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Nanowired Scaffolds for Cardiac Tissue Engineering

Final Report Summary - NW CARDIAC TISSUES (Nanowired Scaffolds for Cardiac Tissue Engineering)

Ischemic heart disease (IHD) is the most common cause of death in the Western world, accounting for more than 741.000 deaths each year in the European Union with yearly costs in excess of € 45 billion. Myocardial infarction (heart attack; MI) captures a significant segment of IHD population and is associated with sudden death as well significant morbidity and mortality. Currently the only cure for end-stage heart failure is cardiac transplantation. As cardiac donors are scarce, there is an urgent need to develop new strategies for regeneration. One experimental approach to treat defected organs is tissue engineering. Engineered cardiac patches to replace scar tissue after MI are produced by seeding cardiac cells within 3D biomaterials. However, success of this approach can be jeopardized by a lack of supporting microenvironment for the organization of a thick tissue and lack of electrical conductivity within the construct, both leading to impaired electrical signal propagation. Another limitation is the lack of an appropriate cell source. In the current proposal we aim to engineer a 3D microenvironment mimicking the natural ECM of the myocardium and supplement it with gold nanostructures to increase electrical signal propagation between cardiac cell bundles. The effect of this special nanocomposite microenvironment will be tested in vitro to evaluate cardiac tissue assembly and in vivo, to evaluate the cardiac patch therapeutic outcome.

During the project we accomplished our objectives:
1. We were able to recreate several aspects of the cardiac tissue microenvironment including scaffolds with micro and nanofibers, spring-like fiber scaffolds, scaffolds with mechanical properties matching the natural matrix and autologous scaffolds with biochemical content as in the natural matrix. In several papers that were recently published we have successfully recapitulated the native microenvironment and studied the effect of these scaffolds on cardiac tissue assembly.
2. In a facile method, gold NPs were evaporated on the surface of the fibers, creating nanocomposites with a nominal gold thickness of 2, 4, and 14 nm. Compared to pristine scaffolds, cardiac cells seeded on the nano-gold scaffolds assembled into more elongated and aligned tissues. The gold NPs on the fibers were able to maintain the ratio of cardiomyocytes to fibroblasts in the culture, to encourage the growth of cardiomyocytes with significantly higher aspect ratio, and promote massive cardiac sarcomeric actinin expression. Finally, engineering cardiac tissues within gold NP-based scaffolds exhibited significantly higher contraction amplitudes and rates, as compared to scaffolds without gold.
3. We developed an autologous biomaterial scaffold. The mechanical properties, biochemical content and the internal morphology of the material were characterized.
4. The autologous biomaterial scaffolds were decorated with gold nanoparticles. We have characterized the scaffolds’ impedance, conductivity, toxicity and biocompatibility. Cardiac cells were cultivated within the scaffolds and assembled into a functioning tissue. The cells exhibited elongated and aligned morphology and their interaction with each other through the gold nanoparticles were evaluated. We have shown that the engineered cardiac tissue expressed higher levels of connexion 43, the electrical coupling gap junction protein, associated with electrical signal transfer in the heart. Moreover, we have evaluated cardiac tissue function, including contraction force, excitation threshold and velocity of signal transfer. In all the above parameters, tissue growth within the gold nanoparticle scaffolds was superior.
5. In an in vivo experiment we were able to assess the therapeutic effect of gold nanocomposite cardiac patches on the infarcted heart. We have induced myocardial infarctions in rats and transplanted the cardiac patches. In this model we have seen a very nice electrical and structural integration of the cardiac patch with the healthy part of the heart.
6. Based on the material described in section 1, we have developed a more advanced, personalized thermoresponsive hydrogel. The material is liquid in room temperature and solidifies in body temperature.
7. We were able to obtain human cardiac stem/progenitor cells and evaluated their differentiation potential on the different scaffolds. NKX2-5/TnT positive cells were cultured on several types of the developed scaffolds, and cell maturation and assembly into a functioning tissue, generating a strong contraction force was shown.

We envision that the developed technology will help to reduce the morbidity and mortality due to MI.

For more information, diagrams and photos please check the published papers or visit the lab's website: