A Preliminary Investigation of UV Crosslinked Alginate- based Hydrogel for Cardiac-tissue Mimicking Material Potential

doi:10.21203/rs.3.rs-4373602/v1

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A Preliminary Investigation of UV Crosslinked Alginate- based Hydrogel for Cardiac-tissue Mimicking Material Potential

https://doi.org/10.21203/rs.3.rs-4373602/v1

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Alginate is a polysaccharide derived from brown seaweed, forming a polymerization network rich in glycosidic bonds. It is recognized for its therapeutic potential, including application in cardiovascular disease treatment. However, due to its unstable molecular structure, it is not widely used for therapeutic purposes. To address this limitation, we have fabricated a UV crosslinked alginate-based hydrogels to create a bioscaffold that is capable of mimicking a cardiac structure. By utilising the low-scalability wavelength and interleaved UV-rays exposure, we can fine-tune alginate hydrogels to simulate cardiac physiological conditions in a controlled setting. We evaluated its mechanical properties using Fourier Transform Infrared Spectroscopy (FTIR), examined the gross morphology, conducted contractile strength tests, and evaluated conductivity. Our results demonstrated a correlation between the wavenumber (cm⁻¹) and the transmittance (%) obtained from FTIR, signifying effective crosslinking. While degradation test showed that UV-rays exposed alginate hydrogel without any supporting buffers may exhibit prolonged stability before degradation (lasting up to 11 weeks). Meanwhile, its contractility capacity appears to emulate that of myocardium with is 0.61 N/cm², while the reference adult myocardium showing 0.50 N/cm². This is further supported by the conductivity test which measured segmentized hydrogels effectively at (3.87, 3.70, 3.20, 3.72, 3.60) mA, below the threshold electrical activity of the heart (5.0 ~ 7.0) mA. In conclusion, our findings demonstrate that the UV crosslinked alginate-based hydrogel has the potential to mimic cardiac tissue structure suggesting a plausible application for tissue replacement and repair.

alginate hydrogels

myocardium

mechanical properties

tensile strength

conductivity

biodegradability

natural polymer

Coronary artery can lead to a range of pathological events, from cellular-scale deterioration culminating to the most severe outcomes, including heart attacks and fatalities [1]. The limited regenerative capacity of adult human myocardium underscores the need for regenerative therapeutic approaches focused on repairing damaged tissues or even contemplating heart replacement [2]. Furthermore, regenerative therapy requires a functional scaffold with the potential to mimic cardiac tissues, in addressing heart pathology effectively. In order to arrive to this realization, several factors have to be considered including scar reduction, the rate of apoptosis (cell death), and improvements in heart function, with an emphasis on the thicker epicardium of the left ventricle. The underlying severity on the profiling of infarcted cardiac tissues has shown the potential benefits of using cardiac patches as the means of advancing this research [3–6].

Natural polymers are widely recognized for their versatility in various applications [7]. For instance, biopolymers sourced from nature have been proven to be effective drug delivery systems. They enhance pharmaceutical effects, preserving tissue conditions and prioritizing healing and restoration [8, 9]. A promising application of biopolymers in the form of alginates (a brown seaweed derivatives) as the main component of cardiac patch is currently of interest. This is inspired by the successful utilization of this FDA approved natural polymer in clinical application, showcasing attributes such as low toxicity, non-antigenicity, excellent biocompatibility, biodegradability, and mild gelation properties. These attributes render it suitable for application in patients with cardiovascular disease (CVD).

Fundamentally, alginates comprise of β-(1–4)-D-mannuronic (M-blocks) and α-l-guluronic acid (G-blocks) connected through robust hydroxyl groups (-OH-), resulting in the formation of a low-density gel with an effective molecular weight distribution across the linkages. The "egg-box" model constructed from alginates can only be effectively utilized with a comprehensive understanding of its characteristics, morphology, structural chemistry, and dynamic behaviour within hydrolysing matrices including scaffolds, decellularized extracellular matrix (ECM) and cardiac patches [11–13]. Previous studies have underscored various undesirable properties of synthetic polymers, presented challenges when contemplated their use as materials for cardiac patches. Foremost among these issues is the significant risk of acute rejection, primarily due to immune responses directed towards the synthetic polymers [14, 15]. However, alginates have exhibited substantial advantages in alleviating immunogenicity. Engineered cardiac patches crafted from alginates have been implanted into living subjects, including rats and cows yielding positive outcomes in enhancing the heart function, especially among subjects afflicted with myocardial infarction (MI) [16].

