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Chitosan is a chitin-derived biopolymer that has shown great potential for tissue regeneration and controlled drug delivery. It has numerous qualities that make it attractive for biomedical applications such as biocompatibility, low toxicity, broad-spectrum antimicrobial activity, and many others. Importantly, chitosan can be fabricated into a variety of structures including nanoparticles, scaffolds, hydrogels, and membranes, which can be tailored to deliver a desirable outcome. Composite chitosan-based biomaterials have been demonstrated to stimulate in vivo regeneration and the repair of various tissues and organs, including but not limited to, bone, cartilage, dental, skin, nerve, cardiac, and other tissues. Specifically, de novo tissue formation, resident stem cell differentiation, and extracellular matrix reconstruction were observed in multiple preclinical models of different tissue injuries upon treatment with chitosan-based formulations. Moreover, chitosan structures have been proven to be efficient carriers for medications, genes, and bioactive compounds since they can maintain the sustained release of these therapeutics. In this review, we discuss the most recently published applications of chitosan-based biomaterials for different tissue and organ regeneration as well as the delivery of various therapeutics.

Cardiac regeneration offers a promising approach to treating ischemic heart disease. Accumulating evidence indicates that maturation limits the proliferative capacity of the adult myocardium. During cardiac development, cardiomyocytes (CMs) undergo genetic reprogramming, leading to maturation characterized by polyploid CMs, increased sarcomere rigidity, and metabolic reprogramming that prepares the heart for efficient, sustained blood pumping capacity throughout life. This maturation process also coincides with cell cycle exit in adult CMs and forms a barrier to replenishing the CM loss after ischemic injury. Over recent decades, studies have shown that forced induction of adult CM proliferation involves reversion to an immature state. Therefore, understanding the changes that occur during maturation is essential to flip the coin to enable the induction of CM proliferation in adulthood, with potential therapeutic applications for ischemic heart disease. This review discusses the relationship between postnatal CM maturation and CM proliferation.

Aging leads to increased cellular senescence and is associated with decreased potency of tissue‐specific stem/progenitor cells. Here, we have done an extensive analysis of cardiac progenitor cells (CPCs) isolated from human subjects with cardiovascular disease, aged 32–86 years. In aged subjects (>70 years old), over half of CPCs are senescent (p16INK4A, SA‐β‐gal, DNA damage γH2AX, telomere length, senescence‐associated secretory phenotype [SASP]), unable to replicate, differentiate, regenerate or restore cardiac function following transplantation into the infarcted heart. SASP factors secreted by senescent CPCs renders otherwise healthy CPCs to senescence. Elimination of senescent CPCs using senolytics abrogates the SASP and its debilitative effect in vitro. Global elimination of senescent cells in aged mice (INK‐ATTAC or wild‐type mice treated with D + Q senolytics) in vivo activates resident CPCs and increased the number of small Ki67‐, EdU‐positive cardiomyocytes. Therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and restore the regenerative capacity of the heart.

The significance of cardiac stem cell (CSC) populations for cardiac regeneration remains disputed. Here, we apply the most direct definition of stem cell function (the ability to replace lost tissue through cell division) to interrogate the existence of CSCs. By single-cell mRNA sequencing and genetic lineage tracing using two Ki67 knockin mouse models, we map all proliferating cells and their progeny in homoeostatic and regenerating murine hearts. Cycling cardiomyocytes were only robustly observed in the early postnatal growth phase, while cycling cells in homoeostatic and damaged adultmyocardium represented various noncardiomyocyte cell types. Proliferative postdamage fibroblasts expressing follistatin-like protein 1 (FSTL1) closely resemble neonatal cardiac fibroblasts and form the fibrotic scar. Genetic deletion of Fstl1 in cardiac fibroblasts results in postdamage cardiac rupture. We find no evidence for the existence of a quiescent CSC population, for transdifferentiation of other cell types toward cardiomyocytes, or for proliferation of significant numbers of cardiomyocytes in response to cardiac injury.

Immune signaling has emerged as a central regulator of cardiac biology, extending far beyond its traditionally recognized roles in pathology. From embryogenesis to adulthood, immune cells orchestrate key processes, including coronary vasculature formation, cardiomyocyte maturation, mitochondrial homeostasis, and extracellular matrix (ECM) remodeling. In the setting of myocardial injury, immune responses unfold in tightly choreographed phases, initially clearing necrotic debris and later facilitating scar formation and, in certain contexts, promoting tissue regeneration. Recent advances in single-cell and spatial transcriptomics have revealed the remarkable heterogeneity and plasticity of immune cell populations in the heart, highlighting their metabolic and phenotypic adaptability across developmental and disease contexts. Alongside these biological insights, therapeutic interest has grown in targeting specific immune pathways to modulate inflammation, enhance repair, and restore cardiac function. This review integrates discoveries from developmental immunology, cardiac injury models, and regenerative medicine to illustrate how the immune system underpins cardiac resilience and plasticity. By synthesizing molecular, cellular, and systems-level data, we present a cohesive view of cardioimmune interactions that opens new avenues for precision therapies aimed at heart repair and regeneration.

