The accumulation of senescent cells during aging contributes to the progression of various age-related pathologies. Ineffective immune clearance, increased half-life of senescent cells, and bystander senescence are considered the primary drivers of this age-associated accumulation. Most of these causes stem from the aging of the immune system, which results in a prolonged persistence of damaged/nonfunctional cells within tissues and allows the internal senescence program to progress to a more severe phenotype. Here, we propose the existence of an additional immune-independent mechanism underlying the accumulation of senescent cells during aging. By reanalyzing existing experimental evidence, we show that cells of diverse identities and tissue origins become increasingly susceptible to senescence with age. The latter implies that epigenetic and molecular changes that cells acquire during aging create a permissive background for the activation of the senescence program. In light of our findings, senotherapeutic interventions alone may be insufficient to substantially alter the trajectory of organismal aging. Effective strategies may need to target upstream drivers of cellular dysfunction, including age-associated epigenetic alterations. Epigenetic rejuvenation could, in principle, enhance cellular stress resilience and thereby reduce the rate at which senescent cells emerge and accumulate.

ObjectiveTo systematically review and quantitatively synthesize in vivo evidence on extracellular vesicle (EV)-based therapies for regenerative endodontic procedures, focusing on mineralization and angiogenesis outcomes.MethodsWe conducted a systematic review and meta-analysis of in vivo preclinical dentoalveolar/regenerative endodontic models comparing EV-based interventions (exosomes/microvesicles/apoptotic bodies), alone or with scaffolds, versus control conditions. Searches were performed in Web of Science Core Collection and Scopus from inception to 31 December 2025, with reference screening. Random-effects meta-analyses pooled standardized mean differences (SMDs) for mineralization and angiogenesis; heterogeneity was assessed using I2. Risk of bias was evaluated using the Systematic Review Centre for Laboratory animal Experimentation tool.ResultsTwenty-one studies met inclusion criteria; seven were included in the mineralization meta-analysis and five in the angiogenesis meta-analysis. EV-based therapies significantly increased mineralization versus controls (SMD = 6.43; 95% confidence interval (CI) [3.13-9.73]; I2 = 91%) and angiogenesis (SMD = 7.89; 95% CI [3.94-11.85]; I2 = 82%). Subgroup analyses suggested stronger effects for EVs derived from dental pulp stem cells, stem cells from human exfoliated deciduous teeth, and stem cells from apical papilla. Risk of bias was predominantly unclear due to limited reporting of randomization and blinding. Considerable heterogeneity, small numbers of pooled studies, and variability in EV isolation, characterization, dosing, and outcome assessment limit generalizability and translation.ConclusionsEV-based therapies enhance mineralization and angiogenesis in preclinical regenerative endodontic models, with dental stem cell-derived EVs showing the greatest apparent potential. However, effect sizes should be interpreted cautiously given very high heterogeneity and methodological/reporting limitations.PROSPERO registration: Centre for Reviews and Dissemination 420251107328.

Glial cells play a critical role in neural development, function, and immune regulation, with microglia serving as the principal immune cells of the central nervous system and retina. Although microglia are central to neuroinflammation and disease progression, progress in understanding human microglial biology has been limited by the lack of physiologically relevant in vitro models. Stem cell-derived brain and retinal organoids provide three-dimensional systems that recapitulate human tissue architecture and developmental trajectories, offering new opportunities to study neuroimmune interactions. This review summarizes strategies for integrating microglia into neural organoids through co-differentiation and transplantation, and outlines methodologies for establishing humanized immune microenvironments and assessing microglial maturation, migration, phagocytic function, and inflammatory activation. We highlight applications of organoid-microglia models in neurodevelopmental and neurodegenerative disorders, including autism spectrum disorder, Alzheimer's disease, and retinal diseases, as well as their potential in drug screening and microglia-targeted interventions. Additionally, emerging technologies-such as organ-on-a-chip platforms, spatial transcriptomics, and multi-omics analyses-are enhancing the physiological relevance and analytical power of these systems. Overall, organoid-microglia platforms bridge a critical gap between conventional cell culture and in vivo models, enabling deeper insights into neuroimmune interactions and accelerating the development of precise immunomodulatory therapies.

