Aug 2026· Biomimetics· Vol 11· 0 citations· 112 references
Medicine
TL;DR
Current evidence demonstrates that injectable hydrogels, extracellular matrix-derived scaffolds, cardiac patches, conductive biomaterials, and multifunctional delivery platforms improve therapeutic retention, prolong paracrine signaling, and actively modulate inflammation, angiogenesis, fibrosis, and extracellular matrix remodeling, resulting in superior functional recovery compared with conventional delivery approaches in preclinical models.
Abstract
Myocardial infarction remains a leading cause of heart failure because current reperfusion therapies cannot prevent adverse ventricular remodeling or restore lost cardiomyocytes. Regenerative strategies based on stem cells and extracellular vesicles (EVs) have emerged as promising approaches; however, their clinical efficacy is limited by poor retention, rapid clearance, and the hostile post-infarction microenvironment. This narrative review critically examines the role of biomaterial-assisted delivery systems in enhancing stem cell and EV-based cardiac regeneration, with particular emphasis on the distinction between biomimetic and bioactive biomaterials, mechanisms of action, preclinical and clinical evidence, translational barriers, and emerging regenerative technologies. Current evidence demonstrates that injectable hydrogels, extracellular matrix-derived scaffolds, cardiac patches, conductive biomaterials, and multifunctional delivery platforms improve therapeutic retention, prolong paracrine signaling, and actively modulate inflammation, angiogenesis, fibrosis, and extracellular matrix remodeling, resulting in superior functional recovery compared with conventional delivery approaches in preclinical models. Nevertheless, robust clinical evidence remains limited because few biomaterial-assisted strategies have advanced beyond early-phase studies. Future progress will depend on integrating smart biomaterials with engineered extracellular vesicles, gene editing, and personalized regenerative approaches, together with standardized manufacturing, harmonized regulatory frameworks, and adequately powered clinical trials.
Decellularized extracellular matrix (dECM) materials derived from cardiac tissues have emerged as multifunctional biomaterials that recapitulate native microenvironmental cues while serving as controlled-release reservoirs of therapeutic agents and cells for cardiac repair. Recent advances have demonstrated that decellularized cardiac ECM (dcECM) hydrogels and patches can localize the release of angiogenic peptides, growth factors, or genes to promote neovascularization and mitigate adverse remodeling. Simultaneously, dcECM platforms have been applied to improve the survival and engraftment of stem cells, cardiomyocytes (CMs), and cardiac progenitor cells (CPCs) in infarcted myocardium, facilitating paracrine signaling and immune modulation. This review summarizes recent progress in the design and translational development of dcECM-based drug and cell delivery strategies for cardiac repair. We emphasized the interactions between matrix composition, its capacity to protect therapeutic factors and enhance cell retention, and therapeutic release profiles that collectively regulate cardiac tissue repair outcomes and highlighted emerging clinical applications and regulatory challenges for next-generation dcECM-based therapeutics.
Jiazhu Xu, Zining Yang, Yufeng Wen et al.· Journal of Controlled Releas...· 0 citations
Heart failure following a myocardial infarction (MI) remains a major global health challenge. This
is largely attributable to the adult human heart’s limited innate regenerative capacity, which results in
ventricular fibrosis, remodeling, and the formation of scar tissue. Early clinical trials evaluating bone
marrow-derived mononuclear cells (BMMNCs) and mesenchymal stromal cells (MSCs) demonstrated
acceptable safety profiles. Still, they produced only modest improvements in cardiac function and failed
to replicate the robust benefits observed in preclinical models. This review examines the biological
and methodological barriers responsible for this translational gap. Biologically, therapeutic efficacy is
limited by the hostile post-infarction environment, which is characterized by hypoxia, inflammation, and
oxidative stress, all of which contribute to extensive donor cell death, poor cell retention, and inadequate
electrical integration with host myocardium. Methodologically, progress is hindered by small clinical
trial sizes with limited statistical power coupled with high heterogeneity in cell preparations, dosing, and
delivery routes. Furthermore, the widespread reliance on surrogate imaging endpoints, particularly on
the left ventricular ejection fraction (LVEF), rather than definitive clinical outcomes, such as mortality,
heart-failure hospitalization, functional status, and quality of life, limits the interpretation of therapeutic
efficacy. In response to these limitations, the field is shifting toward cell-free therapies utilizing
extracellular vesicles and exosomes to deliver cardiovascular bioactive molecules, as well as direct
cardiac reprogramming to convert resident scar-forming fibroblasts into functional cardiomyocytes.
Successfully overcoming these translational barriers will require standardized trial designs, rigorous
product characterization criteria, and greater emphasis on clinically meaningful endpoints.
