wall stress.

At the moment, polymers like collagen, fibrin, alginate, etc have been evaluated for their ability to form hydrogels in cardiac cell therapy/tissue engineering [5,17]. In table 1 are presented some examples of natural polymers and their principal properties.

Collagen: Collagen is a fibrillar protein which is found at the vertebrate organisms existing in different forms in various tissues such as bones, skin, blood vessels, cornea, tendons, cartilage, etc, and also it is the most abundant protein from the invertebrate organism’s constitution (cilia). Its role in the body is both structurally and functionally, as being involved in complex mechanisms regulating of tissue growth and recovery [3,17,25]. Collagen is wildly used in medical applications due its biocompatibility, biodegradability, weak antigenicity and mostly because can be mixed with therapeutic proteins and drugs [3,17,18]. This protein presents an environment conducive to cell viability, promoting cell attachment and proliferation [3].

Collagen gels are viscoelastic (they are semisolid at rest and become liquid at stress). Ye Z. et al.,, reported a study where after MI it was applied collagen gel to thicken the infarct wall and it was observed that the volume of left ventricle was improved, preventing paradoxical systolic bulging [17].

In another study, collagen injections were administered at 1-week-old rat infarcts and it was observed that infarct thickness, stroke volume and ejection fraction have increased compared to the control (saline injection) [6]. Suuronen E.J. et al.,, reported that by adding CD133+ cells to the collagen matrix and then injecting it to the ischemic hindlimb of rats it was observed an increase of arteriole density. In comparison with the control (cells without collagen matrix) it was reported that the retention of transplanted cells in the target tissue was done for a long time [26]. Also, it was reported that a collagen patch has been successfully used like a delivery vehicle for human mesenchymal stem cells and human embryonic stem cell derived mesenchymal cells for cardiac repair [27].

In one study, Chiu L.L. et al., injected a collagen – chitosan hydrogel with encapsulated thymosin β4 (Tβ4) into the infarct after performing left anterior descending artery ligation in rats. It was reported that was observed a significant reduction of tissue loss of 13 ± 4% in comparison with the control 58 ± 3% tissue loss (for no treatment applied) and 30 ± 8% tissue loss (for only Tβ4 free). Also, it was reported that the controlled release of Tβ4 in the case of MI enhances angiogenesis and presence of cardiomyocytes that are necessary for cardiac repair [28].

Gelatin: Gelatin is formed by decomposing the collagen triple-helix structure into single strand molecules. The preparation of gelatin refers to the post breakage treatment of the collagen structure, gelatin of type A is obtained with acidic treatment while gelatin of type B is obtained with alkaline treatment. Gelatin is a natural polymer with a high potential for application in cardiac repair after MI, due to their high biocompatibility, biodegradation, complete bioresorbability and simplicity [7].

Several studies have confirmed that the gelatin hydrogel microspheres incorporating basic fibroblast growth factor (bFGF) shown to be beneficial in acute MI models. For example, it was reported that the bFGF-loaded gelatin microspheres tested on rat and pig models led to angiogenesis induction and improved left ventricle systolic and diastolic function in the infarcted myocardium [29-31]. In another study, by injecting bFGF - gelatin microspheres it was reported that the presence of bFGF in vivo increased from 3 to 15 days and also increases vessel density in infarcted and border zone myocardium [32]. Also, Nakamura T. et al., administered bFGF - gelatin hydrogel alone, human cardiosphere derived cells (hCDCs) alone or the combination of both (bFGF - gelatin and hCDCs) to the infarcted porcine myocardium and the sustained release of bFGF from the gelatin lasted up to three weeks. It was reported that in the case of bFGF - gelatin hydrogel alone it was observed an improvement of the left ventricular ejection fraction, in the case of hCDCs alone it was reduced the infarct volume, while in the case of bFGF - gelatin and hCDCs combination was reported an improvement of the left ventricular ejection fraction and reductions in infarct size [33].

In another study, the erythropoietin - gelatin hydrogel drug delivery system was used for post-MI treatment rabbit model and it was reported a significant improvement to the remodeling and functions of left ventricular in two months after MI by activating pro-survival signaling, antifibrosis and angiogenesis without causing any side effect [34].

Hyaluronic acid (HA): Hyaluronic acid is a linear glycosaminoglycan polymer that is found in the ECM of mammalian tissues, it’s a natural material and plays a variety of roles in tissue structure and function. HA is formed into hydrogels by covalent cross-linking with hydrazine derivatives. The main disadvantage of this polymer refers to their week mechanical properties, but these properties can be improved by modifying the molecular structure and composition with various functionalization [3,7,35-37].

