Diabetic foot ulcers (DFUs) are the leading cause of non-traumatic amputations, and its efficient management remains a clinical challenge, particularly in treating severe infections. Current treatment strategies often fail to address the multifactorial nature of DFUs. Combining antimicrobial peptides (AMPs) with the intrinsic properties of alginate hydrogels offers a promising solution for handling the complex etiology of DFUs. In this study, we designed alginate-based hydrogels for delivery of AMPs, namely the AMPs human β-defensin 2 (hBD-2) and PP4-3.1, to enhance diabetic wound healing. The hydrogels exhibited high storage modulus, low swelling ratio, and a nanometric porous structure, enabling sustained AMP release for over three days. Rheology analyses further confirmed their stability across pH 6 to 8. In vitro, hBD-2 hydrogels displayed excellent biocompatibility and promoted better cell migration than PP4-3.1 hydrogels, for up to 48 h. Thus, hBD-2 hydrogels were used in a streptozotocin-induced diabetic mouse model of wound healing. The hBD-2 hydrogels significantly accelerated wound closure and improved wound maturation, enhancing re-epithelialization and tissue remodeling, compared to controls. Furthermore, hBD-2 hydrogels reduced the microbial load from the wounds and attenuated inflammation at the wound site by decreasing the number of M1-like macrophages, M1/M2 ratio, and CD3+ cells. Lastly, a pro-reparative environment was promoted through a decrease in reactive oxygen species (ROS) levels, and an increase in neovascularization and collagen deposition. Altogether, these findings suggest that hBD-2 alginate hydrogels hold promise as a novel therapeutic option for managing DFUs, offering a combined anti-inflammatory, ROS-scavenging and tissue-regenerative effect.

Design and construction of novel dressings with appropriate structure and multiple bio-functions are urgently required for the wound treatment applications. In this study, a series of wound dressings composed of amine-modified polysuccinimide (PSI)/polycaprolactone (PCL) hydrogel nanofibers were fabricated by using the conjugated electrospinning and the chemical crosslinking post-treatment. All the dressings with different PSI/PCL ratios could effectively maintain the fibrous morphology even after the chemical crosslinking process. The ultimate stress and Young's modulus of the PSI-NH2/PCL dressings significantly increased with higher PCL content. In particular, when the proportion of PCL reached 40 % (with a PSI/PCL mass ratio of 60/40), the PSI-NH2/PCL dressing exhibited the most excellent mechanical properties, with a Young's modulus of 31.9 ± 8.9 MPa and an ultimate stress of 7.4 ± 0.4 MPa, which were significantly higher than the other samples. Furthermore, all samples exhibited a high swelling ratio of over 350 %, although a noticeable decrease in swelling properties was observed when the content of PCL increased. In addition, all the PSI-NH2/PCL dressings showed a high antibacterial activity (> 99 %) against both Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), which demonstrated that the addition of PCL has no significant influence on the antibacterial activity of the PSI. Moreover, all the PSI-NH2/PCL nanofiber hydrogel dressings had excellent biocompatibility to human dermal fibroblasts (HDFs). Importantly, all the PSI-NH2/PCL nanofiber hydrogel dressings presented excellent hemostatic capacity. Notably, even the dressing with the highest PCL content still demonstrated a 71.8 % reduction in bleeding compared to the control group. In summary, our PSI-NH2/PCL nanofiber hydrogel dressings with high absorption, biocompatibility and extracellular matrix (ECM)-mimicking capacities, as well as great mechanical, antibacterial, and hemostatic properties are excellent as a promising wound dressing.

Tissue engineering and regenerative medicine have emerged as crucial disciplines focused on the development of new tissues and organs to overcome the limitations of traditional treatments for tissue damage caused by accidents, diseases, or aging. Strontium ion (Sr2+) has garnered significant attention for its multifaceted role in promoting regeneration medicine and therapy, especially in bone tissue regeneration. Recently, numerous studies further confirm that Sr2+ also plays a critical in soft tissue regeneration. This review firstly summarizes the influence of Sr2+ on critical biological processes such as osteogenesis, angiogenesis, immune modulation, matrix synthesis, mineralization, and antioxidative defence mechanisms. Then details the classification, properties, advantages, and limitations of Sr-containing biomaterials (SrBMs). Additionally, this review extends to the current applications of SrBMs in regenerative medicine for diverse tissues, including bone, cartilage, skeletal muscle, dental pulp, cardiac tissue, skin, hair follicles, etc. Moreover, the review addresses the challenges associated with current SrBMs and provides insights for their future designing and applications in regenerative medicine.

Diabetic wounds manifest significant clinical challenge with approximately 50-70 % reporting non-traumatic lower limb amputations annually. This review examines the intricate relationship between impaired wound healing in diabetes mellitus and two crucial signaling pathways: Wnt/β-catenin and MAPK/ERK. Chronic hyperglycemia in diabetes mellitus leads to peripheral neuropathy, vascular dysfunction, and compromised immune responses, resulting in delayed wound healing. The Wnt/β-catenin pathway, which is essential for cellular proliferation, differentiation, and tissue homeostasis, shows altered activity in diabetic wounds, particularly through decreased R-spondin 3 protein expression. Similarly, the MAPK/ERK pathway, which regulates cellular proliferation and differentiation through hierarchical kinase cascades, exhibits dysregulation under diabetic conditions. This review describes the current understanding of normal wound healing processes, diabetic wound pathophysiology, and the molecular mechanisms of both signaling pathways. Evidence suggests that targeting these pathways, either individually or synergistically offer promising therapeutic approaches for diabetic wound management. Future directions include, developing targeted delivery systems, exploring pathway cross-talk, and investigating dual-pathway modulators to enhance wound healing outcomes in diabetic patients. This comprehensive analysis provides insights into potential therapeutic strategies and emphasizes the necessity of research in this crucial area of diabetes treatment. (Graphical Abstract).

Open wounds are prone to bacterial infiltration mostly resistant strains like methicillin-resistant Staphylococcus aureus (MRSA), which affects healing of open wounds. Topical linezolid nano-dispersion using essential oils as nanoemulgel can increase solubility of drug and bypass side-effects like GI-irritation of oral administration. Pseudo-ternary phase diagram was built to optimise nanoemulsion. Surfactant/co-surfactant mixture (3:1), deionised water and Oilmix (4:1) with drug were vortexed and then ultrasonicated. 1% carbopol gel of optimised nanoemulsion was prepared and characterised, exposed to antimicrobial study, cytocompatibility study using HEK293 cell-line, and in vivo wound healing study using rat excision model. Histological study was performed to confirm growth of stratum corneum. Optimised formulation has particle size (244.6 ± 178.66 nm), polydispersity index (25%), entrapment efficiency (92.3 ± 3.38%) and in vitro drug release (87.58 ± 4.16%) best fitted in Korsmeyer-Peppas kinetics model. Nanoemulgel F6 (0.2%w/w) was found with viscosity of 5345 ± 6 cP constituting a very excellent antimicrobial effect against MRSA. HEK293 cells had shown good cytocompatibility with formulation. The wound contraction rate was 99.66 ± 0.57% at day 15 on daily application of nanoemulgel and stratum corneum was almost fully regenerated. The developed nanoemulgel has potential antimicrobial efficacy and can promote wound healing.

Superficial surgical site infection (SSI) is a significant risk factor for the development of periprosthetic joint infection (PJI), particularly in diabetic patients. A high-glucose microenvironment is observed to compromise phagocytosis by inducing cellular senescence, which leads to impaired antibacterial immune function. Exosomes derived from umbilical cord stem cells (H-Exos) can reverse the immunosuppressive microenvironment by rejuvenating senescent cells, thereby terminating excessive, persistent, and ineffective inflammatory responses. Thus, a novel exosome-based immunotherapeutic antibacterial strategy to reverse fate is proposed. Vancomycin & lysostaphin-loaded exosomes are incorporated in a customizable microneedle patch (ExoV-ExoL@MN) for controlled release, enabling tailored treatments for diverse clinical scenarios. While rejuvenating macrophage senescent phenotype, the antibiotics encapsulated within exosomes can be responsively released by the hemolysin secreted by bacteria, triggering rapid bacterial killing. Post-infection clearance, they induce a shift from M1 to M2 macrophage polarization, thereby enhancing anti-inflammatory and reparative responses. Furthermore, the components can be mixed on demand and at any time, allowing for real-time customization and fabrication directly at the clinic (fabrication@clinic). This strategy reverses the immunosuppressive microenvironment by rejuvenating senescent macrophages and effectively combats bacterial invasion into deep tissues through bacteria-responsive antibiotic release, providing a promising approach for preventing and treating SSI-induced PJI.

The transdisciplinary nature of nanotechnology has facilitated its application across various fields, especially in biological sciences. The primary aim of this review is to consolidate the many facets of nanomedicine, theranostics, and nanotechnology in food preservation into a unified framework and to underscore established research methodologies in the medical domain. Nanoparticles serve a crucial function in improving the bioavailability of orally delivered bioactive substances. This review demonstrated that nanoparticles can enhance the bioavailability of micronutrients, such as vitamin B12, vitamin A, folic acid, and iron. New advances in nanotechnology have made big differences in finding pathogens and killing them specifically, helping people to get better health through medication delivery and imaging, improving food packaging better so it lasts longer, and making foods healthier overall. Nanotechnology currently enhances the safety of delivering highly hazardous medicines through the use of nanozymes that exhibit antioxidant and antibacterial characteristics. Moreover, wearable devices can identify significant alterations in vital signs, medical problems, and infections occurring within the body. We anticipate that these technologies will provide physicians with enhanced direct access to crucial information about the causes of changes in vital signs or diseases, as they are directly connected to the source of the problem. This review paper thoroughly examines the latest developments in nanomaterials and nanozymes as antimicrobial agents in food science and nutrition, wound healing, illness diagnostics, imaging, and potential future uses. The paper presents a concise and structured report on nanotechnology, which will be beneficial to researchers and scientists for future research opportunities.

Infected wounds are common clinical injuries that often complicated by inflammation and oxidative stress due to bacterial invasion. These wounds typically suffer from impaired vascularization, which delays healing and increases the risk of complications such as sepsis and chronic wounds. Therefore, developing an effective treatment for infected wounds is highly necessary. Egg white can promote cell regeneration and repair, while chitosan is effective in resisting bacterial invasion. Sildenafil is believed to have the potential to promote angiogenesis. Based on these properties, we have prepared a new type of hydrogel using egg white and chitosan as the framework, loaded with sildenafil (CEHS). The hydrogel combines the benefits of its components, exhibiting good biocompatibility and promoting the proliferation and migration of NIH 3T3 (3T3) cells and human umbilical vein endothelial cells (HUVEC), as well as the angiogenesis in HUVEC. It also exhibits significant antioxidant, anti-inflammatory, and antibacterial properties against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Additionally, in a mouse model of infected wounds, the CEHS effectively promoted wound healing through its excellent antioxidant and anti-inflammatory properties, antibacterial activity, and pro-angiogenic effects. In summary, this simple-to-prepare, multifunctional natural hydrogel shows great promise for the treatment of infected wounds.

Urogenital fistulas are characterized by communication tracts that connect two surfaces or distinct organ systems. A vaginocutaneous fistula is a rare type of urogenital fistula that is characterized by persistent perineal discharge. This case report describes a female patient who suffered from recurrent labial abscesses and a fistula that connected the lower vagina to the inner thigh. There were symptoms of persistent perineal discharge, and the patient had an offensive odor. The patient had a history of six recurrent right labial abscesses over a period of two years prior to the formation of two fistulous openings. The right medial aspect of the inner thigh, adjacent to the labia majora, was found to have a 0.7 cm opening, which was confirmed by magnetic resonance imaging. Intraoperatively, the fistulous tract was readily delineated using dye. Complete fistulectomy was performed. This report highlights an unusual presentation of a urogenital fistula, the diagnostic challenges, and the management strategies. It emphasizes the need for timely identification and intervention in such cases.

Wounds are highly prone to infection, which can delay healing and lead to severe complications such as gangrene and sepsis. Non-healing wounds significantly impact patients' physical and mental well-being and place a substantial financial burden on healthcare systems. Timely and effective treatment of wound infections is critical, but the rise of antibiotic-resistant pathogens complicates this process. In this study, we investigate a potent protease resistant antimicrobial peptide (AMP), PLNC8 αβ, for the treatment of wound infections and present a strategy for localized AMP delivery using functionalized advanced nanocellulose (NC) wound dressings. Two types of NC dressings were explored: bacterial cellulose (BC) and TEMPO-oxidized nanocellulose derived from wood powder (TC). In a porcine wound infection model, PLNC8 αβ exhibited high antimicrobial activity, successfully eradicating the infection while promoting wound re-epithelialization. To achieve controlled release of PLNC8 αβ from the NC dressings, the peptides were either physisorbed directly onto the nanofibrils or encapsulated within mesoporous silica nanoparticles (MSNs) that were incorporated into the dressings. The PLNC8 αβ functionalized dressings demonstrated low cytotoxicity toward human primary fibroblasts and keratinocytes. Both BC and TC dressings showed efficient contact inhibition of bacteria but were less effective in inhibiting bacteria in suspension. In contrast, MSN-functionalized dressings, displayed significantly enhanced peptide-loading and sustained release capacities, resulting in improved antimicrobial efficacy. These findings highlight the potential of PLNC8 αβ and PLNC8 αβ-functionalized nanocellulose wound dressings for the treatment of infected wounds, offering an effective alternative to conventional antibiotic therapies.

Type 2 inflammation and epithelial-to-mesenchymal transitions (EMTs) play critical roles in airway repair after damage from allergens or parasites. The matricellular protein periostin (POSTN) has increased expression in inflammatory conditions and has been implicated in fibrosis and EMT, suggesting a role in airway repair. This study investigates the role of periostin in airway epithelial and lung fibroblast wound repair using an in vitro wound model. Our results demonstrate that the type 2 cytokine IL-13 induces periostin secretion from primary human airway epithelial basal cells. Periostin knockdown in human airway epithelial cells (HAEs) and human lung fibroblasts (HLFs) impairs wound closure, indicating that periostin is required for airway repair. In a coculture model of HAE and HLFs, fibroblast-secreted POSTN is required for airway epithelial wound repair, suggesting that periostin is involved in paracrine signaling between the two cell types. These findings highlight periostin's critical function in epithelial and fibroblast-mediated wound repair, suggesting its potential as a therapeutic target for diseases characterized by aberrant wound healing and fibrosis, such as asthma and idiopathic pulmonary fibrosis.NEW & NOTEWORTHY This article highlights the critical role of periostin (POSTN) in airway epithelial and fibroblast-mediated wound repair. Moreover, the study reveals a paracrine signaling loop between airway epithelial basal cells and lung fibroblasts, emphasizing periostin's therapeutic potential for diseases like asthma and idiopathic pulmonary fibrosis.

Cyclin-dependent kinase 5 (CDK5) plays a critical role in the inflammatory response. Macrophages are pivotal orchestrators of inflammation, fibrosis, and wound repair. However, the effectiveness of CDK5 in macrophages on cutaneous wound healing remains inadequately characterized. We determined the role of CDK5 signaling pathway in macrophages in mouse cutaneous wound healing through the established macrophage-specific deletion of CDK5 (myeCDK5-/-) mice and the pharmacological CDK5 inhibitor Roscovitine. Phosphorylated proteomics, western blotting, Masson staining, and dualimmunofluorescence staining were performed to investigate the potential mechanisms underlying CDK5-mediated inflammatory regulation in macrophages in wound healing. CDK5 expression and phosphorylation were both elevated significantly in cutaneous wound healing process in mice. Moreover, an accelerated wound healing in myeCDK5-/- mice was exhibited with the reduced pro-inflammatory mediators (IL-1β and iNOS) and the elevated anti-inflammatory markers (IL-10 and CD163) expression significantly. CDK5 deficiency in macrophages enhanced tissue remodeling, evidenced by increased collagen deposition and capillary density (CD31+ cells). Consistently, Roscovitine-treated mice also showed accelerated wound healing, accompanied by decreased pro-inflammatory factors and increased anti-inflammatory markers at the wound site. Mechanistically, the decreased phosphorylation of SIRT1 at the Ser14 and Ser47 sites, as a substrate of CDK5, was confirmed in myeCDK5-/- mice. These data are the first to indicate that CDK5 signaling-dependent regulation of SIRT1 phosphorylation in macrophage-mediated inflammation is required for the wound healing process, warranting consideration of the CDK5-SIRT1 pathway as a therapeutic target for cutaneous wound healing.

To address the challenge of achieving faster wound healing, we present an innovative approach using hydrogel wound dressings that leverage the mechano-electric synergistic effect. This method incorporates piezoelectric zinc oxide nanoparticles (ZnO NPs) and conductive carbon nanotubes (CNTs) into a thermosensitive poly(N-isopropylacrylamide) (PNIPAM) hydrogel matrix. The engineered hydrogel demonstrates exceptional mechanical strength, optimal swelling properties, enhanced antibacterial activity, and excellent biocompatibility and biosafety. Upon application to a wound site, the hydrogel undergoes temperature-induced centripetal contraction, which enhances the wound closure process. Moreover, the morphological changes in the hydrogel caused by self-contraction and alterations in skin shape can trigger a piezoelectric effect, generating stable and lasting bioelectric signals that promote fibroblast migration. Consequently, a wound approximately 1 cm2 in size can nearly completely heal within 14 days, thanks to the hydrogel's multifaceted therapeutic potential, including anti-inflammatory effects, promotion of cell migration, induction of fibroblast-to-myofibroblast differentiation, and enhancement of angiogenesis. This breakthrough represents a significant advancement over conventional hydrogel wound dressings, offering considerable promise for clinical application.

The extracellular matrix (ECM) plays a critical role in cancer progression by influencing tumor growth, invasion, and metastasis. This review explores the emerging therapeutic strategies that target the ECM as a novel approach in cancer treatment. By disrupting the structural and biochemical interactions within the tumor microenvironment, ECM-targeted therapies aim to inhibit cancer progression and overcome therapeutic resistance. We examine the current state of ECM research, focusing on key components such as collagen, laminin, fibronectin, periostin, and hyaluronic acid, and their roles in tumor biology. Additionally, we discuss the challenges associated with ECM-targeted therapies, including drug delivery, specificity, and potential side effects, while highlighting recent advancements and future directions. This review underscores the potential of ECM-focused strategies to enhance the efficacy of existing treatments and contribute to more effective cancer therapies.

Uncontrolled bleeding post-surgery or trauma presents a significant medical challenge that often leads to complications such as hypotension, organ dysfunction, and mortality. Effective hemostatic agents are characterized by facilitating rapid bleeding cessation, adequate wet tissue adhesion, easy removal, and minimal hemolysis rate. Building on our previous work with tsPBA@PVA hydrogel, we developed a modified synthesis approach to yield Fe3O4@gel, designed to enhance hemostasis. This system is composed of Fe3O4, N1-(4-boronobenzyl)-N3-(4-boronophenyl)-N1,N1,N3,N3-tetramethylpropane-1,3-diaminium, tsPBA, and polyvinyl alcohol, PVA, which undergo a reaction to yield a borate ester. The hydrogel demonstrated excellent self-healing and adhesion properties by forming covalent bonds with diols on material surfaces. Moreover, the presence of polar functional groups within the hydrogel such as -OH, -CH, and -CO groups enabled strong hydrogen bonding with tissue surfaces. The hydrogel could also be easily removed from the wound site without causing rebleeding. In vitro, Fe3O4@gel exhibited a hemolysis rate of less than 5%. Both our in vivo and in vitro results demonstrated the formation of a blood clot enhanced by the presence of Fe3O4 in the hydrogel. These findings suggest the potential of Fe3O4@gel as a promising candidate for promoting hemostasis in wound healing.

Engineered extracellular vesicles (EVs), which are EVs modified to enhance certain biological properties, offer a promising therapeutic strategy for the treatment of skin defects. Conventional nanomaterials often encounter clinical translation challenges due to potential toxicity and limited targeting. Engineered EVs, utilizing inherent biocompatibility and effective physiological barrier traversal, can ameliorate the limitations of conventional EV therapies to some extent, including detection, isolation, purification, and therapeutic validation. Recent advances in EV engineering, such as genetic modification of production cells to control cargo, surface engineering for targeted delivery, and pre-treatment of parental cells to optimize production and bioactivity, have improved therapeutic efficacy in laboratory studies through enhanced targeting, prolonged retention time, and increased yield. Many studies have suggested the potential ability of engineered EVs to treat a variety of skin defects, including diabetic wounds, burns, and hypertrophic scars, providing a promising avenue for their clinical translation in this area. This paper reviews the therapeutic potential of engineered EVs in skin regeneration, highlighting their role in promoting cell migration and angiogenesis, modulating inflammation and reducing scar formation during wound healing. In addition, given the investment in this rapidly evolving field and the growing clinical trial activity, this review also explores recent global advances and provides an outlook on future application opportunities for EVs in the treatment of skin defects.

Stem cell therapy has emerged as a groundbreaking approach in regenerative medicine, offering immense potential for tissue regeneration and wound healing. Stem cells, with their ability to self-renew and differentiate into specialized cell types, provide innovative therapeutic strategies for variety of medical conditions. Key stem cell types, including embryonic, induced pluripotent, and adult stem cells such as mesenchymal and hematopoietic stem cells, play pivotal roles in regenerative processes and wound repair. In tissue regeneration, stem cells replenish damaged or necrotic cells by differentiating into specialized cell types like bone, muscle, or nerve cells, thus restoring the structural and functional integrity of tissues. In wound healing, stem cells stimulate angiogenesis, generate new skin cells, and modulate immune responses to enhance repair. This multifaceted therapeutic potential has paved the way for clinical applications in cardiovascular, neurological, musculoskeletal, and autoimmune disorders, as well as skin and burn injuries. This review highlights recent advancements in stem cell therapy, exploring its clinical applications and addressing challenges such as immune rejection, ethical concerns, scalability, and the need for long-term clinical trials. The article underscores the importance of continued research to fully realize the transformative potential of stem cell therapy in modern medicine.

Background/Objective:Bougainvillea x buttiana of the Nyctagenaceae family is widely used in traditional Mexican medicine for treating different diseases. This study was planned to estimate the healing effect of the acetonic extract obtained from Bougainvillea x buttiana (var. Rose). Methods: The bracts with flowers were subjected to extraction using maceration and concentrated in vacuo. Fractionation with a similar profile resulted in 11 fractions, which were determined using TLC. A mouse wound excision model was tested to evaluate the wound healing effect of the topical treatment pre-formulated with fractions of acetonic extract, which were determined using image analysis techniques. Cytokine levels present in the sera of mice treated or not treated with the acetonic extract were determined using the ELISA method. Results: The results obtained showed that the crude acetonic extract of B. x buttiana and/or its fractions in a pre-formulated hydrogel had wound healing capacity. The wound contraction rate and the healing speed in groups of animals treated with the pre-formulated crude extract and/or its fractions were significantly higher compared with the negative control (p < 0.001). Fraction 2 demonstrated more significant healing, reduced the production of cytokines such as IL-6 and TNF-α, and enhanced the levels of IL-10. Conclusion: The present study showed that the fractions obtained from the acetonic extract of B. x buttiana bracts were able to accelerate the wound healing process through anti-inflammatory mechanisms by regulating inflammatory cytokines. The results presented demonstrate that the extracts from B. x buttiana contain compounds that may be responsible for their healing properties.

Treatment of chronic or non-healing wounds has faced a considerable clinical challenge and impose several detrimental effects on individuals, society, the healthcare system, and the economy. Bioactive peptides have been employed to accelerate wound healing in active wound treatment efficiently and effectively. In the current study, a novel wound-healing peptide, WHP1, was designed from 23 existing wound-healing peptides by a rational template-assisted approach. It demonstrated the ability to enhance migration and proliferation of human keratinocyte cell lines (HaCaT) without exhibiting cytotoxic effects on human red blood cells and HaCaT cells. By quantitative proteomic analysis, WHP1 exerted a multifaceted role on diverse cellular processes in human keratinocyte. Notably, it increased the expression of intracellular proteins of HaCaT cells involved in cell cycle regulation and focal adhesion, including centromeric histone H3 variant CENPA, ubiquitin-conjugating enzyme E2 C, thyroid receptor-interacting protein 6, and ribosomal components essential for cell adhesion and migration. WHP1 upregulated the key enzyme glyceraldehyde-3-phosphate dehydrogenase, orchestrating metabolic biosynthesis particularly glycolysis, cell cycle regulation, and cytoskeletal processes. An intriguing observation was the antioxidant activity of WHP1, protecting cells from reactive oxygen species-induced senescence. This is consistent with the upregulation of GAPDH expression and reduction of histone H2A.J levels. WHP1 also stimulated macrophages to secrete transforming growth factor-β (TGF-β), a crucial growth factor necessary for the remodeling phase of wound healing. This investigation highlighted the feasibility of rational design to create novel wound-healing peptides. Such advancements hold promise for improving patients' quality of life and elevating the standard of care in contemporary healthcare.

Osteoporotic bone defect and fracture healing remain significant challenges in clinical practice. While traditional therapeutic approaches provide some regulation of bone homeostasis, they often present limitations and adverse effects. In orthopedic procedures, bone cement serves as a crucial material for stabilizing osteoporotic bone and securing implants. However, with the exception of magnesium phosphate cement, most cement variants lack substantial bone regenerative properties. Recent developments in biomaterial science have opened new avenues for enhancing bone cement functionality through innovative modifications. These advanced materials demonstrate promising capabilities in modulating the bone microenvironment through their distinct physicochemical properties. This review provides a systematic analysis of contemporary biomaterial-based modifications of bone cement, focusing on their influence on the bone healing microenvironment. The discussion begins with an examination of bone microenvironment pathology, followed by an evaluation of various biomaterial modifications and their effects on cement properties. The review then explores regulatory strategies targeting specific microenvironmental elements, including inflammatory response, oxidative stress, osteoblast-osteoclast homeostasis, vascular network formation, and osteocyte-mediated processes. The concluding section addresses current technical challenges and emerging research directions, providing insights for the development of next-generation biomaterials with enhanced functionality and therapeutic potential.

Malignant fungating wounds (MFWs) are cancer-related complications that arise from metastases in advanced cancers. They appear in 5-14% of cancer patients, with higher prevalence in breast (66%) and head and neck (24%) cancers. Novel therapeutic routes for the management of MFWs rely on plant-based treatments, e.g. oxymatrine (OXM), an alkaloid derived from a Chinese plant with anticancer and anti-inflammatory properties. The objective of this work was to assess the potential of polyvinyl alcohol/casein (PVA/CAS) hydrogels to be used as dressings for OXM delivery. CAS can stimulate the immune system, while PVA is one of the most used synthetic polymers in the composition of hydrogels for medical applications. Six different hydrogel formulations were prepared following different procedures: freeze-thawing (FT) and cast drying (CD) for 24 or 48 h, with and without the addition of genipin (GE), a crosslinking agent. The hydrogels were loaded with OXM, and their release behaviour was studied. PVA/CAS-24CD + GE showed the best release profile. After being subjected to sterilisation by high hydrostatic pressure, it was further investigated in terms of physicochemical properties, mechanical characteristics and biocompatibility. Overall, this hydrogel revealed adequate characteristics to be used as a biocompatible medicated dressing for OXM release.

Mohs micrographic surgery (MMS) is the gold standard treatment for skin cancers of the face, but scarring in these cosmetically sensitive areas remains a challenge, with no clear consensus on the most effective treatments. This study reviews the literature on therapies for specifically facial scars following Mohs surgery, emphasizing their mechanism of action and evidence of efficacy. Non-invasive options such as topical silicone and pressure therapy have shown benefits, while advanced techniques like dermabrasion, microneedling, or energy devices like the pulse-dye, CO2, Erbium, and Nd:YAG lasers, show promise in improving scar pliability and visibility. Intralesional injections of corticosteroids, botulinum toxin, and dermal fillers also have supportive data. Conversely, treatments like topical onion extract and vitamin E lack evidence of efficacy. Managing hypertrophic granulation tissue (HGT) also remains critical to reduce aberrant scarring from second-intention healing (SIH). To ensure optimal clinical outcomes, clinicians should remain updated on the wide range of scar therapies available, focusing on those with established biochemical mechanisms and evidence of efficacy.

Cerebral infarction is a predominant cause of global disability and mortality, characterized by pathogenesis that includes vascular stenosis, thrombosis, ischemic necrosis, and neuroinflammation. Despite progress in medical science, effective treatments for cerebral infarction are still constrained, prompting the investigation of alternative therapeutic strategies.

The objective of this review is to assess the efficacy of Traditional Chinese Medicine (TCM) as a treatment for cerebral infarction, emphasizing its mechanisms of action, effectiveness, and clinical relevance.

An extensive review of the existing literature regarding the role of TCM in the management of cerebral infarction, encompassing investigations on specific remedies, Chinese medicinal formulations, and contemporary advancements in preparation methodologies.

This review analyzes diverse TCM remedies recognized for their antioxidant, anti-inflammatory, and neuroprotective properties. Furthermore, it examines the synergistic effects of Chinese medicine formulations in modulating inflammation, enhancing blood circulation, and facilitating neural repair. Contemporary technological advancements that improve the accuracy and efficacy of Chinese medicine are also taken into account.

TCM has shown considerable promise in tackling the complex aspects of cerebral infarction. Specific remedies and formulations have demonstrated potential in modulating inflammatory responses, enhancing cerebral blood flow, and promoting neural repair mechanisms. Contemporary formulations have enhanced these effects, facilitating more precise and effective treatment.

While TCM presents a promising multi-faceted and multi-tiered strategy for addressing cerebral infarction, obstacles such as elucidating mechanisms and achieving standardization must be addressed. Continued research and clinical trials are crucial to fully exploit the therapeutic potential of TCM in the management of cerebral infarction.

Diabetic ulcers are associated with oxidative stress, inflammation, decreased synthesis of pro-healing mediators, and impaired vascularization, which convert the wound from acute to chronic and delay healing. An extended duration of wound healing raises the possibility of complications such as infection, sepsis, and even amputation. The objective of this study is the synthesis of a plasticized cross-linked hyaluronic acid (HA)-grafted poly(acrylamide-co-itaconic acid) nanogel as a nontoxic adhesive, swellable, antibacterial wound dressing with good mechanical properties to protect the wound from pathogens and accelerate the healing process, in addition to decreasing oxidative stress and inflammatory cytokines while increasing anti-inflammatory cytokines and angiogenesis. Nanogel H3 with a ratio (AM/IA) (3:1) showed excellent adhesion with good mechanical properties, biocompatibility, swelling, antioxidant, and antibacterial efficiencies. It showed great wound closure in vitro and in vivo with downregulation of inflammatory cytokines, upregulation of anti-inflammatory cytokines, and enhanced angiogenesis in vivo on diabetic and nondiabetic wounds.

Understanding the biochemistry and pharmacodynamics of chronic wounds is of key importance, due to the millions of people in the UK affected and the significant cost to the NHS. Chronic wounds are characterised by elevated concentrations of matrix metalloproteinases (MMPs) that destroy the surrounding extracellular matrix (ECM). However, fibroblasts can produce tissue inhibitors of MMPs (TIMPs) in order to regulate wound healing. Therefore, the role of TIMPs in both acute and chronic wounds needs to be properly understood in order to develop therapeutic treatments. In this work, we propose a reaction-diffusion system of four partial differential equations that describe the interaction of the ECM, fibroblasts, MMPs, and TIMPs in a wound. We observe that, subject to parameter sets corresponding to both acute and chronic wound healing, this mathematical model gives rise to travelling wave solutions. Using bifurcation analysis, we demonstrate that excessive degradation of the ECM results in the emergence of chronic wounds, and the reversal of these chronic wounds is prohibited for lower TIMP production values. These results are replicated within a simplified model obtained via a parameter sensitivity analysis. This model is further extended to more realistic spatial domains where we demonstrate the effectiveness of a therapeutic hydrogel containing TIMPs as a treatment for chronic wounds.

WP255/2 is a Thai traditional wound healing formula documented on the Wat-Phra-Chetuphon (Wat Pho) marble inscriptions. Previous studies have demonstrated its wound healing efficacy in rat models and diabetic patients with chronic foot ulcers. Sesame oil, the major component of WP255/2, plays a key role in the wound healing process, with sesamol identified as a potent bioactive compound involved in these effects.

This study aimed to investigate how different processing conditions influence the sesame lignan profile and wound healing activity of WP255/2 ointment formulations.

WP255/2 preparations were formulated under 61 different conditions, and their sesame lignan profiles were analyzed using high-performance liquid chromatography (HPLC). The wound-healing potential was evaluated in Sprague-Dawley rats with excision wounds, focusing on wound contraction and histopathological analysis.

Sesamol concentrations varied among the 61 WP255/2 preparations, with WP-02 exhibiting the highest concentration (0.258 mg/g) and WP-03 containing none (0.000 mg/g). In the excision wound model, WP-03 and WP-01 significantly enhanced wound contraction compared to the non-treated group (p < 0.05) and exhibited anti-inflammatory effects. Additionally, all tested formulations (WP-01, WP-02, WP-03) promoted a balanced synthesis and degradation of collagen types I and III.

The wound healing efficacy of WP255/2 is not directly proportional to sesamol concentration. Optimal activity was observed in formulations with low or undetectable sesamol levels, particularly those processed at 70 °C or 180 °C for 90 min. These findings highlight the critical role of processing conditions in modulating chemical composition and therapeutic efficacy, offering insights for standardizing traditional herbal formulations for clinical use.

The skin acts as a vital barrier against external threats and regulates moisture levels. The skin's repair and rejuvenation encompass complex molecular and cellular mechanisms, constituting an essential yet intricate process to preserve skin integrity following trauma or surgical intervention. Acute wound repair unfolds through different interrelated stages, whereas chronic wounds pose significant healthcare challenges, often linked to conditions like diabetes and vascular diseases. Understanding of wound physiology is crucial for developing effective treatments. Chronic wounds require more comprehensive treatments, including surgical debridement, glycemic control, and antibiotic therapy. Ascorbic acid (AA) emerges as a promising wound-healing agent because it facilitates collagen synthesis, enhances antioxidant defense, promotes re-epithelialization and angiogenesis, regulates pH, and exhibits antimicrobial properties. Research outcomes on applying AA-based formulations on wound environment demonstrated its potential to accelerate wound closure and tissue regeneration, offering hope for improved wound management and reduced healthcare burdens associated with chronic wounds. The application of AA, which often utilizes innovative delivery methods and synergistic combinations with other actives, shows promise in preclinical studies for superior efficacy, biocompatibility, and controlled release profiles. Overall, AA-based therapies represent a significant avenue for advancing wound care and addressing the challenges of chronic wounds in healthcare systems.

Hyperactivation of M1 macrophages or delayed macrophage M2/M1 polarization during wound healing is a major obstacle to wound healing. Polysaccharide, as a biomaterial, has shown great potential and advantages in the field of wound dressings, but little is known about the role of polysaccharide (PSP) in wound healing. The aim of this study was to investigate the promotional effect of PSP on wound healing through its effect on macrophage M2/M1 polarization. The results showed that PSP treatment polarized the macrophage population toward an M2 phenotype, significantly accelerating wound closure in vivo, as evidenced by increased levels of collagen deposition, decreased levels of pro-inflammatory cytokines (INOS, IL-6, and IL-1β), and increased expression of CD31 (an angiogenic marker) and Ki67 (a cell proliferation marker). Functional changes in skin macrophages during wound healing were analyzed using single-cell RNA sequencing (scRNA-seq). The results highlighted a unique transcriptional signature associated with PSP-induced polarization of M2 macrophages. Moreover, PSP was found to upregulate the PI3K/Akt signaling pathway, which is crucial for cell survival, migration, and tissue repair. These results reveal that PSP can promote skin wound healing, emphasizing its potential as a natural product for treating skin wounds.

Diabetic wounds healing is often severely slowed by hyperglycemia, elevated oxidative stress, bacterial infections, and persistent inflammation. This review focuses on the development of hydrogels derived from carbohydrate polymer and protein to facilitate diabetic wound healing. We discuss the primary sources of cellulose, chitosan, hyaluronic acid, sodium alginate, collagen, and gelatin along with their advantages in the preparation of hydrogels. Based on the microenvironment of diabetic wounds, i.e., hyperglycemia, increased oxidative stress, and persistent inflammation, the application of multifunctional hydrogels in promoting diabetic wounds, including stimulus responsiveness, injection self-healing, antibacterial, antioxidant, anti-inflammatory, and synergistic effects, is discussed. We address the main challenges and future perspectives of multifunctional hydrogels based on carbohydrate polymer and protein in the treatment of diabetic wounds.

The treatment of chronic refractory skin wounds still remains a serious clinical challenge. Stem cells and hydrogels are widely used in healing of skin wound of various types due to their superior bioactivities and biocompatibility. This study aimed to demonstrate the wound healing effect of a hydrogel compound loaded with enucleated stem cells expressing the platelet-derived growth factor (PDGF).

An injectable hydrogel was formulated using 22% poloxamer 407, 1% poloxamer 188, and 1% hyaluronic acid. A PDGF-B transgenic cell line of mouse bone marrow mesenchymal stem cells (BMSCs) was generated by lentiviral infection. Cells were enucleated and embedded in hydrogel. The healing effects of the compound was tested in a full-thickness skin wound model of Balb/c mice. The wound models were randomly divided into four groups: the control group applied with PBS buffer; the hydrogel group with hydrogel only; the BMSC group with hydrogel mixed with normal BMSCs; and the BMSC-PDGF group with hydrogel mixed with enucleated BMSCs expressing PDGF.

Overexpression of PDGF-B in transgenic cell line of BMSCs was verified by RT-PCR, immunofluorescence staining and western blot. When enucleated, the viability measured by Calcein-AM staining reduced to 54.29% at 48 h. Conditioned medium was collected with or without hydrogel layered over cells. PDGF concentration measured by ELISA reached 14.66 ng/μL and 257.89 ng/μL respectively after 48-h cultivation, suggesting a possible slow releasing effect in the presence of hydrogel. When applied to the skin wound, the healing rates of the BMSC-PDGF group was significantly higher than that of the control group on day 3. BMSC-PDGF group had significantly more neovascularization and cutaneous appendages from day 7. The proliferation of collagen fibers in BMSC-PDGF group was significantly higher than the control group on day 3 and day 7. Finally, BMSC-PDGF group had significantly lower amount of the inflammatory factors TNF-α, IL-1β, IL-6, MMP-3 and MMP-9 than that of the control group on day 7.

PDGF-stem cell-hydrogel compound significantly improved wound healing and reduced wound inflammatory factor expression in Balb/c mice. This biomaterial-based approach provides a new powerful reference for the treatment of chronically wounded skin.

Uncontrolled bleeding and infections, particularly from drug-resistant bacteria like Methicillin-Resistant Staphylococcus aureus (MRSA), pose significant challenges in clinical wound management, delaying healing, increasing patient discomfort, and elevating healthcare costs. This study introduces a novel reactive oxygen species (ROS)-responsive collagen-based hemostatic sponge designed to enhance wound healing and minimize blood loss, especially in MRSA-infected wounds. By chemically modifying the carboxyl groups of collagen with amino-rich oligomers, the primary amino content was increased, enhancing drug loading capacity-particularly for vancomycin-while also improving the sponge's mechanical properties, hemostatic performance, and biological stability. The ROS-responsive covalent bonding of vancomycin facilitated controlled vancomycin release in response to ROS, offering superior antibacterial efficacy and specifically targeting MRSA more effectively than conventional non-ROS-responsive approaches. In MRSA-infected full-thickness skin repair models, the ROS-responsive vancomycin-loaded sponge significantly enhanced wound healing and skin regeneration compared to both the physical adsorption group and the non-ROS-responsive release group. These results underscore the potential of the ROS-responsive collagen composite as an advanced hemostatic material with enhanced antibacterial capabilities, providing rapid hemostasis and improved healing outcomes for complex or infected wounds.

Bacterial infections in wounds and bacteremia present significant global health challenges, driving the urgent need for innovative alternatives to traditional antibiotics. Here, the development of PEI-EDTA-2Na carbon quantum dots (PECDs) synthesized via a hydrothermal method is reported. Synthesis conditions affect PECDs' antibacterial efficacy; those at 180 °C have optimal -NH2 functionalization for better adhesion and activity. PECDs are pH - responsive, eradicating bacteria in weakly acidic conditions by disrupting DNA and proteins. Following the resolution of infection, PECDs adapt to neutral and alkaline environments, where they scavenge reactive oxygen species (ROS), reduce inflammation, promote macrophage polarization, and accelerate wound healing. Furthermore, PECDs significantly improve survival in bacteremia models. Their intrinsic fluorescence enables real-time pH monitoring of wounds, offering a non-invasive diagnostic tool. Genomic and transcriptomic analyses reveal that PECDs disrupt bacterial metabolism and resistance pathways, while simultaneously supporting antibacterial and anti-inflammatory responses during tissue repair. This dual functionality-combining therapeutic efficacy in wound healing with antimicrobial and anti-inflammatory properties in bacteremia-positions PECDs as a versatile platform for smart wound management and an emerging candidate for advanced biomedical applications.

Delayed healing and fibrosis at the wound site present significant challenges in the wound care industry, often leading to complications such as infections, chronic wounds, and impaired tissue regeneration. Therefore, there is a critical need for advanced wound dressing materials that promote faster healing, prevent bacterial infections, and support effective tissue repair. This study aims to develop a Lysozyme (Lys)-based wound dressing with enhanced wound closure rates by incorporating nitrogen-doped graphene quantum dots (N-GQDs) as a functionalized nanofiller to strengthen its antibacterial properties. The wound dressing, formulated with a carboxymethyl cellulose (CMC) crosslinked polyvinylpyrrolidone (PVP) matrix, creates a porous structure that enhances swelling capacity and water vapor transmission rates (WVTR), while cytotoxicity studies confirm its biocompatibility, showing 100 % cell viability in HCT 116 and MCF7 cell lines. The in vivo wound healing performance of the designed nanocomposite hydrogel reflects complete wound closure in 5 h for Drosophila Melanogaster, aided by the shorter life span and faster metabolic processes in Drosophila, and 14 days in Sprague Dawley rat models. These results qualify the material as a promising candidate for wound dressing applications, bridging the gap between material science and medical science for effective wound management.

Despite decades of research, impaired extremity wound healing in type 2 diabetes remains a significant driver of patient morbidity, mortality, and health care costs. Advances in surgical and medical therapies, including the advent of endovascular interventions for peripheral artery disease and topical therapies developed to promote wound healing, have not reduced the frequency of lower leg amputations for nonhealing wounds in type 2 diabetes. This brief report is aimed at reviewing the roles of various cell types in tissue repair and summarizing the known dysfunctions of these cell types in diabetic foot ulcers. Recent advances in our understanding of the epigenetic regulation in immune cells identified to be altered in type 2 diabetes are summarized, and particular attention is paid to the developing research defining the epigenetic regulation of structural cells, including keratinocytes, fibroblasts, and endothelial cells. Gaps in knowledge are highlighted, and potential future directions are suggested based on the current state of the field.

The development of drugs to accelerate wound healing is an important area of clinical research. Recent advancements have highlighted the prospects of microRNAs as therapeutic targets for various disorders, although their involvement in mice wound healing remains unclear. Peptides have been proved to be unique and irreplaceable molecules in the elucidation of competing endogenous RNAs mechanisms (ceRNA) involved with skin wound healing. In the present work, CyRL-QN15, a peptide characterized by its minimal length and maximal wound healing efficacy, was applied as a probe to explore the ceRNA mechanism in regard to accelerated wound healing. Results showed that the use of CyRL-QN15 significantly reduced the expression of miRNA-365-2-5p at the wound in mice. In mouse keratinocytes, miRNA-365-2-5p inhibition increased SIRT1 and FOXO1 protein expression and decreased STAT2 protein expression, promoting cell proliferation, migration, and reducing inflammatory factors. Similarly, inhibiting miRNA-365-2-5p at mouse wounds promoted Full-thickness injured skin wounds healing, increased SIRT1 and FOXO1 protein expression, decreased STAT2 protein expression, and reduced inflammatory factors. Overall, these findings demonstrate that miRNA-365-2-5p serves a crucial function in the biological processes underlying cutaneous wound healing in mice, offering a novel target for future therapeutic interventions in wound healing.

The human oral cavity harbors a diverse microbiota, including Streptococcus species. Oral mucosal wounds heal rapidly, although the exact cause remains unclear. This study investigates the impact of Streptococcus mutans-derived extracellular vesicles (Sm EVs) on wound healing in both oral mucosal organoids and mouse skin. To explore whether microbial EV RNA cargo influences wound healing, RNA sequences from Sm EVs were identified, and the most abundant sequences were synthesized into oligomers and encapsulated in E. coli EVs (Ec EVs) for further in vivo testing. We assessed the role of Toll-like receptor 3 (TLR3) in the wound healing mechanism in TLR3 knockout (KO) mice.

Sm EVs significantly enhanced cell proliferation and migration in oral mucosa, with enhanced focal adhesion complex formation. Sm EVs improved wound healing in mouse dorsal skin compared to PBS controls. RNA sequencing revealed that bacterial tRNAs, particularly the tRNA-Met variant (Oligo 1), were the most abundant RNAs in Sm EVs. Ec EVs carrying Oligo 1 produced similar wound healing effects to Sm EVs in mucosal organoids and mouse dorsal skin. However, in TLR3 knockout mice, Oligo 1 did not improve wound healing.

This study highlights the role of Sm EVs, particularly their tRNA variants, in promoting skin wound healing through a TLR3-dependent mechanism. These findings suggest that EVs from oral commensal bacteria may offer therapeutic potential for chronic, non-healing skin wounds.

The importance of electrospun membranes for biomedical applications has increased, especially when it comes to skin regeneration and wound healing. This review presents the production and applications of electrospun membranes based on polyurethane (PU) and silk fibroin (SF) and highlights their benefits as a skin substitute. This review also highlights the electrospinning technique used to prepare nanofibers for these biomedical applications. Silk, well-known for its excellent biocompatibility, biodegradability, structural properties, and low immunogenic response, is extensively investigated by addressing its molecular structure, composition, and medical uses. PU is a candidate for potential biomedical applications because of its strength, flexibility, biocompatibility, cell-adhesive properties, and high resistance to biodegradation. PU combined with silk offers a number of enhanced properties. The study offers a comprehensive overview of the advanced developments and applications of PU/SF composites, highlighting their significant potential in wound healing. These composite membranes present promising advancements in wound healing and skin regeneration by combining the unique properties of silk and PU, opening up the possibilities for innovative treatments.

Rapid hemostasis and wound healing are crucial severe trauma treatment. Natural mechanisms often prove insufficient, spurring research for innovative biomaterials. This review focuses on cellulose-based materials, which are promising due to their absorbency, biocompatibility, and processability. The novelty lies in exploring how these materials promote clotting and tissue regeneration. They operate via extrinsic and intrinsic mechanisms. Extrinsically, they create a matrix at the wound to activate coagulation; intrinsically, they maintain clotting factors. Additionally, they aid healing through physical, chemical, and biological means, such as maintaining moisture, incorporating antimicrobial agents, and stimulating cell activity. The innovative fabrication strategies include material selection and chemical modification. Techniques like oxidation enhance performance. Structural engineering methods like freeze-drying and 3D printing optimize porosity and alignment. Cellulose-based dressings are versatile and effective in various forms. They address different wound needs and show benefits like rapid coagulation and tissue repair. This review also covers challenges and future trends, emphasizing the need to enhance mechanical properties and biodegradability. Further, new technologies offer potential improvements to the nanocomposites. Overall, continued research on cellulose-based dressing is vital, and unlocking their potential could revolutionize wound care, providing suitable solutions for trauma management.

Achieving rapid and scar-free wound repair is a key goal in the field of regenerative medicine. Herein, a dynamically Schiff base-crosslinked hydrogel (F/R gel) with phase-adaptive regulating functions is constructed to integratedly promote rapid re-epithelization with suppressed scars on chronic infected wounds. Specifically, the gel effectively eliminates multidrug-resistant bacterial biofilm at infection stage via antimicrobial activity of ε-polylysine firstly dissociated from hydrogel matrix in infectious microenvironment, and interrupts the severe oxidative stress-inflammation cycle at wound site by the released ceria nanozyme, thus stimulating a pro-regenerative environment to ensure tissue repair. Subsequently, fibroblast growth factor/c-Jun siRNA co-loaded microcapsules gradually disintegrate to release drugs, facilitating neoangiogenesis and cell proliferation but simultaneously blocking c-Jun overexpression for fibrotic scar suppression. Notably, the F/R gel facilitates normal-like skin regeneration with no perceptible scars formed on infected male mouse wound and female rabbit ear wound models. Our work offers a promising regenerative strategy emphasizing immunomodulatory and fibroblast subtype modulation for scarless wound repair.

Objective: The healing process following connective tissue (CT) injuries is complex, resulting in variable and often suboptimal outcomes. Patients undergoing CT repair frequently experience healing failures, compromised function, and chronic degenerative diseases. The identification of biomarkers to guide improved clinical outcomes after CT injuries remains an emerging but promising field. [Figure: see text] [Figure: see text] Design: Systematic review. Data sources: Databases, including PubMed, MEDLINE Ovid, Web of Science, and Google Scholar, were searched up to August 2024. Eligibility criteria: To achieve the research objective, randomized control trials, cohort studies, and case-control studies on biomarkers associated with CT repair and healing outcomes were selected. The present analysis was confined to clinical and preclinical models, excluding imaging studies. The entire process of this systematic review adhered strictly to the guidelines outlined in the Preferred Reporting Items for Systematic Review and Meta-Analyses protocol checklist. Results: A total of 1,815 studies on biomarkers of CT repair were initially identified, with 75 studies meeting eligibility criteria and 55 passing quality assessments. For biomarkers associated with CT healing outcomes, 281 studies were considered, with 30 studies meeting eligibility criteria and 24 passing quality assessments. Twenty-one overlapping studies investigated the effects of biomarkers on both CT repair and healing outcomes. Specific biomarkers identified, and ranked from highest to lowest quality, include complement factor D, eukaryotic elongation factor-2, procollagen type I N-terminal propetide, procollagen type III N-terminal propetide, lactate, pyruvate, platelet-derived growth factor-BB, tissue inhibitor of metalloproteinase-3 (TIMP-3), cysteine-rich protein-1, plastin-3, periostin, protein S100-A11, vimentin, matrix metalloproteinases (MMP-2, MMP-7, and MMP-9), hepatocyte growth factor, interferon-γ, interleukins (IL-6, IL-8, and IL-10), MMP-1, MMP-3, tumor necrosis factor-α, fibroblast growth factor-2, IL-1α, chondroitin-6-sulfate, inter-alpha-trypsin inhibitor heavy chain-4, transforming growth factor-beta 1, vascular endothelial growth factor, C-C chemokine receptor 7, C-C chemokine ligand 19, IL-1β, IL-1Ra, IL-12p40, granulocyte-macrophage colony-stimulating factor (GM-CSF), and TIMP-1. Conclusions: All of the 37 identified potential biomarkers demonstrated regulatory effects on CT repair and mediated healing outcomes. Notably, the identified biomarkers from human studies can potentially play an essential role in the development of targeted treatment protocols to counteract compromised healing and can also serve as predictors for detecting CT healing processes and long-term outcomes.