Additionally, natural polymers harbour reactive sites that can be strategically modified to suit specific applications [17]. Although alginates may initially exhibit limitation in terms of mechanical properties, they offer the advantage of ease in enhancement and adjustment as required [18]. From an understanding of the in-situ process, the crosslinking formation of sodium alginate hydrogels is initiated by the use of ultraviolet (UV) light exposure which is a typical laboratory practice [19]. Compared to other methods in molecular weight distributions suitable for fabricating hydrogels from alginates such as ultrasonic and gamma irradiation in aqueous solutions, UV radiation is relatively superior in terms of chemical degradation rate for dissolving glycosidic bonds between the M and G blocks [20]. The initiation of the polymerization process in photo-crosslinked hydrogels aims to enhance the gel stability with tuneable characteristics to match the composition of the myocardium, considering the mechanical properties, degradation rate, and swelling capacity profiles. This approach of using UV-exposed alginate hydrogels has generated interest in cell encapsulation and tissue regeneration studies. The normal gelation of calcium alginate may degrade over time due to the release of ions from the hydrogel composition. Hence, UV irradiation addresses this issue by reinforcing the alginate structural matrix through the embedded photoinitiated calcium ions (Ca2+) across the M and G blocks. This stabilizing method enables precise spatial control for cell encapsulation within the matrix, extending the efficacy of site regeneration, primarily targeting the infarcted areas [22–24].

Over the last few decades, the development of cardiac patches has gradually gained traction, emerging as a promising foundation for heart disease treatment, potentially revolutionizing the therapeutics approach for patients with heart conditions [3, 25]. The idea of applying cardiac patches to the damaged layers of pericardium and myocardium is designed to bolster the functional behavior of the cardiac muscles and enhance their roles in delivering various biologically reactive factors. This approach demonstrates a potential curative effect in the clinical treatment of MI under controlled bioactive factors and biomaterial conditions [26–29]. Therefore, leveraging the functionality and benefits of alginates is crucial for optimizing the design of cardiac patches for practical applications in tissues engineering. This promising scaffold can be employed to offer mechanical support to failing hearts, ensuring that cardiomyocytes receive adequate nutrients throughout the process whilst maintaining the transmission of the regenerative activity of cardiac stromal cells over time [30].

The utilization of these derived brown algal cellular walls as a cardiac patch has been investigated to enhance the treatment of cardiovascular disease, promoting healing and repair at the injury site [32–34]. An alternative strategy involving adjustment of saline concentration and consistent injection of 2mL of alginates solution (every 2 months as a controlled variable) demonstrate remarkable outcomes, leading to a significant reduction of 53% in scar thickness in the myocardium [35, 36]. Hence, the correlation between calcium concentrations and the rate of gelation serves as a critical determinant during the hydrogel fabrication stage [37]. Additionally, one should assess the systemic blood circulation to comprehensively gauge the impact of the pathological activity of the heart. It heavily relies on the flexibility and tensile properties of the myocardium, estimated at 10-20kPa at the beginning of the diastole reaching a maximum pressure of 200-500kPa towards the end of diastole [38]. Moreover, it is essential to select conductive materials and porous filaments with a 90% penetration rate allowing accessibility for the electrical activity of the heart (in order to generate action potential connectivity) [39–41]. To date, the cardiac patch crafted from calcium alginate hydrogels fulfils the essential biological requirements. These includes facilitating the conveyance of bioactive factors, exhibiting morphological characteristic in melding, maintaining a controlled gelation form through the stabilization of the enhanced cross-linking M and G blocks, and demonstrating versatility to undergo safe disintegration [42, 43].

Alginate cardiac patch is prone to a decline shortly after implantation owing to its low retention ability. Consequently, this prompts the heart to engage in action potential forcibly, influenced by the electrical signals surrounding the alginate hydrogel [44, 45]. Moreover, unbound alginate with weak tensile properties may lead to low blood pressure, given the diminished contractile forces [46]. The present state-of-the-art alginate cardiac patches also lack the capacity to maintain long-term stability, consequently reducing the cellular productivity [47]. In turn, the identified factors for conducting an analytical study to enhance sodium alginate can pave the way for further research. In this study, we utilise UV exposure in enhancing the crosslinked alginate-based hydrogel during fabrication. The experimental demonstration will be a central aspect of this study, showcasing how to formulate a consistent and rigid materials that mimic the mechanical characteristics of myocardium. This preliminary data holds significance for potential clinical application.