Saanvi Vadlamudi· American Journal of Student...· 0 citations
Abstract Regenerative medicine is undergoing a paradigm shift from live-cell therapies to cell-free strategies. Within this evolving field, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a leading platform. These nanoscale vesicles deliver bioactive cargo that mediates critical therapeutic functions, including immunomodulation, angiogenesis, and anti-fibrosis. Furthermore, they offer improved safety, greater potential for standardization, and enhanced scalability compared to traditional live-cell therapies. However, clinical translation remains constrained by several challenges, such as inherent vesicle heterogeneity, limited targeting specificity, and bottlenecks in large-scale manufacturing. This review systematically examines the biogenesis of MSC-EVs, focusing specifically on exosomes, microvesicles, and apoptotic vesicles. We evaluate their functional performance across diverse regeneration contexts, encompassing orofacial, barrier, musculoskeletal, and visceral tissue regeneration. We further highlight innovative engineering strategies designed to enhance therapeutic efficacy, such as surface modification, cargo loading, and biomaterial-integrated delivery systems. In addition, we introduce an emerging approach utilizing engineered MSC aggregate-derived EVs inspired by organ morphogenesis. Finally, this article details the strategic framework required for clinical translation. The framework encompasses scalable production, rigorous quality control, comprehensive non-clinical studies, evolving regulatory pathways, and the current clinical trial landscape. Collectively, this work provides an integrated roadmap for advancing MSC-EVs as a next-generation precision platform for cell-free therapeutics.
Shi‐Han Mu, Rang Li, Peng‐fei Wang et al.· Burns & Trauma· 0 citations
Myocardial infarction (MI) remains a major challenge in clinical practice, as the irreversible loss of cardiomyocytes and the limited repair capacity of the adult heart constrain cardiac repair. Traditional cell therapy once held great promise, but its clinical application has been constrained by issues such as low cell survival, immune rejection and procedural complexity. Against this background, extracellular vesicles (EVs) have attracted attention as a paracrine delivery strategy. By delivering bioactive cargo, including proteins, nucleic acids and lipids, EVs mediate intercellular communication and thereby support cardiac repair. This review focuses on the clinical potential of EVs, comparing the advantages, limitations and safety risks of EVs from different cellular origins, and places particular emphasis on engineered delivery strategies aimed at improving targeting, retention and therapeutic efficacy. In parallel, we examine the core barriers to clinical translation, including large scale manufacturing challenges, batch to batch consistency, storage stability, and regulatory and ethical issues; it is these barriers, rather than insufficient efficacy, that constitute the key bottleneck to the clinical application of EVs. Compared with existing reviews, this review, by emphasizing a clinical translation perspective, systematically analyzes the key issues facing EV-based therapeutic strategies in their progression from experimental research to clinical application, providing a practical theoretical framework for EV-based myocardial repair therapies and clarifying the prospects for EVs in the treatment of MI.
Kaiyi Zhu, Jing Bai, Liangfu Xu et al.· Journal of Controlled Releas...· 0 citations
Cardiovascular diseases are the leading cause of death worldwide, from which myocardium infraction (MI) is the most common one. Treatment of MI patients is difficult mainly due to the limited regeneration capacity of the heart, derived from the low proliferative activity of cardiomyocytes. Moreover, local administration and retention of therapeutic molecules is also difficult to be executed in a constantly beating heart, making the development of delivery vehicles that can retain therapeutics at the damaged heart tissue, and release them at a sustained rate, an unmet clinical need. Herein we review recent advancements in the development of polysaccharide-based and supramolecular hydrogels designed for cardiac repair and regeneration emphasising their application as delivery vehicles for various drugs, bioactive compounds (e.g., peptides, growth factors, genetic material, etc.) and biologics (cells, secretomes, etc.) to provide their sustained local release (or improved retention and survival of delivered cells) enhancing therapeutic outcomes and minimising off-target and side effects.
Annalisa Perioli, Ariana Gomes, Rui L Reis et al.· Journal of Controlled Releas...· 0 citations
Ischemic stroke induces acute oxidative damage followed by prolonged inflammation and incomplete tissue reconstruction, creating a need for local therapies that provide sustained neuroprotection and repair support. Here, an injectable hybrid scaffold is developed that integrates a brain-compliant hydrogel with short electrospun nanofibers for sustained local delivery of morroniside (MOR), a pleiotropic small molecule with antioxidant, anti-inflammatory and pro-regenerative activities. The hydrogel provides early MOR release to mitigate acute injury, while the nanofibers enable sustained delivery together with extracellular-matrix-mimetic cues that support angiogenesis, neurogenesis, and axonal remodeling. In vitro, MOR enhanced endothelial and neuronal survival and promoted their migration and lineage-specific differentiation under ischemic conditions. In a rat cortical stroke model, MOR-loaded scaffolds significantly improved motor recovery, reduced infarct volume, enhanced vascularization, suppressed glial scarring, and facilitated axonal regeneration. Transcriptomic analysis revealed broad microenvironmental reprogramming, including suppression of inflammatory pathways and enrichment of PI3K-AKT-related repair signaling with increased p-PI3K and p-AKT immunofluorescence. These results demonstrate that coupling a structurally engineered scaffold with a small molecule supports multiple repair-associated responses following ischemic stroke and offers a translational strategy for repairing ischemic brain injury.
Li Ruan, Wenzhe Du, Huaqi Wang et al.· Bioactive Materials· 0 citations
A new method for surgically removing training examples from a model reveals that as datasets grow, the link between what a model learns and what it produces dissolves.
