Tissue Repair Research Articles

Intervertebral disc degeneration is a primary cause of chronic low back pain (LBP), which affects people worldwide and leads to disability. Intervertebral discs (IVDs) are a mechanically dynamic tissue where the annulus fibrosus (AF) absorbs axial load, supports spinal motions, and resists disc deformation and degeneration. Axial stress applied to the disc translates into interlamellar radial stress, potentially leading to AF tears and nucleus pulposus (NP) extrusion, especially in the lumbar region. We developed a hyaluronan-coated type-I collagen (Col-I HA) hydrogel scaffold to promote AF tissue repair and mechanically stabilize IVD. These scaffolds exhibit high tensile strength (∼5 MPa), comparable to that of the annulus fibrosus, which is attributed to the alignment of collagen fibrils with preserved secondary structures. The developed scaffolds demonstrated high cell viability and alignment of isolated primary AF cells and rat bone marrow stem cells (RBMSCs) along the collagen fibrils. Notably, primary AF cells and RBMSCs cultured on the Col-I HA hydrogel scaffold showed high expression of native ECM markers, such as collagen-I and aggrecan, reflecting the regenerative potential of the developed scaffold. Elevated levels of CD146 and Acta2 indicated a shift toward a contractile phenotype in both cell types. Ex vivo and in vivo studies using annulotomy-induced rat coccygeal disc model following Col-I HA implantation demonstrated mechanical restoration of IVD when investigated for uniaxial compressive strength. Histological and immunohistochemical analyses revealed significant collagen and glycosaminoglycan (GAG) deposition in Col-I HA-treated discs compared with the untreated AF-defective disc. Interestingly, fibrotic changes were observed in the Col-I HA-treated groups, as confirmed by the upregulation of profibrotic markers, including fibronectin, transforming growth factor, and α-smooth muscle actin, in the in vivo model. Thus, the Col-I HA hydrogel scaffold exhibited fibrotic changes in the AF and contributed to IVD stabilization.

Primary Sjögren's syndrome (pSS) is a systemic autoimmune exocrinopathy affecting salivary and lacrimal glands. This study presents an exploratory single-cell transcriptomic analysis of labial salivary glands to generate hypotheses about B-cell-associated gene modules in pSS, and to uncover novel therapeutic targets for B cell modulation in pSS. The high-dimensional weighted gene co-expression network analysis (hdWGCNA) was performed on gene expression data obtained from single-cell RNA sequencing (scRNA-seq) of 32,337 cells from labial glands of three pSS patients and three healthy controls. Gene Ontology (GO) enrichment analysis was subsequently conducted to investigate the functional roles of the identified gene modules. Additionally, the scRank method was applied to evaluate the responsiveness of key B cell-related targets across different cell types, providing new insights into the role of B cells in the pathogenesis of pSS. Through hdWGCNA analysis, we resolved seven co-expression modules in pSS. Module 5, restricted to plasma cells, contains POU2AF1, SLAMF7, SPCS2, CD79A and PDIA6 and is highly enriched for COPI/II-mediated vesicle trafficking and B-cell-receptor signaling, thereby driving autoantibody production and chronic inflammation. Modules 1, 2, 4, 6 and 7 align with extracellular-matrix remodeling, epithelial stress and metabolic reprogramming, underscoring the disease's multifactorial pathobiology. scRank ranked Module 5 as the most drug-responsive cluster and highlighted POU2AF1, SLAMF7 and CD79A as tractable B-cell targets for restoring immune homeostasis in pSS. Our study identified distinct gene modules associated with pSS, with a particular emphasis on B cells, unveiling novel potential therapeutic targets. The activation of B cells, coupled with immune dysregulation and epithelial dysfunction, appears to play a critical role in pSS pathogenesis, offering valuable insights for developing targeted therapeutic strategies that address both immune activation and tissue repair. These findings nominate B-cell-associated modules-including a plasma cell-enriched module featuring POU2AF1, SLAMF7, and CD79A-as hypotheses for future functional validation.