It was reported that the modified HA hydrogel provided a significantly higher ejection fraction, increased wall thickness and better vessel formation, suggesting that the HA hydrogels can offer promising solution for cardiac tissue repair after MI [38]. On the other hand, Ifkovits J.L. et al., compared two formulations of injectable HA hydrogels to determine the importance of material properties on treatment of myocardial infarction. It was reported that the hydrogel with the higher modulus reduced infarct area and led to better functional outcomes after treatment [39]. Also, Yoon S.J. et al., reported that in the case of MI regeneration are involved two major factors: the molecular weight of HA and the progression of MI (sub-acute or chronic). Rat MI model was prepared by ligating the left anterior descending coronary artery and then different molecular weight HA hydrogels (50 kDa, 130 kDa and 170 kDa) were injected to the infarcted area. After four weeks, functional analysis of the heart and histological analysis was evaluated. It was observed that the most significant regeneration of myocardium as well as functional recovery occurss in the case of 50 kDa HA hydrogel. Also, to observe the disease progression 50 kDa HA hydrogels were injected to sub-acute and chronic MI models. It was reported that the regeneration activity was significantly decreased in the chronic models in comparison with the sub-acute models. These results suggest that composition of hydrogels and the progression of MI are very importans in treating MI [36].

Yoon S.J. et al., prepared HA hydrogel by chemical functionalization with acryl groups and via Michael-type addition it could react with PEG tetra-thiols. After four weeks of treatment, it was observed that the myocardial structure begin to regenerate, prevent fibrous tissue formation and significantly recover heart function in a rat MI model [38].

Fibrin: Fibrin is formed during the wound healing process by combining fibrinogen and thrombin under the catalysis of calcium ions. Fibrin gel is biodegradable, biocompatible, non-toxic, present the ability to sustain cells adhesion and it has been extensively used as a tissue sealant and for the delivery of growth factors specific for tissue repair [18,35,40-42]. The most important characteristic for fibrin as a biomaterial is that was approved by Food and Drug Administration (FDA) [43].

Christman K.L. et al., reported that fibrin glue used as an injectable scaffold with or without skeletalmyoblasts decreases infarct size, improves cardiac function and increases blood flow to ischemic myocardium at rat models. In a subsequent research, they demonstrated that the cell survival was better when transplanted cells were delivered in fibrin glue compared to the cell alone injection [44,45].

In one study, it was used a fibrin patch seeded with swine bone marrow derived MSCs and surgically implanted on the surface of the scarred myocardial area in pigs. It was observed that the cells were found in MI and peri-scar regions 20 days post-transplantation and the exogenous cells were able to differentiate into cells with myocyte like characteristics and to improve the left ventricle function [46]. Also, Ryu J.H. et al., injected mixtures of bone marrow mononuclear cells (BMMNCs) and fibrin gel into the MI and it was observed that in eight months after treatments that implantation of BMMNCs using fibrin matrix resulted in more extensive tissue regeneration in the infarcted myocardium compared to control (BMMNCs implantation without matrix) and in the case of BMMNCs – fibrin neovascularization in infarcted myocardium was more extensive in comparison with the control [47].

Alginate: Alginate is a negatively charged polysaccharide derived from brown algae and composed of β-D-mannuronic acid and α-L-guluronic acid units. Based on the source and processing, its molecular weight ranges between 10 and 1000 kDa and it can be crosslinked in the presence of calcium ions to form a gel structure and has recently been applied in myocardial tissue engineering, as an injectable cell delivery vehicle [48-51]. Due to its biocompatibility has been approved by FDA for human use as wound dressing material [52]. The major disadvantage of this polymer is its release of divalent ions to surrounding, resulting in limited long-term stability, but this mechanism can be counteracted with covalent cross-linking using molecules [53].

In several studies it was demonstrated that the implantation of acellular alginate biomaterial in situ with bioactive molecules into the infarcted heart induced neovascularization and improved left ventricle function [26]. Also, Leor J. et al., used the swine model for intracoronary injection of alginate scaffold and reported an improvement in left ventricle function [54].

In a study, was reported that alginate with calcium chloride solution co-injected in a rat MI model formed gel and attenuates infarct expansion and cardiac dysfunction [55]. In another study it was reported that the myocardial injection of an alginate-chitosan hydrogel prevents adverse cardiac remodeling in a rat MI model attenuating inflammation and reduces cardiac cell apoptosis [56].

Chitosan: Chitosan is a cationic polysaccharide, obtained as partially deacetylated derivative of chitin (1,4 β-linked N-acetyl-D-glucosamine) from the shells of crabs and shrimps. Its final degradation products are biocompatible chitosan oligosaccharides of variable length. The main properties of chitosan are hydrophilicity, biocompatibility and non-toxicity; these properties make it suitable for therapeutic applications such as drug delivery, tissue engineering, wound healing, etc [7,57-60]. In several studies have been reported that chitosan can increase the compression modulus of collagen based injectable hydrogel that reduce heart dilatation upon MI [56]. Wang H. et al., injected brown adipose derived stem cells (BADSCs) with chitosan hydrogel into infarcted rat hearts chitosan hydrogel. It was observed by histological staining that chitosan enhanced the survival of engrafted BADSCs, increased the differentiation rate of BADSCs and preserved heart function [61]. Also, it was reported that Fibroblast Growth Factor-2 (FGF-2) incorporated chitosan hydrogels were immobilized on the surface of ischemic myocardium of rabbit models of chronic MI by UV-irradiation. It was observed by histopathological analyses a significantly larger amount of viable myocardium and it was concluded that these preliminary results indicated the induction of angiogenesis [62]. Lu W - N. et al., performed a study where was used a temperature-responsive chitosan hydrogel injected into the infarcted heart wall of rat infarction models alone or together with mouse embryonic stem cells (ESCs). After four weeks it was reported that both groups showed better results than the control (phosphate buffered saline), but in the case of chitosan-ESCs were the best results [63].

