Intelligent Hydrogels in Myocardial Engineering: History
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Contributor:
Christian Doescher
,
An Thai
,
Ed Cha
,
Pauline V. Cheng
,
Devendra K. Agrawal
,
Finosh G. Thankam

Hydrogels are water-enriched polymeric biomaterials used as scaffolds that mimic the extracellular matrix and are employed in various tissue engineering applications. Interestingly, the hydrogels can be tuned by altering the functional groups of the parent polymeric backbone, resulting in structural rearrangements depending on the physiochemical alterations in the surrounding medium and forming intelligent/smart/stimuli-responsive hydrogels. Myocardial infarction (MI) causes impaired cardiac function due to the loss of cardiomyocytes following an ischemic attack. Intelligent hydrogels offer promising solutions for post-MI cardiac tissue therapy to aid in structural support, contractility, and targeted drug therapy. Hydrogels are porous hydrophilic matrices used for biological scaffolding, and upon the careful alteration of ideal functional groups, the hydrogels respond to the chemistry of the surrounding microenvironment, resulting in intelligent hydrogels.

  • intelligent hydrogels
  • tissue engineering
  • cardiac regeneration

1. Intelligent Hydrogels and Cardiac Tissue Engineering

Intelligent hydrogels alter their physiochemical structure in response to environmental factors such as temperature, pH, hypoxia, ischemia, and the presence of reactive oxygen species (ROS) [1]. Moreover, intelligent hydrogels possess a multitude of applications in regenerative cardiology, from controlled drug release to direct implantation onto the left ventricle (LV) for post-MI cardiac tissue repair [2]. Furthermore, intelligent hydrogels have considerable potential for cardiac tissue repair due to the complexity of post-ischemic environments. For instance, the hydrogel-based delivery of angiogenic factors such as basic fibroblast growth factor (bFGF) and angiopoietin-1 (Ang-1) promotes angiogenesis and significantly improves cardiac healing [3]. Electro-responsive and ion-responsive matrices have been utilized and directly implanted onto post-ischemic left ventricles of animal models as patches to provide conductive and structural support to the area [4]. Generally, the base polymer utilized determines the responsive function of the hydrogel matrix in vivo [5]. At the target site, intelligent hydrogels react appropriately in response to their environment [5]. The major approaches and the commonly used polymers for designing intelligent hydrogels for cardiac applications are displayed in Figure 1 and Figure 2, respectively, and Table 1.
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Figure 1. Intelligent hydrogels responsive to various environmental factors such as temperature, pH, ion, ROS, and electrical stimulation are utilized in post-MI cardiac tissue regeneration therapy.
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Figure 2. Commonly used polymers for fabricating intelligent hydrogels.

