Diabetic skin, a major clinical challenge due to impaired wound healing, is often exacerbated by a hypoxic microenvironment at the wound site. Exosomes have been proven to have excellent biological activities and applied to solve many bioengineering problems. However, the wide application of exosomes is still limited by their short in vitro lifetime and low yield. To overcome these application limitations, this study specifically enhances the pro-angiogenic biological efficacy of exosomes through hypoxic treatment and achieves sustained release using hydrogel loading. In vitro, hypoxia-induced exosomes (Hp-Exo) significantly enhanced endothelial cell migration, proliferation, and angiogenic capacity. In vivo, Gelman hydrogels loaded with Hp-Exo accelerated wound closure, promoted collagen deposition, and increased vascularization in diabetic mice. miRNA sequencing of Hp-Exo revealed that exosomes induced under hypoxic conditions contain various miRNAs, which enhance vascular endothelial cell proliferation, migration, and angiogenesis through the PTEN/PI3K/AKT pathway. These results highlight that hypoxia-induced exosomes, when delivered through a biocompatible hydrogel platform, provide potential therapeutic approach to improve diabetic wound healing by stimulating angiogenesis and tissue regeneration.

Cardiovascular disease (CVD) remains one of the leading causes of high mortality and morbidity worldwide, posing a substantial threat to global health. Mesenchymal stem cell (MSC) therapy has emerged as a promising treatment approach, primarily through the secretion of various bioactive factors. Exosomes (Exos), in particular, stand out as the most effective components, as their noncoding RNA and proteins play a crucial role in promoting the repair of cardiac function, positioning them a promising cell-free therapy for CVD. However, challenges such as poor stability, low delivery efficiency, weak targeting, and rapid immune-mediated clearance hinder the broader application of Exos, presenting significant obstacles for further clinical translation. Recent advancements in biomaterials, particularly hydrogels, offer new avenues for Exos-based CVD therapies. Hydrogels, with their ability to improve stability, release control, and targeting, have gained considerable attention in the biomedical field. This review explores the latest research developments regarding the treatment of CVD using Exos, and highlights their synergistic application with hydrogels, which provide valuable insights for advancing Exos-based therapies and developing novel therapeutic strategies for CVD.

Delayed diabetic wound healing is partially attributed to the functional disorder of skin repair cells caused by high glucose (HG). Small extracellular vehicles (sEVs) loaded with small-molecule drugs represent a highly promising therapeutic strategy. This study aims to evaluate the therapeutic efficacy of ellagic acid-encapsulated small extracellular vesicles (EA-sEVs) in diabetic wound regeneration and to unravel related mechanisms. Cytotoxicity tests of ellagic acid (EA) as liposomal small molecules (LSMs) were performed with the CCK8 assay. EA was incorporated into sEVs obtained from chorionic plate-mesenchymal stem cells (CP-MSCs) to construct EA-engineered sEVs. The protective effects of EA-sEVs on human dermal fibroblasts (HDFs) and human epidermal keratinocytes (HEKs) induced by high glucose (HG) were assessed through the evaluation of their proliferative, migrative and differentiative capabilities. Furthermore, to illustrate the underlying mechanism, the specific biological targets of EA were predicted and confirmed. Finally, EA-sEVs were encapsulated in GelMA hydrogel for investigating the pro-healing effects on diabetic wounds. EA was harmless to cell viability, increasing the possibility and safety of drug development. EA-engineered sEVs were fabricated by loading EA in sEVs. In vitro, EA-sEVs promoted the proliferation, migration, and transdifferentiation of HG-HDFs and the proliferation and migration of HG-HEKs. Mechanism analysis elucidated that epidermal growth factor receptor (EGFR) was the specific biological target of EA. EA interacting with EGFR was responsible for the functional improvement of HG-HDFs and HG-HEKs. In vivo, EA-sEVs encapsulated in GelMA promoted the healing of diabetic wounds by improving re-epithelialisation, collagen formation and the expression of EGFR. Gel-EA-sEVs promoted diabetic wound healing by improving biological functions of HDFs and HEKs. EGFR was first identified as the specific biological target of EA and was responsible for the functional improvement of HG-HDFs and HG-HEKs by Gel-EA-sEVs. Hence, Gel-EA-sEVs can serve as a new promising active dressing for diabetic wound treatment.

Skin diseases are a broad category of diseases and each has complex conditions, which makes it challenging for dermatologists to provide targeted treatment. Exosomes are natural vesicles secreted by cells and play a key role in cell communication. Due to their unique characteristics, including inherent stability, minimal immunogenicity, high biocompatibility, and exceptional ability to penetrate cells, exosomes are being explored as potential delivery vehicles for therapeutics across various diseases including skin problems. Utilizing exosomes for drug delivery in skin diseases can improve treatment outcomes and reduce the side effects of traditional drug delivery methods. Indeed, exosomes can be engineered or utilized as an innovative approach to deliver therapeutic agents such as small molecule drugs, genes, or proteins specifically to affected skin cells. In addition to targeting specific skin cells or tissues, these engineered exosome-based nanocarriers can reduce off-target effects and improve drug efficacy. Hence, this article highlights the transformative potential of this technology in revolutionizing drug delivery in dermatology and improving patient outcomes.

Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, are released into the extracellular space by almost all known cell types. They facilitate communication between cells by transferring bioactive molecules, which impact both physiological processes and the development of diseases. EVs play a crucial role in the pathogenesis of various diseases by participating in multiple pathological processes. They contribute to disease progression by triggering cytokine release, modulating immune cell activity, and inducing inflammatory and immune responses. Beyond their pathological implications, EVs also offer significant therapeutic potential. Both natural and engineered EVs show great potential in the fields of targeted therapy, drug delivery, and immune modulation in dermatological applications. The development of EV-based treatments is showing promise in advancing patient outcomes, particularly in chronic inflammatory and immune-mediated skin conditions. This review comprehensively examined the biogenesis, classification, and functional roles of EVs, including advanced methods for their isolation and characterization. Furthermore, we summarized recent studies highlighting the involvement of EVs in four major inflammatory skin diseases: psoriasis, atopic dermatitis, systemic lupus erythematosus, and wound healing.

Skin wound healing remains challenging due to a lack of ideal wound dressings suitable for acute and chronic wounds. This study introduced a biocompatible hydrogel wound dressing, synthesized through a green chemistry approach, specifically designed to meet the dual needs of acute and chronic wound care. The innovative strategy utilized sustainable biomaterials, soy protein, and vanillin, to construct a physical-reversible chemical dual-cross-linked hydrogel exhibiting high mechanical strength, excellent adhesion, and toughness. Schiff base reversible covalent bonds enabled rapid self-healing within 10 s, significantly improving durability. In a rat liver hemorrhage model, the hydrogel rapidly sealed wounds, achieving effective hemostasis, indicating great potential for acute wound care. Furthermore, vanillin imparted the hydrogel with antimicrobial and antioxidant properties, effectively accelerating diabetic chronic wound healing. This safe and efficient advanced biobased hydrogel offers a novel perspective for wound treatment and holds significant promise for clinical applications.

In the field of large-area trauma flap transplantation, preventing avascular necrosis remains a critical challenge. Key mechanisms for improving flap viability include angiogenesis promotion, oxidative stress inhibition, and cell death prevention. Recently, two-dimensional ultrathin Ti3C2TX (MXene) nanosheets have gained attention for their potential contributions to these processes, though MXene's physiological impact on flap survival had not been previously investigated. This study is the first to confirm MXene's biological effects on the ischaemic microenvironment post-skin flap transplantation. Findings indicated that MXene significantly decreased the necrotic area in ischaemic flaps (37.96% ± 2.00%), with reductions of 30.40% ± 1.86% at 1 mg/mL and 20.19% ± 2.11% at 2 mg/mL in a concentration-dependent manner. Mechanistically, MXene facilitated in situ angiogenesis, mitigated oxidative stress, suppressed pro-inflammatory pyroptosis, and activated the PI3K-Akt pathway, particularly influencing vascular endothelial cells. Comparative transcriptome analysis of skin tissues with and without MXene treatment provided additional evidence, highlighting mechanisms such as pro-inflammatory pyroptosis, ROS metabolic processes, endothelial cell proliferation regulation, and PI3K-Akt signaling pathway activation. Overall, MXene demonstrated biological activity, effectively promoting ischaemic flaps survival and presenting a novel strategy for addressing ischaemic necrosis in skin flaps.

The rigid inflammatory microenvironment and impaired vascular regeneration capability are two core barriers for diabetic wound healing. As hydrogels have unique 3D porous networks and hydrophilic structure, which can facilitate oxygen exchange and function as a functional delivery system for loading cells and other biomolecules, hydrogels have clinical potentials for treating diabetic wounds. Here we developed a 3D-printed grid-like hydrogel composed of hyaluronic acid-based acrylamide (HA-AM), oxidized mannan oligosaccharide (OMOS), and deferoxamine (DFO). We demonstrated that the developed hydrogel (HA-AM/OMOS@DFO) exhibited favorable swelling, reasonable degradation time, good biocompatibility and structural support strength. Moreover, the HA-AM/OMOS@DFO hydrogel exerted antioxidative effects and inflammatory regulation functions. In addition, the loaded DFO effectively promoted vascular regeneration in the wound, which facilitated the healing of chronic diabetic wounds. Findings suggested the developed material has potential for clinical application in treating diabetic wounds.