2.1. Fabrication of UV exposed calcium alginate hydrogel.

The alginate hydrogel fabrication was prepared based on the following factors including the solute-solvent concentrations, mixing rate, and UV-light exposure rate. The gelation process of the alginate hydrogels was initiated by the solute calcium chloride at concentrations of 1%, 2%, 3%, 4%, and 5% mixed with 100ml distilled water. The mixture was stirred using a magnetic stirrer for 30 minutes at 600rpm and maintained at room temperature [48]. Similarly, the constant variable of sodium alginate (3g) was prepared using the same protocol as the calcium chloride solution and allowed to sit for 30 minutes. Subsequently, the 3% alginate solution was added into the various calcium chloride (CaCl₂) solution (1%, 2%, 3%, 4%, and 5%) in a sterile petri dish and allowed to sit for 10 minutes (The protocol is depicted in Fig. 1). Following this, the cooled calcium alginate mixture was exposed to low-intensity UV light, emitting 465 W/m², for 120 minutes [49]. The most stable gelation for the hydrogel was achieved by the combining 5% CaCl₂ and 3% sodium alginate, allowed to sit for 120 minutes of UV-light exposure. For characterization, the UV-light-exposed alginate hydrogels were cut into dimensions of 2.0 cm x 2.0 cm x 2.0 cm and allowed to dry for 10 minutes before further analysis.

2.2. Characterization of UV exposed calcium alginate hydrogel.

To assess the mechanical properties of the fabricated hydrogel, we performed a series of tests to determine its suitability as a tissue equivalent for myocardium. The tests include Fourier-Transform Infrared Spectroscopy (FTIR), which assesses the efficacy of UV-rays for molecular crosslinking mechanisms, Gross Morphological observational test to identify the degradability of the scaffold, a Contractile Strength test to measure the scaffold’s contractility to match the mechanical profile of the myocardium, and a Conductivity test to confirm the allowable current in entering the action potential state of the heart.

2.2.1. Fourier-Transform Infrared Spectroscopy (FTIR) test analysis.

The fabricated alginate hydrogel was prepared with the requested dimension of 4cm² in area and 0.2cm in thickness. The wavelengths generated from the FTIR reader were analysed using the Origin(Pro), Version Number ("Version 2023"). OriginLab Corporation, Northampton, MA, USA.).

2.2.2. Gross Morphological observation test.

The prepared alginate-gel sample (2.0 cm x 2.0 cm x 2.0 cm) was left in the absence of controlled buffer solutions at room temperature. The degradation rate and the duration for which the gel could sustain its composition matrix over time were recorded. Observational analysis was conducted through weekly observations, accompanied by surface analysis of the hydrogel using sensory evaluation.

2.2.3. Contractile Strength test.

The typical thickness of a healthy adult myocardium ranges from 3 to 6 cm. It plays a crucial role in the contraction and relaxation states of the heart [51]. The gel measured at 9 cm², underwent testing using an Advance Force Gauge 500N, with a focus on the selected area based on the analysis of tensile strength calculation. Both UV-exposed and non-UV-exposed gels were subjected to force in Newtons in a dry state condition, given as:

Equation 1: \(Pascal \left(Pa\right) = Applied force in Newton \left(N\right) / hydrogel area \left(c{m}^{2}\right)\)

Using Eq. 1, the tensile profile for both alginate scaffold (UV and non-UV) can be accurately measured. The obtained value, derived by applying the force over the hydrogel area, represents the contractile potential of the materials (N/cm²).