Ovarian cancer remains the most lethal gynecologic malignancy due to strong interpatient heterogeneity and immune evasion. Traditional two-dimensional cultures and animal models lack the ability to maintain interactions among tumors, immune cells, and stromal cells and have limitations in clinical translation. This review discusses the organoid construction methods using adult stem cells (normal epithelium, tumor tissues and ascites), and induced pluripotent stem cells, comparing various culture platforms from air-liquid interface to microfluidic devices. We highlight organoids containing immune components are valuable for assessing T cell exhaustion, NK cell cytotoxicity, and stromal communication, which help to screen immunotherapy, discover biomarker, and profile drug resistance. The persistent challenges include limited vascularization, short-term maintenance of immune components and lack of standard protocols. We present new solutions that integrate multi-omics, biomaterials and automated perfusion to improve physiological fidelity and scalability. Collectively, ovarian cancer organoids with immune microenvironment can bridge preclinical gaps and accelerate the development of personalized immune therapy.

Extracellular signal-regulated kinase 5 (ERK5), a unique member of the mitogen-activated protein kinase (MAPK) family, plays a critical role in cell fate determination due to its distinct structure. This review aims to systematically summarize the central role of the ERK5 signaling pathway in cell specification and differentiation. Substantial evidence indicates that, by integrating diverse extracellular signals and regulating key transcription factors, ERK5 precisely controls the fate specification and differentiation of various cell types, including stem cells, neural cells, immune cells, endothelial cells, and osteoblasts. Furthermore, aberrant MEK5/ERK5 signaling is closely linked to the pathogenesis and progression of various diseases, particularly cancer, and is associated with drug resistance. By delineating the signaling mechanisms and functions of ERK5 across different cellular contexts, this review seeks to deepen the understanding of its physiological and pathological activities and to provide new potential targets and insights for regenerative medicine and cancer therapy.

Endometrial receptivity (ER) is a pivotal determinant of successful embryo implantation, and its dysfunction is a major cause of infertility and recurrent implantation failure. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic strategy due to their multipotency, self-renewal capacity, and potent paracrine activity. This review elucidates the multifaceted mechanisms through which MSCs enhance ER, including direct differentiation into endometrial cells, promotion of angiogenesis via secretion of factors like VEGF, immunomodulation by inducing Treg cells and M2 macrophages, and remodeling of the extracellular matrix. Crucially, we highlight emerging clinical evidence; for instance, in a recent clinical trial, intrauterine infusion of umbilical cord-derived MSCs in women with intrauterine adhesions significantly increased endometrial thickness from a mean of 4.2 ± 0.5 mm to 6.8 ± 0.7 mm and improved the clinical pregnancy rate to 38.5%. Furthermore, we discuss ongoing clinical trials and future directions, such as the development of engineered MSC-derived exosomes and biomaterial-scaffold combinations. Despite challenges in standardization and long-term safety, MSC-based therapy represents a novel and potent approach for regenerating dysfunctional endometrium, offering new hope for refractory infertility.

Neuroinflammation plays a fundamental role in several neurodegenerative diseases, including Alzheimer's disease (AD), the leading cause of dementia worldwide. As the main defense response of the central nervous system (CNS), neuroinflammation can be either protective or detrimental depending on the stage of the disease. The pivotal role of neuroinflammation in AD has led to increasing investigations into neuroinflammatory mechanisms, aiming to develop AD-modifying therapies. A significant advance in the field was the emergence of the human induced pluripotent stem cell (hiPSC) model, enabling the study of patient-derived cells. Moreover, the development of hiPSC-derived brain organoids, which mimic specific aspects of the human CNS, has expanded our understanding of neuroinflammation in AD. Here, we review how AD organoid models have evolved, focusing on the integration of microglia-the brain's primary immune surveillance cells. We also summarize recent findings on how glial activation and the crosstalk between microglia and other CNS cells affect AD progression. Lastly, we address the potential of hiPSC-derived organoids as a preclinical model for screening AD drugs.

Type 2 diabetes (T2D) and its complications represent a complex disorder involving multiple pathophysiological processes. Although conventional therapeutic approaches partially regulate blood glucose, they fail to fundamentally reverse disease progression or effectively prevent complications. This review summarizes the current research advance and challenges of using different forms of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in treating T2D and complications. It begins with an introduction to the characteristics of MSC-EVs. Subsequently, the mechanisms and therapeutic prospects of natural MSC-EVs are analyzed, with a focus on their roles in inflammatory modulation, tissue regeneration, and improving insulin resistance. Engineering MSC-EVs, covering strategies including optimizing MSC culture conditions, modifying EV contents, and establishing MSC-EV delivery systems based on bioactive materials are then discussed, which boost EV yield and quality while enhancing therapeutic efficacy. Current challenges, including the limited yield and high heterogeneity of natural MSC-EVs, as well as issues related to long-term safety, immunocompatibility, and large-scale production of engineered MSC-EVs are finally overviewed, with emphasizing artificial intelligence in guiding future research directions. These summaries are crucial for clinical translation of MSC-EVs and will ultimately provide T2D patients with an effective and safe treatment option.

