Toward Regeneration of the Heart: Bioengineering Strategies for Immunomodulation

Abstract

Myocardial Infarction (MI) is the most common cardiovascular disease. An average-sized MI causes the loss of up to 1 billion cardiomyocytes and the adult heart lacks the capacity to replace them. Although post-MI treatment has dramatically improved survival rates over the last few decades, more than 20% of patients affected by MI will subsequently develop heart failure (HF), an incurable condition where the contracting myocardium is transformed into an akinetic, fibrotic scar, unable to meet the body's need for blood supply. Excessive inflammation and persistent immune auto-reactivity have been suggested to contribute to post-MI tissue damage and exacerbate HF development. Two newly emerging fields of biomedical research, immunomodulatory therapies and cardiac bioengineering, provide potential options to target the causative mechanisms underlying HF development. Combining these two fields to develop biomaterials for delivery of immunomodulatory bioactive molecules holds great promise for HF therapy. Specifically, minimally invasive delivery of injectable hydrogels, loaded with bioactive factors with angiogenic, proliferative, anti-apoptotic and immunomodulatory functions, is a promising route for influencing the cascade of immune events post-MI, preventing adverse left ventricular remodeling, and offering protection from early inflammation to fibrosis. Here we provide an updated overview on the main injectable hydrogel systems and bioactive factors that have been tested in animal models with promising results and discuss the challenges to be addressed for accelerating the development of these novel therapeutic strategies.

Engineering Immunomodulatory Biomaterials for Regenerating the Infarcted Myocardium

“…Soft alginate biomaterials are specifically designed (1) to gel at 37 • C in 5-10 min, being optimal carriers for in situ gel formation; (2) to optimize timing and location of the treatment, tailoring their release to target the circulating monocytes and macrophages during the acute infarct phase (0-4 days) and prior to the formation of granulation tissue (4-14 days) (Ferrini et al, 2019); and (3) to rapidly biodegrade in vivo after releasing the therapeutics to avoid biomaterial-induced arrhythmias (Hernandez and Christman, 2017 ; Figures 1, 2).…”

“…Cardiomyocyte death following ischemia activates the innate immune response, and monocytes and inflammatory macrophages are rapidly recruited into the infarcted wound bed to remove dead cells and tissue debris. However, if a rapid polarization toward reparative macrophage phenotypes is not achieved within a few days, the heart progresses rapidly through left ventricular remodeling, accompanied by deposition of collagenous scar and more severe functional decline, that can lead to heart failure (Ferrini et al, 2019).…”

Stimuli‐Responsive Delivery of Growth Factors for Tissue Engineering

“…[ 118–120 ] Similar to musculoskeletal diseases, dysfunction of cardiac muscle is troublesome as well. [ 121 ] Myocardial infarction (MI), as well as its consequent process of heart failure, is one major type of cardiovascular diseases. [ 122 ] Resulting from the obstruction of the flow of oxygenated blood to the heart, MI can lead to localized myocardial hypoxia and, subsequently, apoptosis or necrosis.…”

“…[ 123 ] Considering the limited regeneration ability of myocardial cells, cell delivery, stem cells in particular, has emerged as a prospective approach to treat MI‐induced scarring of the cardiac muscle. [ 121,124 ] However, unsolved problems such as limited cell survival in the ischemic area and toxicity caused by cell diffusion restrict the efficacy of clinical treatments, resulting in a poor prognosis for MI patients. [ 2,125 ] In this case, regulating the cellular microenvironment to accelerate endogenous cardiac stem or progenitor cell regeneration is a promising method for myocardial remodulation.…”

Biomaterials Loaded with Growth Factors/Cytokines and Stem Cells for Cardiac Tissue Regeneration

“…For example, the systemic administration of growth factors/cytokines is not efficient due to a short in vivo half-life and poor bioavailability at the target sites. This, in turn, requires repeated injections, resulting in more side effects and greater treatment costs [ 10 , 11 ]. Moreover, simultaneous and rapid diffusion can lead to formation of immature and unstable blood vessels in the case of therapy with angiogenic growth factors [ 12 ].…”