In another study, it was reported the obtaining of a chitosan hydrogel without any external crosslinking agent by inducing the gelation of a viscous chitosan solution with aqueous NaOH or gaseous NH3. It was evaluated the hydrogel capacity for regeneration of MI and the results demonstrated that the chitosan hydrogel was successfully incorporated into the epicardial surface of the heart [64].

Synthetic hydrogels

Besides the numerous advantages of natural polymers, their variability in physical properties, low mechanical properties, risks of pathogen, these issues represent a problem for many applications. A solution to these problems was represented by synthetic polymers. Synthetic polymers are capable of being tailored to meet specific applications because of their properties like porosity, tensile strength, elastic modulus and degradation rate [65-67]. For cardiac tissue engineering applications are used some synthetic polymers including poly (ethylene glycol) (PEG), polylactic acid (PLA), poly (lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polyurethane (PU), etc [14].

Poly (ethylene glycol) (PEG): Poly (ethylene glycol) (PEG) a synthetic polymer of ethylene glycol used in several biomedical applications due to its biocompatible and to its capacity in the controlled release of growth factors [68]. In a study, PEG alone was injected into the myocardium in a rat model of MI and it was reported the improvement of wall thickness [69]. Similar results were seen by Nair L.S. using PEG functionalized with vinyl sulfones (VS) and mixed with dithiothreitol (DTT) resulting non-degradable injectable PEG hydrogels. The hydrogels were injected two minutes post-MI in a rat model and after four weeks it was reported that the wall thickness was significantly improved [37]. Also, Dobner S. et al., used a non-degradable injectable PEG hydrogel to treat MI in a male Wistar rat model. It was observed that the injection of non-degradable PEG was effective in ameliorating pathological remodeling in the immediate post-infarction healing phase, but it were found a macrophage mediated inflammatory reaction, which is undesirable [68].

Wang T. et al., encapsulated bone marrow-derived stem cells (BMSCs) in α-cyclodextrin/MPEG–PCL–MPEG hydrogel. Seven days after MI were injected into the MI simultaneously 100 µl of α-cyclodextrin solution containing BMSCs and 100 µl of MPEG–PCL–MPEG and four weeks after treatment histological analysis showed that the hydrogel was absorbed, cell retention and vessel density in the infarcted tissue were increased and the left ventricle ejection function [70].

Poly(N-isopropylacrylamide) (PNIPAAm): PNIPAAm is a thermosensitive and a non-biodegradable polymer with a thermal transition temperature of 32°C, at room temperature it’s an aqueous solution and at body temperature (37°C) it is forming a hydrogel [71]. This polymer was often used in the cardiac repair due to its ability for rapid gelation post-injection as temperature of the material is raised above its lower critical solution temperature in the myocardium [12, 72]. In a study, a PNIPAAm hydrogel synthesized via free radical polymerization was injected in a chronic rat MI model and it was observed significant improvements in wall thickness, capillary density and percent LV fractional area change [73].

Miyagawa S. et al., cultured neonatal rat cardiomyocytes on PNIPAAm - grafted polystyrene dishes and detached as a square cell sheet at 20°C and then were implanted to rats. After two weeks the rats were divided into three groups: the first group was treated with cardiomyocyte sheet implantation, the second group was treated with fibroblast sheet implantation and the last (the control group) underwent no additional treatment. After eight weeks it was observed that the first group showed the best recovery because the cardiomyocyte sheets became attached to the MI, showed angiogenesis [74].

Polyvinyl alcohol (PVA): PVA is a hydrophilic biocompatible polymer which shows semi-crystallinity and it is obtained by polymerization of vinyl alcohol formed through the partial hydrolysis of vinyl acetate [75]. The PVA hydrogel is developed using chemical or physical cross-linking, but it has been demonstrated that the chemical cross-linking shows some disadvantages and in the last years the chemical cross-linking was replaced with photocrosslinking. In several studies was reported that PVA as a hydrogel presents low adhesion properties, but this disadvantage can be enhanced by mixing it with biological factors [76, 77].

Due to its properties (biocompatibility, strong mechanical properties, elasticity) PVA can be used in various tissue engineering applications, especially cardiac tissue repair [78].

Hybrid and composite hydrogels

In the last years, a number of hybrid and composite hydrogels have been developed for MI applications [7]. A natural material presents better biocompatibility and cell affinity than a synthetic material, but presents low properties like mechanical strength, degradation rate and water content. The combination of two materials (natural-synthetic) in order to obtain hydrogels seems to be a good solution when it comes to capitalizing on the advantages of both [14,79]. Nanocomposite hydrogels are represented by nanoparticles such as polymeric nanoparticles, inorganic nanoparticles, metallic-metal oxide based nanoparticles and carbon-based nanomaterials which can be incorporated in hydrogels [7].

