{"paper_id":"72e9785d-7ae2-4ddd-ab66-aa6532ac3d3b","body_text":"Tissue injury initiates\na highly orchestrated and dynamic sequence\nof cellular, molecular, and biochemical events designed to restore\nstructural integrity and functional homeostasis. \n , \n  Successful\nwound healing relies on the precise coordination of four interdependent\nand overlapping phases, hemostasis, inflammation, proliferation, and\nremodeling or resolution, each governed by a complex interplay of\nimmune cells, cytokines, and growth factors.  The timely and balanced transition between these phases is critical\nfor effective repair. However, dysregulation of the immune response\ncan disrupt this sequence, leading to chronic inflammation, and impaired\nregeneration.\nIn the skeletal system,\nexcessive or unresolved inflammation exerts\nparticularly detrimental effects. An exacerbated inflammatory milieu\ncan stimulate osteoclastogenesis, enhancing bone resorption and compromising\nthe stability of the surrounding tissue.  Bone defects frequently arise from trauma, infection, tumor resection,\nor chronic inflammatory diseases and may surpass the intrinsic regenerative\ncapacity of the host.  In extensive or\ncomplex lesions, spontaneous healing becomes unfeasible due to persistent\ninflammation, inadequate vascularization, and the absence of osteogenic\nor osteoinductive cues required for new bone formation.  Such critical-size defects, defined as defects\nincapable of spontaneous healing even after surgical stabilization,\nrequire adjunctive therapeutic strategies, including autologous bone\ngrafting or engineered biomaterials to restore structural and functional\ncontinuity.  Consequently, bone regeneration\nremains one of the most demanding challenges in regenerative medicine,\ninfluenced by anatomical location, defect size, and local biological\nconditions.\nTo counteract inflammation-associated\ntissue destruction and promote\nregenerative healing, a variety of therapeutic strategies have been\ndeveloped. \n , \n  Conventional interventions include the debridement\nof necrotic tissue, rigorous infection control, surgical revascularization,\nand bone grafting procedures employing autologous, allogeneic, or\nsynthetic substitutes. \n , \n  Although clinically effective,\nthese approaches are frequently limited by donor-site morbidity, immune\nincompatibility, infection risk, and suboptimal osteogenic potential.\nAs a result, increasing attention has been directed toward alternative\nor complementary strategies, particularly those involving bioactive\nnatural compounds and biomaterials endowed with intrinsic regenerative\nand immunomodulatory properties. \n −\nAmong these emerging\ntherapeutic approaches, the medicinal potential\nof  Cannabis sativa  L. has attracted\nrenewed scientific interest. Historical evidence documents its therapeutic\napplication as early as 1550 BCE in ancient Egyptian papyri.  The plant’s remarkable ecological adaptability\nhas enabled its widespread cultivation across diverse geographic regions,\nleading to the identification of more than 450 bioactive constituents,\nincluding approximately 70 phytocannabinoids. \n , \n  Structurally, these compounds share a conserved dibenzopyran core\nlinked to a hydrophobic alkyl side chain, a configuration that confers\nmarked lipophilicity and facilitates their interaction with membrane-bound\nreceptors  ( Figure  \n ).\nWidely distributed cannabinoid receptors (CB1,\nCB2, GPR55 and GPR18)\nin the human body. Created in BioRender. de Avila, E. (2026)  https://BioRender.com/u8xbeyf .  License: RC29JN1JK5 .\nThe biological effects of phytocannabinoids are\nprimarily mediated\nthrough the endocannabinoid system (ECS), a complex signaling network\ncomposed of endogenous ligands, metabolic enzymes, and cannabinoid\nreceptors CB 1  and CB 2 .  CB 1  receptors are predominantly expressed in the central\nand peripheral nervous systems but are also detected in peripheral\ntissues, including bone, adipose tissue, myocardium, reproductive\norgans, and retina.  CB 2  receptors\nare more abundant in immune cells, yet they are also present in the\nliver, gastrointestinal tract, brain, and skeletal tissues.  Importantly, both CB 1  and CB 2  receptors have been identified in bone marrow–derived\nstromal cells and within the bone immune microenvironment.  Experimental evidence indicates that pharmacological\nactivation or genetic modulation of these receptors influences osteoblast\nand osteoclast activity, attenuates pathological bone turnover, and\nregulates remodeling dynamics  ( Figure  \n ).\nBeyond this\nclassical CB 1 /CB 2  framework,\nincreasing evidence supports the existence of an expanded endocannabinoid\nnetwork that includes noncanonical receptors operating through CB 1 /CB 2 -independent pathways.  Among these, GPR18 and GPR55 have emerged as putative cannabinoid-responsive\nreceptors capable of being modulated by endocannabinoids, phytocannabinoids,\nand synthetic ligands. GPR18, also referred to as the N-arachidonoylglycine\n(NAGly) receptor, is predominantly expressed in immune cells and plays\na role in neutrophil migration, macrophage phenotype modulation, and\nlymphocyte maturation.  It is also highly\nexpressed in microglial cells, which are key components of the central\nnervous system immune network, where it participates in chemotactic\nsignaling and leukocyte recruitment to sites of injury.  Cannabidiol (CBD) has been described as a modulator\nof orphan receptors, including GPR18, acting as an antagonist or inverse\nagonist under certain conditions. These interactions may partly explain\nCBD’s anti-inflammatory properties independent of CB 1  activation, thereby avoiding the psychotropic effects associated\nwith Δ 9 -tetrahydrocannabinol (Δ 9 -THC).\nGPR55, in contrast, signals\nprimarily via  G \n 12/13  and  G \n q  proteins rather than\nGi-coupled mechanisms typical of CB receptors. This distinction leads\nto activation of intracellular pathways such as RhoA and calcium mobilization,\nprocesses involved in cell proliferation, migration, and angiogenesis.  GPR55 expression has been identified in multiple\ncentral nervous system regions, including the caudate-striatal complex,\nas well as in peripheral tissues such as endothelial cells, adrenal\nglands, and the gastrointestinal tract.  Its wide distribution suggests involvement in innate and adaptive\nimmune regulation.  Collectively, these\nfindings underscore the complexity of cannabinoid-related signaling\nand reinforce the concept that phytocannabinoid effects extend beyond\nthe classical CB 1 /CB 2  paradigm, engaging a broader\nreceptor repertoire relevant to immune modulation and tissue homeostasis.\nAmong phytocannabinoids, Δ 9 -THC and cannabidiol\n(CBD) are the most extensively studied due to their distinct pharmacological\nprofiles.  Δ 9 -THC, isolated\nin 1964, is the principal psychoactive constituent of the plant and\nexerts its central effects primarily via CB 1  activation. \n , \n  In contrast, CBD is nonpsychoactive and exhibits low affinity for\nCB 1  and CB 2  receptors. Instead, it modulates\nthe ECS indirectly and interacts with additional molecular targets,\nincluding TRPV1, PPARγ, and 5-HT1A receptors.\nCBD has garnered substantial attention due to its\nwide range of\nreported therapeutic effects, encompassing anti-inflammatory, antioxidant,\nneuroprotective, and regenerative properties. \n , \n  These pleiotropic actions suggest that CBD may act as a multimodal\nagent capable of modulating several signaling pathways relevant to\ntissue homeostasis and repair. From a regenerative perspective, an\nideal bioactive compound should attenuate inflammation and oxidative\nstress, exhibit antimicrobial activity, and promote cellular proliferation,\nmatrix deposition, and angiogenesis. \n , \n  In this context,\npreclinical evidence has demonstrated the pro-healing capacity of\nCBD. For instance, Yan et al.  reported\nthat topical CBD administration enhanced wound closure and vascularization\nthrough the upregulation of vascular endothelial growth factor (VEGF)\nin granulation tissue. Additional studies have shown that CBD modulates\ninflammatory responses, promotes collagen synthesis, and stimulates\nneovascularization, thereby supporting its potential role in tissue\nregeneration.\nDespite this promising evidence, the precise molecular\nand cellular\nmechanisms underlying CBD-mediated tissue remodeling remain incompletely\nunderstood. Considering the pivotal role of inflammation in regulating\nbone remodeling and the detrimental effects of excessive immune activation\non bone integrity, the immunomodulatory functions of CBD are of particular\nrelevance.  Notably, Li et al.  demonstrated that CBD reduced the mRNA expression\nof proinflammatory cytokines such as TNF-α and IL-6 in lipopolysaccharide-stimulated\nbone marrow mesenchymal stem cells, while concurrently enhancing the\nexpression of osteogenic markers, including Runx2, alkaline phosphatase\n(ALP), and osteocalcin (OCN).\nGiven the multifactorial nature\nof wound healing and bone regeneration,\nelucidating the biological mechanisms through which natural compounds\nlike CBD modulate inflammation and stimulate reparative processes\nis crucial for advancing translational regenerative strategies. The\nexploration of such bioactive molecules offers novel opportunities\nto overcome the limitations of conventional therapies and improve\nclinical outcomes. Accordingly, this review aims to provide a comprehensive\nanalysis of the chemical and biological mechanisms underlying the\neffects of CBD in wound healing and bone regeneration, with particular\nemphasis on its immunomodulatory and osteogenic properties. Furthermore,\nit addresses key considerations regarding dosage, administration routes,\nformulation strategies, and regulatory aspects to optimize its therapeutic\npotential in regenerative medicine.