Bats are recognized for harboring a diverse array of viruses without manifesting disease symptoms. In this study, we explored the single-cell atlas of wild Rhinolophus affinis (R. affinis) using Viral-Track and identified transcript expression of eight viral species in the R. affinis lung and three viral species in the kidney. Within the R. affinis lung, these viruses were detected across all cell types except ciliated cells. Compared to uninfected cells, virus-infected cells exhibited activation of pathways associated with protein synthesis, tissue repair, and immune responses, as evidenced by increased expression of corresponding genes. Ligand-receptor based analysis revealed that viral infection reshapes intercellular communication networks in the bat lung, with infected fibroblasts and infected proliferative T cells exhibiting enhanced signaling linked to tissue remodeling and immune activation. Through gene module analysis, we identified an immune cell activation-related module by high expression of CD14, CD74, and MRC1, as well as an antiviral related module by elevated expression of SAMHD1, SLC11A1, TYROBP, and IL18 in R. affinis pulmonary macrophages. Additionally, a cross-species single-cell transcriptomic comparative analysis demonstrated that R. affinis pulmonary macrophages exhibit elevated expression of pro-inflammatory genes (IRF9, DDX5, IL6ST and ITGA4), which are associated with antiviral activity and immune activation, and anti-inflammatory genes (IRF2, PTPRE and GPR65), which play critical roles in mitigating excessive immune responses. Compared to the other species, R. affinis pulmonary macrophages exhibited upregulation of genes enriched in pathways related to vacuolar acidification and negative regulation of response to external stimulus. These findings suggest that the R. affinis lung possesses a unique immune system that enables it to balance immune responses during viral infections, thereby preventing excessive immune damage and maintaining lung tissue homeostasis. Our study provides valuable insights into the viral infection risk organs in R. affinis and their distinctive antiviral immune responses.

Severe hemorrhage and wound inflammation are major risk factors contributing to high mortality after tissue trauma. Therefore, there is an urgent need to develop emergency materials that can rapidly and effectively close wounds while simultaneously controlling bleeding and infection. Although current clinical bioadhesives can fill surgical voids and support tissue repair, they generally lack sufficient adhesive strength and anti-inflammatory properties, which limit their effectiveness in inflammatory wound environments. In this study, a kind of bioadhesive hydrogel was developed using a simple heating and mixing strategy with natural building blocks, including polysaccharides, lipoic acid, and natural polyphenol extracts. Through multiple non-covalent interactions (such as hydrogen bonding and electrostatic interactions), the resulting bioadhesive hydrogels exhibited excellent tissue adhesion and hemostatic properties. Moreover, these hydrogels also demonstrated outstanding anti-inflammatory effects, biocompatibility, and favorable biodegradability, effectively promoting both linear and burn wound healing. This work presents a novel strategy for achieving strong bioadhesion using natural molecules and provides a promising approach for the development of multifunctional wound dressings designed to support tissue regeneration.

Stem cells from the apical papilla (SCAPs) represent a unique population of mesenchymal stem cells (MSCs) located in the apical papilla of immature permanent teeth. These cells exhibit essential MSC characteristics, including specific marker expression, self-renewal, proliferation, migration, multipotent differentiation, and immunosuppressive properties. Additionally, SCAPs secrete bioactive factors that promote tissue regeneration, making them promising candidates for stem cell-based therapies. Their regenerative potential encompasses diverse applications in dentistry, bone repair, neural regeneration, and vascular engineering, thereby positioning SCAPs as a versatile tool in regenerative medicine. However, challenges such as phenotypic instability during long-term culture and inconsistent regenerative outcomes impede their clinical translation. Addressing these challenges is crucial for advancing the clinical application of SCAPs. This review examines the advantages and therapeutic applications of SCAPs, identifies barriers to their clinical implementation, and highlights opportunities for optimizing their efficacy. By synthesizing current knowledge and proposing future research directions, this work aims to facilitate the development of SCAP-based strategies for tissue repair, bridging the gap between laboratory research and clinical practice.

Macrophages play a crucial role in bone repair associated with apical periodontitis. NeoSEALER Flo is a promising sealer for root canal obturation, but its effects on macrophages have not been evaluated. This study aims to investigate the impact of NeoSEALER Flo on the cytotoxicity, polarization, and activation of macrophages, in comparison with the commonly used sealer iRoot SP. Briefly, bone marrow-derived macrophages (BMDMs) were exposed to varying concentrations of NeoSEALER Flo or iRoot SP extracts for 24h and 48h to assess their cytotoxicity. BMDMs were stimulated with NeoSEALER Flo or iRoot SP, in the presence or absence of the M1 agonist lipopolysaccharide (LPS) and the M2 stimuli interleukin 4 (IL-4), respectively. Immunofluorescence, western blotting, and qPCR were used to evaluate the expression of M1 markers (iNos, IL-1β, Ccl12) and M2 marker Cd206 and Arginase 1 (Arg1). The results showed that both iRoot SP and NeoSEALER Flo exhibited favorable biocompatibility, with a sharp decline at high concentrations (50mg/mL). Moreover, NeoSEALER Flo and iRoot SP each demonstrated immunomodulatory capacity by suppressing M1 markers and fostering M2 macrophage activation. Notably, NeoSEALER Flo displayed a markedly stronger response, achieving superior efficacy in both suppressing M1 markers and promoting the expression of M2 markers relative to iRoot SP. In conclusion, NeoSEALER Flo demonstrated a consistently favorable biocompatibility profile, suppressing pro-inflammatory M1 activation while amplifying anti-inflammatory M2 polarization, highlighting NeoSEALER Flo's potential to mitigate inflammation and promote tissue repair in clinical applications.

USP7 inhibition promotes wound healing by suppressing M1 macrophage polarization via NF-κB/MAPK signaling pathway.

Platelet-rich plasma (PRP) is an autologous blood-derived concentrate increasingly utilized in regenerative medicine for its ability to accelerate healing and tissue repair. PRP is broadly classified by leukocyte content, fibrin architecture, and platelet concentration, with classification systems developed to standardize characterization. Preparation methods, including single- or double-spin centrifugation and buffy coat techniques, influence the final composition of PRP, determining the relative proportions of platelets, leukocytes, plasma proteins, and extracellular vesicles. These components act synergistically, with platelets releasing growth factors (e.g., VEGF, PDGF, TGF-β) that stimulate angiogenesis and matrix synthesis, leukocytes providing immunomodulation, plasma proteins facilitating scaffolding, and exosomes regulating intercellular signaling. Mechanistically, PRP enhances tissue repair through four key pathways: platelet adhesion molecules promote hemostasis and cell recruitment; immunomodulation reduces pro-inflammatory cytokines and favors M2 macrophage polarization; angiogenesis supports vascular remodeling and nutrient delivery; and serotonin-mediated pathways contribute to analgesia. These processes establish a regenerative microenvironment that supports both structural repair and functional recovery. Clinically, PRP has been applied across multiple specialties. In orthopedics, it promotes tendon, cartilage, and bone healing in conditions such as tendinopathy and osteoarthritis. In dermatology, PRP enhances skin rejuvenation, scar remodeling, and hair restoration. Gynecology has adopted PRP for ovarian rejuvenation, endometrial repair, and vulvovaginal atrophy. In dentistry and oral surgery, PRP accelerates wound closure and osseointegration, while chronic wound care benefits from its angiogenic and anti-inflammatory effects. PRP has also favored gingival recession coverage, regeneration of intrabony periodontal defects, and sinus grafting. Although preparation heterogeneity remains a challenge, PRP offers a versatile, biologically active therapy with expanding clinical utility.

Stem cell adhesion and migration are fundamental processes in tissue regeneration and repair; however, their efficiency in vivo is often limited by the complexity of the microenvironment. Endogenous bioelectrical cues, such as electric fields present during development and wound healing, play a critical role in guiding these cellular behaviors. Piezoelectric biomaterials, which can convert mechanical stimuli into electrical signals, have recently emerged as promising platforms for recapitulating these bioelectric cues without the need for external power sources. In this mini-review, we summarize the recent advances in the use of piezoelectric scaffolds to modulate stem cell adhesion and migration. We highlight the underlying mechanisms, including integrin/focal adhesion kinase activation, calcium signaling, and electrotaxis, which mediate enhanced adhesion, focal adhesion maturation, and directed cell migration. Representative applications in bone, cartilage, nerve, and muscle tissue engineering are discussed, with an emphasis on how piezoelectric scaffolds improve regeneration by providing dynamic and self-sustained electrical stimulation. Finally, we outline the major challenges, such as balancing piezoelectric output with biocompatibility, controlling in vivo stimulation parameters, and elucidating precise sensing mechanisms, and propose future directions for clinical translation. By integrating insights from materials science, mechanobiology, and regenerative medicine, piezoelectric biomaterials hold strong potential as next-generation smart scaffolds for orchestrating stem cell behavior and accelerating functional tissue repair.

Neuroinflammation plays a central role in a wide spectrum of neurological diseases, driven generally by reactive microglia and astrocytes. Inflammatory stimulation of microglia and astrocytes leads to a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis, which is required to support pro-inflammatory effector functions. This metabolic reprogramming is associated with impaired mitochondrial dynamics, including reduced biogenesis, increased fragmentation, and loss of membrane potential. Targeting microglia and astrocyte metabolism may offer a novel therapeutic approach for modulating neuroinflammation and restoring homeostatic immune functions. Here, we examined the potential of 2-Deoxy-D-Glucose (2DG), a glycolysis inhibitor, to attenuate neuroinflammation by restoring mitochondrial dynamics. In BV2 and primary glial cultures, low-dose 2DG reversed LPS-induced metabolic reprogramming, restoring OXPHOS, reducing mitochondrial fragmentation, and enhancing biogenesis. In vivo, it preserved spare respiratory capacity and increased complex-V activity in brain mitochondria from LPS-treated mice without affecting oxidative stress. At a mechanistic level, 2DG restored activation of AMP-activated protein kinase, a master regulator of mitochondrial dynamics. In conjunction with these metabolic effects, 2DG suppressed LPS-induced pro-inflammatory gene expression while enhancing markers associated with the resolution of inflammation and tissue repair. Critically, systemic low-dose 2DG reduced neuroinflammation and restored immune homeostasis in two LPS-induced mouse models, highlighting its therapeutic potential in neurological disorders.

As a frontier interdisciplinary breakthrough, magnetically controlled 4D printing integrates smart materials, additive manufacturing, and magnetic actuation, and is offering more improvements for healthcare practices. By introducing time as the fourth dimension, magnetic 4D-printed devices can dynamically transform their structure and function in response to physiological or external magnetic stimuli, enabling minimally invasive interventions with enhanced adaptability and precision. Integrating AI into magnetically controlled 4D printing accelerates material discovery, optimizes design and manufacturing, and enables intelligent navigation and control in complex in vivo environments. Recent advances highlight promising applications in interventional therapy, targeted drug delivery, and tissue repair, yet challenges remain in achieving biocompatible multifunctional materials, scalable fabrication, and safe clinical translation. Looking ahead, synergistic integration of AI with multimodal actuation, digital twins, and biomimetic systems may unlock unprecedented opportunities for personalized, adaptive, and intelligent medical robots. This perspective outlines current progress, key challenges, and future directions of AI-enhanced magnetically controlled 4D printing, underscoring its transformative potential in redefining next-generation medical robotics.

A combined in-silico and in-vitro evaluation of cyanoacrylate-based dental materials as an adhesive for applications in prosthodontics: molecular docking and cytocompatibility analysis.

Tissue homeostasis requires a precise balance between stem cell self-renewal and differentiation. While fate decisions are known to be closely linked with cell cycle progression, the functional significance of this relationship is unclear. We propose a mechanistic framework to analyse cellular dynamics when cell fate is coupled to cell cycle duration. Our model highlights a unique aspect of cell cycle regulation where mitogens serve as control parameters for a bifurcation governing the G1-S transition. Under competitive feedback from cell-cell interactions, the cell cycle regulatory network fine-tunes near the critical point of this bifurcation. Critical positioning lengthens G1 while amplifying cell-to-cell variability in mitogenic signalling and biochemical states. Such regulation confers significant advantages for controlling cell population dynamics, with alternative topologies enabling rapid tissue growth and repair or efficient mutant rejection. Counter-intuitively, we propose that stem cells may couple prolonged G1 with increased self-renewal propensity to efficiently suppress mis-sensing mutants. Our theory provides a distinct explanation to dynamical and statistical patterns of G1 lengthening and predicts regulatory strategies across development, homeostasis, and ageing.

Prospective cohort study. To evaluate the impact of smoking on intervertebral disc degeneration (IDD) by analyzing inflammatory and anti-inflammatory biomarkers-interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and alpha-1 proteinase inhibitor (A1PI, also known as AAT)-in disc tissue samples from smokers and nonsmokers undergoing microdiscectomy. IDD is a leading cause of chronic lower back pain and disability, often requiring surgical intervention. Smoking is a well-established risk factor, promoting oxidative stress, inflammation, and impaired tissue repair. However, few studies have directly compared biochemical changes in surgically removed disc tissue from smokers and nonsmokers. Sixty-seven patients undergoing microdiscectomy for lumbar disc herniation were enrolled, with 34 classified as smokers and 33 as nonsmokers. Intervertebral disc tissue was collected intraoperatively and analyzed through enzyme-linked immunosorbent assay (ELISA) to quantify IL-1β, IL-6, TNF-α, and AAT levels. Independent t tests and Mann-Whitney U tests were applied for group comparisons. Receiver Operating Characteristic (ROC) curves assessed biomarker diagnostic accuracy. Smokers were significantly younger ( P <0.001) and had lower BMI ( P =0.031) than nonsmokers. Levels of IL-1β ( P <0.001), IL-6 ( P <0.001), and TNF-α ( P <0.001) were significantly higher in smokers, while AAT levels were lower ( P <0.001). ROC analysis showed high discriminatory power for IL-1β (AUC=0.912), IL-6 (AUC=0.899), TNF-α (AUC=0.895), and AAT (AUC=0.881) in identifying smoking-related disc degeneration. Smoking increases inflammatory activity and reduces anti-inflammatory protection in intervertebral discs, accelerating degeneration. Elevated IL-1β and TNF-α are reliable biomarkers of smoking-related inflammation, while reduced AAT indicates compromised protective mechanisms. These results support smoking cessation as a preventive strategy and highlight biomarker-based approaches for early detection and targeted therapy in IDD.

Angiogenesis is critical for tissue repair in chronic ischemia. Chromatin modified protein 4C (CHMP4C), a subunit of the endosomal sorting complex required for transport -III (ESCRT-III), is involved in endocytic progress and cell proliferation. Recent evidence suggests ESCRT-III plays a vital role in endothelial function. This study aimed to determine the role of endothelial CHMP4C in angiogenesis, as well as the underlying molecular mechanisms. Hind-limb ischemia (HLI) was surgically induced in both CHMP4C-/- mice and wild-type C57BL/6J mice. Loss of CHMP4C was associated with significant decreases in blood perfusion and post-ischemia capillary density. Invitro, knockdown of CHMP4C by small interfering RNAs (siRNAs) impaired the angiogenic and proliferative functions of endothelial cells (ECs) and induced G1/S cell cycle arrest under hypoxic conditions. RNA-Seq data and further analysis revealed repression of the Wnt/β-catenin pathway and hyperactivation of GSK3β in CHMP4C-deficiency ECs. Selective inhibition of GSK3β significantly ameliorated the inhibitory effects of CHMP4C deficiency on the Wnt/β-catenin pathway and proliferative functions invitro. Electron microscopy and immunohistochemical colocalization analysis further revealed that CHMP4C deficiency impedes endocytic trafficking of GSK3β. Overall, these findings reveal that CHMP4C regulates angiogenesis by modulating endocytic trafficking of GSK3β, indentifying it as a potential therapeutic target for ischemic diseases.