2. Temperature-Responsive Hydrogels

Temperature-responsive hydrogels reversibly change conformations in response to alterations in the temperature in the vicinity. Basically, at lower critical solution temperature (LCST), thermo-responsive hydrogels undergo a reversible transition of soluble-liquid to insoluble-gel phase, and at temperatures above the LCST causes a transition from hydrophilic to hydrophobic, leading to the expulsion of water and volumetric reduction [6]. The applications of thermosensitive hydrogels include wound healing, tumor treatment, tissue regeneration via cell delivery, and on-demand drug delivery [7][8][9][10][11][12][13][14]. Temperature-responsive hydrogels based on the amphiphilic polymer, poly(N-isopropylacrylamide) (PNIPAAm), have an LCST of about 37 °C, and the polymerization occurs at temperatures above the LCST, forming a hydrophobic shrunken configuration [6]. This is due to the expulsion of water molecules, decreased hydrogen bonding with the amide group, and increasing intramolecular hydrogen bonding [15]. Owing to the temperature sensitivity, capability to solidify at body temperature, and modifiable biocompatibility, PNIPAAm has been widely used for applications in cardiac tissue engineering [16].
In addition, many other synthetic polymers, such as poly(ethylene glycol) (PEG), have shown promising biomedical applications due to their biocompatible, water-soluble, and non-immunogenic properties [17][18][19][20]. Copolymers such as PLGA-PEG-PLGA (poly-(DL-lactic acid co-glycolic acid) are formulated to increase the gel’s stability and drug-delivering capabilities [20].
Pluronics® F-127 is a synthetic polymer made up of units of ethylene oxide (PEO) and propylene oxide (PPO) with appreciable bio-adhesiveness and biocompatibility [21]. Pluronics® F-127 has shown promising results in toxin neutralization, drug delivery, and cell delivery [22][23][24][25]. The hydrogel transitions from liquid to gel at the critical gelation temperature of 37 °C, at which micelles molecules self-assemble into a hard sphere crystallization structure through interactions of the hydrophilic chains of the copolymers [21][26]. Initial studies regarding Pluronics® demonstrated weak mechanical strength, poor durability, and rapid drug release; however, recent applications of Pluronics® in ocular drug delivery showed the gel’s ability for sustained drug release [27].
In addition, poly(N-vinylcaprolactam) (PVCL) possesses LCST in the physiological range, where the temperature sensitivity is determined by the concentration and molecular weight. Moreover, the excellent physiochemical properties and biocompatibility reflect its biomedical applications [28]. Interestingly, Renata et al. [29] demonstrated the successful tissue engineering potential of PVCL-based hydrogels, which show promising potential for cardiac regeneration. Similarly, poly(N,N-dimethylaminoethyl methacrylate methacrylate) (PDMAEMA)-based hydrogels have been attempted in biomedical systems, especially as controlled drug delivery vehicles owing to their temperature and pH sensitivity [30]. Importantly, the structure–property driven sol–gel transition of PDMAEMA shows promise for these supramolecular sol–gel reversible hydrogels in diverse biomedical applications [31]. Unfortunately, the literature regarding the application of PVCL and PDMAEMA-based hydrogels in cardiac regeneration is limited; however, the superior biophysical properties and responsiveness propose the cardiac applications of these biomaterials, which warrants further research.
Moreover, the thermo-responsive hydrogels have been made into an injectable form for minimally invasive delivery [32][33][34][35]. Importantly, the temperature-responsive hydrogels allow the injection of the components at the liquid phase via a catheter, which solidifies into a gel under physiologic conditions (37 °C). This is specifically useful for localized injections, such as in the setting of an MI, as it provides mechanical support for cardiac muscles [36]. Targeted thermo-responsible hydrogel therapy, along with drug pro-angiogenic mediators, leads to ameliorating cardiac remodeling and accelerating cardiac regeneration.

3. pH-Responsive Hydrogel

pH-sensitive hydrogels are composed of a polymer backbone with a weakly basic or acidic group that ionizes depending on the pH. Generally, the transitions from gel to liquid of pH-sensitive hydrogels are attributed to the ionization of carboxylic acid moieties of the polymeric backbone in basic environments [37][38]. pH-sensitive hydrogels have proven to be promising in pathological niches such as cancer, infection, and ischemia, as demonstrated in disease-controlled drug release, owing to pH changes in pathological environments. Rasool et al. [39] explored pH-sensitive hydrogels for the oral delivery of insulin using vinyltriethoxysilane to crosslink a kappa carrageenan biopolymer with acrylic acid, forming a pH-sensitive hydrogel capable of mucoadhesion in the small intestine. The hydrogel accelerated insulin secretion at pH = 6.8 compared to pH = 1.2 [39]. Interestingly, infarcted myocardial tissue exhibits lower pH (pH of 6–7) than healthy cardiac tissue [17], suggesting the potential opportunities for designing pH-responsive hydrogel systems for the targeted delivery of stem cells, drugs, and regenerative mediators.