\n\nWound healing follows a tightly regulated physiological cascade\ninvolving overlapping cellular and molecular events that collectively\nrestore tissue integrity and function. \n , \n  Under normal\nconditions, this process proceeds in a coordinated manner through\nthe sequential phases of hemostasis, inflammation, proliferation,\nand remodeling, ultimately culminating in the re-establishment of\ntissue homeostasis. However, the persistence of inflammatory stimuli,\nmicrobial contamination, ischemia, or metabolic dysfunction can disrupt\nthis orderly sequence, leading to delayed, chronic, or pathological\nhealing outcomes. Such disturbances often result in excessive inflammation,\nimpaired cell migration and proliferation, and aberrant extracellular\nmatrix deposition, all of which compromise functional tissue restoration.\nA clear understanding of the fundamental differences between physiological\n(natural) and dysregulated (non-natural or impaired) healing processes\nis essential for the rational design of therapeutic interventions\ntargeting tissue regeneration. This distinction provides a critical\nconceptual framework for evaluating the pharmacological potential\nof bioactive compounds, such as cannabidiol (CBD), in modulating the\nwound-healing response. Prior to developing any therapeutic formulation\naimed at enhancing repair in acute or chronic wounds, it is imperative\nto establish a comprehensive understanding of the molecular mechanisms\nthat distinguish the natural from the impaired course of healing ( Figure  \n ).\nSchematic overview of\nthe natural versus dysregulated course of\ninflammation during wound healing. Under physiological conditions,\nwound healing proceeds through a tightly coordinated sequence of overlapping\nphases, hemostasis, inflammation, proliferation, and remodeling, that\ncollectively restore tissue structure and function. Controlled inflammation\nplays a pivotal role in initiating repair by recruiting immune cells,\nclearing debris, and releasing cytokines and growth factors that guide\nsubsequent regenerative events. In contrast, when inflammatory stimuli\npersist or become excessive, this delicate balance is disrupted, leading\nto prolonged immune activation, oxidative stress, and the overproduction\nof proinflammatory mediators. Such dysregulation impairs angiogenesis,\nfibroblast function, and extracellular matrix remodeling, ultimately\nresulting in delayed or chronic wound healing. The illustration highlights\nthe key cellular and molecular differences between the natural and\npathological inflammatory trajectories and their respective outcomes\nin tissue repair. Created in BioRender. de Avila, E. (2026)  https://BioRender.com/lmp1tiu .  License: YM29ED40J1 .\nThe physiological (natural) course of wound\nhealing is a highly orchestrated process that progresses through four\ndynamic and overlapping phases: hemostasis, inflammation, proliferation,\nand remodeling  ( Figure  \n ). Hemostasis, the immediate response to\ntissue injury, involves vascular constriction, platelet aggregation,\nand fibrin clot formation, establishing a provisional matrix and limiting\nblood loss. Inflammation follows, characterized by the sequential\nrecruitment and activation of neutrophils and macrophages, which remove\ndebris and pathogens while releasing cytokines and growth factors\nthat orchestrate subsequent regenerative events. The proliferative\nphase entails fibroblast proliferation, extracellular matrix deposition,\nangiogenesis, and epithelial migration, collectively restoring tissue\narchitecture. Finally, remodeling (maturation) involves the reorganization\nof collagen fibers, resolution of neovasculature, and restoration\nof tissue tensile strength, culminating in functional repair.\nSchematic representation\nof the overlapping and sequential phases\nof the natural wound-healing process. The figure illustrates the dynamic\nprogression from hemostasis and inflammation to proliferation and\nremodeling, highlighting the temporal and cellular interplay among\nkey events such as clot formation, immune cell infiltration, angiogenesis,\nextracellular matrix deposition, and tissue maturation. Created in\nBioRender. de Avila, E. (2026)  https://BioRender.com/dlw1s68 .  License: VQ29EDBNCG .\nThis well-regulated sequence provides the benchmark\nfor assessing\nthe therapeutic potential of bioactive compounds, such as CBD. By\nmodulating inflammatory responses, promoting fibroblast and endothelial\ncell activity, and facilitating the transition from inflammation to\nproliferation and remodeling, CBD may enhance the efficiency and quality\nof tissue repair, particularly in chronic or nonhealing wounds. Understanding\nthe natural course of healing is therefore essential for interpreting\nCBD’s regenerative mechanisms and optimizing its application\nin tissue engineering and regenerative medicine.\nThe initial\nphase of wound healing, hemostasis, functions as a\nprotective mechanism that limits blood loss and establishes a provisional\nmatrix for subsequent tissue repair.  Immediately\nfollowing injury, vasoconstrictive mediators, including endothelin,\nreleased by damaged endothelium, and systemic factors such as epinephrine,\nstimulate contraction of vascular smooth muscle, transiently reducing\nblood flow at the injury site.  Concurrently,\nmediators such as bradykinin and fibrinopeptides initiate the coagulation\ncascade, leading to platelet aggregation and the formation of a primary\nhemostatic plug.\nCoagulation proceeds\nvia two principal pathways: the extrinsic\npathway, triggered by tissue factor exposed at the site of vascular\ninjury, and the intrinsic pathway, activated by contact between blood\ncomponents and negatively charged surfaces, such as exposed collagen\nor matrix proteins. \n , \n  Both pathways converge on the\nactivation of factor X, initiating the common pathway that leads to\nthe conversion of prothrombin into thrombin.  Thrombin subsequently catalyzes the transformation of fibrinogen\ninto fibrin, forming an insoluble network that stabilizes the platelet\nplug and establishes a secondary hemostatic structure, often referred\nto as the provisional matrix.\nThis\nfibrin-based matrix serves as a scaffold for cellular infiltration,\ninitiating the inflammatory phase of wound healing. Neutrophils are\namong the first immune cells recruited to the wound site, where they\nperform essential functions including pathogen clearance, phagocytosis\nof debris, and secretion of proinflammatory mediators to orchestrate\nthe subsequent reparative response.  The\nmigration of inflammatory cells is guided by chemotactic signals generated\nby tissue-resident cells in response to damage-associated molecular\npatterns (DAMPs) and pathogen-associated molecular patterns (PAMPs),\nalerting neutrophils in the bone marrow to the site of injury and\nfacilitating their directed movement into the wound. \n ,\nUpon arrival at the injury site, neutrophils release cytotoxic\ngranules containing proteolytic enzymes and reactive oxygen species,\nwhich directly target and eliminate invading pathogens.  They also perform phagocytosis via surface antigen\nreceptors, engulfing and degrading microbial and cellular debris.  Concurrently, macrophages infiltrate the wound,\ninitially adopting a pro-inflammatory (M1) phenotype, characterized\nby the production of cytokines such as interleukin (IL)-6, tumor necrosis\nfactor-α (TNF-α), and IL-1β, thereby amplifying\nthe antimicrobial response.  Macrophages\nalso contribute to resolution of inflammation by phagocytosing senescent\nneutrophils that fail to return to the bone marrow, effectively terminating\nthe inflammatory phase. \n , \n  Following this, M1\nmacrophages undergo phenotypic switching to the anti-inflammatory,\ntissue-repair-promoting M2 phenotype, which supports angiogenesis,\nextracellular matrix (ECM) deposition, and immunoregulation.\nThe proliferative phase is initiated with\nthe replacement of the\nfibrin clot by granulation tissue and the restoration of vascular\nsupply via angiogenesis, ensuring delivery of oxygen and nutrients\nto the regenerating tissue. \n , \n  This phase involves\ncoordinated activity of keratinocytes, fibroblasts, macrophages, and\nendothelial cells, aimed at reestablishing a functional tissue barrier.  Endothelial cells respond to hypoxia by upregulating\nvascular endothelial growth factor (VEGF), proliferating, and forming\nnew capillary networks, thereby facilitating nutrient and oxygen delivery\nessential for effective tissue repair. \n , \n  Meanwhile,\nfibroblasts, stimulated by signals from platelets, endothelial cells,\nand M2 macrophages, deposit a provisional extracellular matrix, predominantly\ncomposed of type III collagen. A subset of fibroblasts differentiates\ninto myofibroblasts, which generate contractile forces that reduce\nwound size and contribute to tissue integrity.\nThe remodeling (maturation) phase represents the\nfinal stage of\nwound healing, during which the granulation tissue is reorganized\ninto mature, functional tissue. M2 macrophages transition to a phenotype\n(M2c) involved in ECM turnover, releasing matrix metalloproteinases\n(MMPs) that degrade excess collagen and remodel the provisional matrix.  During this phase, type III collagen is gradually\nreplaced by type I collagen, restoring the tensile strength of the\ntissue. \n , \n  Additional structural components, such as\nelastin, are also reincorporated into the regenerating tissue, contributing\nto the functional and mechanical properties of the scar.  Together, these tightly regulated events ensure\nthe successful resolution of the wound and the restoration of tissue\nhomeostasis.