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  1. ; ; ; ( , Journal of Biomechanical Engineering)
    Abstract Tissue engineered cardiac patches have great potential as a regenerative therapy for myocardial infarction. Yet, the mutual interaction of cardiac patches with healthy tissue has not been completely understood. Here, we investigated the impact of acellular and cellular patches on a beating two-dimensional (2D) cardiac cell layer, and the effect of the beating of this layer on the cells encapsulated in the patch. We cultured human-induced pluripotent stem cell-derived cardiomyocytes (iCMs) on a coverslip and placed gelatin methacryloyl hydrogel alone or with encapsulated iCMs to create acellular and cellular patches, respectively. When the acellular patch was placed on the cardiac cell layer, the beating characteristics and Ca+2 handling properties reduced, whereas placing the cellular patch restored these characteristics. To better understand the effects of the cyclic contraction and relaxation induced by the beating cardiac cell layer on the patch placed on top of it, a simulation model was developed, and the calculated strain values were in agreement with the values measured experimentally. Moreover, this dynamic culture induced by the beating 2D iCM layer on the iCMs encapsulated in the cellular patch improved their beating velocity and frequency. Additionally, the encapsulated iCMs were observed to be coupled with the underlying beating 2D iCM layer. Overall, this study provides a detailed investigation on the mutual relationship of acellular/cellular patches with the beating 2D iCM layer, understanding of which would be valuable for developing more advanced cardiac patches. 
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    Free, publicly-accessible full text available August 1, 2024
  2. ; ; ; ; ( , Health Science Reports)
    Abstract Background and Aims

    Fibrotic tissue formed after myocardial infarction (MI) can be as detrimental as MI itself. However, current in vitro cardiac fibrosis models fail to recapitulate the complexities of post‐MI tissue. Moreover, although MI and subsequent fibrosis is most prominent in the aged population, the field suffers from inadequate aged tissue models. Herein, an aged human post‐MI tissue model, representing the native microenvironment weeks after initial infarction, is engineered using three‐dimensional bioprinting via creation of individual bioinks to specifically mimic three distinct regions: remote, border, and scar.

     Methods

    The aged post‐MI tissue model is engineered through combination of gelatin methacryloyl, methacrylated hyaluronic acid, aged type I collagen, and photoinitiator at variable concentrations with different cell types, including aged human induced pluripotent stem cell‐derived cardiomyocytes, endothelial cells, cardiac fibroblasts, and cardiac myofibroblasts, by introducing a methodology which utilizes three printheads of the bioprinter to model aged myocardium. Then, using cell‐specific proteins, the cell types that comprised each region are confirmed using immunofluorescence. Next, the beating characteristics are analyzed. Finally, the engineered aged post‐MI tissue model is used as a benchtop platform to assess the therapeutic effects of stem cell‐derived extracellular vesicles on the scar region.

     Results

    As a result, high viability (>74%) was observed in each region of the printed model. Constructs demonstrated functional behavior, exhibiting a beating velocity of 6.7 μm/s and a frequency of 0.3 Hz. Finally, the effectiveness of hiPSC‐EV and MSC‐EV treatment was assessed. While hiPSC‐EV treatment showed no significant changes, MSC‐EV treatment notably increased cardiomyocyte beating velocity, frequency, and confluency, suggesting a regenerative potential.

     Conclusion

    In conclusion, we envision that our approach of modeling post‐MI aged myocardium utilizing three printheads of the bioprinter may be utilized for various applications in aged cardiac microenvironment modeling and testing novel therapeutics.