2.2.4. Conductivity test.

The circuit configuration to measure conductivity is relatively straightforward, involving the use of a multimeter, a prepared hydrogel (measuring 2.0 cm x 2.0 cm x 2.0 cm) and 9V battery as depicted in Fig. 2. The multimeter was set to ammeter mode to analyze the current in milliampere (mA) by taking an average of 5 readings for both samples (UV-exposed and non-UV-exposed)

3.1. UV exposed calcium alginate hydrogel

Within the parameters discussed in this study, the gelation form of the alginate was significantly influenced by the varying solute-solvent concentration and UV exposure (i.e., the duration of exposure). Given the chemical structure of alginate, (which features an abundance of glycosidic bonds with a defined oligosaccharides) it is recommended to maintain a fixed alginate concentration of 3% (3g sodium alginate + 100ml distilled water) while manipulating the interference of calcium ions using different concentration sets (1%, 2%, 3%, 4% and 5%) of calcium chloride solution (Ref. Figure 3) [52, 53]. The study indicates that the maximum concentration of calcium chloride should not surpass 5%, as exceeding this limit may lead to agglomeration of the hydrogel caused by excessive disruption of divalent ionic linkages [36]. Moreover, the resulting gelation of an unstable hydrogel with excess calcium ions also shows a decrease in flexibility, impacting the exertion of tensile strength (where the gel is most likely solidified with a covering ratio of over 90%).

The fabricated hydrogel, consisting of the 3% sodium alginate and 5% calcium chloride, was exposed to a low wavelength of 465 W/m² for 120 minutes. An exposure time of 120 minutes has been determined as the most optimal duration for analyzing the impactful results of calcium alginate gelation, as compared to hydrogels observed for less than 120 minutes or more than 120 minutes. In this study, the hydrogels were systematically exposed for 24 hours to investigate the ionic crosslinking mechanism. In our case, the hydrogels still exhibit the same gelation consistency as the hydrogel exposed to UV light for 120 minutes. This suggested that both calcium concentrations and ionic crosslinking plays an important role in enhancing the mechanical ability as discussed in [54].

3.2. Characterisation of UV exposed calcium alginate.

3.2.1. FTIR test analysis.

The transmittance (%) across the spectral linkage area displays an unstable phase characterized by numerous diffractions, as discussed in the FTIR analysis of sodium alginate in [55]. These diffractions can be ascribed to molecular interference between the M and G blocks, particularly in the extension of the hydroxyl group (⁻OH), observed in the wavenumber range from 3600 cm^− 1 to 3200 cm^− 1 (as depicted in Fig. 4A). We examine the effectiveness of ionic crosslinking photoinitiation in the gelation formation by producing hydrogels exposed to UV (both UV and non-UV).

The efficacy of the hydrogel's cross-linking is validated through the correlation between wavenumber (cm^− 1) and transmittance (%) values [55]. In FTIR spectrum analysis, transmittance (%) serves as a metric indicating the amount of infrared light that penetrates the sample. The FTIR analysis of the standardized sodium alginate [55] indicates that the non-UV exposed hydrogel exhibits a transmittance-wavenumber pattern similar to the one observed in our analysis. The stretching hydroxyl group shifts from the reference by ± 50 cm^− 1. The observed similarity confirms that the hydrogel fabrication is consistent with the FTIR sodium alginate reported in [55] (Ref. Figure 4B).

In contrast, the UV-exposed fabricated calcium hydrogels showed a linear waveform of transmittance, indicating that the incident light penetrates and is absorbed across the divalent ionic crosslinks of Ca²⁺ as a result from the photoinitiation process (as depicted in Fig. 4C). The resulting photochemical process from the UV exposure highlights an increased formation of glycosidic bonds between the M and G blocks of the alginate. This contributed to the stabilization of the chemical composition, ultimately forming a more robust hydrogel [56]. Moreover, the transmittance (%) decreases within the intervals from 3600 cm^− 1 to 3200 cm^− 1 (compared to Figs. 4 and 5) indicating that the hydroxyl group (⁻OH) was stretched slightly due to increased ionic spatial stability across the gel. Therefore, based on the FTIR analysis, the integrated approach of employing UV light exposure has shown an enhancement in the alginate hydrogel gelation matrix. This approach has simultaneously improved its mechanical capabilities, especially as a bioscaffold or in this case, a cardiac patch.

3.2.2. Gross Morphological observation test analysis

In this study, we observed the degradation rate and effectiveness of a control buffer solution to assess the maintenance the hydrogel’s gelation form over time. This allowed us to evaluate the mechanical improvements of alginate, specifically for better cell adhesion and retentions. The buffer solution typically consists of calcium chloride (5%) to facilitate the formation of ionic crosslinks, which are responsible for stabilizing the matrix composition [57]. Here, we adopted a different approach. Both UV-exposed and non-UV-exposed alginate hydrogels were left unsupported to investigate the efficacy of UV photoinitiation and the subsequent degradation rate.