\nIn contrast to the tightly regulated\nsequence of cellular, humoral, and molecular events that characterize\nphysiological wound healing, certain pathological conditions disrupt\nthis process, leading to impaired regeneration. Such wounds may either\nform excessive scar tissue or develop into chronic lesions that exhibit\nminimal reduction in size (typically <40–50%) and fail to\nheal effectively  ( Figure  \n ). In these scenarios, the anti-inflammatory\nand immunomodulatory properties of cannabidiol (CBD) may provide therapeutic\nbenefit by attenuating persistent inflammation and promoting progression\ntoward tissue repair.\nSchematic representation of the pathological course of\na chronic\nwound. Chronic wounds are characterized by a prolonged and amplified\ninflammatory phase, with excessive infiltration of neutrophils and\npro-inflammatory (M1) macrophages. This sustained immune activation\nleads to elevated production of reactive oxygen species (ROS) and\npro-inflammatory cytokines, which collectively impair angiogenesis\nand tissue perfusion, contributing to necrosis and delayed or disrupted\nre-epithelialization. Persistent inflammation is further reinforced\nby lymphocyte recruitment and the presence of biofilms, which protect\npathogens from host immune responses and antimicrobial therapies.\nThe figure illustrates the key cellular and molecular features that\nperpetuate chronic inflammation, ECM degradation, and impaired tissue\nrepair in nonhealing wounds. Created in BioRender. de Avila, E. (2026)  https://BioRender.com/eedgtyc .  License: TF29ED7GCB .\nChronic wound development is influenced by intrinsic\nfactors, including\nage, malnutrition, diabetes, and immunosuppression, as well as extrinsic\nfactors such as local temperature, humidity, and infection. \n , \n  Pathologically, chronic wounds are characterized by sustained inflammation,\nrecurrent infections, necrosis, impaired re-epithelialization, reduced\nangiogenesis, and excessive production of reactive oxygen species\n(ROS).  Dysregulation may begin as early\nas the hemostatic phase; for example, hypercoagulable states can lead\nto thrombosis, which occludes blood vessels, restricts oxygen delivery,\nand induces tissue ischemia. Similarly, conditions such as hyperglycemia\nin diabetic individuals can elevate ROS levels, which, beyond their\nphysiological role in vasoconstriction during hemostasis and vasodilation\nduring proliferation, disrupt endothelial cell function, impair angiogenesis,\nand promote apoptosis. \n ,\nPersistent inflammation\nis the primary driver of the non-natural\nhealing trajectory.  Chronic wounds are\nmarked by prolonged infiltration of myeloid cellsincluding\nneutrophils, monocytes, and macrophagesinto the late inflammatory\nphase.  Within these wounds, there is\nan imbalance between pro-inflammatory (M1) and anti-inflammatory (M2)\nmacrophages, with insufficient resolution of inflammation.  Impaired clearance of apoptotic neutrophils\nexacerbates the inflammatory milieu, sustaining high levels of cytokines\nsuch as TNF-α and IL-1β, which perpetuate tissue degradation. \n , \n  Additionally, macrophage-derived matrix metalloproteinases (e.g.,\nMMP-2 and MMP-9) degrade extracellular matrix components, further\ndelaying the proliferative phase.  Fibrocytes,\na subset of macrophage-derived cells responsible for ECM deposition,\nmay contribute to excessive fibrosis when dysregulated.\nCrosstalk between immune cells and nonhematopoietic\ncells, such\nas keratinocytes, is also disrupted in chronic wounds. Aberrant expression\nof microRNAs, including miR-34a/c, miR-203, miR-19a/b, and miR-20a,\nalters keratinocyte-mediated immune regulation, delays re-epithelialization,\nand amplifies inflammation via upregulation of the NF-κB pathway,\nresulting in increased pro-inflammatory cytokine and chemokine production. \n , \n  Collectively, these failures in immune coordination prevent proper\ntissue repair, resulting in chronic wounds or pathological scarring. \n ,\nMoreover, microbial colonization plays a central role in perpetuating\nchronic inflammation and impairing tissue repair. A systematic review\nencompassing 185 chronic wounds reported that 78.2% contained polymicrobial\nbiofilms, which provide structural and biochemical protection to pathogens\nagainst host immune defenses and antimicrobial therapies. \n , \n  In addition, coinfection with microorganisms such as Candida spp.\nand  Porphyromonas gingivalis  has been\nshown to inhibit cellular migration  in vitro , underscoring\nthe contribution of complex microbial communities to delayed healing,\nparticularly in oral mucosal lesions following cancer therapy.\nIn contrast, the wound healing process\ndiffers substantially between\ncutaneous and oral mucosal tissues. Experimental models demonstrate\nthat oral mucosal wounds exhibit reduced pro-fibrotic signaling and\nan expansion of fibroblast populations, which collectively promote\nearlier re-epithelialization, accelerated wound closure, and diminished\nscar formation compared with comparable skin lesions. \n , \n  Interleukin-1 (IL-1) signaling appears to play a tissue-specific\nrole in the oral mucosa, being essential for efficient healing and\nprotection of open wounds from bacterial invasion, while exerting\ncomparatively limited effects on cutaneous wound closure under similar\nconditions.  Supporting the concept that\noral tissues are primed for a heightened inflammatory responsiveness\ndue to continuous microbial exposure, ex vivo gingival biopsies have\nbeen shown to secrete higher levels of pro-inflammatory cytokines,\nincluding IL-6, IL-8, IL-1β, IL-10, and TNF-α, than skin\nbiopsies.  Furthermore, salivary secretions\nplay a critical role in oral tissue repair, as evidenced by hyposalivation\nmodels demonstrating delayed palatal wound healing, thereby highlighting\nthe importance of locally derived soluble factors in mucosal regeneration.  Collectively, these findings emphasize the distinct\nimmunobiological environment of oral tissues and its implications\nfor wound healing dynamics, particularly in the context of microbial\nburden and local regulatory factors.\n\nCBD, a nonpsychoactive phytocannabinoid\nisolated from  C. sativa  L., has attracted\nconsiderable attention\nfor its broad therapeutic potential, encompassing anti-inflammatory,\nanalgesic, antioxidant, and pro-regenerative effects.  While early cannabinoid research predominantly addressed\npsychoactive properties, emerging evidence since the early 2000s highlights\nCBD’s capacity to modulate immune responses, cellular signaling\npathways, and tissue repair mechanisms.  In the context of wound healing, CBD exerts effects across multiple\noverlapping phases, including the inflammatory, proliferative, and\nremodeling stages, by regulating immune cell function, oxidative stress,\nextracellular matrix deposition, and angiogenesis.\nWhile inflammation is essential for initiating\nthe natural wound-healing process , its\ndysregulation can shift healing toward a nonphysiological trajectory,\ncharacterized by chronic inflammation, delayed repair, and fibrosis.  This underscores the therapeutic importance\nof modulating, rather than suppressing, the inflammatory response\nto promoting effective tissue regeneration.\nCannabidiol (CBD)\noffers a promising strategy for controlling excessive inflammation\ndue to its multifaceted biological and chemical mechanisms. Unlike\nclassical anti-inflammatory agents, which typically act via cyclooxygenase\ninhibition, CBD does not entirely suppress inflammation; instead,\nit modulates the response by reducing excessive cytokine release,\nlimiting oxidative stress, and attenuating aberrant immune cell infiltration,\nthereby facilitating the resolution phase of healing. \n ,\nMechanistically, cannabidiol (CBD) exerts its biological effects\nprimarily through inhibition of the nuclear factor kappa B (NF-κB)\nsignaling pathway, a key regulator of pro-inflammatory gene interleukin-1\nreceptor antagonist (IL-1Ra) and selected cytokines \n , \n  ( Figure  \n ).  In vitro  studies further elucidate these molecular mechanisms.\nFor example, Sangiovanni et al.  demonstrated\nin HaCaT keratinocytes that CBD significantly reduced the release\nof vascular endothelial growth factor (VEGF), a central mediator of\nangiogenesis, and downregulated matrix metalloproteinase-9 (MMP-9),\nan enzyme critically involved in extracellular matrix degradation,\nin a dose-dependent manner. Additionally, CBD attenuated tumor necrosis\nfactor-α (TNF-α) expression via NF-κB inhibition,\nhighlighting its ability to modulate pro-inflammatory signaling without\ncompletely suppressing physiological inflammatory responses.  Beyond canonical pathway regulation, CBD also\ninteracts with targets within the expanded endocannabinoid system,\nincluding GPR18. Emerging evidence indicates that CBD may function\nas a partial agonist of GPR18, promoting activation of the MAPK p44/42\nsignaling cascade, which is implicated in cellular processes essential\nfor tissue repair and regeneration, such as proliferation, migration,\nand the regulation of apoptosis and autophagy.  Collectively, these findings underscore the pleiotropic\nsignaling profile of CBD and its potential therapeutic relevance in\nmodulating inflammation while supporting regenerative tissue outcomes.\nCollectively, these findings suggest that CBD acts as a regulatory\nmodulator of inflammation, creating a favorable environment for the\nsubsequent proliferative and remodeling phases of wound healing.