Parkinson's disease (PD) is an illness that causes both motor and non-motor symptoms in the patient which occurs as a result of a progressive loss of dopamine-producing neurons in the substantia nigra. Even though the success of symptomatic treatments is promising, at the same time there is currently no effective therapy that can halt or reverse disease progression. Key genes such as SNCA, LRRK2, and PINK1 are considered as the main hopefuls aspect for the treatment of Parkinson's because mutations of these genes are the reason for the appearance of the familial and sporadic kinds of the disease, respectively. The CRISPR-Cas system, a breakthrough genome-editing technology which enables precise and targeted genetic modifications, renders the possibilities of both PD research and therapy. Examining the mechanics of prime editing, base editing, and CRISPR-Cas9 highlights how effective and precise these methods are for modifying genes. An overview of recent developments in the use of CRISPR to create PD models is also included in the current review, with a focus on the roles these models play in clarifying disease pathways and locating new treatment targets. These models include isogenic cell lines, transgenic animals, and induced pluripotent stem cells (iPSCs). This review highlights the potential of CRISPR-based strategies to correct PD-associated mutations, modulate pathogenic gene expression, and develop neuroprotective interventions targeting key processes such as mitochondrial dysfunction. Furthermore, it critically evaluates the role of CRISPR-based technologies as transformative tools in PD research and therapy while highlighting key challenges for their clinical translation.

Orthopedic surgery is transitioning from a mechanical repair paradigm to intelligent biological restoration driven by advances in regenerative medicine and artificial intelligence (AI). This review synthesizes the science and clinical translation of stem cell therapies, bioactive and 'smart' scaffolds, growth factor strategies, and AI-enabled planning and delivery systems.

Cell competition is an evolutionarily conserved quality control mechanism that eliminates less-fit cells to ensure optimal tissue integrity during development, homeostasis, and regeneration. Beyond these physiological roles, recent evidence implicates a role for cell competition in disease, particularly in cancer, where it can function by either suppressing or promoting malignant progression. In this review, we provide an overview of the different molecular mechanisms that drive cell competition and their impact on cancer development and progression. We will evaluate the current state-of-the-art in vitro experimental systems that can be employed to study these processes. Ranging from classical 2D co-culture systems to advanced organoid and organ-on-chip platforms, these model systems collectively enhance our understanding of the complex cellular interactions that underlie the competitive differences between cells. By integrating insights from diverse model systems, we highlight how cell competition shapes tumor dynamics and discuss how this knowledge could inspire novel therapeutic strategies to prevent or control tumor growth.

Theranostic nanogels have emerged as a promising class of biomaterials proficient in integrating therapeutic delivery with real-time diagnostic feedback, offering a new level of precision in regenerative medicine. Recent advances in multifunctional nanogel systems have been designed to predict pathological microenvironments, deliver targeted therapeutics, and enable non-invasive monitoring of tissue repair. Key developments in stimuli-responsive drug release, bioinspired surface functionalisation, and advanced imaging combination are critically discussed across applications, including wound healing, cartilage and bone repair, and myocardial regeneration. This review highlights how intelligent nanogels can respond dynamically to biochemical gradients, such as hypoxia, oxidative stress, and inflammatory markers, enabling closed-loop therapeutic control. Despite significant progress, major translational barriers remain, particularly in scalable manufacturing, regulatory harmonisation, long-term biosafety, and reproducibility under GMP conditions. This review concludes that while Theranostic nanogels represent a transformative platform for personalised regenerative therapies, coordinated advances in materials engineering, regulatory science, and clinical validation are essential to realise their full clinical potential.