4. Ion-Responsive Hydrogels

Ion-sensitive hydrogels demonstrate electrical/conductive properties in response to the ionic environment of the surrounding medium. Mostly, ion-sensitive hydrogels are synthesized in the liquid phase [4]. Ion-responsive gels transition from a liquid to a gel in an electric field and exhibit a potential gradient [40]. The magnitude of this swelling is dependent on the degree of crosslinking of the hydrogel, the density of charge in the hydrogel, the magnitude of applied voltage, and the electric properties of the surrounding medium. While in solution, the hydrogel has fixed charges on the polymer backbone, whereas, under an electric field, the charged ions and counterions interact to form a network and gel.
Polysaccharides such as cellulose, starch, chitosan, and gelatin are ideal candidates due to their ionic nature and biocompatibility [41]. Chitosan is a cationic polysaccharide that adheres to tissue surfaces, such as skin and mucosa, owing to the negative charge densities of the tissues [41]. In addition, ion-sensitive hydrogels are beneficial for drug administration in the gastrointestinal tract, where both the pH and ionic environment impact drug release. Importantly, cationic polysaccharides are ideal for the absorption and delivery of negatively charged drugs and proteins such as insulin [6]. Wei et al. [42] demonstrated a polysaccharide-based hydrogel by the copolymerization of salecan (a polysaccharide from Agrobacterium) and poly(3-(methacryloylamino)propyl-trimethylammonium chloride) (PMAPTAC) (acrylic acid-based polymer used in developing superabsorbent hydrogel matrixes) for drug delivery applications. Interestingly, the hydrogel exhibited excellent positive charge density, apart from the promising physiochemical properties and biocompatibility, facilitating the loading and tunable release kinetics of small molecules and macromolecular drugs depending on the ionic composition of the surrounding medium [42].
Polyacrylic acid (PAA) is another polymer that displays strong electrical conductivity, which is ideal for ionic polymers due to its numerous carboxyl functional groups [4]. Song et al. [4] combined PAA with oxidized alginate and gelatin to form a macro-porous ionic conductive hydrogel (POG) matrix for cardiac applications. POG displayed uniform conductivity and elasticity as well as self-healing abilities following MI in a rat model with promising cardiac applications [4]. However, the cardiac cells (following MI) lose the ability to contract due to tissue remodeling resulting in significant impairment in the conductivity and thus challenging the performance of electroconductive or ion-responsive hydrogels.
Table 1. Overview of the commonly used stimuli-responsive hydrogels.
Type of Smart Hydrogel Molecular Compound Function of Hydrogel Advantages Limitations References
Temperature -Responsive Poly(NIPAAm-co-HEMA-co-MAPLA) Provides mechanical support to left ventricular wall via thickening and decreasing mechanical stress Biodegradable through modification of copolymers, effective site-specific drug delivery, decrease in systemic side effects, evade toxic solvents, high solvent swelling Decreased pH via acidic degradation, lacks biocompatibility [38][43][44]
Temperature-Responsive PLGA-PEG-PLGA Liquid between the temperatures of 2 °C and 15 °C and transitions into a gel at body temperature Biocompatible, water-soluble, and non-immunogenic, gradual drug release for both hydrophobic and hydrophilic drugs Hydrophobic/hydrophilic imbalance could lead to no phase change, narrow gel transition temperature window [17][18][19][20][21][22][23][24][25][26][27][32][33][34][35][36][37][38][39][40]
Temperature -Responsive Pluronics® At concentration of 20 wt%, exist in liquid form <25 °C and transitions to a gel at 37 °C Sustained drug release, good bioadhesiveness, good biocompatibility Poor gel durability, weak mechanical strength [21][22][24][25][26][35]
Temperature- Responsive and pH-responsive p [NIPAAm-co-PAA-co-BA] Exists in liquid form at room temperature with a pH of 7.4 but transitions into a gel at 37 °C with a pH of 6.8. Able to deliver drug motifs such as bFGF Gel dissolution and elimination once target is back at normal physiology pH Increased inflammatory response [45]
Electroconductive PVV-PANI, PAA, PAMB Enhanced neural and glial differentiation with electrical stimulation Drug loading capacity, high bioactivity and cytocompatibility, increased tensile strength and compression Enhanced cell growth leading to cell death, loss of conductivity, inability to control arrhythmia [46][47][48][49]
Ion-responsive Salecan + PMAPTA, POG Binding with negatively charged drugs and stable drug release. Display uniform conductivity and elasticity. Drug loading capacity, biocompatible, injectable liquid form, controlled biodegradation Drug release impacted by pH changes, differing affinities to drug binding, and release dependent on charge strength [4][41][42]
Hypoxia-responsive RAFT, ALOA, PLGA Increase cell retention, greater oxygen partial pressure capabilities Excellent biocompatibility, no substantial increase in inflammation Can trigger ROS burst [50][51][52][53][54][55]
ROS-responsive CSCl-GSH, TEMPO, NO-RIG, HBPAK, PEDGA Antioxidant properties effective in facilitating tissue recovery, ROS scavenging, and reduce inflammation Successfully diminished ROS microenvironment and alleviated hypoxia Limited retention time to optimize ROS-scavenging capability [50][51][52][55][56][57][58]