\nSchematic\nrepresentation of the anti-inflammatory mechanisms of\ncannabidiol (CBD) through modulation of the NF-κB signaling\npathway. CBD exerts multifactorial anti-inflammatory effects by interfering\nwith key molecular events that control the transcription of pro-inflammatory\ngenes. Mechanistically, CBD suppresses the phosphorylation and subsequent\ndegradation of IκBα, thereby preventing NF-κB translocation\nfrom the cytoplasm to the nucleus. This results in the downregulation\nof NF-κB–dependent gene expression, including tumor necrosis\nfactor-α (TNF-α), interleukin-1β (IL-1β),\ninterleukin-6 (IL-6), and prostaglandin E2 (PGE2). In addition, CBD\nmodulates oxidative stress by reducing reactive oxygen species (ROS)\ngeneration and inhibits the expression of matrix metalloproteinases\n(MMP-2 and MMP-9), which are responsible for extracellular matrix\ndegradation. Collectively, these mechanisms contribute to the resolution\nof inflammation and restoration of tissue homeostasis, highlighting\nCBD’s potential as a therapeutic modulator in both acute and\nchronic wound environments. Created in BioRender. de Avila, E. (2026)  https://BioRender.com/11yguh7 .  License: KS29EDEUJ8 .\nKongkadee et al.  and\nTran et al.  corroborated these findings\nby demonstrating\nthat CBD downregulates pro-inflammatory mediators, particularly TNF-α\nand IL-1β, in macrophage-like and monocyte-derived cells. Both\nstudies showed that CBD effectively inhibits phosphorylation of the\np65 subunit of NF-κB, a critical step for its nuclear translocation\nand activation of inflammatory gene transcription. Specifically, Kongkadee\net al.  identified CBD as the most potent\nbioactive compound within hemp extract, showing that treatment with\n1 μg/mL maximally suppressed TNF-α production in RAW 264.7\nmacrophages. Moreover, CBD at concentrations ranging from 5 to 50\nμg/mL significantly decreased IL-1β secretion, further\nconfirming its dose-dependent immunomodulatory potential. Similarly,\nTran et al.  reported that treatment of\nTHP-1 cells with 6.6 μM CBD markedly reduced IL-6 and TNF-α\nproduction, concomitant with inhibition of IκB degradationan\ninhibitory protein that prevents NF-κB activation. In agreement\nwith these findings, Kozela et al.  demonstrated\nthat CBD impedes phosphorylation of the NF-κB p65 subunit, thereby\npreventing its nuclear translocation and subsequent transcription\nof pro-inflammatory cytokines ( Figure  \n ).\nEvidence from in vivo studies further substantiates\nthe anti-inflammatory\nproperties of CBD. Klein et al.  investigated\nthe effects of CBD on oral wound healing in Wistar rats and observed\nsignificantly lower inflammatory scores in CBD-treated animals compared\nto vehicle controls by the third day postinjury, indicating accelerated\nresolution of inflammation. Likewise, Genovese et al.  demonstrated that oral administration of CBD (10 mg/kg)\nreduced endometriosis-associated inflammation in Sprague–Dawley\nrats. This was characterized by increased IκB-α expression,\ndecreased cytosolic cyclooxygenase-2 (COX-2) levels, and reduced nuclear\nlocalization of NF-κB within lesion tissues. Moreover, the treatment\nled to reduced levels of TNF-α, IL-1β, and prostaglandin\nE2 (PGE2) in the peritoneal environment, collectively confirming CBD’s\nability to modulate both systemic and localized inflammatory responses.\nExpanding on these findings, Zhou et al.  recently developed a multifunctional hydrogel incorporating CBD\nto promote the repair of radiation-induced and cutaneous wounds. The\nhydrogel markedly reduced inflammation, enhanced collagen deposition,\nand accelerated tissue regeneration. Mechanistically, CBD treatment\nwas associated with modulation of key cytokines and chemokines, including\nIL-6, IL-17A, IL-22, CCL3, and CCL11, which are closely linked to\nthe regulation of macrophage polarization and attenuation of chronic\ninflammatory signaling cascades. The authors proposed that these effects\nhighlight CBD’s capacity to promote a shift toward a pro-resolving\nimmune environment, thereby facilitating wound closure and tissue\nremodeling.\nTaken together, the current body of evidence underscores\nCBD’s\npotential as a natural bioactive compound capable of attenuating inflammation\nand promoting wound repair through NF-κB pathway modulation\nand immune homeostasis restoration. Nonetheless, further studies are\nwarranted to optimize therapeutic dosing, elucidate biodistribution\ndynamics, and assess long-term safety to ensure the translational\nviability of CBD-based interventions in regenerative medicine.\nPersistent\ninflammation is often accompanied by oxidative stress due to an imbalance\nbetween reactive oxygen species (ROS) and antioxidant defenses.  High levels of ROS impair angiogenesis, damage\nDNA, and disrupt cellular signaling pathways essential for healing.  CBD acts as a potent antioxidant by scavenging\nROS and enhancing endogenous antioxidant systems such as glutathione\nperoxidase and superoxide dismutase (SOD). \n ,\nAntioxidant enzymes like SOD, glutathione peroxidase, and\ncatalase help to protect the cells in the human body from harmful\nreactive oxygen substances.  In this context,\nprevious studies have shown the beneficial effects of CBD on the reduction\nof the oxidation process. \n , , , \n  For instance, Genovese et al.  demonstrated that daily administration of CBD\nto Sprague–Dawley rats with endometriosis reduced oxidative\nstress. The thiobarbituric acid reactive substances (TBARS) assay\nrevealed a decrease in lipid peroxidation, while levels of glutathione\n(GSH) and SOD activity were restored. Furthermore, Western blot analysis\nshowed elevated expression of NADPH oxidase 1 (Nox-1) and Nox-4 in\ncontrol rats, which was significantly reduced with CBD treatment.\nAdditionally, recent studies have focused\non new biomaterials loaded\nwith CBD, including a hydrogel made from alginate-zinc infused with\nCBD (CBD/Alg-Zn), which demonstrated effective antioxidant activity\nin reducing ROS in an  in vivo  model.  In another study, Chelminiak-Dudkiewicz et al.  examined chitosan-based orodispersible films\nenriched with cannabis oil as a source of CBD on L929 mouse fibroblasts,\nrevealing noteworthy results in the context of antioxidant activity.\nThe antioxidant activity of pure chitosan film was modest (9.5%),\nbut the inclusion of CBD markedly enhanced radical-scavenging potentialup\nto 63.2%. DPPH assays revealed CBD concentration-dependent increases\nin antioxidant activity: 42.5% (1% CBD), 64.8% (5% CBD), and 72.7%\n(10% CBD). These findings highlight the strong antioxidant capacity\nof CBD-infused biomaterials for potential wound healing applications.\nAs previously discussed, the proliferative\nphase involves granulation tissue formation, and collagen depositon\nto create proteins in the extracellular matrix.  The presence of fibroblasts in the wound area is crucial\nfor the formation of granulation tissue and the synthesis and deposition\nof collage.  A study shows that CBD may\nalso support this phase by promoting fibroblast migration and matrix\nremodeling without impairing cellular proliferation.\nStyrczewska et al.  developed\na flax fiber dressing infused with CBD, which demonstrated promising\noutcomes in promoting cell proliferation and migration  in\nvitro . Although CBD did not significantly influence fibroblast\nor keratinocyte morphology or proliferation, it enhanced matrix metalloproteinase\nactivity and exerted notable anti-inflammatory effects. In wound healing\nassays, fibroblasts treated with CBD achieved full wound coverage\nwithin 48 h, with significantly fewer unhealed areas compared to controls.  Similarly, Kongkadee et al.  used an  in vitro  scratch assay to evaluate\nCBD’s effect on wound closure. At a concentration of 0.5 μg/mL,\nCBD significantly enhanced wound closure at 24-, 36-, and 48 h post-treatment,\nsupporting the potential of CBD in wound healing.  Futhermore, granulation tissue formation is also critical\nfor wound stabilization.\nDuring the granulation phase of wound healing,\nfibroblasts play a pivotal role in synthesizing and depositing extracellular\nmatrix (ECM) components, thereby providing structural integrity to\nthe developing tissue. Concurrently, keratinocytes at the wound margins\nproliferate and migrate centripetally to re-establish the epithelial\nbarrier.  Recent advances in biomaterial-based\ndelivery systems have sought to potentiate these cellular events through\nthe incorporation of bioactive molecules such as cannabidiol (CBD).\nIn this context, Zheng et al.  developed\na CBD-loaded alginate–zinc hydrogel (CBD/Alg–Zn) and\nevaluated its regenerative potential in a full-thickness excisional\nwound model in Sprague–Dawley rats. The CBD/Alg–Zn-treated\nwounds exhibited markedly enhanced granulation tissue formation, accelerated\nre-epithelialization, and reduced inflammatory cell infiltration compared\nwith both the Alg–Zn-only and untreated control groups. These\nfindings indicate that CBD, when combined with zinc and alginate,\nexerts synergistic effects likely attributable to its anti-inflammatory\nand antioxidant activities, as well as its potential to modulate fibroblast\nproliferation and ECM remodeling. Despite these promising outcomes,\nthe precise molecular pathways by which CBD influences fibroblast\nactivity, collagen deposition, and keratinocyte migration during granulation\nremain insufficiently characterized. Thus, further mechanistic studies,\nparticularly those integrating molecular profiling and advanced biomaterial\nsystems, are warranted to fully elucidate CBD’s role in this\ncritical phase of wound repair.\nCollagen constitutes the primary structural protein of the extracellular\nmatrix (ECM) in skin and connective tissues, providing mechanical\nstrength, structural integrity, and a scaffold for cell adhesion and\nmigration during tissue repair. \n , \n  The synthesis, organization,\nand remodeling of collagen fibers are tightly regulated processes\nthat determine the quality and strength of the healed tissue. Dysregulation\nof collagen deposition may result in impaired healing or excessive\nscar formation, underscoring the importance of modulating this pathway\nfor optimal wound repair.