Nikkhah M. developed crosslinkable hydrogels (gold nanorod-incorporated gelatin) with improved electrical and structural properties for cardiac tissue engineering. It was reported that because of these hybrid hydrogels, the cardiomyocytes shown greater cell retention and a high level of viability over the whole duration of culture. Also, it was observed that these hydrogels provide a perfect microenvironment for cardiac cells to grow and integrate to the native heart tissue with superior electrical and structural properties [80]. In another study, it was obtained a hybrid hydrogel formed of a two-component PEG and fibrinogen for cardiac tissue engineering [17]. Mihardja S.S. et al., mixed polypyrrole (a conductive polymer) with alginate and used an ischemia-reperfusion rat myocardial infarction model to observe the effects. The animal model was treated with a local injection of 0.025% polypyrrole in alginate polymer blend into the infarct zone. After five weeks post-treatment it was observed that the presence of hydrogel significantly enhanced infiltration of myofibroblasts into the infarct area compared to control (saline solution) [81]. Pok S. et al., developed a multi-layered scaffold formed by geletin and chitosan and supported by a polycaprolactone (PCL) (a biodegradable polymer). It was observed that the hydrogel have sufficient mechanical strength and can maintain cardiomyocytes viability and the best cell spreading, viability and scaffold integrity resulted from a hydrogel with equal parts of gelatin and chitosan [82].

In several studies it has been reported that the DNA can be efficiently deliver to the infarcted site when is administered intramyocardially with the help of naturally derived methacrylated gelatin hydrogel [83]. Paul A. et al., obtained an injectable nanocomposite hydrogel formed from polyethylenimine, graphene oxide nanosheets and growth factors incorporated into the methacrylated gelatin. For in vivo tests were used a rat model with acute myocardial infarction and the therapeutic hydrogel was injected intramyocardially in the peri-infarct regions. It was reported that the experiment not only confirmed the biocompatibility aspects of the system but also confirms the in vivo efficacy of the hydrogel for cardiac repair [84].

The role of stem cells

The first cells tested for transplantation in patients were skeletal muscle precursor cells, but it has been showed that this type of cells presented a high risk of arrhythmias [79]. Interests have therefore shifted to other stem cells with cardiomyogenic potency such as bone marrow mesenchymal stem cells, embryonic, cardiac stem cells, cardiomyocyte progenitor cells, hematopoietic cells, skeletal myoblast, fetal or umbilical cord blood cells [85-88].

Bone marrow stem cells (BMSCs): Bone marrow contains a population of differentiated cells, but also a small amount of stem/progenitor cells like mesenchymal stem cells (MSCs), hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPCs). Mesenchymal stem cells (MSCs) are multipotent adult stem cells and are used in tissue engineering and cell-based therapies in all fields ranging from orthopedic to cardiovascular medicine. MSCs can be isolated from the bone marrow and subsequently expand in vitro and they are candidates for various therapeutic applications [89,90]. The main advantage of MSCs is that they can be easily isolated and expanded in culture; and after a MI are preferred for use due to their self-renewal and proliferation potential. It was reported that MSCs not only differentiate into cardiomyocytes and vascular cells, but also secrete cytokines and growth factors, which induce neovascularization, anti-apoptosis or anti-inflammation [85]. Also, Kudo M. et al., reported that bone marrow derived mononuclear cells (BMMNCs) that could reduce infarct size and differentiate into cardiomyocytes [91].

Cardiac stem cells (CSCs): Cardiac stem cells are stem cells specific to the heart. They can differentiate into three lineages; cardiomyocytes, endothelial cells and vascular smooth muscle cells both in vitro and in vivo. Once injected intracoronarily or directly into the rat MI, these cells led to myocardium regeneration and improved cardiac function. Also, it was reported the in vivo cardiomyogenic potential in animal MI models. CSCs express three cell-surface markers MDR-1 (multi-drug resistant protein), C-kit (the receptor for stem cell factor) and Sca-1 (Stem cell antigen 1) [92-94].

Conclusions and Perspectives

Hydrogels for cardiac tissue repair and/or regeneration for the treatment of MI continues to be a promising approach. The injectable hydrogels are superior to other forms of biomaterials beside their properties like cell/drug delivery vehicle or because it provides a platform for elucidating cardiogenic stem cell biology, the most important thing is due to the property that these hydrogels can be injected. It has been demonstrated that a variety of materials with suitable properties are being explored to prevent the progression of MI and these materials can be naturals (biocompatible, biodegradable, low toxicity, relatively low cost, bioactive), synthetics (porosity, tensile strength, elastic modulus, degradation rate) or hybrids (which combine the characteristics of both natural and synthetic materials). In future, the researchers will deepen on the survival and integration of the delivered cells in the cardiac environment and their differentiation into the required myogenic phenotypes and, as it was discussed in this review, a topic of interest refers to the replacement of chemical cross-linking (which can often be harmful for the cells) with photocrosslinking or ionic cross-linking [7].

Presently, all the research been done on repair of infarcted heart tissue using injectable hydrogels in small animals like mice and rats and at this time they have not been reported researches on application of hydrogel therapies on large primates and humans.

  1. Figure 1:
    Flow chart describing systematic research and study selection process.

  1. avatar

    Table 1:

    Baseline characteristics of included trials.