As depicted in Fig. 5, the UV exposed hydrogel exhibited stability for a. duration of 10 weeks (60 days) before undergoing degradation. In comparison, a recent study [58] suggests a shorter lifespan of 28 days, attributed to the loss of shear modulus and the release of divalent ions in the alginate chemical structure. The inability to sustain the crosslinking formation of the alginate glycosidic bonds eventually leads to the degradation of the external shape of the hydrogel, resulting in a loss of formation (by day 54 for the UV-exposed hydrogel and day 37 for the non-UV-exposed hydrogel). Therefore, the fabricated alginate hydrogel demonstrates that UV light exposure can extend the preservation of the gel while providing oxidative stability for clinical purposes. Additionally, this finding rules out the possibility of a calcification process resulting from continuous calcium chloride injection as a buffer over time [59–60].

By day 73, both hydrogels were completely dehydrated and disintegrated upon minimal applied force, indicating that the matrix was no longer a viable option as a scaffold due to the loss of viscoelasticity. The loss of the hydrogel’s capability to stretch progressed more quickly after week 7. This is because the glycosidic bonds were breaking down when they were no longer being supplied with Ca²⁺ ions, resulting in a rigid state of the current gel (solidified).

As shown in Fig. 6, the deformation of the hydrogel was monitored weekly by analyzing the percentage loss in dimensions and shape from the initial fabrication. We observed that changes can be effectively monitored when the hydrogel is not influenced by any buffers (e.g., CaCl₂). This allows us to analyze the survival time of fabricated hydrogel before deteriorating (i.e., losing all its characteristics as a potential gel for mimicking cardiac tissue). By week 8, the 12% deformation loss from the non-UV-exposed and 30% from the UV-exposed alginate hydrogel indicate that both hydrogels have entered a degrading phase, rendering them impractical to provide the desired environment intended to mimic cardiac tissue.

3.2.3. Tensile strength and myoelastic of cardiac tissues behaviour analysis.

A healthy person with a myocardium thickness ranging from 3 to 4 mm (0.3 to 0.4 cm) typically exhibits a contractile potential strength of 5mN/mm² (or 0.5 N/cm²) [61]. To explore the contractility of myocardium, we identify the overall tensile properties of myocardium during both the relaxation and contraction phases (i.e., heartbeat). Tensile strength calculations involved measuring hydrogels prepared at a fixed size of 0.3 cm and 9cm². Applied forces were calculated using the AFG 500N settings in Newton (N), and the derived equations provided the tensile strength potential expressed in Pascal (N/cm²) as illustrated in Fig. 7.

Our findings revealed that the tensile strength of the fabricated UV-exposed alginate hydrogels shows only marginal differences compared to a healthy myocardium. This suggests that UV exposure is capable of stabilizing the gel matrix and additionally enhances the hydrogel, which align perfectly with the intended specifications for cardiac mimicry in physiological studies. Without UV exposure, the hydrogel becomes more than 50% more solidified, with viscoelasticity exceeding the tensile profiles of cardiac tissue. This characteristic makes it suitable for clinical wound dressings due to its high guluronic acid content [62, 63]. (V = value used for subject contractility forces).

From Fig. 8, the extensive ability to contract up to 8mm (maximum) before reaching the breaking point shows the improved flexibility of the alginate after being exposed to the UV rays exceptionally. It is also important to note that by achieving such mechanical adjustments, the alginate was proven to be in match of those actual myocardium tissue during elongation and contraction phase in mimicking the systemic heart physiology.

3.2.4. Conductivity test analysis.

The conductivity of the scaffold regulates cell migration and alignment, leading to a stable cell construct through cellular wall elongation and striation [64–65]. Direct alternating current induction may cause sudden muscular contractions and pose significant risks (e.g., irregular heart rhythm), particularly if the threshold exceeds 6–7 mA (0.06 A to 0.07 A) [64, 65]. We conducted an analytical study on the electrical conductivity of the fabricated alginate hydrogel to ascertain its safety in facilitating electrical activity. In doing so, we can assess the gel’s capability indirectly engaging with potential electrical activity of the heart.