Hepatectomy is the primary therapeutic intervention for liver disorders. Nonetheless, an increased risk of liver failure and postoperative mortality exists due to the rapid reduction in liver size after surgery. Human umbilical cord mesenchymal stem cell (hucMSC) exosomes (Exos) have been recognized in the promotion of liver regeneration. However, intravenous administration of Exos faces several challenges including poor targeting and rapid clearance. Herein, we employed CMCS/OHA/LA-loaded hucMSCs derived Exos (hydrogel-Exos) to address liver regeneration after hepatectomy. Release and uptake studies showed hydrogel-Exos enables localized release of Exos, prolonging their presence and concentration in liver tissue. Meanwhile, the hydrogel-Exos exhibited good characteristics in injectability, self-healing, biocompatibility, liver adhesion, swelling performance, postoperative hemostasis and minimization of peritoneal adhesions post-resection. Moreover, proliferation and scratch wound healing assays demonstrated the ability of hydrogel-Exos to promote liver cell proliferation and migration. During in vivo studies, the Exos-containing hydrogel was injected into the resected surface of a 70 % hepatectomy rat model. The result indicated Exos was released into the liver tissue through the hydrogel to promote angiogenesis and liver regeneration. Bioinformatics analysis revealed liver regeneration mechanisms involve cell cycle-related pathways. As such, hydrogel-encapsulated Exos appeared promising to be employed following hepatectomy.

Chronic diabetic wounds are characterized by prolonged inflammation and excessive accumulation of M1 macrophages, which impede the healing process. Therefore, resolving inflammation promptly and transitioning to the proliferative phase are critical steps for effective diabetic wound healing. Exosomes have emerged as a promising therapeutic strategy. In this study, a smart hydrogel capable of responding to pathological cues in the inflammatory microenvironment to promote the transition from inflammation to proliferation by delivering M2 macrophage-derived exosomes (M2-Exos) is developed. The smart hydrogel is synthesized through the cross-linking of oxidized dextran, a matrix metalloproteinase (MMP)-9-sensitive peptide, and carboxymethyl chitosan containing M2-Exos. In response to elevated MMP-9 concentrations in the inflammatory microenvironment, the hydrogel demonstrates diagnostic logic, adjusting the release kinetics of M2-Exos accordingly. The on-demand release of M2-Exos facilitated macrophage polarization from the M1 to the M2 phenotype, thereby promoting the transition from the inflammatory to the proliferative phase and accelerating diabetic wound healing. The transcriptomic analysis further reveals that the MMP-9-responsive hydrogel with M2-Exos delivery exerts anti-inflammatory and regenerative effects by downregulating inflammation-related pathways. This study introduces an innovative, microenvironment-responsive exosome delivery system that enables precise control of therapeutic agent release, offering a personalized approach for the treatment of chronic diabetic wounds.

With the aging population, the incidence of diabetes is increasing. Diabetes often leads to restricted neovascularization, antibiotic-resistant bacterial infections, reduced wound perfusion, and elevated reactive oxygen species, resulting in impaired microenvironments and prolonged wound healing. Hydrogels are important tissue engineering materials for wound healing, known for their high water content and good biocompatibility. However, most hydrogels suffer from poor mechanical properties and difficulty in achieving sustained drug release, hindering their clinical application. Inspired by the incorporation of fibers to enhance the mechanical properties of "adobe," core-shell fibers were introduced into the hydrogel. This not only improves the mechanical strength of the hydrogel but also enables the possibility of sustained drug release. In this study, we first prepared core-shell fibers with PLGA (poly(lactic-co-glycolic acid)) and PCL (polycaprolactone). PLGA was loaded with P2 (Parathyroid hormone-related peptides-2), developed by our group, which promotes angiogenesis and cell proliferation. We then designed a QTG (QCS/TA/Gel, quaternary ammonium chitosan/tannic acid/gelatin) hydrogel, incorporating the core-shell fibers and the anti-inflammatory drug celecoxib into the QTG hydrogel. This hydrogel exhibits excellent antibacterial properties and biocompatibility, along with good mechanical performance. This hydrogel demonstrates excellent water absorption and swelling capabilities. In the early stages of wound healing, the hydrogel can absorb the wound exudate, maintaining the stability of the wound microenvironment. This hydrogel promotes neovascularization and collagen deposition, accelerating the healing of diabetic wounds, with a healing rate exceeding 95 % by day 14. Overall, this study provides a promising strategy for developing tissue engineering scaffolds for diabetic wound healing.