Cancer-associated fibroblasts (CAFs) are the predominant stromal components within the tumor microenvironment (TME), playing multifaceted roles in cancer progression through dynamic interactions with neoplastic and immune cells. Emerging evidence has revealed remarkable heterogeneity and plasticity of CAFs, which originate from diverse cellular precursors. This cellular diversity, coupled with dynamic epigenetic reprogramming and bidirectional cross-talk with tumor cells, generates distinct CAF subsets with specialized functional outputs. Here, we systematically review the current understanding of CAF biology, encompassing their cellular origins, molecular heterogeneity, and the complex signaling networks. We discuss the functional of CAFs, detailing their protumorigenic roles in extracellular matrix (ECM) remodeling, immunosuppressive niche formation, metabolic reprogramming, angiogenesis, therapy resistance, and maintenance of cancer stem cell properties, while also highlighting emerging evidence for tumor-restrictive CAF subsets. We critically evaluate therapeutic strategies targeting CAFs, including direct depletion approaches, ECM modulation, disruption of CAF-tumor cross-talk, and emphasis on clinical trials and associated challenges. Finally, we outline future directions leveraging single-cell multiomics, patient-derived models and combinatorial regimens to translate current understanding of CAF biology into effective stroma-targeted therapies. This comprehensive framework not only positions CAFs as central architects of tumor ecosystems but also reveals actionable therapeutic vulnerabilities at the intersection of stromal biology and precision oncology.

Background and Objectives: Soft tissue regeneration in oral surgery has undergone remarkable progress in the last decade, supported by the development of innovative laser technologies, advanced biomaterials, platelet-rich plasma (PRP), mesenchymal stem cells (MSCs), and three-dimensional (3D) printing. Lasers are increasingly used not only for incision and coagulation but also for photobiomodulation, promoting cellular proliferation, angiogenesis, and tissue healing. The purpose of this review is to analyze the current advances in soft tissue regeneration, with a particular focus on the clinical use of lasers and their integration with other regenerative strategies. In parallel, hard tissue regeneration has evolved through the synergistic use of bioactive scaffolds, recombinant human growth factors (rhBMP-2, rhPDGF-BB), MSCs, and 3D-printed constructs. These innovations have enhanced alveolar bone regeneration, implant osseointegration, and periodontal tissue repair, offering predictable clinical outcomes. Materials and Methods: A review of the literature published between 2015 and 2025 was conducted through PubMed, Scopus, Web of Science, Embase, and Google Scholar. Clinical and preclinical studies on the use of CO2, Nd:YAG, Er:YAG, diode, and 445 nm lasers, biomaterials, PRP, MSCs, growth factors, and 3D-printed scaffolds were included. Results: Laser applications demonstrated significant benefits in epithelialization, biostimulation, and reduction in postoperative discomfort in soft tissues. For hard tissues, the combined use of MSCs, bioactive scaffolds, and growth factors promoted osteogenic differentiation, bone volume preservation, and improved mechanical stability. Photobiomodulation enhanced osteoblastic activity and accelerated bone remodeling, while 3D-printed scaffolds provided personalized architecture for optimal integration. Conclusions: Regenerative approaches integrating lasers, biomaterials, PRP, MSCs, growth factors, and 3D printing represent safe, minimally invasive, and effective strategies for the regeneration of both soft and hard oral tissues. These multidisciplinary techniques improve healing quality, functional recovery, and esthetic outcomes, reflecting the growing trend toward precision and technology-driven regenerative oral surgery.

Oral squamous cell carcinoma (OSCC) represents a major global health burden and remains one of the most prevalent and aggressive malignancies of the head and neck region. Despite significant advances in surgical techniques, chemotherapy, and radiotherapy, patient outcomes have improved only modestly over recent decades. The high recurrence rate, metastatic potential, and resistance to therapy underscore the complexity of OSCC biology and the limitations of conventional treatment approaches. In recent years, the concept of cancer stem cells (CSCs) has reshaped the understanding of tumor initiation, progression, and therapeutic failure in OSCC. These cells, characterized by self-renewal capacity and phenotypic plasticity, are believed to sustain tumor growth, drive recurrence, and mediate resistance to therapy. Parallel to this, insights into epigenetic regulation, including DNA methylation, histone modifications, and non-coding RNAs, have revealed new layers of molecular heterogeneity and adaptability in oral carcinogenesis. The integration of CSC biology with epigenetic modulation offers a promising foundation for the development of targeted and personalized therapeutic strategies. Novel approaches aim to eradicate CSCs, induce their differentiation, or reprogram their malignant phenotype through the use of epigenetic inhibitors and molecular modulators. This review summarizes current knowledge on the molecular and cellular mechanisms driving OSCC pathogenesis, highlights the emerging role of CSCs and epigenetic regulators, and discusses the challenges and perspectives of translating these findings into effective clinical therapies.