\nIn this context, cannabidiol (CBD),\na nonpsychoactive phytocannabinoid derived from  C.\nsativa , has emerged as a bioactive compound with potential\nregulatory effects on ECM remodeling. Zheng et al.  demonstrated that topical application of a CBD-loaded alginate-zinc\nhydrogel (CBD/Alg-Zn) significantly enhanced collagen deposition during\nthe wound healing process in Sprague–Dawley rats. Histological\nanalysis using Masson’s trichrome staining revealed a denser\nand more organized collagen network in both CBD/Alg-Zn- and Alg-Zn-treated\ngroups at days 7 and 14 postinjury, with the CBD-enriched hydrogel\nexhibiting superior performance compared to the zinc-only formulation.\nThese findings suggest that CBD may potentiate the reparative effects\nof zinc and alginate by synergistically promoting fibroblast activity\nand ECM synthesis.\nFurther supporting this notion, Qi et al.  investigated the osteogenic and extracellular\nmatrix-modulatory\neffects of CBD in human dental pulp stem cells (hDPSCs). After 6 h\nof CBD exposure, there was a marked upregulation in the expression\nof collagen type I and II genes, indicating that CBD can stimulate\nthe early stages of matrix protein synthesis in mesenchymal-derived\ncells. Type I collagen is the predominant fibrillar form found in\ndermal and bone tissues, while type II collagen is characteristic\nof cartilaginous structures, highlighting CBD’s broad influence\nacross different tissue types.\nAlthough the precise molecular\nmechanisms underlying CBD-induced\ncollagen deposition remain incompletely understood, emerging evidence\npoints toward the involvement of cannabinoid receptors (CB1 and CB2)\nand peroxisome proliferator-activated receptor γ (PPARγ)\npathways, which can regulate fibroblast proliferation, differentiation,\nand ECM turnover. Additionally, CBD’s antioxidant and anti-inflammatory\nactivities may create a microenvironment favorable to collagen maturation\nby reducing oxidative stress and pro-inflammatory cytokine release,\nboth of which are known to impair matrix assembly.\nDespite these\nencouraging findings, comprehensive mechanistic and\ntranslational studies are still required to confirm the direct targets\nof CBD in collagen biosynthesis, fiber organization, and cross-linking.\nFuture research should integrate molecular, histological, and biomechanical\nanalyses to elucidate how CBD influences ECM dynamics during various\nphases of wound healing and tissue regeneration.\nWound contraction constitutes a fundamental component of the proliferative\nphase of tissue repair, contributing to wound closure through centripetal\nmovement of the wound edges. This process is predominantly mediated\nby the differentiation of fibroblasts into contractile myofibroblasts,\na transition that typically occurs within 10–14 days postinjury.  Myofibroblasts express α-smooth muscle\nactin (α-SMA) within stress fibers, generating contractile forces\nthat reorganize the collagenous matrix and promote mechanical closure\nof the wound bed.  The fibroblast-to-myofibroblast\ntrans differentiation is orchestrated by a complex interplay of cytokines\nand growth factors, including transforming growth factor-β1\n(TGF-β1), platelet-derived growth factor (PDGF), and connective\ntissue growth factor (CTGF), which collectively regulate cytoskeletal\nassembly, matrix remodeling, and integrin-mediated cell–matrix\ninteractions.\nAlthough the role\nof cannabidiol (CBD) in modulating wound contraction remains incompletely\nelucidated, growing evidence suggests it may influence fibroblast\nactivity, ECM remodeling, and inflammatory resolutionfactors\nindirectly linked to contractile efficiency. Gangopadhyay et al.  demonstrated that a polyherbal Ayurvedic formulation\ncontaining  C. sativa  accelerated wound\ncontraction in full-thickness excision wounds in Wistar rats, achieving\na significantly smaller wound area within 6 days of treatment. While\nthis study did not isolate CBD as the active component, the findings\nimply a potential cannabinoid-mediated enhancement of granulation\ntissue formation and matrix remodeling.\nIn contrast, Klein et\nal.  evaluated\nthe effect of pure CBD in an oral mucosal injury model in Wistar rats.\nAlthough topical CBD application did not significantly reduce lesion\nsize on days 3 and 7, histological analyses revealed markedly reduced\ninflammatory cell infiltration and lower inflammatory scores at day\n3. These results indicate that CBD does not inhibit inflammation outright\nbut rather modulates its resolution, likely through suppression of\nexcessive pro-inflammatory cytokine release (e.g., TNF-α, IL-1β)\nand promotion of the transition to the proliferative phase. This immunomodulatory\naction may indirectly favor wound contraction by establishing a microenvironment\nconducive to fibroblast proliferation and differentiation, even if\nimmediate contraction effects were not evident in oral tissue.\nFurther insights were provided by McIver et al.,  who investigated the topical application of a CBD-manuka\nhoney formulation in equine limb wounds. Despite the known pro-healing\nand antimicrobial properties of manuka honey, the combination did\nnot significantly alter wound contraction rates or overall healing\ntime compared to controls. These findings highlight the complexity\nof translating rodent and in vitro data to large-animal and clinical\nmodels, where differences in skin architecture, wound tension, and\npharmacokinetic profiles can markedly influence therapeutic outcomes.\nAt the molecular level, preliminary studies have suggested that\nCBD may modulate the TGF-β/Smad signaling axis, a central pathway\nin myofibroblast differentiation and matrix contraction. In addition,\nCBD’s antioxidant and endocannabinoid receptor-mediated actionsparticularly\nthrough CB2 and PPARγ activationcould attenuate excessive\noxidative stress and inflammatory signaling, thereby optimizing the\nwound microenvironment for balanced matrix remodeling and contraction. \n , \n  However, direct evidence linking CBD to α-SMA expression or\nmechanical wound contraction remains scarce.\nAltogether, these\nfindings suggest that CBD’s influence\non wound contraction is likely indirect, mediated through its effects\non inflammatory resolution, fibroblast activation, and ECM dynamics,\nrather than through direct stimulation of contractile mechanisms.\nFuture research should aim to clarify these interactions through well-controlled\ndose–response studies, standardized delivery systems, and mechanistic\nanalyses involving molecular markers of myofibroblast differentiation\n(e.g., α-SMA, vimentin, and FAK phosphorylation). Understanding\nthese pathways will be critical to harnessing CBD’s potential\nas a regulator of balanced tissue repair and fibrosis prevention.\nThe remodeling or maturation phase represents the\nfinal stage of wound healing, typically commencing 2 to 3 weeks after\ninjury and persisting for several months. This phase is characterized\nby the replacement of the provisional extracellular matrix (ECM) with\na mature, functionally organized matrix, predominantly composed of\ntype I collagen, and by the re-establishment of tissue architecture\nand mechanical strength.  Key cellular\nprocesses include re-epithelialization, collagen fiber cross-linking\nand alignment, regression of neovasculature, and apoptosis of myofibroblasts\nonce sufficient wound tension is achieved. The interplay between fibroblasts,\nkeratinocytes, endothelial cells, and immune cells determines the\nstructural and functional outcome of the healed tissue.\nEmerging\nevidence suggests that cannabidiol (CBD) exerts modulatory effects\nduring the remodeling phase through its influence on epithelial differentiation,\nECM reorganization, and vascular stabilization. In a study by Klein\net al.,  topical administration of CBD\non traumatic tongue ulcers in Wistar rats resulted in enhanced epithelial\ntissue structuring and organization during the late stages of healing.\nHistological evaluation revealed increased epithelial thickness, acanthosis,\nand hyperkeratinization, accompanied by more organized collagen fiber\ndeposition and pronounced neovascularization. These histopathological\nfeatures collectively indicate a stimulatory effect of CBD on tissue\nmaturation and ECM remodeling.\nComplementary findings from noncutaneous\nmodel further support\nCBD’s role in tissue remodeling. For instance, Zhang et al.  demonstrated that CBD treatment attenuated tissue\nswelling, fiber rupture, and inflammatory cell infiltration in a murine\nmodel of myocardial injury (C57BL/6 mice). These improvements were\nassociated with reduced oxidative stress markers and enhanced organization\nof myocardial fibers, suggesting a broader role of CBD in postinjury\ntissue restoration and ECM homeostasis.\nMechanistically, CBD’s\nregulatory influence on remodeling\nis thought to involve several convergent pathways. Through activation\nof cannabinoid receptor type 2 (CB2) and peroxisome proliferator-activated\nreceptor γ (PPARγ), CBD modulates fibroblast activity,\npromotes collagen maturation, and attenuates excessive matrix metalloproteinase\n(MMP) activity, thereby preventing aberrant degradation of newly synthesized\ncollagen.  Additionally, CBD’s\nantioxidant capacity mitigates reactive oxygen species (ROS)-induced\ncollagen cross-link disruption, while its anti-inflammatory effects\ncontribute to the resolution of the wound milieu, allowing for balanced\nfibroblast-to-myofibroblast transition and appropriate ECM turnover.