     
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  3. ; ; ; ; ; ( , Biophysics Reviews)
    In the modern world, myocardial infarction is one of the most common cardiovascular diseases, which are responsible for around 18 million deaths every year or almost 32% of all deaths. Due to the detrimental effects of COVID-19 on the cardiovascular system, this rate is expected to increase in the coming years. Although there has been some progress in myocardial infarction treatment, translating pre-clinical findings to the clinic remains a major challenge. One reason for this is the lack of reliable and human representative healthy and fibrotic cardiac tissue models that can be used to understand the fundamentals of ischemic/reperfusion injury caused by myocardial infarction and to test new drugs and therapeutic strategies. In this review, we first present an overview of the anatomy of the heart and the pathophysiology of myocardial infarction, and then discuss the recent developments on pre-clinical infarct models, focusing mainly on the engineered three-dimensional cardiac ischemic/reperfusion injury and fibrosis models developed using different engineering methods such as organoids, microfluidic devices, and bioprinted constructs. We also present the benefits and limitations of emerging and promising regenerative therapy treatments for myocardial infarction such as cell therapies, extracellular vesicles, and cardiac patches. This review aims to overview recent advances in three-dimensional engineered infarct models and current regenerative therapeutic options, which can be used as a guide for developing new models and treatment strategies. 
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  4. ; ; ; ( , Gels)
    The generation of 3D tissue constructs with multiple cell types and matching mechanical properties remains a challenge in cardiac tissue engineering. Recently, 3D bioprinting has become a powerful tool to achieve these goals. Decellularized extracellular matrix (dECM) is a common scaffold material due to providing a native biochemical environment. Unfortunately, dECM’s low mechanical stability prevents usage for bioprinting applications alone. In this study, we developed bioinks composed of decellularized human heart ECM (dhECM) with either gelatin methacryloyl (GelMA) or GelMA-methacrylated hyaluronic acid (MeHA) hydrogels dual crosslinked with UV light and microbial transglutaminase (mTGase). We characterized the bioinks’ mechanical, rheological, swelling, printability, and biocompatibility properties. Composite GelMA–MeHA–dhECM (GME) hydrogels demonstrated improved mechanical properties by an order of magnitude compared to the GelMA–dhECM (GE) hydrogels. All hydrogels were extrudable and compatible with human induced pluripotent stem cell derived cardiomyocytes (iCMs) and human cardiac fibroblasts (hCFs). Tissue-like beating of the printed constructs with striated sarcomeric alpha-actinin and connexin 43 expression was observed. The order of magnitude difference between the elastic modulus of these hydrogel composites offers applications in in vitro modeling of the myocardial infarct boundary. Here, as a proof of concept, we created an infarct boundary region with control over the mechanical properties along with the cellular and macromolecular content through printing iCMs with GE bioink and hCFs with GME bioink. 
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  5. ; ; ; ; ; ; ; ( , Acta Biomaterialia)
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  6. ; ; ; ; ( , Acta Biomaterialia)
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  7. ; ; ( , Gels)
    Gelatin methacryloyl (GelMA) hydrogels have been used in tissue engineering and regenerative medicine because of their biocompatibility, photopatternability, printability, and tunable mechanical and rheological properties. However, low mechanical strength limits their applications in controlled drug release, non-viral gene therapy, and tissue and disease modeling. In this work, a dual crosslinking method for GelMA is introduced. First, photolithography was used to pattern the gels through the crosslinking of methacrylate incorporated amine groups of GelMA. Second, a microbial transglutaminase (mTGase) solution was introduced in order to enzymatically crosslink the photopatterned gels by initiating a chemical reaction between the glutamine and lysine groups of the GelMA hydrogel. The results showed that dual crosslinking improved the stiffness and rheological properties of the hydrogels without affecting cell viability, when compared to single crosslinking with either ultraviolet (UV) exposure or mTGase treatment. Our results also demonstrate that when treated with mTGase, hydrogels show decreased swelling properties and better preservation of photolithographically patterned shapes. Similar effects were observed when three dimensional (3D) printed and photocrosslinked substrates were treated with mTGase. Such dual crosslinking methods can be used to improve the mechanical properties and pattern fidelity of GelMA gels, as well as dynamic control of the stiffness of tissue engineered constructs. 
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