One of the long-standing challenges in the field of tissue repair and regeneration is the rapid establishment of local microvascular circulation and restoration of perfusion at the site of defects or injuries. Recently, adipose tissue-derived microvascular fragments (ad-MVFs) have attracted increasing attention from researchers. Adipose tissue is rich in blood vessels, and significant progress has been made in the extraction and preservation techniques for microvascular fragments within it. Ad-MVFs promote tissue and organ repair and regeneration through three main mechanisms. First, they accelerate rapid and efficient vascularization at the injury site, enabling early vessel perfusion. Second, the stem cell components within ad-MVFs provide a rich source of cells for tissue and organ regeneration. Third, they play a role in immune regulation, facilitating integration with host tissues after implantation. The application methods of ad-MVFs are diverse. They can be directly implanted or pre-cultivated, facilitating their combination with various scaffolds and broadening their application scope. These properties have led to the wide use of ad-MVFs in tissue engineering, with promising prospects. This review demonstrates that ad-MVFs can serve as a reliable and highly feasible unit for tissue regeneration.

The intercellular communication role of extracellular vesicles has been widely proved in various organisms. Compelling evidence has illustrated the involvement of these vesicles in both physiological and pathological processes. Various studies indicate that extracellular vesicles surpass conventional synthetic drug carriers, owing to their abundance in organisms, enhanced targeting ability and low immunogenicity. Therefore, extracellular vesicles have been deemed to be potential drug carriers for the treatment of various diseases, and related studies have increased rapidly. Here, we intend to provide a comprehensive and in-depth review of recent advances in the sources, delivery function, extraction and cargo-loading technologies of extracellular vesicles, as well as their clinical potential in constructing emerging nanomedicine therapeutic platforms. In particular, microfluidic-based isolation and drug-loading technologies, as well as the treatment of various diseases, are highlighted. We also make comparisons between extracellular vesicles and other conventional drug carriers and discuss the challenges in developing drug delivery platforms for clinical translation.

Compared to traditional 2D-cultured mesenchymal stem cells (MSCs), 3D-MSCs offer distinct advantages in disease treatment. However, large-scale culture of 3D-MSCs remains labor-intensive and time-consuming. Thus, developing cryopreservation method for 3D-MSCs is essential for clinical application. Existing cryopreservation techniques primarily focus on 2D-cultured MSCs, and vitrification methods such as Cryotop are not suitable for large-scale applications, often leading to cytotoxicity due to high concentrations of cryoprotective agents. To address these challenges, we developed an innovative vitrification method using microfluidics, which involved encapsulating 3D human umbilical cord MSCs in GelMA hydrogel to create 3D-MSCs hydrogel microspheres (3D-MSCsHM). This approach significantly enhanced the survival rates of MSCs while reducing the need for cryoprotective agents. The entire process could be completed in 30 min, yielding 96 % viability and functionality upon rewarming. Proteomic analysis further revealed that improved viability and functions post rewarming were linked to enhance mitochondrial function, increased antioxidant proteins, and elevated growth factors. Furthermore, this method showed effective therapeutic outcomes in wound healing in a mouse model, comparable to those achieved with fresh 3D-MSCs. The presented vitrification technique offers a practical solution for the cryopreservation of multicellular stem cell tissues, enhancing their therapeutic applications.

Poor wound healing is a refractory process that places an enormous medical and financial burden on diabetic patients. Exosomes have recently been recognized as crucial players in the healing of diabetic lesions. They have excellent stability, homing effects, biocompatibility, and reduced immunogenicity as novel cell-free therapies. In addition to transporting cargos to target cells to enhance intercellular communication, exosomes are beneficial in nearly every phase of diabetic wound healing. They participate in modulating the inflammatory response, accelerating proliferation and reepithelization, increasing angiogenesis, and regulating extracellular matrix remodeling. Accumulating evidence indicates that hydrogels or dressings in conjunction with exosomes can prolong the duration of exosome residency in diabetic wounds. This review provides an overview of the mechanisms, delivery, clinical application, engineering, and existing challenges of the use of exosomes in diabetic wound repair. We also propose future directions for biomaterials incorporating exosomes: 2D or 3D scaffolds, biomaterials loaded with wound healing-promoting gases, intelligent biomaterials, and the prospect of systematic application of exosomes. These findings may might shed light on future treatments and enlighten some studies to improve quality of life among diabetes patients.

Autologous or allogeneic platelet-derived extracellular vesicles (pEVs) show potential in enhancing tissue recovery and healing chronic wounds. pEVs promote neovascularization and cell migration while reducing inflammation, oxidative stress, and scarring. However, their efficacy in clinical settings is challenged by their susceptibility to washout by wound exudate. Hydrogel-based bandages are effective carriers that stabilize pEVs for optimal personalized wound care. These bandages can be tailored for easy removal to minimize damage to regenerated tissue and can incorporate antibacterial or moisture-retaining properties. Furthermore, the possibility of integrating sensors in the wound bed will enable a theragnostic approach to healing. This review explores advancements in pEV-loaded hydrogels and their potential for personalized clinical applications.

