AK BioLabs - CARDIAC

CARDIAC REGENERATION AND IMPLANTABLE DEVICES

Cardiovascular diseases (CVDs) are leading cause of deaths worldwide. An estimated 17.7 million people died from CVDs in 2015, representing 31% of all global deaths. The current status of heart disease in India is alarming, with projections suggesting that by the year 2020, the burden of cardiovascular diseases in India will surpass that of any other country in the world. About 25% of all deaths in India is attributed to cardiovascular diseases.

Myocardial infarction (MI) can be tackled by implanting cardiac patches which provide mechanical support to the heart. However, most tissue-engineered scaffolds face difficulty in attenuating oxidative stress, maintaining mechanical stability, and regenerating damaged cardiomyocytes. Here, we fabricated elastic cryogels using polyurethane modified with antioxidant gallic acid in its backbone (PUGA) and further coated them with decellularized extracellular matrix (dECM) to improve adhesiveness, biocompatibility and hemocompatibility. The scaffold was functionalized with exosomes (EXO) isolated from adipose-derived stem cells having regenerative potential. PUGA-dECM + EXO was tested in a rat model with induced MI where echocardiography after 8 weeks of implantation showed significant recovery in treatment group. Histological analysis revealed a decrease in fibrosis after application of patch and promotion of angiogenesis with reduced oxidative stress was shown by immunostaining. Expression of cardiac tissue contractile function marker was also observed in treatment groups. Thus, the proposed biomaterial has a promising application to be utilized as a patch for cardiac regeneration. More detailed studies with larger animal species are needed for using these observations for specific applications.
■ Das, A., Nikhil, A., Shiekh, P. A., Yadav, B., Jagavelu, K., & Kumar, A. (2024). Ameliorating impaired cardiac function in myocardial infarction using exosome-loaded gallic-acid-containing polyurethane scaffolds. Bioactive Materials, 33, 324-340.

Tissue engineering in recent years has developed as one of the emerging strategies for the treatment of cardiovascular diseases including myocardial infarction (MI), arrhythmia and atherosclerosis. MI generates a very hostile environment which gives rise to the development of strategies to combat this hostile environment. Reactive oxygen species (ROS) produced at the site of infarction have been seen to modulate the cardiac remodeling process after myocardial infarction. ROS modulate membrane lipids, proteins and DNA of the transplanted cells causing massive cell death and is one of the primary obstacles in treating MI. Elastomeric biomaterials with robust, tunable mechanical properties having antioxidant properties in their backbone structure will be suitable for the development of tissue engineering regenerative scaffold to treat myocardial infarction.
■Shiekh, P.A., Singh, A. and Kumar, A., (2018). Engineering bioinspired antioxidant materials promoting cardiomyocyte functionality and maturation for tissue engineering application. ACS applied materials & interfaces, 10(4), pp.3260-3273.
■Shiekh, P.A., Singh, A. and Kumar, A., (2018). Oxygen-Releasing Antioxidant Cryogel Scaffolds with Sustained Oxygen Delivery for Tissue Engineering Applications. ACS applied materials & interfaces, 10(22), pp.18458-18469.

Live−dead staining of cardiomyocytes on PUAO film

Beating Cardiomyocytes on Antioxidant Polyurethane (PUAO) film

SEM image of C2C12 cells on PUAO film

Oxidative stress generated at the site of assault or injury in diseased conditions is closely associated with the availability of oxygen. So we are also looking to functionalize these scaffolds to release oxygen for longer periods of time. Besides cardiovascular diseases, these scaffolds will find promising application in tissue engineering in general and in particular diseases where oxygen and oxygen stress is a concern such as chronic wound healing, diabetic foot ulcers.

SEM image of PUAO 3D scaffold

Constant oxygen supply is inevitable for cardiac tissue function and survival. Myocardial infarction (MI) leaves heart tissue in a state of oxygen deficiency, causing oxidative stress and irreversible death of cardiomyocytes. Although vital in treating MI, restoration of oxygen supply and attenuation of oxidative stress has not been successfully utilized as a therapeutic strategy. Herein, we developed and evaluated an oxygen releasing antioxidant nanofibrous bi-layered cardiac patch (PUAO-CPO-Collagen) supplemented with adipose derived stem cell exosomes (ADSC-EXO) to promote heart repair. Antioxidant polyurethane was synthesised and calcium peroxide (CPO) was incorporated as an oxygen releasing material. The bilayered cardiac patch consists of an oxygen releasing antioxidant polyurethane, electrospun over a porous collagen scaffold and supplemented with adipose derived stem cell exosomes. The patch demonstrated sustained release of oxygen and exosomes. Under in-vitro conditions, bilayered patch and ADSC exosomes illustrated proliferative, pro-angiogenic and pro-survival effect. In an in-vivo rat MI model, the bi-layered patch demonstrated enhanced cardiac function, reduced scar formation, significantly attenuating adverse cardiac remodelling through improved angiogenesis and decreased oxidative stress. Our study demonstrated an innovative and promising cell free biomaterial approach for delivering oxygen, promoting angiogenesis, and attenuating oxidative stress for enhanced heart regeneration after myocardial infarction.
■ Shiekh, P.A., Mohammed, S.A., Gupta, S., Das, A., Meghwani, H., Maulik, S.K., Banerjee, S.K. and Kumar, A., (2022). Oxygen releasing and antioxidant breathing cardiac patch delivering exosomes promotes heart repair after myocardial infarction. Chemical Engineering Journal, 428, p.132490.

Micro-CT images of bioresorbable stents

SEM image of electrospun stents

Atherosclerosis is one of the underlying causes for the occurrence of MI. The classical approach for its treatment is the use of vascular stents. Most of the stents used in the clinics are redundant and the chances of its failure increase with time. Oxidative stress has been seen to induce smooth muscle cell proliferation over these stents leading to their failure. We are looking to develop antioxidant polymeric biodegradable and bioresorbable stents using advanced technologies of electrospinning and 3D bioprinting.
■Das, A., Shiekh, P.A. and Kumar, A., (2020). A coaxially structured trilayered gallic acid-based antioxidant vascular graft for treating coronary artery disease. European Polymer Journal, p.110203

Tissue plasminogen activators induce enzymatic activation of plasminogen to plasmin that cleaves fibrin strands in blood clots. In the present study, extracellular vesicles such as exosomes from fibrosarcoma cell line HT1080 were utilized as clot-busting agents. These exosomes were being used for clot lysis of whole blood which showed lysis activity comparable to that of the streptokinase (commercial plasmin activator) with no significant difference. These exosomes were able to facilitate the migration of endothelial cells in a scratch wound assay and aided in attenuation of oxidative stress generated on the cells, thereby maintaining cell viability. These exosomes were further encapsulated in a thermo-responsive polymer for better localized delivery that showed no cytotoxic effects, and sustained delivery was achieved. Thus, it proves the potential of this combinatorial approach which can be effectively used for thrombus degradation and healing of endothelium lining in damaged blood vessels.
■ Das, A., Nikhil.A. and Kumar, A., (2021).Preparation of thermo-responsive polymer encapsulated exosomes and its role as a therapeutic agent for blood clot lysis, Colloids and Surfaces B: Biointerfaces. doi:https://doi.org/10.1016/j.colsurfb.2022.112580

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