Bioactive Compounds from Medicinal and Edible Plants for Anti-Aging: A Systematic Review of Molecular Mechanisms, Delivery Systems, and Clinical Evidence.

Spinal cord injury (SCI) is a serious neurological condition that can cause permanent motor, sensory, and autonomic impairment []. SCI is most commonly traumatic, resulting from mechanisms such as sports injuries, traffic accidents, falls, and violence, although non-traumatic causes include infection, tumors, and spinal degeneration. According to the World Health Organization (WHO), the global annual incidence of SCI ranges from 10 to 83 cases per million population, with approximately 90% of cases caused by trauma and 10% caused by non-traumatic etiologies [,,]. The socioeconomic burden of SCI is substantial; in high-income countries, lifetime medical care costs are estimated at approximately USD 2–5 million per patient, including productivity losses and caregiving costs []. Although acute trauma care and rehabilitation have improved, approximately 30% of people with SCI experience severe lifelong disability accompanied by secondary pathologies, including neuropathic pain, urinary and respiratory tract infections, and cardiovascular dysfunction [,]. Current standard care remains largely supportive, and no therapy has yet achieved meaningful functional restoration, underscoring the urgent need for regenerative medicine approaches [,]. Traditionally, two-dimensional (2D) monolayer cultures have been widely used as foundational in vitro models in SCI research, but they have important limitations. Cell monocultures grown in rigid 2D microenvironments cannot recreate the three-dimensional (3D) architecture, extracellular matrix (ECM) interactions, multicellular complexity, or dynamic microenvironmental cues, such as fluid flow, oxygen gradients, and mechanical stimulation, that regulate spinal cord biology in vivo [,]. Importantly, the blood–spinal cord barrier (BSCB), a key pathological feature of SCI and a major determinant of drug permeability into the spinal cord, cannot be adequately reproduced in conventional 2D culture systems []. In vivo rodent models have provided fundamental mechanistic insights, but a substantial translational gap persists between preclinical findings and clinical outcomes. Rodents differ substantially from humans in corticospinal tract organization, white-to-gray matter ratio, spontaneous regenerative capacity, and neuroinflammatory gene-expression profiles. This limitation is reflected in several high-profile clinical failures, including methylprednisolone, riluzole, minocycline, Cethrin, and anti-Nogo antibody therapies [,]. Although large-animal models, such as pigs and non-human primates, offer greater anatomical and physiological relevance, their use is constrained by high costs, ethical concerns, and limited genetic tractability. Together, these limitations, along with the ethical principles of the 3Rs paradigm (replacement, reduction, and refinement), have driven the development of more physiologically relevant human in vitro platforms for SCI research []. Spinal cord organoids (SCOs) are 3D self-organizing structures derived from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs), and they have emerged as promising models of human spinal cord biology. SCOs can recreate key features of cellular diversity, cytoarchitectural organization, and electrophysiological function []. Mechanistically, sequential neural induction through dual SMAD inhibition, followed by caudalization through Wnt/fibroblast growth factor 2 (FGF-2) signaling and dorsoventral patterning through sonic hedgehog (SHH) or bone morphogenetic protein 4 (BMP4), produces organoids containing motor neurons (ISL1, HB9), interneurons, astrocytes, and oligodendrocyte precursors (OLIG) [,]. SCOs also exhibit functional electrophysiological properties, including spontaneous action potentials, synaptic transmission, and oscillatory network activity, which can be recorded using microelectrode arrays (MEAs) and calcium imaging. In addition, single-cell RNA sequencing analyses have shown transcriptomic convergence with primary human spinal cord tissue, supporting the use of SCOs as emerging human-specific disease models [].