Extracellular vesicles (EVs) are secreted from biological cells and contain many molecules with diagnostic values or therapeutic functions. There has been great interest in academic and industrial communities to utilize EVs as tools for diagnosis or therapeutics. In addition, EVs can also serve as delivery vehicles for therapeutic molecules. An indicator of the enormous interest in EVs is the large number of review articles published on EVs, with the focus ranging from their biology to their applications. An emerging trend in EV research is to produce and utilize "engineered EVs", which are essentially the enhanced version of EVs. EV engineering can be conducted by cell culture condition control, genetic engineering, or chemical engineering. Given their nanometer-scale sizes and therapeutic potentials, engineered EVs are an emerging class of nanomedicines. So far, an overwhelming majority of the research on engineered EVs is preclinical studies; there are only a very small number of reported clinical trials. This Review focuses on engineered EVs, with a more specific focus being their applications in therapeutics. The various approaches to producing engineered EVs and their applications in various diseases are reviewed. Furthermore, in vivo imaging of EVs, the mechanistic understandings, and the clinical translation aspects are discussed. The discussion is primarily on preclinical studies while briefly mentioning the clinical trials. With continued interdisciplinary research efforts from biologists, pharmacists, physicians, bioengineers, and chemical engineers, engineered EVs could become a powerful solution for many major diseases such as neurological, immunological, and cardiovascular diseases.

This study introduced a hydrogel dressing, termed SODex-gel, which was constructed by establishing Schiff base and hydrogen bonds with the precursors of oxidized dextran (ODex) and succinic dihydrazide (SD)-modified sodium alginate (SD-mod-SA). Through comprehensive in vitro and in vivo studies, the adhesive properties, self-healing capabilities, hemostatic potential, and wound healing efficacy of the SODex-gel dressing were meticulously evaluated. The 1H NMR, FTIR, and TGA analyses confirmed the fabrication of the SODex-gel dressing and its constituent elements. Scanning electron microscopy (SEM) imaging showcased the uniform pore structures in the SODex-gel dressing. In vitro assessments demonstrated that the SODex-gel dressing was noncytotoxic and exhibits strong adhesion, enabling it to attach to various surfaces. Noteworthy findings from studies of mouse liver incisions and tail amputation models proved the hemostatic ability of the SODex-gel dressing. Moreover, their remarkable wound-healing capabilities were prominently demonstrated through the treatment of a mouse model afflicted with burn skin injuries. Evidence of neovascularization effects was corroborated by the upregulation of CD31 and vascular endothelial growth factor (VEGF) expression in the treated skin samples. Collectively, the experimental data unequivocally established that the SODex-gel dressing is a promising therapeutic approach to accelerate wound recovery, thereby exhibiting substantial potential for clinical applications in treating burn injuries.

Wound healing is a complex biological process involving multiple cellular and molecular mechanisms. Ubiquitination, a crucial post-translational modification, plays a vital role in regulating various aspects of wound healing through protein modification and degradation. This review comprehensively examines the molecular mechanisms of ubiquitination in wound healing, focusing on its regulation of inflammatory responses, macrophage polarization, angiogenesis, and the activities of fibroblasts and keratinocytes. We discuss how ubiquitination modifies key signaling pathways, including TGF-β/Smad3, NF-κB, and HIF-α, which are essential for proper wound healing. Understanding these mechanisms provides insights into potential therapeutic strategies for treating impaired wound healing, particularly in conditions such as diabetes. The review highlights recent advances in understanding ubiquitination's role in wound healing and discusses future research directions for developing targeted therapeutic approaches.

Complex perianal fistulas, challenging to treat and prone to recurrence, often require surgical intervention that may cause fecal incontinence and lower quality of life due to large surgical wounds and potential sphincter damage. Human umbilical cord-derived MSCs (hUC-MSCs) and their exosomes (hUCMSCs-Exo) may promote wound healing.

This study assessed the efficacy, mechanisms, and safety of these exosomes in treating complex perianal fistulas in SD rats. We established a rat model, divided rats with fistulas into the control and the exosome groups. We assessed treatment efficacy through ultrasound, clinical observations, and histopathological analysis. We also evaluated the activation of the HIF-1α/TGF-β/Smad signaling pathway via PCR and Western blot and assessed serological markers for HIF-1α and inflammatory indices through ELISA. We analyzed gut microbiota and the systemic metabolic environment via untargeted metabolomics.

The hUCMSCs-Exo effectively promoted healing of wound, regulated the immune balance enhanced collagen synthesis and angiogenesis in the perianal fistulas model of rats, and regulated the gut microbiota and metabolomic profiles. Results of PCR and Western blot analyses indicated that the exosomes activated HIF-1α/TGF-β/Smad signaling pathways. To the dosages tested, the 10ug/100ul concentration (medium dose) was found to be the most effective to the treatment of complex perianal fistulas.