\nCBD may also influence keratinocyte behavior during re-epithelialization.\nStudies have shown that cannabinoids can regulate keratinocyte proliferation\nand differentiation through TRPV1, CB1, and CB2 receptor-mediated\npathways. \n , \n  By modulating intracellular\ncalcium signaling and cytokine release, CBD may foster a microenvironment\nconducive to epithelial barrier restoration and stratified epidermal\nregenerationprocesses essential for complete tissue closure\nand long-term wound stability.\nDespite these promising indications,\ncurrent literature remains\ninsufficient to establish a definitive understanding of CBD’s\nrole in ECM remodeling and re-epithelialization. The available studies\nare limited by heterogeneous experimental designs, variations in CBD\nconcentrations, and lack of standardization regarding formulation\ntype (topical vs systemic) and administration timing. Furthermore,\nlong-term effects on scar quality, tensile strength, and fibrosis\nrisk have not been systematically evaluated.\nFuture investigations\nshould integrate quantitative biomechanical\nassessments, molecular profiling of ECM components (e.g., type I/III\ncollagen ratio, MMP/TIMP balance), and high-resolution imaging techniques\nto clarify CBD’s influence on the architectural and functional\noutcomes of tissue remodeling. Elucidating the optimal dosage and\ndelivery method will be crucial for translating CBD’s reparative\npotential into therapeutic strategies for chronic wounds, fibrotic\ndisorders, and implant-tissue interfaces.\n\nBone healing is a dynamic and tightly regulated\nprocess comprising\nthree overlapping phases: inflammation, repair, and remodeling.  Intraoral bone remodeling is also influenced\nby the mechanical load from mastication.  Unlike extraoral skeletal sites where remodeling is predominantly\nregulated by systemic factors such as estrogen deficiency, parathyroid\nhormone levels, aging, and biomechanical stimuli, intraoral bone is\npersistently challenged by microbial stimuli. \n − \n \n  Continuous exposure to microbial challenge decisively modulates\nthe cellular and molecular mechanisms involved in tissue repair, characterizing\nbone healing in the intraoral region as a unique osteoimmune microenvironment.\nDuring the remodeling phase, bone turnover\ndepends on the rigorously\ncoordinated coupling between osteoclast-mediated resorption and osteoblast-driven\nbone formation.  In intraoral sites,\nthis coupling is frequently compromised by chronic low-grade inflammation\ntriggered by dysbiotic biofilms enriched with key pathogens such as  P. gingivalis ,  Treponema denticola , and  Tannerella forsythia . \n , \n  These microorganisms activate host pattern recognition receptors,\nparticularly Toll-like receptors (TLR2 and TLR4), in resident immune\ncells, osteoblasts, and periodontal ligament fibroblasts, leading\nto NF-κB activation and the transcription of pro-inflammatory\ncytokines such as TNF-α, IL-1β, and IL-6.\nAnother fundamental mechanism for intraoral\nbone resorption is\nthe dysregulation of the RANK/RANKL/OPG axis.  In situations such as periodontal inflammation, there is\nan increase in the expression of receptor activator of nuclear factor\nkappa B (RANKL) ligand by activated T and B lymphocytes, osteoblastic\nlineage cells, and periodontal ligament cells, while simultaneously\nreducing the levels of its decoy receptor, osteoprotegerin (OPG).  This increased RANKL/OPG ratio intensifies\nthe binding of RANKL to RANK in osteoclastic precursors, activating\nintracellular signaling pathways such as TRAF6, NF-κB, MAPKs,\nand NFATc.  This signaling cascade promotes\nthe differentiation, polarization, and fusion of multinucleated osteoclasts,\nincreasing the expression of tartrate-resistant acid phosphatase (TRAP),\ncathepsin K, and integrin αvβ3, culminating in extracellular\nmatrix degradation and mineral dissolution. In addition, mechanisms\ninitiated by virulence factors such as lipopolysaccharides (LPS) from\nGram-negative anaerobes can directly or indirectly stimulate the differentiation\nof osteoclastic precursors through the activation of stromal and immune\ncells.  Furthermore, Th17 cells and IL-17\nhave been shown to amplify osteoclastogenic signaling, connecting\nadaptive immunity to alveolar bone destruction.  Collectively, evidence from osteoimmunology demonstrates\nthat intraoral bone remodeling represents a paradigmatic model of\ninflammation-induced bone loss, in which host-microorganism interactions\ncritically determine the balance between tissue regeneration and destruction.\nPrevious studies have demonstrated that CBD, the main nonpsychoactive\ncomponent of cannabis, can enhance healing and recovery after bone\ninjuries. \n , − \n \n  The current knowledge is rather limited and partly contradictory\nregarding the effect of exogenous cannabinoids on bone cells, and\nthe more elaborate knowledge on the endocannabinoid system with respect\nto bone. Bone wellness depends on the coordinated action of osteoclast\n(OC) and osteoblast (OB) cells. The OC is a multinucleated bone cell\nderived from the hematopoietic lineage and formed through fusion of\nmononucleated precursors of the myeloid lineage. While OC cells can\nresorb bone matrix, OB are the bone-forming cells originating from\nthe mesenchymal lineage. From an inflammatory perspective, OC and\nOB cells have been shown to express CB1 and CB2 receptors, both involved\nin the pathways of the endocannabinoid system.  CBD has been demonstrated to function as a molecule that\nacts like a noncompetitive antagonist for CB1 and CB2, primarily for\nCB, \n , \n  inhibiting the receptor’s activity\nwithout directly blocking the agonist binding site. However, inconsistent\ninformation has been reported regarding the effects of endocannabinoids\non OCs. In a controlled  in vitro  study, Idris et\nal.  observed a stimulation of RANKL-induced\nOC formation by the addition of the substances: HU308, 2-AG or AEA,\nin the cell culture medium. Conversely, in 2016, Ofek et al.  observed an opposite effect, i.e., the inhibition\nof RANKL-induced OC formation by HU308, as a selective CB2 endocannabinoid\nagonist.  In fact, AEA reveals a conflicting\nrole, since this endocannabinoid agonist may stimulate human OCs to\nform actin rings as well as to resorb bone  in vitro , depending on its concentration. More recently, Nielsen et al.  raised an important question regarding the\nneed to ensure that the dosage of CBD used to treat cultured cells\nis of pharmacological relevance. In this sense, the authors found\nthat no or only weak inhibition of OC differentiation occurred in\nthe lower doses tested (≤10 μM). Indeed, the number of\nnuclei per osteoclast cell significantly impacts its function, particularly\nin bone resorption. Previous studies have already indicated a strong\ncorrelation between number of nuclei and OC morphology, with bone\nformation/resorption, strongly suggesting that multinucleated osteoclast\nimproves resorption efficiency  ( Figure  \n ).\nProposed mechanisms underlying\nthe modulatory effects of cannabidiol\n(CBD) on bone resorption. Cannabidiol may influence bone remodeling\nby modulating osteoclast (OC) differentiation and activity through\ninteraction with the endocannabinoid system. Both cannabinoid receptors\nCB1 and CB2 are expressed in osteoclast lineage cells, and CB2 expression\nis markedly upregulated under inflammatory conditions, suggesting\nan active role in the regulation of osteoclastogenesis and bone turnover.\nMultinucleated, mature osteoclasts exhibit enhanced resorptive capacity;\nhowever, CBD is proposed to attenuate excessive osteoclastic activity\nby reducing pro-inflammatory signaling cascades and cytokine production,\nincluding tumor necrosis factor-α (TNF-α), interleukin-1β\n(IL-1β), and receptor activator of nuclear factor κB ligand\n(RANKL). Through CB2 receptor activation and downstream signaling\nmodulation, CBD may exert anti-inflammatory and homeostatic effects,\ndampening nuclear factor κB (NF-κB) and mitogen-activated\nprotein kinase (MAPK) pathways while promoting osteoprotective mediators.\nCollectively, these actions may contribute to a reduction in inflammation-driven\nbone resorption and to the maintenance of balanced bone remodeling.\nCreated in BioRender. de Avila, E. (2026)  https://BioRender.com/11yguh7 .  License: IA29EDLMOS .\nImportantly, recent mechanistic study supports\nthat CBD can directly\npromote osteogenesis under inflammatory conditions in a receptor-\nand pathway-dependent manner. Li et al. demonstrated that CBD enhanced\nosteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs)\nexposed to inflammatory stimulation, restoring osteogenic markers\nand mineralization while reducing inflammatory mediator expression;\ncritically, these effects were linked to CB2-dependent activation\nof p38 MAPK signaling, reinforcing the concept that CBD may “re-couple”\nosteogenesis during inflammation rather than acting solely as an antiresorptive\nagent.  This is consistent with evidence\nthat CBD can activate or modulate MAPK-related programs associated\nwith osteogenic differentiation, including increased ALP activity,\nupregulation of osteoblast lineage markers, and enhanced mineral deposition\nin osteoblast-like cells.\nExtending\nthese observations to oral craniofacial contexts, CBD\nhas also been shown to promote odonto/osteogenic responses in dental-derived\nprogenitors. Qi et al. reported that CBD induced odonto/osteogenesis\nin human dental pulp cells (HDPCs), supporting the feasibility of\nCBD-mediated hard-tissue regenerative programs in oral settings.  