  1. Ahmadi A (2014) Application of Collagen Matrices for Enhancing Cardiac Regeneration. Université d'Ottawa/University of Ottawa. Link:
  2. Ungerleider JL, Johnson TD, Rao N, Christman KL (2015) Fabrication and characterization of injectable hydrogels derived from decellularized skeletal and cardiac muscle. Methods 84: 53-59. Link:
  3. Radhakrishnan J, Krishnan UM1, Sethuraman S (2014) Hydrogel based injectable scaffolds for cardiac tissue regeneration. Biotechnol Adv 32: 449-461. Link:
  4. Wang H, Zhou J, Liu Z, Wang C (2010) Injectable cardiac tissue engineering for the treatment of myocardial infarction. J Cell Mol Med 14: 1044-1055. Link:
  5. Christman KL, Lee RJ (2006) Biomaterials for Treating Myocardial Infarctions. J Am Coll Cardiol 48: 907-913. Link:
  6. Tous E, Purcell B, Ifkovits JL, Burdick JA (2011) Injectable acellular hydrogels for cardiac repair. J Cardiovasc Transl Res 4: 528-542. Link:
  7. Hasan A, Khattab A, Islam MA, Hweij KA, Zeitouny J, et al. (2015) Injectable hydrogels for cardiac tissue repair after myocardial infarction. Adv Sci (Weinh) 2. Link:
  8. Fang R, Qiao S, Liu Y, Meng Q, Chen X, Song B, et al. (2015) Sustained co-delivery of BIO and IGF-1 by a novel hybrid hydrogel system to stimulate endogenous cardiac repair in myocardial infarcted rat hearts. Int J Nanomedicine 10: 4691-4703. Link:
  9. Tan H, Marra KG (2010) Injectable, biodegradable hydrogels for tissue engineering applications. Materials 3: 1746-1767. Link:
  10. Tian S, Liu Q, Gnatovskiy L, X Ma P, Wang Z (2015) Heart regeneration with embryonic cardiac progenitor cells and cardiac tissue engineering. J Stem Cell Transplant Biol 1: 104. Link:
  11. dos Santos CCL, Farias IAP, dos Reis Albuquerque AJ, de Freitas e Silva PM, da Costa One GM, et al, (2014) Antimicrobial activity of nano cerium oxide (IV)(CeO2) against Streptococcus mutans. BMC Proc 8: 48. Link:
  12. Reis L (2014) 3 - Injectable biomaterials for cardiac regeneration and repair, in Cardiac Regeneration and Repair. Woodhead Publishing 49-81.
  13. Camci-Unal G, Annabi N, Dokmeci MR, Liao R, Khademhosseini A (2014) Hydrogels for cardiac tissue engineering. NPG Asia Mater 6: e99. Link:
  14. Li Z, Guan J (2011) Hydrogels for cardiac tissue engineering. Polymers 3: 740-761. Link:
  15. Vunjak-Novakovic G, Tandon N, Godier A, Maidhof R, Marsano A, et al. (2009) Challenges in cardiac tissue engineering. Tissue Eng Part B Rev 16: 169-187. Link:
  16. Li RK, Weisel RD (2014) Cardiac Regeneration and Repair: Biomaterials and Tissue Engineering. Elsevier. Link:
  17. Ye Z (2011) Myocardial regeneration: Roles of stem cells and hydrogels. Advanced drug delivery reviews 63: 688-697. Link:
  18. Wu J, Zeng F, Weisel RD, Li RK (2009) Stem cells for cardiac regeneration by cell therapy and myocardial tissue engineering, Adv Biochem Eng Biotechnol 107-128. Link:
  19. Rodríguez-Vázquez M, Vega-Ruiz B, Ramos-Zúñiga R, Saldaña-Koppel DA, Quiñones-Olvera LF (2015) Chitosan and its potential use as a scaffold for tissue engineering in regenerative medicine. BioMed research international 2015. Link:
  20. Lekka M, Laidler P, Ignacak J, Łabedz M, Lekki J, et al. (2001) The effect of chitosan on stiffness and glycolytic activity of human bladder cells. Biochim Biophys Acta 1540: 127-136. Link:
  21. Menaa F, Menaa A, Menaa B (2011) Hyaluronic Acid and Derivatives for Tissue Engineering. Journal of Biotechnology & Biomaterials 2013. Link:
  22. Shen YI, Abaci HE1, Krupsi Y1, Weng LC1, Burdick JA, et al. (2014) Hyaluronic acid hydrogel stiffness and oxygen tension affect cancer cell fate and endothelial sprouting. Biomater Sci 2: 655-665. Link:
  23. Lee KY, Mooney DJ (2012) Alginate: properties and biomedical applications. Progress in polymer science 37: 106-126. Link:
  24. Ikada Y (2011) Tissue engineering: fundamentals and applications. 8: Academic Press. Link:
  25. Trandafir V, Albu MG (2007) Bioproduse pe bază de colagen. Ars Docendi.
  26. Suuronen EJ, Veinot JP, Wong S, Kapila V, Price J, et al. (2006) Tissue-engineered injectable collagen-based matrices for improved cell delivery and vascularization of ischemic tissue using CD133+ progenitors expanded from the peripheral blood. Circulation 114: I-138-I-144. Link:
  27. Hastings CL, Roched ET, Ruiz-Hernandeza E, Schenke-Laylandf K, Walsh CJ, et al. (2015) Drug and cell delivery for cardiac regeneration. Advanced drug delivery reviews 84: 85-106. Link:
  28. Chiu LL, Reis LA, Momen A, Radisic M (2012) Controlled release of thymosin β4 from injected collagen–chitosan hydrogels promotes angiogenesis and prevents tissue loss after myocardial infarction. Regen Med 7: 523-533. Link:
  29. Iwakura A, Fujita M, Kataoka K, Tambara K, Sakakibara Y, et al. (2003) Intramyocardial sustained delivery of basic fibroblast growth factor improves angiogenesis and ventricular function in a rat infarct model. Heart Vessels 18: 93-99. Link:
  30. Sakakibara Y, Tambara K, Sakaguchi G, Lu F, Yamamoto M, et al. (2003) Toward surgical angiogenesis using slow-released basic fibroblast growth factor. Eur J Cardiothorac Surg 24: 105-112. Link:
  31. Liu Y, Sun L, Huan Y, Zhao H, Deng J (2006) Effects of basic fibroblast growth factor microspheres on angiogenesis in ischemic myocardium and cardiac function: analysis with dobutamine cardiovascular magnetic resonance tagging. Eur J Cardiothorac Surg 30: 103-107. Link:
  32. Sakakibara Y, Nishimura K, Tambara K, Yamamoto M, Lu F, et al. (2002) Prevascularization with gelatin microspheres containing basic fibroblast growth factor enhances the benefits of cardiomyocyte transplantation. J Thorac Cardiovasc Surg 124: 50-56. Link:
  33. Nakamura T, Mizuno S, Matsumoto K, Sawa Y, Matsuda H, et al. (2000) Myocardial protection from ischemia/reperfusion injury by endogenous and exogenous HGF. J Clin Invest 106: 1511-1519. Link:
  34. Kobayashi H, Minatoguchi S, Yasuda S, Bao N, Kawamura I, et al. (2008) Post-infarct treatment with an erythropoietin–gelatin hydrogel drug delivery system for cardiac repair. Cardiovasc Res 79: 611-620. Link:
  35. Johnson TD, Christman K (2013) Injectable hydrogel therapies and their delivery strategies for treating myocardial infarction. Expert Opin Drug Deliv 10: 59-72. Link:
  36. Yoon SJ, Hong S, Fang YH, Song M, Son KH, et al. (2014) Differential regeneration of myocardial infarction depending on the progression of disease and the composition of biomimetic hydrogel. J Biosci Bioeng 118: 461-468. Link:
  37. Nair LS (2015) Injectable Hydrogels for Regenerative Engineering. World Scientific. Link:
  38. Yoon SJ, Fang YH, Lim CH, Kim BS, Son HS, et al. (2009) Regeneration of ischemic heart using hyaluronic acid‐based injectable hydrogel. J Biomed Mater Res B Appl Biomater 91: 163-171. Link:
  39. Ifkovits JL, Tous E, Minakawa M, Morita M, Robb JD, et al. (2010) Injectable hydrogel properties influence infarct expansion and extent of postinfarction left ventricular remodeling in an ovine model. Proc Natl Acad Sci U S A 107: 11507-11512. Link:
  40. Shoichet MS (2009) Polymer scaffolds for biomaterials applications. Macromolecules 43: 581-591. Link:
  41. Shaikh FM, Callanan A, Kavanagh EG, Burke PE, Grace PA, et al. (2008) Fibrin: a natural biodegradable scaffold in vascular tissue engineering. Cells Tissues Organs 188: 333-346. Link:
  42. Li Y, Meng H, Liu Y, Lee BP (2015) Fibrin gel as an injectable biodegradable scaffold and cell carrier for tissue engineering. The Scientific World Journal 2015. Link:
  43. Nelson DM, Ma Z, Fujimoto KL, Hashizume R, Wagner WR (2011) Intra-myocardial biomaterial injection therapy in the treatment of heart failure: Materials, outcomes and challenges. Acta Biomater 7: 1-15. Link:
  44. Christman KL, Fok HH, Sievers RE, Fang Q, Lee RJ (2004) Fibrin glue alone and skeletal myoblasts in a fibrin scaffold preserve cardiac function after myocardial infarction. Tissue Eng 10: 403-409. Link:
  45. Christman KL, Vardanian AJ, Fang Q, Sievers RE, Fok HH, et al. (2004) Injectable fibrin scaffold improves cell transplant survival, reduces infarct expansion, and induces neovasculature formation in ischemic myocardium. J Am Coll Cardiol 44: 654-660. Link:
  46. Liu J, Hu Q, Wang Z, Xu C, Wang X, et al. (2004) Autologous stem cell transplantation for myocardial repair. Am J Physiol Heart Circ Physiol 287: H501-H511. Link:
  47. Ryu JH, Kim IK, Cho SW, Cho MC, Hwang KK , (2005) Implantation of bone marrow mononuclear cells using injectable fibrin matrix enhances neovascularization in infarcted myocardium. Biomaterials 26: 319-326. Link:
  48. Madden LR, Mortisenb DJ, Sussmana EM, Duprasc SK, Fugate JA. et al. (2010) Proangiogenic scaffolds as functional templates for cardiac tissue engineering. Proceedings of the National Academy of Sciences 107: 15211-15216.