The hUCMSCs-Exo significantly promoted the healing of wound in perianal fistulas of rats and demonstrated higher safety. The underlying mechanism facilitating the healing process was likely associated with the activation of the HIF-1α/TGF-β/Smad signaling pathway.

Chronic wounds in diabetic patients experience significant clinical challenges due to compromised healing processes. Hypoxia-inducible factor-1 alpha (HIF-1α) is a critical regulator in the cellular response to hypoxia, enhancing angiogenesis and tissue restoration. Nevertheless, the cellular response to the developed chronic hypoxia within diabetes is impaired, likely due to the destabilization of HIF-1α via degradation by prolyl hydroxylase domain (PHD) enzymes. Researchers have extensively explored HIF-1α activation as a potential pathway for diabetic wound management, focusing mainly on deferoxamine (DFO) as a potent agent to stabilize HIF-1α. This review provides an update of the other recent pharmacological agents managing HIF-1α activation, including novel PHD inhibitors (roxadustat and daprodustat) and Von Hippel-Lindau protein (VHL) antagonists, which could be potential alternatives for the local treatment of diabetic wounds. Furthermore, it highlights how localized delivery via advanced nanostructures can enhance the efficacy of these novel therapies. Importantly, by addressing these points, the current review can offer a promising area for research. Given that, these novel drugs have minimal applications in diabetic wound healing, particularly in the context of local application through nanomaterials. This gap presents an exciting opportunity for further investigation, as combining these drugs with localized nanotechnology could avoid undesired systemic side effects and sustain drug release within wound site, offering a transformative platform for diabetes wound treatment.

Adequate vascularization essential for delivering nutrients critical to wound healing, yet impaired angiogenesis is a major barrier in diabetic wound repair. This study investigates the impact of hyaluronic acid on interpenetrating network sponge scaffolds derived from an acellular dermal matrix, with the aim of enhancing vascularization and healing of diabetic wounds via photothermal warm bath therapy. We prepared three-dimensional porous sponges (H1P4D2@DFO) using molecular interpenetration and ion crosslinking of porcine acellular dermal matrix (PADM), hyaluronic acid, and polydopamine nanoparticles loaded with deferoxamine mesylate (PDA@DFO). This resulting extracellular matrix-based sponge demonstrated properties suitable for wound repair, including high cell adhesion, biocompatibility, bioactivity, porosity (85 %), and water absorption (4500 %). The near-infrared (NIR) photothermal effect of PDA@DFO and the sustained release of deferoxamine mesylate (DFO) enhanced wound vascularization within the wound site. These findings suggest that our sponge scaffold can simulate skin-like structures and establish a supportive microenvironment conducive to microvascular reconstruction. By combining the photothermal warm bath approach with the scaffold's tailored 3D structure, we observed enhanced angiogenesis and accelerated diabetic wound healing, indicating potential clinical applications of these scaffolds in chronic wound management.

One of the key obstacles to the healing of diabetic wound is the persistence of active inflammation. We previously demonstrated the potential of cell-free fat extract (CEFFE) to promote the healing of diabetic wounds, and annexin A5 (A5) is a crucial anti-inflammatory protein within CEFFE. This study aimed to evaluate the therapeutic potential of A5 in diabetic wounds.

A5 was loaded into GelMA hydrogels and applied to skin wounds of diabetic mice in vivo. The diabetic wounds with the treatment of GelMA-A5 were observed for 14 days and evaluated by histological analysis. Accessment of inflammation regulation were conducted through anti-CD68 staining, anti-CD86 and anti-CD206 staining, and qRT-PCR of wound tissue. In presence of A5, macrophages stimulated by lipopolysaccharide (LPS) in vitro, and detected through qRT-PCR, flow cytometry, and immunocytofluorescence staining. Besides, epithelial cells were co-cultured with A5 for epithelialization regulation by CCK-8 assay and cell migration assay.

A5 could promote diabetic wound healing and regulate inflammations by promoting the transition of macrophages from M1 to M2 phenotype. In vitro experiments demonstrated that A5 exerted a significant effect on reducing pro-inflammatory factors and inhibiting the polarization of macrophages from M0 toward M1 phenotype. A5 significantly promoted the migration of epithelial cells.

Annexin A5 has a significant impact on the regulation of macrophage inflammation and promotion of epithelialization.