5. Hypoxia-Responsive Hydrogels

The increased hypoxic insults trigger abnormal ROS production resulting in the loss of membrane integrity, accelerating the apoptosis of CM. Strategies have been attempted to mitigate hypoxia and promote cell survival, including the development of thermosensitive hydrogels with oxygen-releasing microspheres [59]. For instance, Fan et al. [59] synthesized a high-oxygen preservation hydrogel through the free radical polymerization of N-isopropylacrylamide (NIPAAm), (Hydroxyethyl)methacrylate (HEMA), and a macromer acrylate-oligolactide (AOLA) at molar ratios of 86:10:4, respectively. The oxygen-releasing microspheres were fabricated with a core–shell structure made of poly lactic-co-glycolic acid (PLGA) and a polyvinylpyrrolidone–hydrogen peroxide (PVP/H2O2) complex. The PVP/H2O2 complex generates oxygen and water by catalase enzymes loaded within the hydrogel and an increase in water content through the catalase reaction, facilitating the degradation of the hydrogel by the hydrolysis of the oligolactide [46]. Interestingly, a seminal study by Alemdar et al. [60] demonstrated an oxygen-releasing hydrogel based on calcium peroxide and photocrosslinked gelatin methacryloyl (GelMa), which was very effective in extreme hypoxic environments. The hydrogel supported the survival and performance of cardiac cells relieving the metabolic stress suggesting its potential application in cardiac regeneration.
In addition to improving oxygen delivery to the targeted tissue, Shiekh et al. [56] synthesized an oxygen-releasing antioxidant polymeric cryogel scaffold (PUAO-CPO) for sustained oxygen release, simultaneously attenuating ROS and oxidative stress. Furthermore, the attenuation of ROS and the inhibition of oxidative stress-induced cell death were alleviated using an antioxidant polyurethane polymer (PUAO) with superior antioxidant capabilities [56]. Furthermore, the addition of a solid calcium peroxide (CPO) in the hydrogel system promotes a longer duration of oxygen release, maintaining the appropriate redox balance [48][56]. CPO reacts with water to release hydrogen peroxide (H2O2), which in turn undergoes a catalase reaction to release oxygen [56]; however, the oxygen release requires tight control, as the accelerated release of oxygen induces damage to the surviving cells due to hyperoxia. Interestingly, this issue has been addressed using a hydrophobic antioxidant polymeric scaffold, PUAO, which was capable of prolonging and controlling the release of oxygen [56].
Zhao et al. [49] discovered that CPO undergoes a thermal decomposition reaction, initially generating calcium hydroxide and hydrogen peroxide, subsequently producing water and oxygen. However, the calcium hydroxide disturbs the acid–base balance and inhibits cell regeneration, and this challenge was successfully overcome by introducing Vitamin C to neutralize the alkaline environment and prevent the excessive production of ROS [49]. In another approach, CPO was incorporated into a dynamic horseradish peroxidase (HRP) crosslinked hydrogel matrix to ensure a gradual production of H2O2 [54]. According to Thi et al. [54], the HRP/H2O2 catalyzed gelation system results in the inactivation of HRP due to the direct addition of H2O2. Hypoxia, being a critical pathological indicator of myocardial ischemic injury and MI, oxygen-releasing hydrogels in response to hypoxic events are crucial for successful cardiac regenerative approaches, warranting further research.

This entry is adapted from the peer-reviewed paper 10.3390/gels8090576

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