  49. Van Vlierberghe S, Dubruel P, Schacht E (2011) Biopolymer-based hydrogels as scaffolds for tissue engineering applications: a review. Biomacromolecules 12: 1387-1408. Link:
  50. Landa N, Miller L, Feinberg MS, Holbova R, Shachar M, et al. (2008) Effect of injectable alginate implant on cardiac remodeling and function after recent and old infarcts in rat. Circulation 117: 1388-1396. Link:
  51. Leor J, Aboulafia-Etzion S, Dar A, Shapiro L, Barbash IM, et al. (2002) Bioengineered cardiac grafts a new approach to repair the infarcted myocardium? Circulation 102: Iii-56-Iii-61. Link:
  52. Koh CJ, Atala A (2004) Tissue engineering, stem cells, and cloning: opportunities for regenerative medicine. J Am Soc Nephrol 15: 1113-1125. Link:
  53. Lee KY, Rowley JA, Eiselt P, Moy EMBouhadir KH, et al. (2000) Controlling mechanical and swelling properties of alginate hydrogels independently by cross-linker type and cross-linking density. Macromolecules 33: 4291-4294. Link:
  54. Leor J, Tuvia S, Guetta V, Manczur F, Castel D, et al. (2009) Intracoronary injection of in situ forming alginate hydrogel reverses left ventricular remodeling after myocardial infarction in Swine. J Am Coll Cardiol 54: 1014-1023. Link:
  55. Leor J (2004) A novel injectable alginate scaffold promotes angiogenesis and preserves left ventricular geometry and function after extensive myocardial infarction in rat. in Circulation. Lippincott Williams & Wilkins 530 Walnut St, Philadelphia, Pa 19106-3621 USA.
  56. Deng C, Zhang P, Vulesevic B, Kuraitis D, Li F, et al. (2010) A collagen–chitosan hydrogel for endothelial differentiation and angiogenesis. Tissue Eng Part A 16: 3099-3109. Link:
  57. Kim IY, Seo SJ, Moon HS, Yoo MK, Park IY, et al. (2008) Chitosan and its derivatives for tissue engineering applications. Biotechnol Adv 26: 1-21. Link:
  58. Wang L, Stegemann JP (2010) Thermogelling chitosan and collagen composite hydrogels initiated with β-glycerophosphate for bone tissue engineering. Biomaterials 31: 3976-3985. Link:
  59. Chenite A, Chaput C, Wang D, Combes C, Buschmann MD, et al. (2000) Novel injectable neutral solutions of chitosan form biodegradable gels in situ. Biomaterials 21: 2155-2161. Link:
  60. Yagi K, Michibayashi N, Kurikawa N, Nakashima Y, Mizoguchi T, et al. (1997) Effectiveness of fructose-modified chitosan as a scaffold for hepatocyte attachment. Biol Pharm Bull 20: 1290-1294. Link:
  61. Wang H, Shi J, Wang Y, Yin Y, Wang L, et al. (2014) Promotion of cardiac differentiation of brown adipose derived stem cells by chitosan hydrogel for repair after myocardial infarction. Biomaterials 35: 3986-3998. Link:
  62. Fujita M, Ishihara M, Morimoto Y, Simizu M, Saito Y, et al. (2005) Efficacy of photocrosslinkable chitosan hydrogel containing fibroblast growth factor-2 in a rabbit model of chronic myocardial infarction. J Surg Res 126: 27-33. Link:
  63. Lu WN, Lü SH, Wang HB, Li DX, Duan CM, et al. (2008) Functional improvement of infarcted heart by co-injection of embryonic stem cells with temperature-responsive chitosan hydrogel. Tissue Eng Part A 15: 1437-1447. Link:
  64. Fiamingo A, Montembault A, Boitard S, Naemetalla H, Agbulut O, et al. (2016) Chitosan Hydrogels for the Regeneration of Infarcted Myocardium: Preparation, Physicochemical Characterization, and Biological Evaluation. Biomacromolecules 17: 1662-1672. Link:
  65. Lutolf M, Hubbell J (2005) Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nature biotechnology 23: 47-55. Link:
  66. Li Y, Rodrigues J, Tomás H (2012) Injectable and biodegradable hydrogels: gelation, biodegradation and biomedical applications. Chem Soc Rev 41: 2193-2221. Link:
  67. Singelyn JM, Christman KL (2010) Injectable materials for the treatment of myocardial infarction and heart failure: the promise of decellularized matrices. J Cardiovasc Transl Res 3: 478-486. Link:
  68. Dobner S, Bezuidenhout D, Govender P, Zilla P, Davies N (2009) A synthetic non-degradable polyethylene glycol hydrogel retards adverse post-infarct left ventricular remodeling. J Card Fail 15: 629-636. Link:
  69. Gaetani RJ Ungerleider, Christman KL (2016) Chapter 25 - Acellular Injectable Biomaterials for Treating Cardiovascular Disease A2 - Perin, Emerson C, in Stem Cell and Gene Therapy for Cardiovascular Disease, LW Miller, DA Taylor, J.T. Willerson, Editors. 2016, Academic Press: Boston. 309-325.