Background: Preterm birth is a leading cause of neonatal mortality and long-term disability worldwide. Injury in premature infants is demonstrated by disrupted organ development from inflammation, oxidative stress, hypoxia, and impaired vascular maturation. Current therapies largely provide supportive care and do not directly promote tissue regeneration. Mesenchymal stem cell (MSC)-based therapies have emerged as a potential strategy to enhance endogenous repair across organ systems commonly affected by prematurity. Results: Evidence indicates that MSCs exert therapeutic effects primarily through transient paracrine signaling rather than long-term engraftment. Following administration, MSCs release cytokines, growth factors, and extracellular vesicles that reduce inflammation, promote angiogenesis, and support tissue repair. In preclinical models of neonatal brain injury, MSC therapy has been associated with improved oligodendrocyte maturation and reduced white matter injury. Early clinical trials in neonatal encephalopathy demonstrate feasibility and short-term safety of both autologous and allogeneic cell products. However, studies remain limited by small sample sizes and short follow-up. Cell-free approaches using MSC-derived extracellular vesicles may offer similar biological benefits with potentially lower safety and regulatory concerns. Conclusions: MSC-based therapies represent a promising regenerative approach for complications of prematurity. Rigorous, large-scale trials with standardized protocols and long-term follow-up are necessary to clarify efficacy, optimize delivery strategies, and define safety in this vulnerable population.

Acute myeloid leukemia (AML) remains a therapeutically challenging malignancy due to high relapse rates driven by leukemic stem cells (LSCs) and adaptive resistance mechanisms. Emerging evidence positions autophagy as a central regulator of AML pathobiology, exerting context-dependent effects that suppress leukemogenesis during disease initiation yet sustain LSC survival and chemoresistance in established AML. Mechanistically, autophagy integrates mitochondrial quality control, lipid droplet turnover, and metabolic rewiring to support oxidative phosphorylation, particularly under hypoxic bone marrow conditions. Lipophagy-driven fatty acid oxidation has emerged as a key metabolic vulnerability distinguishing LSCs from normal hematopoietic stem cells. Furthermore, non-coding RNAs critically modulate autophagy networks, reinforcing therapy resistance. Preclinical and clinical studies demonstrate that both inhibition and activation of autophagy may yield therapeutic benefit depending on genetic context, mutational landscape, and disease stage. We propose that integrating multi-omics approaches, particularly lipidomics, with artificial intelligence and machine learning will enable precise identification of autophagy-dependent AML subsets. Rational, biomarker-guided modulation of autophagy may overcome resistance while preserving normal hematopoiesis, offering a path toward personalized metabolic targeting in AML.

Background: Myocardial ischemic injury, encompassing acute myocardial infarction (MI) and ischemia/reperfusion (I/R) injury, remains a major cause of cardiac morbidity and mortality worldwide, and is driven by interconnected molecular and cellular processes, including cardiomyocyte apoptosis, inflammatory activation, mitochondrial dysfunction, oxidative stress, and impaired angiogenesis. Mesenchymal stem cell (MSC)-derived exosomes have emerged as a promising cell-free nanotherapeutic strategy for cardiac repair due to their ability to transfer bioactive molecules that modulate multiple signaling networks involved in myocardial survival and regeneration. This systematic review aimed to synthesize evidence on the mechanistic basis of MSC-derived exosome mediated cardioprotection in myocardial ischemic injury. Methods: A systematic search of Ovid MEDLINE, Scopus, and Web of Science was conducted to identify studies investigating the effects of MSC-derived exosomes on myocardial ischemic injury. Eligible studies included clinical and preclinical models of MI or I/R injury assessing functional, biochemical, and molecular outcomes. Results: Seven preclinical studies published between 2015 and 2025 met the inclusion criteria. Exosome administration consistently improved cardiac function, reduced infarct size, and preserved myocardial architecture. Biochemical analyses revealed decreased cardiac injury markers, alongside suppressed apoptosis, inflammation, and oxidative stress. Mechanistically, MSC-derived exosomes delivered regulatory miRNAs (e.g., miR-19a, miR-125b, miR-205, miR-294) and lncRNAs (HAND2-AS1) that modulated key signaling pathways including PI3K/Akt, JAK2/STAT3, HAND2-AS1/miR-17-5p/Mfn2, and HIF-1α/VEGF. These molecular effects collectively inhibited apoptotic and inflammatory responses, enhanced mitochondrial integrity, and promoted angiogenesis and myocardial repair. Conclusions: MSC-derived exosomes confer robust cardioprotection against myocardial ischemic injury through integrated anti-apoptotic, anti-inflammatory, antioxidant, and pro-angiogenic mechanisms. Their multifaceted bioactivity, low immunogenicity, and potential for targeted delivery highlight their potential as a next-generation nanomedicine for ischemic heart disease. Future studies should emphasize standardized exosome production, mechanistic profiling, and translational validation in large-animal and clinical models.