As observed in Fig. 8, the conductivity test showed values below the dangerous electrical threshold. This enables reliable test to be performed directly on the bio-scaffold location using the fabricated hydrogel as a cardiac patch without any negative consequences. The consistent values observed in UV-exposed hydrogels as compared to non-UV-exposed hydrogels, demonstrate that the photochemical process involves photoelectrical accessibility due to the chemical photoinitiated links between the M and G blocks of alginates.

From our findings, the UV-exposed alginate hydrogel of calcium chloride solutions (5%) and sodium alginate (3%) demonstrates the significance of fine-tuning hydrogels to serve as a prospective substitute for myocardial tissue. the potential of the fabricated hydrogel to mimic the native myocardium properties based on outcomes of contractility, degradation rate and conductivity. Although it was shown that the fabricated hydrogel was only suitable from the mechanical standpoint; further research is still needed to assess its biological qualities. The biological factors including the cell retention, cell restoration and cell viability as the loss cardiac functional replacement are necessary parameters to be investigated in the proceeding study. In brief, this research verified that the improved mechanical characteristics of UV-exposed alginate hydrogel has the potential to replicate the physiological characteristics of a native myocardium, making it suitable to be applied as a cardiac patch in cardiovascular therapies.

Conflicts of Interest:

The authors declare no conflict of interest.

Funding:

This publication is prepared as part of the collaborative work under the Fundamental Research Grant Scheme (FRGS) project funded by the Ministry of Higher Education Malaysia (Project no: DP KPT FRGS/1/2021/SKK06/UM/02/4)

Author Contribution

This research study was designed for the final year Biomedical Engineering students in University Malaya as our final project research paper. W.S.W.K.Z was the main supervisor for the initial experiments and gave a direct guidance towards the project completion for the whole 6 months. M.H.I was the final year student who performs every experiment and wrote the dissertation in the whole process. Prior to submission for publication uses, E.I helps with reviewing, technical writing, simplifying figures and tables, for the ease of the article declaration of information. This research article was completed in the degree-level studies and the performance of the fabricated alginate is outstanding enough to confirm its viability in terms of mechanical properties as a replicant materials to the myocardium (cardiac cells). You consideration in reading this article is highly appreciated, stay safe and always be in the pink.

Data Availability

Data Declaration -Data is provided within the manuscript or supplementary information files. All of the data were made publicly available and will be shared publicly for the novelty data and the secondary data reuses. For the citing data, all of the data has been requested and made available for sharing as a secondary data reference instead of reusing the whole data to produce the results. Data Citing -Non-citing supporting figures/tables on the manuscript indicates the novel result. Sodium Alginate Fourier Transform Infrared Spectroscopy indicating the characterization of the polymer that support the findings of this paper is available at https://doi.org/10.1038/s41598-021-96202-0.Tensile Strength of Myocardium Assessment for confirming the fabricated hydrogel tensile potential result may be referred in https://doi.org/10.1038/s44161-021-00007-3. Biodegradation Rate in analyzing the Fabricated Hydrogel potential and the reference study (polymer hydrogel) were compared with https://doi.org/10.1038/s41569-020-0388-6.Allowable Electric Current for Human as a reference material to support the experimental result can be found at https://hypertextbook.com/facts/2000/JackHsu.shtml.

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No competing interests reported.

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A Preliminary Investigation of UV Crosslinked Alginate- based Hydrogel for Cardiac-tissue Mimicking Material Potential

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Abstract

Figures

1. Introduction

2. Materials and Methods

2.1. Fabrication of UV exposed calcium alginate hydrogel.

2.2. Characterization of UV exposed calcium alginate hydrogel.

2.2.1. Fourier-Transform Infrared Spectroscopy (FTIR) test analysis.

2.2.2. Gross Morphological observation test.

2.2.3. Contractile Strength test.

2.2.4. Conductivity test.

3. Results and Discussion

3.1. UV exposed calcium alginate hydrogel

3.2. Characterisation of UV exposed calcium alginate.

3.2.1. FTIR test analysis.

3.2.2. Gross Morphological observation test analysis

3.2.3. Tensile strength and myoelastic of cardiac tissues behaviour analysis.

3.2.4. Conductivity test analysis.

4. Conclusion

Declarations

Conflicts of Interest:

Funding:

Author Contribution

Data Availability

References

Additional Declarations

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