Systemic delivery remains insufficient for targeting myocardial tissue, creating a clinical need for localized epicardial therapeutics.Microneedles (MNs) enable localized, sustained delivery of therapeutics directly into the myocardium.MNs improve drug retention, enhance tissue adherence, and minimize off-target effects.MNs can be tailored to mimic myocardial mechanics, conductivity, extracellular matrix architecture, and biological functionality.Cardiac MN implantation is challenged by the heart’s continuous motion and the weakened nature of the infarcted tissue. Local myocardial delivery remains an unmet need in cardiovascular disease, as systemic therapies are hindered by cardiac motion, heterogeneous perfusion, and post-infarction extracellular matrix remodeling. Preclinical microneedle (MN) systems enable direct, localized, and sustained epicardial delivery of drugs, proteins, growth factors, and cells while minimizing systemic exposure. Recent studies have demonstrated tangible benefits: galunisertib-loaded MNs reduced fibrosis from ~14% to ~7%, and vascular endothelial growth factor (VEGF)-based MNs increased vascular density from ~0.2 to ~0.5 vessels per field. Mechanically adaptive and biodegradable MN platforms maintain stable contact with the beating heart and support programmable release profiles. This review synthesizes the current preclinical landscape of cardiac MN technologies and outlines the engineering and translational considerations that will guide their advancement toward future clinical applications. Local myocardial delivery remains an unmet need in cardiovascular disease, as systemic therapies are hindered by cardiac motion, heterogeneous perfusion, and post-infarction extracellular matrix remodeling. Preclinical microneedle (MN) systems enable direct, localized, and sustained epicardial delivery of drugs, proteins, growth factors, and cells while minimizing systemic exposure. Recent studies have demonstrated tangible benefits: galunisertib-loaded MNs reduced fibrosis from ~14% to ~7%, and vascular endothelial growth factor (VEGF)-based MNs increased vascular density from ~0.2 to ~0.5 vessels per field. Mechanically adaptive and biodegradable MN platforms maintain stable contact with the beating heart and support programmable release profiles. This review synthesizes the current preclinical landscape of cardiac MN technologies and outlines the engineering and translational considerations that will guide their advancement toward future clinical applications.

A large number of clinical trials have shown stem cell therapy to be a promising therapeutic approach for the treatment of cardiovascular diseases. Since the first transplantation into human patients, several stem cell types have been applied in this field, including bone marrow derived stem cells, cardiac progenitors as well as embryonic stem cells and their derivatives. However, results obtained from clinical studies are inconsistent and stem cell-based improvement of heart performance and cardiac remodeling was found to be quite limited. In order to optimize stem cell efficiency, it is crucial to elucidate the underlying mechanisms mediating the beneficial effects of stem cell transplantation. Based on these mechanisms, researchers have developed different improvement strategies to boost the potency of stem cell repair and to generate the “next generation” of stem cell therapeutics. Moreover, since cardiovascular diseases are complex disorders including several disease patterns and pathologic mechanisms it may be difficult to provide a uniform therapeutic intervention for all subgroups of patients. Therefore, future strategies should aim at more personalized SC therapies in which individual disease parameters influence the selection of optimal cell type, dosage and delivery approach.

Despite significant developments in medical and surgical strategies, cardiac diseases remain the leading causes of morbidity and mortality worldwide. Numerous studies involving preclinical and clinical trials have confirmed that stem cell transplantation can help improve cardiac function and regenerate damaged cardiac tissue, and stem cells isolated from bone marrow, heart tissue, adipose tissue and umbilical cord are the primary candidates for transplantation. During the past decade, menstrual blood-derived endometrial stem cells (MenSCs) have gradually become a promising alternative for stem cell-based therapy due to their comprehensive advantages, which include their ability to be periodically and non-invasively collected, their abundant source material, their ability to be regularly donated, their superior proliferative capacity and their ability to be used for autologous transplantation. MenSCs have shown positive therapeutic potential for the treatment of various diseases. Therefore, aside from a brief introduction of the biological characteristics of MenSCs, this review focuses on the progress being made in evaluating the functional improvement of damaged cardiac tissue after MenSC transplantation through preclinical and clinical studies. Based on published reports, we conclude that the paracrine effect, transdifferentiation and immunomodulation by MenSC promote both regeneration of damaged myocardium and improvement of cardiac function.

Myocardial injury causes death to cardiomyocytes and leads to heart failure. The adult mammalian heart has very limited regenerative capacity. However, the heart from early postnatal mammals and from adult lower vertebrates can fully regenerate after apical resection or myocardial infarction. Thus, it is of particular interest to decipher the mechanism underlying cardiac regeneration that preserves heart structure and function. RNA-binding proteins, as key regulators of post-transcriptional gene expression to coordinate cell differentiation and maintain tissue homeostasis, display dynamic expression in fetal and adult hearts. Accumulating evidence has demonstrated their importance for the survival and proliferation of cardiomyocytes following neonatal and postnatal cardiac injury. Functional studies suggest that RNA-binding proteins relay damage-stimulated cell extrinsic or intrinsic signals to regulate heart regenerative capacity by reprogramming multiple molecular and cellular processes, such as global protein synthesis, metabolic changes, hypertrophic growth, and cellular plasticity. Since manipulating the activity of RNA-binding proteins can improve the formation of new cardiomyocytes and extend the window of the cardiac regenerative capacity in mammals, they are potential targets of therapeutic interventions for cardiovascular disease. This review discusses our evolving understanding of RNA-binding proteins in regulating cardiac repair and regeneration, with the aim to identify important open questions that merit further investigations.