Cartilage is an important yet vulnerable tissue with limited self-healing capacity, where damage often progresses to joint degeneration, which eventually leads to severe osteoarthritis (OA). Current tissue engineering strategies focus on biocompatible scaffolds for cartilage regeneration, particularly amnion (or amniotic membrane), emerging as a promising biomaterial due to its wide availability, low immunogenicity, and naturally derived microenvironment that is advantageous for cartilage regeneration. This systematic review aims to evaluate the existing evidence on the efficacy of amnion as a tissue scaffolding material for cartilage regeneration in both preclinical and clinical studies. Using terms such as "cartilage damage", "cartilage injuries", "amnion" and "amniotic membrane", 19 relevant studies were identified across three major databases (PubMed, Scopus and Web of Science) until 25 December 2025. All preclinical and clinical studies that utilized amnion for cartilage repair or as cartilage tissue engineering scaffolding materials were included. Evidence quality was assessed using the OHAT and MINORS risk of bias tool. This study is prospectively registered in the PROSPERO database under the ID 1178444. The findings consistently indicate that amniotic scaffolds, regardless of processing methods or cell seeding, yield favorable outcomes without adverse effects across different species. In vitro analysis revealed that treatment groups with amnion show better cell attachment, viability, and proliferation, and higher content of cartilage-related markers expressed by the seeded cells, either chondrocyte, bone marrow-derived mesenchymal stem cells (MSCs), adipose tissue-derived MSCs, placenta-derived MSCs, umbilical cord-derived MSCs, amniotic MSCs or amniotic epithelial cells. In in vivo and ex vivo studies, amnion-treated groups demonstrated improved quality of the treated cartilage, with better integration, as indicated by higher histological scores and the presence of type II collagen (COL-II). There was an inconsistency in the reporting of cartilage defect dimensions in the in vivo models across the different studies. Nevertheless, the outcome measurements were consistently reported with histological analysis, with or without International Cartilage Repair Society (ICRS) scoring and immunohistochemistry (IHC) analysis, across the studies. Clinically, most subjects show improvement in the Knee Injury and Osteoarthritis Outcome Score (KOOS) Sports and Recreation score and KOOS Quality of Life score, as well as reduced Visual Analogue Scale (VAS) average and maximum pain scores. In conclusion, preclinical and clinical studies support amnion as an ideal scaffold material for cartilage tissue engineering and regeneration. Future research should focus on optimizing and standardizing amnion scaffold preparation at a production scale to facilitate the translation of these positive outcomes into clinical applications. This study is funded by the Ministry of Higher Education Malaysia via Prototype Research Grant Scheme (PRGS/1/2021/SKK01/UM/02/1) and UM International Collaboration Grant-2023 SATU Joint Research Scheme Program: ST007-2024.

Background: Mastoid obliteration following canal wall down mastoidectomy reduces cavity-related morbidity. Conventional obliteration materials act primarily as passive fillers, whereas tissue engineering (TE) strategies aim to achieve biologically active bone regeneration. Methods: This systematic review was conducted in accordance with PRISMA 2020 guidelines. PubMed/MEDLINE, Embase, Scopus, and the Cochrane Library were searched from January 2010 to December 2025. Studies evaluating tissue engineering-assisted mastoid obliteration involving growth factors, mesenchymal stem cells, polymer scaffolds, or 3D-printed constructs were included. Results: Fifteen studies met inclusion criteria (12 preclinical and three clinical). Polymer-supported MSC constructs demonstrated the most consistent osteogenic enhancement in animal models. Clinical evidence remains limited to small PRP-based case series. Conclusions: Preliminary evidence suggests that tissue engineering-assisted mastoid obliteration has regenerative potential, although the evidence is limited by predominantly preclinical data and a moderate-to-high risk of bias. Standardized outcome measures and well-designed prospective clinical studies are required to confirm long-term safety and efficacy.