Optimization Criteria of Engineered Cardiac Patches for Myocardial Regeneration Therapy

Current cardiovascular therapies and interventions have failed to solve the progressive loss of cardiomyocytes after myocardial infarction, making cardiac regenerative therapy both necessary and challenging

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Cardiovascular diseases including myocardial infarction remain the leading cause of death worldwide. Due to the intrinsic inability of the myocardium to self-regenerate, patients who survive heart attacks develop end-stage heart failure leading to death. Despite significant advances in cardiovascular treatments, current therapies have failed to solve the fundamental problem, the progressive loss of cardiomyocytes after myocardial infarction. As such, there has been a great interest in cardiac regenerative medicine to repair myocardial infarction.

Myocardial regenerative therapy aims to promote myocardium regeneration by cell delivery into the injured myocardium. In general, there is an agreement that a biodegradable and biocompatible carrier is required for cell implantation in the injured myocardium. Two promising approaches in cardiac tissue engineering are injection of cell-encapsulating hydrogels into the myocardial wall and implantation of cell-impregnated cardiac patches on the ischemic/infarcted myocardium. In particular, cardiac patches can be used not only to deliver cells but also to recapitulate the native cardiac tissue structure [1]; however, to achieve a non-immunogenic and functional construct that mimic native cardiac tissue, it is crucially important to optimize physicochemical, bio-electromechanical, and biological properties of the cardiac patches.

In terms of mechanical strength, the choice between natural or synthetic biopolymers remains a challenge. Natural biomaterials benefit some surface receptors but they generally suffer poor mechanical properties. On the other hand, synthetic biopolymers can be customized for a wide range of properties but they are poor with respect to cellular interactions. Combining natural and synthetic biopolymers decorated with regulatory molecules, composite cardiac patches can offer suitable mechanical support with a more in-vivo like environment [2]. Furthermore, 3D-bioprinting techniques can be used to fabricate porous composite patches with well defined cellular alignment in a hierarchy structure [3].

From biomechanical point of view, the stiffness of a composite cardiac patch should not largely increase the diastolic stiffness while should withstand the stretching-relaxing stress of the beating myocardium. The patch stiffness should be optimized so that it does not physically hinder full contraction of myocardium after implantation whereas allowing cardiomyocytes in the patch to exert their own contractile effect [4]. Furthermore, it is important that the biomaterial degradation rate matches vascularization and regeneration rate of the host myocardium and does not compromise the mechanical support of the patch.

Another challenge to achieve a functional cardiac patch is the lack of efficient electrical coupling between cells to synchronize beating between the patch and the heart. Composite patches can be integrated with nanoscale conductors serving as electrical couplers between cells. Embedding gold nanowires or carbon nanotubes on the pore walls of the patch, growing cardiomyocytes can interact with the nanowires to electrically bridge the pores for signal propagation [5]. Such nanocomposite cardiac patches can be precisely micro-patterned using 3D-bioprinting techniques to obtain cell-laden patches with conducting pores.

Since cardiomyogenesis and angiogenesis are highly regulated processes relying on timely action of a number of growth factors, the ability of the patch to control the release of the growth factors is crucially important. Moreover, because the growth factors have a short lifespan when exposed to the microenvironment, the patch must be able to protect them from denaturation. Chemical immobilization and non-covalent incorporation of growth factors have been used as delivery strategies in cardiac patches; however, there are some shortcomings such as:

  1. Possible loss of growth factor functional groups during chemical immobilization and/or bond-cleaving reactions during release,
  2. Growth factor short lifetime due to the exposure to the microenvironment,
  3. Inability to provide spatiotemporal control of growth factor release.

Recently, rate-programming of polymeric nanoparticles loaded with growth factors have emerged as an advanced release strategy to orchestrate the release of multiple growth factors in cardiac patches [6]. While protecting the loading growth factors, the nanoparticles embedded on the walls of the pores deliver the growth factors to the cells based on predefined release rates corresponding to specific designs of the nanoparticles [7]. Such advanced delivery systems will have important roles in promoting angiogenesis and stem cell-based cardiomyogenesis in cardiac patches [8].

In summary, an ideal cardiac patch must be:

  1. Non-immunogenic, biocompatible and biodegradable, and allow for easy handling and suturing,
  2. Mechanically strong enough to withstand continuous stretching-relaxing motion of the heart without hindering full contraction of ventricle
  3. Provide physical and chemical cues to improve cell adhesion and viability,
  4. Able to be electrically synchronized with the beating myocardium,
  5. Porous with a hierarchical structure to allow for cell proliferation, migration and infiltration,
  6. Provide a proper degradation rate matching the myocardium regeneration while producing no toxic degradation by-product, and
  7. Able to orchestrate the presentation of multiple growth factors to promote vascularization and cardiomyogenesis in the patch.

Moreover, suitable cell source, cell density, rapid vascularization, and implantation time post-infarction are other key factors to be optimized for cardiac regenerative therapy.

References

  1. Sarig U, Machluf M. Engineering cell platforms formyocardial regeneration. Expert. Opin. Biol. Ther. 11, 1055–1077 (2011).
  2. Fleischer S, Miller J, Hurowitz H, Shapira A, Dvir T. Effect of fiber diameter on the assembly of functional 3D cardiac patches. Nanotechnology. 26, 291002 (2015).
  3. Izadifar M, Kelly ME, Chen XB. Thermal impact on the fabrication of 3D cardiac scaffolds for cardiovascular tissue engineering, The 37th International Conference of Engineering in Medicine and Biology, Milan, Italy, 24–30 August 2015.
  4. Camci-Unal G, Annabi N, Dokmeci MR, Liao R, Khademhossein A. Hydrogels for cardiac tissue engineering. NPG Asia Materials 6, e99 (2014).
  5. Shevach M, Fleischer S, Shapira A, Dvir T. Gold nanoparticle-decellularized matrix hybrids for cardiac tissue engineering. Nano. Lett. 14, 5792–5796 (2014).
  6. Izadifar M, Haddadi A, Chen XB, Kelly ME. Rate-programming of nano-particulate delivery systems for smart bioactive scaffolds in tissue engineering. Nanotechnology 26, 012001 (2015).
  7. Izadifar M, Kelly ME, Chen XB, Characterization of double-layered nanoparticles for time-delayed release of growth factors in cardiovascular tissue engineering. The 37th International Conference of Engineering in Medicine and Biology, Milan, Italy, 24–30 August 2015.
  8. Izadifar M, Kelly ME, Haddadi A, Chen XB. Optimization of nanoparticles for cardiovascular tissue engineering. Nanotechnology 26, 235301 (2015).
Go to the profile of Mohammad Izadifar (Ph.D.)

Mohammad Izadifar (Ph.D.)

Cardiovascular Tissue Engineering, University of Toronto

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