Wound healing is often impaired in patients with diabetes. Mesenchymal stem cells (MSCs) and MSCs-derived nanovesicles (MNVs) hold promise as therapeutic agents for managing diabetic wounds. However, efficient delivery and controlled release of MNVs within these wounds are essential for maximizing therapeutic effectiveness. In this study, we developed a dual-responsive hydrogel designed to respond to elevated levels of glucose and reactive oxygen species. This hydrogel combines polyvinyl alcohol with phenylboronic acid-grafted chitosan, referred to as PBA-CP, while MNVs were produced by shearing MSCs through membranes with varying pore sizes. The composite PBA-CP/MNVs hydrogel significantly accelerated wound healing in a diabetic wound model by promoting epithelialization, dermal reconstruction, hair follicle formation, and angiogenesis. MNVs were readily taken up by keratinocytes, fibroblasts, and endothelial cells, stimulating their proliferation and migration. Altogether, the chitosan-based PBA-CP/MNVs composite hydrogel presents a promising therapeutic strategy for diabetic wound treatment.

Diabetic wounds have become a global healthcare burden owing to impaired angiogenesis and persistent infections. Extracellular vesicles (EVs) can improve diabetic wounds, though their targeting ability is limited. In this study, we investigated the performance of a novel hydrogel dressing comprised of gelatin methacryloyl, glycoengineered EVs, and polylysine in treating infected diabetic wounds. High-throughput single-cell RNA sequencing (scRNA-seq) and immunofluorescence staining revealed that E-selectin (SELE) levels were higher in diabetic wounds than in non-diabetic wounds. Mesenchymal stromal cells (MSCs) were transfected with a lentivirus containing fucosyltransferase VII (FUT7) and a CD63-P19-Nluc vector to enhance the expression of sialyl Lewis X (sLeX), the ligand of E-selectin, on the surface of EVs (s-EVs) derived from transfected MSCs (s-MSCs). s-EVs can target human umbilical vein endothelial cells (HUVECs) under lipopolysaccharide stimulation and promote the function of stimulated HUVECs in vitro. To promote and sustain the release of s-EVs, we fabricated a gelatin methacryloyl (Gel)/poly-L-lysine methacryloyl (PL)-5 hydrogel with good antibacterial ability, biocompatibility and mechanical properties. In a mouse experiment, s-EV@Gel/PL-5 exhibited excellent angiogenesis and anti-inflammatory abilities and further promoted the healing of infected diabetic wounds. Our findings demonstrated the potential of the s-EV@Gel/PL-5 hydrogel in the clinical treatment of diabetic infectious wounds.

Diabetic foot ulcer (DFU) is a chronic and serious complication of diabetes mellitus. It is mainly caused by hyperglycaemia, diabetic peripheral vasculopathy and diabetic peripheral neuropathy. These conditions result in ulceration of foot tissues and chronic wounds. If left untreated, DFU can lead to amputation or even endanger the patient's life. Single-cell RNA sequencing (scRNA-seq) is a technique used to identify and characterise transcriptional subpopulations at the single-cell level. It provides insight into cellular function and the molecular drivers of disease. The objective of this paper is to examine the subpopulations, genes and molecules of cells associated with chronic wounds of diabetic foot by using scRNA-seq. The paper aims to explore the wound-healing mechanism of DFU from three aspects: inflammation, angiogenesis and extracellular matrix remodelling. The goal is to gain a better understanding of the mechanism of DFU wound healing and identify possible DFU therapeutic targets, providing new insights for the application of DFU personalised therapy.

Diabetic wounds pose a significant challenge in healthcare due to their complex nature and the difficulties they present in treatment and healing. Impaired healing processes in individuals with diabetes can lead to complications and prolonged recovery times. However, recent advancements in wound healing provide reasons for optimism. Researchers are actively developing innovative strategies and therapies specifically tailored to address the unique challenges of diabetic wounds. One focus area is biomimetic hydrogel scaffolds that mimic the natural extracellular matrix, promoting angiogenesis, collagen deposition, and the healing process while also reducing infection risk. Copper nanoparticles and copper compounds incorporated into hydrogels release copper ions with antimicrobial, anti-inflammatory, and angiogenic properties. Copper reduces infection risk, modulates inflammatory response, and promotes tissue regeneration through cell adhesion, proliferation, and differentiation. Utilizing copper nanoparticles has transformative potential for expediting diabetic wound healing and improving patient outcomes while enhancing overall well-being by preventing severe complications associated with untreated wounds. It is crucial to write a review highlighting the importance of investigating the use of copper nanoparticles and compounds in diabetic wound healing and tissue engineering. These groundbreaking strategies hold the potential to transform the treatment of diabetic wounds, accelerating the healing process and enhancing patient outcomes.