  70. Wang T, Jiang XJ, Tang QZ, Li XY, Lin T, et al. (2009) Bone marrow stem cells implantation with α-cyclodextrin/MPEG–PCL–MPEG hydrogel improves cardiac function after myocardial infarction. Acta Biomater 5: 2939-2944. Link:
  71. Klouda L, Mikos AG (2008) Thermoresponsive hydrogels in biomedical applications. Eur J Pharm Biopharm 68: 34-45. Link:
  72. Cohen S, Leor J (2004) Rebuilding broken hearts. Scientific American 291: 44-51. Link:
  73. Fujimoto KL, Ma Z, Nelson DM, Hashizume R, Guan J, et al. (2009) Synthesis, characterization and therapeutic efficacy of a biodegradable, thermoresponsive hydrogel designed for application in chronic infarcted myocardium. Biomaterials 30: 4357-4368. Link:
  74. Miyagawa S, Sawa Y, Sakakida S, Taketani S, Kondoh H, et al. (2005) Tissue cardiomyoplasty using bioengineered contractile cardiomyocyte sheets to repair damaged myocardium: their integration with recipient myocardium. Transplantation 80: 1586-1595. Link:
  75. Seif-Naraghi SB, Horn D, Schup-Magoffin PJ, Christman KL (2012) Injectable extracellular matrix derived hydrogel provides a platform for enhanced retention and delivery of a heparin-binding growth factor. Acta biomaterialia 8: 3695-3703. Link:
  76. Slaughter BV, Khurshid SS, Fisher OZ, Khademhosseini A, Peppas NA (2009) Hydrogels in regenerative medicine. Adv Mater 21: 3307-3329. Link:
  77. Lee KY, Mooney DJ (2001) Hydrogels for tissue engineering. Chem Rev 101: 1869-1879. Link:
  78. Millon LE, Mohammadi H, Wan WK (2006) Anisotropic polyvinyl alcohol hydrogel for cardiovascular applications. J Biomed Mater Res B Appl Biomater 79: 305-311. Link:
  79. Janani A, Skylab RS (2014) Injectable Hydrogel for Cardiac tissue Engineering. International Journal of ChemTech Research 6: 2233-2236. Link:
  80. Nikkhah M (2015) Gold nanorod-incorporated Gelatin-based Hybrid Hydrogels for Cardiac Tissue Engineering. Link:
  81. Mihardja SS, Sievers RE, Lee RJ (2008) The effect of polypyrrole on arteriogenesis in an acute rat infarct model. Biomaterials 29: 4205-4210. Link:
  82. Pok S, Myers JD, Madihally SV, Jacot JG (2013) A multilayered scaffold of a chitosan and gelatin hydrogel supported by a PCL core for cardiac tissue engineering. Acta biomaterialia 9: 5630-5642. Link:
  83. Paul A (2015) Nanocomposite hydrogels: an emerging biomimetic platform for myocardial therapy and tissue engineering. Nanomedicine 10: 1371-1374. Link:
  84. Paul A, Hasan A, Kindi HA, Gaharwar AK, Rao VT, et al. (2014) Injectable graphene oxide/hydrogel-based angiogenic gene delivery system for vasculogenesis and cardiac repair. ACS nano 8: 8050-8062. Link:
  85. rishna KA (2011) Myocardial infarction and stem cells. Journal of Pharmacy and Bioallied Sciences 3: 182-188. Link:
  86. Smits AM, van Vliet P, Hassink RJ, Goumans MJ, Doevendans PA (2005) The role of stem cells in cardiac regeneration. J Cell Mol Med 9: 25-36. Link:
  87. Gersh BJ, Simari RD, Behfar A, Terzic CM, Terzic A (2009) Cardiac cell repair therapy: a clinical perspective. Mayo Clin Proc 84: 876-892. Link:
  88. Hou J, Wang L, Jiang J, Zhou C, Guo T, et al. (2013) Cardiac stem cells and their roles in myocardial infarction. Stem Cell Rev 9: 326-338. Link:
  89. Bara JJ, Richards RG, Alini M, Stoddart MJ (2014) Concise Review: Bone Marrow‐Derived Mesenchymal Stem Cells Change Phenotype Following In Vitro Culture: Implications for Basic Research and the Clinic. Stem cells 32: 1713-1723. Link:
  90. Murry CE, Field LJ, Menasché P (2005) Cell-based cardiac repair reflections at the 10-year point. Circulation 112: 3174-3183. Link:
  91. Kudo M, Wang Y, Wani MA, Xu M, Ayub A, et al. (2003) Implantation of bone marrow stem cells reduces the infarction and fibrosis in ischemic mouse heart. J Mol Cell Cardiol 35: 1113-1119. Link:
  92. Hierlihy AM, Seale P, Lobe CG, Rudnicki MA, Megeney LA (2002) The post‐natal heart contains a myocardial stem cell population. FEBS lett 530: 239-243. Link:
  93. Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, et al. (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114: 763-776. Link:
  94. Bollini S, Smart N, Riley PR (2011) Resident cardiac progenitor cells: at the heart of regeneration. J Mol Cell Cardiol 50: 296-303. Link:

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