In an inflammatory mimic, Yu et al. further\ndemonstrated that CBD rescued TNF-α–inhibited proliferation,\nmigration, and osteogenic/odontogenic differentiation of dental pulp\nstem cells (DPSCs), while concomitantly reducing TNF-α–induced\nexpression of pro-inflammatory cytokines (TNF-α, IL-1β,\nIL-6) and upregulating pro-angiogenic VEGF expressionfeatures\nhighly relevant to bone regeneration and vascularized repair in infected\nor inflamed microenvironments.  Collectively,\nthese studies strengthen the biological plausibility of CBD as a dual-action\nmodulator in oral bone regeneration, simultaneously counteracting\ninflammatory suppression of osteogenesis and supporting pro-reparative\ncellular behaviors (migration, angiogenic signaling) in MSC-like populations.\nOn the other hand, CBD also influences bone biology through nonclassical\ntargets. Previously, CBD has been reported to modulate the orphan\nG protein-coupled receptor GPR55, which plays a functional role in\nbone remodeling.  Whyte et al.  showed that activation of GPR55 by its agonists\nincreased OC polarization and intensified resorptive activity, whereas\nthese effects were markedly reduced in OC derived from GPR55–/–\nmice and after CBD treatment, consistent with CBD acting as a functional\nantagonist of GPR55. In addition, CBD has been reported to promote\nOB migration and mesenchymal stem cell differentiation in vitro via\nantagonism of GPR55.  More recent evidence\nreinforces the relevance of the LPI–GPR55 axis as a regulator\nof osteoclast differentiation and function and provides additional\nmechanistic support for CBD-mediated antagonism in this pathway. Mosca\net al. (2021) demonstrated that GPR55 signaling modulates osteoclast\nactivity in RANKL-driven differentiation systems, where lysophosphatidylinositol\n(LPI) enhanced osteoclast activity and GPR55 antagonism reduced resorptive\nfunction.\nIndeed, the stimulatory\nand inhibitory effects of cannabinoids\non bone cells is a complex matter. Although cannabis is portrayed\nas a dangerous drug, also due to its ability to reduce bone mineral\ndensity, CBD, as a nonpsychoactive component of  C.\nsativa , also presents therapeutic properties in bone\nrepair/remodeling that are not yet fully understood. In 2020, Kang\net al.  investigated the impact of CBD\non osteoblastic differentiation and found that the CBD treatment upregulated\nthe expression of angiopoietin-1, enhanced alkaline phosphatase (ALP)\nactivity, and stimulated cell migration and calcium deposition. The\nresults also demonstrated a time-dependent increase in the expression\nof osteoblast-related proteins that induce bone, including distal-less\nhomeobox 5 (DLX5), bone sialoprotein (BSP), osteocalcin (OCN), type\nI collagen, Runx2, osterix (OSX), and ALP matrix-related mineralization.\nMechanistically, Kang et al. (2020) further\nlinked these osteogenic\neffects to strengthened interactions among RUNX2/OSX and phosphorylated\np38 MAPK, suggesting that CBD can facilitate transcriptional control\nof osteoblast lineage commitment via MAPK-driven osteogenic signaling.  Together with the CB2–p38-dependent\nosteogenic rescue observed in inflammatory BMSC models,  these findings support a convergent theme in\nwhich CBD may promote osteoblastogenesis through p38 MAPK–associated\npathways, with receptor dependence likely varying by cell type and\ninflammatory context.\nDuring the repair phase, vascular invasion\nand collagen matrix\ndeposition lead to callus formation. Fibroblasts contribute by forming\na stroma conducive to vascular growth.  In this sense, Kogan et al.  examined\nthe influence of CBD on fracture healing in a rat model and demonstrated\nthat CBD enhanced the biomechanical strength of the fracture callus\nwithout affecting its volume or mineral content. The increased mechanical\nintegrity was attributed to upregulation of PLOD1, an enzyme responsible\nfor collagen cross-linking, in osteoblast cultures treated with CBD.\nThese findings highlight the specific role of CBD in improving fracture\nhealing in long bones, increasing the biomechanical quality of the\nnewly formed bone.\nThis observation\nis particularly relevant for craniofacial and\nperi-implant regeneration, where collagen cross-linking and matrix\nmaturation influence the mechanical quality of newly formed bone and\nthe stability of the implant–bone interface. Although long-bone\nfracture models cannot be directly extrapolated to intraoral bone,\nthe mechanistic emphasis on collagen cross-linking enzymes suggests\nthat CBD may affect not only osteogenic differentiation but also the\nmaterial properties of repair tissue, an aspect often overlooked in\noral regenerative discussions.\nThe final stage of fracture healing\nis the remodeling phase, during\nwhich bone regains its original architecture, function, and mechanical\nstrength. This process, which can span several months to years, is\nmodulated by mechanical stimuli.  Under\naxial loading, bone is formed in regions experiencing stress and resorbed\nin areas where it is not required.  A\nrecent study by Kamali et al.  reported\nthat CBD accelerated healing and improved biomechanical properties\nin a rat model of critical-sized bone defect through the mesenchymal\nstem cell migration and osteogenic differentiation, leading to a more\neffective bone bridge formation at the defect site.  Although literature regarding the effect of CBD on this\nprocess remains scarce, the found information reinforces the idea\nthat CBD could be a promising therapeutic option for promoting bone\nhealing and remodeling.\nNotably, emerging oral-focused literature\nhighlights an additional\ntranslational layer: beyond host cell modulation, CBD may also influence\nthe microbial drivers of osteoimmune dysfunction. For instance, CBD\ndemonstrated antimicrobial activity against multispecies subgingival\nbiofilms  in vitro , supporting the possibility that\nCBD-based local delivery platforms might provide dual benefits: reducing\nmicrobial burden while modulating host inflammation and bone remodeling\npathways.  This is particularly aligned\nwith periodontal and peri-implant pathogenesis, where persistent biofilm\nchallenge sustains NF-κB signaling, elevates RANKL, and prolongs\nosteoclastogenic cues.\n\nRegarding the commercial availability of cannabinoid-based\nmedicines,\nonly a few have been rigorously tested to assess their safety and\nefficacy. They have therefore been approved for use at the national\nlevel by regulatory agencies. Epidiolex is an oral solution of 98%\npure cannabidiol (CBD). The medicine is approved for the treatment\nof seizures in pediatric patients with Lennox-Gastaut syndrome or\nDravet syndrome.  The biological effects\nof cannabinoids, the major constituents of the ancient medicinal plant  C. sativa  (marijuana) are mediated by two members\nof the G-protein coupled receptor family, cannabinoid receptors 1\n(CB1R) and 2. The CB1R is the prominent subtype in the central nervous\nsystem (CNS) and has drawn great attention as a potential therapeutic\navenue in several pathological conditions, including neuropsychological\ndisorders and neurodegenerative diseases. Furthermore, cannabinoids\nalso modulate signal transduction pathways and exert profound effects\nat peripheral sites. Despite the therapeutic potential of cannabinoids,\ntheir clinical application has been significantly hindered by their\npsychoactive effects. In this review, we briefly summarized our knowledge\nof cannabinoids and the endocannabinoid system, focusing on the CB1R\nand the CNS, with emphasis on recent breakthroughs in the field. We\naim to define several potential roles of cannabinoid receptors in\nthe modulation of signaling pathways and in association with several\npathophysiological conditions. We believe that the therapeutic significance\nof cannabinoids is masked by the adverse effects and here alternative\nstrategies are discussed to take therapeutic advantage of cannabinoids.  Sativex is also a mouth spray formulated from\nthe extract of the  C. sativa  L. plant,\ncontaining mainly Δ 9 -THC and CBD in almost equal\nproportions. It is indicated for the treatment of spasticity.  However, although there are CBD-based medicines,\nnone of them are indicated for promoting tissue and bone regeneration.\nNow, CBD is being studied in several\npreclinical studies, showing\nsurprising results. However, CBD has limitations due to its highly\nlipophilic nature with a log  P  of 6.3, which\nrepresents the logarithm of the partition coefficient of a drug between\nn-octanol and water and, it has low water solubility, measuring at\n12.6 mg/L. These characteristics allow CBD as a Class II substance\nin the Biopharmaceutical Classification System (BCS), characterizing\nit as a substance with low water solubility.  CBD is extensively metabolized in the liver, mainly through hydroxylation,\nforming 7-OH–CBD. This compound undergoes further metabolization,\ngenerating various metabolites, which are eliminated from the body\nvia feces and urine.\nBioavailability\nrefers to the proportion of a drug that reaches\nsystemic circulation unchanged. Intravenous administration provides\n100% bioavailability, while oral, inhaled, or transdermal routes reduce\nit due to incomplete absorption. CBD’s bioavailability clearly\nvaries depending on the method of administration.  When clinically applied, the bioavailability of aerosolized\nCBD has been reported to be capable of generating rapid peaks in plasma\nconcentration between five and 10 min, with significantly higher bioavailability\n(around 31%) compared to oral administration.  Oral bioavailability was estimated at 6%, mainly due to\nextensive first-pass metabolism, where drug molecules are metabolized\nbefore entering systemic circulation, which can reduce their bioavailability.  