Conventional platelet-rich plasma (PRP) typically requires erythrocyte removal in clinical practice. However, emerging evidence suggests that erythrocytes and leukocytes play key roles in tissue repair. This study investigated whether PRP retaining physiological concentrations of erythrocytes and enriched leukocytes (PRP-RE&EL) affects its functional capabilities. An automatic hematology analyzer and enzyme-linked immunosorbent assay were used to detect differences in component composition and cytokine levels between PRP-RE&EL and conventional PRP. The CCK-8 assay, vascular capillary network formation assay, and Western blot analysis were employed to evaluate their performance differences. The regenerative repair effects of PRP-RE&EL versus conventional PRP on fresh articular osteochondral injuries were compared in vivo. Compared with conventional PRP, PRP-RE&EL contained higher cytokine concentrations. In vitro, it more effectively promoted cell proliferation and facilitated capillary network formation. PRP-RE&EL also significantly influenced the abundance of HIF1-α and VEGF proteins in related cells and the differentiation of bone marrow mesenchymal stem cells. In vivo, PRP-RE&EL was more effective than conventional PRP in treating fresh articular osteochondral injuries. Thus, PRP-RE&EL significantly increases cytokine concentrations, thereby enhancing its ability to promote the regenerative repair of articular osteochondral injuries and holding potential for clinical application.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13018-025-06406-7.

Organoid models have significantly enhanced our understanding of adult stem cell function, however, uncovering regulatory mechanisms governing rare and often quiescent stem cells in glandular organs remains challenging. Here, we employ an integrative multi-omics approach, combining single-cell RNA sequencing, bulk ATAC and RNA sequencing, to profile the cellular populations and signaling pathways characterizing a mouse salivary gland organoid model across different temporal stages and after radiation-induced damage. Our findings identify Sox9- and Itgb1/Cd44-expressing cells as primitive adult stem/progenitor populations with a critical migratory role in tissue repair. Notch signaling is a key driver of self-renewal and migration in response to irradiation. Additionally, scRNA-seq analysis of irradiated salivary gland tissue confirms these findings in an in vivo setting. Extending these findings to murine and patient-derived salivary, mammary and thyroid gland organoids, we reveal the conserved role of Notch signaling in coordinating stem/progenitor cell-mediated regeneration across glandular tissues. These insights position Notch signaling as a central regulator of glandular stem cell-like populations and as a promising therapeutic target for enhancing glandular tissue regeneration following cancer therapies.

Flap viability remains a major challenge in reconstructive surgery due to ischemia–reperfusion injury, excessive inflammation, and impaired tissue regeneration. Boron, a trace element with pro-healing and anti-inflammatory properties, has shown therapeutic promise in various wound models; however, its role in flap healing remains unclear. In this study, we aimed to evaluate the therapeutic potential of sodium pentaborate pentahydrate (SPP)-containing hydrogel, a boron compound we developed, for enhancing flap survival and tissue repair. A dorsal random-pattern flap model was established in male Wistar rats, which were treated topically with an SPP-containing formulation twice daily for seven days. Histological changes were evaluated using hematoxylin–eosin and Masson’s trichrome staining, and proteomic alterations were analyzed using label-free nanoLC-MS/MS followed by bioinformatics analysis. The treatment significantly improved flap survival (p &lt; 0.0001), enhanced granulation tissue formation, promoted organized collagen deposition, and reduced inflammatory infiltration. Proteomic profiling identified 179 differentially expressed proteins, with 14 upregulated and 165 downregulated. Upregulated proteins were enriched in pathways related to complement activation, antioxidant defense, and extracellular matrix remodeling, whereas downregulated proteins were associated with immune overactivation, cellular stress, and senescence, indicating a shift toward regulated inflammation and tissue homeostasis. To our knowledge, this is the first study to demonstrate that an SPP-containing hydrogel promotes flap healing by supporting vascularization, modulating immune responses, and enhancing extracellular matrix remodeling. These findings highlight SPP as a promising therapeutic strategy for improving flap viability in reconstructive surgery.

Extracellular vesicles (EVs) play a critical role in intercellular communication and have shown great potential in disease treatment and tissue repair. However, large-scale production and clinical application of EVs still face challenges such as donor heterogeneity, batch-to-batch variability, and high production costs. This study aimed to establish a stable and reproducible EV production platform using hTERT-immortalized placental mesenchymal stromal cells (PC-MSCs). We demonstrated that stable expression of the TERT gene promotes cell proliferation in vitro while retaining surface marker expression patterns and differentiation capabilities similar to those of primary cells. The EVs produced by immortalized cells maintain similar particle size distributions, protein markers, and protein expression profiles to those of their parental cells, and their therapeutic efficacy was validated in a bleomycin (BLM)-induced pulmonary fibrosis (PF) rat model. In summary, we systematically described the effect of immortalization via ectopic hTERT gene expression on EVs produced from PC-MSCs. These findings provide a new theoretical basis for the sustainable production and scale-up of EVs, as well as a new solution for the treatment of PF.

Regenerative medicine is a very promising and new discipline that uses genetic material, tissues, or cells to replace or repair damaged organs and tissues, aiming to restore normal function. It solves the drawbacks of traditional treatments by utilizing cutting-edge techniques, including tissue engineering, three-dimensional organoids, and stem cell therapy. Effective treatment of organ transplant recipients, people with chronic wounds, cardiovascular, neurological, and other degenerative disorders are among the applications of regenerative medicine. Since the prevalence of chronic diseases has skyrocketed, regenerative medicine research and development has intensified. Microbes have a number of roles in regenerative medicine that impact tissue repair and regeneration. These include direct involvement in tissue repair, the generation of beneficial biopolymers, and immune system regulation. Because bacterial metabolites are highly versatile, non-toxic, biocompatible, and biodegradable, they are used in tissue engineering. Additionally, microbes can be used to create nanoparticles. We go into great detail in this overview about the function of microorganisms in regenerative medicine, including its uses and difficulties. The articles for this review were accessed through Google Scholar, Web of Science, PubMed, and Scopus archives using keywords like "chronic wounds," "degenerative diseases," "bacterial metabolites," "microorganisms," "cancer", and "regenerative medicine" AND "microbes". The information from the articles was specifically examined, and only English-language, fully peer-reviewed articles were included. This review identified that although regenerative medicine has ancient roots, it has undergone a major metamorphosis due to modern scientific and technological advancements. It is possible to use microbes in regenerative medicine to treat both infectious and non-communicable diseases. Because microorganisms can produce harmful compounds that harm host cells, they are rarely employed in regenerative medicine. The field of regenerative medicine practice is in dire need of terms pertaining to clinical and social preparedness, proven treatments with measurable benefits, and methods for integrating regenerative medicine technology into patient care in a responsible manner. Notwithstanding its potential, regenerative medicine has disadvantages like exorbitant costs, moral and ethical dilemmas, and legal and regulatory restrictions. The scientific community, regulators, health services, and public policy makers' awareness of the advantages and disadvantages of regenerative medicine will play a significant role in the nomenclature's ongoing improvement and enrichment.