Thus, administering cannabinoids via inhalation\nor oral mucosal routes provides an alternative method that by passes\nor minimizes extensive first-pass metabolism, as seen with oral cannabinoid\nadministration.\nThe effective\ndose of CBD shows great variability between individuals,\ninfluenced by factors such as metabolism, body weight, age, gender,\nand clinical conditions, which represents a challenge for the development\nof universal release systems.  One study\nshowed that in humans, after ingesting an oral capsule containing\n5.4 mg of CBD, the average maximum plasma concentration (Cmax) was\n0.93 ng/mL, which was higher in women than in men.  Furthermore, in one experiment, coadministration of lipids\nwith oral CBD increased systemic availability by almost three times\nin rats.  These findings reinforce the\nneed for personalized strategies to optimize its administration in\ndifferent patient profiles.\nIn the past decade, there has been\na growing number of studies\nfocused on enhancing the solubility of class II drugs. Schedule II\ndrugs, according to the Biopharmaceutical Classification, substances\nor chemicals are defined as drugs with a high potential for abuse,\nwith use potentially leading to severe psychological or physical dependence.  The bioavailability of these drugs is directly\ninfluenced by their dissolution rate, which is closely related to\nsolubility, consequently, an improved solubility leads to enhanced\nbioavailability. Various strategies can be employed to optimize the\ndissolution rate, such as nanonization, which involves reducing the\nparticle size of the active pharmaceutical ingredient (API) to a nanometric\nscale.  According to the Noyes-Whitney\nequation, which indicates the dissolution rate of a solid in a solvent,\nreducing the particle size of a drug increases its surface area, resulting\nin a proportional increase in the dissolution rate. Consequently,\nthis leads to better absorption of drugs with low solubility.  In this context, the use of nanotechnology\nas a drug delivery system has gained prominence due to its unique\nproperties, which include advantages in controlling the physicochemical\nbehavior of the drug, such as solubility and release, as well as directing\nthe drug to the target site, reducing adverse effects.  Nanosystems play a vital role in safeguarding\ndrugs from damage in the gastrointestinal region, thereby facilitating\nthe efficient administration of class II drugs to their intended targets.  One notable characteristic of these nanodrug\ndelivery systems is their remarkable versatility in terms of application\nroutes. These routes include parenteral, oral, nasal, pulmonary, ocular,\nand transdermal routes.  Among various\nnanomaterials, liposomes, vesicles, micelles, nanoparticles, nanosuspensions,\nmicroemulsions, and nanoemulsions are notable  to enhance the solubility of CBD.\nTran et al. developed\na CBD-based nanoemulsion to evaluate its\nregenerative potential and bioavailability using an  in vitro  human corneal substitute model. The formulation demonstrated superior\nphysicochemical stability, retaining 93.57% of cannabidiol (CBD) content,\nwhereas pure CBD exhibited only 53.58% retention after 4 h of exposure.  This difference was attributed to degradation\nand metabolic susceptibility of the free compound, while the nanoemulsion\nmatrix provided a protective environment that enhanced CBD chemical\nstability during topical application.\nIn the context of dental applications, recent investigations\nhave\nexplored CBD-loaded biomaterials as local delivery platforms, particularly\nin scenarios requiring prolonged retention and controlled release\nwithin the oral cavity. For example, a chitosan-based mucoadhesive\nhydrogel incorporating CBD-loaded poly­(lactic- co -glycolic\nacid) (PLGA) nanospheres was designed to improve mucosal permeability\nand local drug availability. In vitro analyses demonstrated a pro-reparative\nprofile characterized by downregulation of inflammatory cytokines,\nsuggesting potential therapeutic applicability in oral inflammatory\nconditions such as gingivitis and periodontitis.  Furthermore, CBD has been incorporated into multifunctional\nregenerative hydrogels targeting bone repair. An alginate-based copper-CBD\nhydrogel exhibiting antibacterial properties was shown to enhance\nboth osteogenic differentiation and angiogenic responses in vitro.  Collectively, these biomaterial systems highlight\nthe potential of nanotechnology-enabled approaches to optimize local\nCBD delivery to oral tissues; however, robust clinical validation\nremains lacking.\nTo date, relatively few studies have investigated\nnanotechnology-based\nstrategies to enhance the biological performance of CBD, and the available\nliterature is limited by the scarcity of comprehensive preclinical\nand clinical investigations. Therefore, further well-designed in vitro\nand in vivo studies are warranted to elucidate the therapeutic benefits\nof CBD and to clarify its underlying mechanisms of action in wound\nhealing and bone regeneration, thereby facilitating translation into\nclinical practice.\nIn November\n2017, the World Health Organization (WHO)  Expert Committee on Drug Dependence (ECDD) concluded that pure CBD\ndoes not appear to pose a risk of abuse or cause harm. The current\nevidence does not justify reclassifying this substance. However, the\ndecision on its legal status is the responsibility of the legislators\nin each country. Some countries, such as Australia, Canada, Switzerland,\nthe United Kingdom, and the United States, have loosened regulations\non CBD, classifying CBD-containing products as medicines.\nFurthermore,\nin 2018, the Food and Drug Administration (FDA) approved the use of\nEpidiolex, a CBD-based drug, for the treatment of seizures associated\nwith tuberous sclerosis complex in patients aged one year and older\nafter concluding that the drug is safe and effective for this indication.\nFollowing its approval, Epidiolex was classified as a Schedule V substance,\nthe least restrictive category, reserved for medicines with a low\npotential for abuse. This removed it from the Schedule I classification,\nwhich includes substances with a high potential for abuse and no accepted\nmedicinal value under the Federal Controlled Substances Act of 1970.\nIn 2019, the European Medicines Agency (EMA) approved the first\ncannabinoid-derived medicine. This drug, composed of isolated CBD,\nhas been authorized for the treatment of children with intractable\nepilepsy and has been designated an orphan drug because there are\nno similar therapeutic alternatives available.\nAlso, in 2019,\nthe National Health Surveillance Agency (Anvisa)  in Brazil regulated the manufacture and sale\nof CBD-based products in pharmacies on prescription to treat serious\nconditions such as refractory epilepsy, autism, and degenerative neurological\ndiseases. The agency has imposed limits on the THC content: products\nwith up to 0.2% can be prescribed for a wide range of patients, while\nthose with a higher content are restricted to patients in palliative\ncare or with no other therapeutic options.\nOn the other hand,\nin most Latin American countries, the medicinal\nuse of cannabidiol (CBD) is authorized, especially for the treatment\nof specific diseases such as epilepsy and other neurodegenerative\nconditions. However, regulations regarding the production, sale, and\nimport of CBD-based products increase considerably between countries.\nIn addition, the recreational use of cannabis remains illegal in almost\nthe entire region, of one except Uruguay. The trend is toward a gradual\nrelaxation of the laws, accompanied by the implementation of standards\nthat ensure the safe and regulated use of the substance.\nDespite the advances in legislation,\nthere is still a need to carry\nout more research, establish clear and accessible regulations, and\nmaintain continuous monitoring to guarantee the efficacy and safety\nof CBD use as a therapeutic medicine.\n\nIn conclusion, this critical\nreview examined the biological mechanisms\nthrough which cannabidiol (CBD) may contribute to wound healing and\nbone repair/regeneration. Current preclinical evidence supports the\ntherapeutic potential of CBD in enhancing both soft- and hard-tissue\nrepair by modulating key molecular pathways involved in inflammation,\ncellular proliferation, angiogenesis, and extracellular matrix remodeling.\nDespite these promising findings, important translational challenges\nremain. In particular, the minimum effective dose required to achieve\ntherapeutic benefits while minimizing adverse effects has not yet\nbeen clearly established, underscoring the need for rigorous dose–response\nand safety studies to enable clinical application in humans.\nWith respect to bone repair and regeneration, several mechanistic\naspects require further clarification, including the interaction of\nCBD with osteoblast and osteoclast receptor systems, its effects on\nosteoclast multinucleation and activity, and the resulting impact\non the balance between bone formation and resorption. The studies\ndiscussed in this review collectively highlight substantial knowledge\ngaps regarding both the local and systemic effects of CBD, as well\nas its integration within complex intracellular signaling networks.\nTherefore, additional well-designed mechanistic investigations, followed\nby robust preclinical and clinical studies, are necessary before routine\nclinical implementation can be considered. Concurrently, comprehensive\nevaluation of optimal dosage regimens, pharmacokinetics, bioavailability,\nand bio efficacy of CBD-based drugs and biomaterials will be essential\nto support their safe and effective translation into oral and craniofacial\nregenerative therapies.","source_license":"CC-BY-4.0","license_restricted":false}