Diabetic foot ulcers (DFUs) represent a serious complication of diabetes with high incidence, requiring intensive treatment, prolonged hospitalization, and high costs. It poses a severe threat to the patient's life, resulting in substantial burdens on patient and healthcare system. However, the therapy of DFUs remains challenging. Therefore, exploring cell-free therapies for DFUs is both critical and urgent. Exosomes, as crucial mediators of intercellular communication, have been demonstrated potentially effective in anti-inflammation, angiogenesis, cell proliferation and migration, and collagen deposition. These functions have been proven beneficial in all stages of diabetic wound healing. This review aims to summarize the role and mechanisms of exosomes from diverse cellular sources in diabetic wound healing research. In addition, we elaborate on the challenges for clinical application, discuss the advantages of membrane vesicles as exosome mimics in wound healing, and present the therapeutic potential of exosomes and their mimetic vesicles for future clinical applications.

Angiogenesis plays a crucial role in the growth of colorectal cancer (CRC). Recent studies have identified extracellular vesicles (EVs) in the tumor microenvironment as important mediators of cell-to-cell communication. However, the specific role and mechanisms of CRC-derived EVs in regulating tumor angiogenesis remain to be further investigated.

EVs were isolated from the conditioned medium of the CRC cells using ultracentrifugation. We investigated the effects of HT-29-derived EVs on tumor growth and angiogenesis in a subcutaneous HT-29 CRC tumor model in mice. Additionally, we evaluated the impact of HT-29-derived EVs on the proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). Subsequently, bioinformatics analysis was performed to identify relevant signaling pathways, and pathway inhibitors were used to block the activation of these pathways, aiming to elucidate their roles in angiogenesis.

We found that HT-29-derived EVs can promote tumor growth and angiogenesis in vivo, as well as significantly enhance the proliferation, migration, and tube formation of HUVECs. Bioinformatics analysis revealed that HT-29-derived EVs may regulate angiogenesis through the JAK/STAT3 signaling pathway. Specifically, we observed that CRC-derived EVs promoted the phosphorylation of STAT3 (p-STAT3) and the expression of VEGFA in the nucleus of HUVECs. Treatment with the STAT3 inhibitor Stattic reduced the nuclear expression of p-STAT3, which impaired its function as a transcription factor, thereby inhibiting VEGFA expression and the pro-angiogenic effects of CRC-derived EVs.

EVs derived from CRC cells promote CRC tumor angiogenesis by regulating VEGFA through the JAK/STAT3 pathway in endothelial cells.

The management of full-thickness skin injuries continues to pose significant challenges. Currently, there is a dearth of comprehensive dressings capable of integrating all stages of wound healing to spatiotemporally regulate biological processes following full-thickness skin injuries. In this study, we report the synthesis of a dandelion-shaped mesoporous strontium-gallium microparticle (GE@SrTPP) achieved through dopamine-mediated strontium ion biomineralization and self-assembly, followed by functionalization with gallium metal polyphenol networks. As a multifunctional wound dressing, GE@SrTPP can release bioactive ions in a spatiotemporal manner akin to dandelion seeds. During the early stages of wound healing, GE@SrTPP demonstrates rapid and effective hemostatic performance while also exhibiting antibacterial properties. In the inflammatory phase, GE@SrTPP promotes M2 polarization of macrophages, suppresses the expression of pro-inflammatory factors, and decreases oxidative stress in wounds. Subsequently, during the stages of proliferation and tissue remodeling, GE@SrTPP facilitates angiogenesis through the activation of the Hypoxia-inducible factor-1α/vascular endothelial growth factor (HIF-1α/VEGF) pathway. Analogous to the dispersion and rooting of dandelion seeds, the root-like new blood vessels supply essential nutrients for wound healing. Ultimately, in a rat chronic wound model, GE@SrTPP achieved successful full-thickness wound repair. In summary, these dandelion-shaped GE@SrTPP microparticles demonstrate comprehensive regulatory effects in managing full-thickness wounds, making them highly promising materials for clinical applications.

Mesenchymal stem cell-derived exosomes(MSCs-Exos) offer promising therapeutic potential for a wide range of tissues and organs such as bone/cartilage, nerves, skin, fat, and endocrine organs. In comparison to the application of mesenchymal stem cells (MSCs), MSCs-Exos address critical challenges related to rejection reactions and ethical concerns, positioning themselves as a promising cell-free therapy. As exosomes are extracellular vesicles, their effective delivery necessitates the use of carriers. Consequently, the selection of hydrogel materials as scaffolds for exosome delivery has become a focal point of contemporary research. The diversity of hydrogel scaffolds, which can take various forms such as injectable types, dressings, microneedles, and capsules, leads to differing choices among researchers for treating diseases within the same domain. This variability in hydrogel materials poses challenges for the translation of findings into clinical practice. The review highlights the potential of hydrogel-loaded exosomes in different fields and introduces the advantages and disadvantages of different forms of hydrogel applications. It aims to provide a multifunctional and highly recognized hydrogel scaffold option for tissue regeneration at specific sites, improve clinical translation efficiency, and benefit the majority of patients.

Oxidative stress caused by excessive reactive oxygen species (ROS) accumulation significantly hinders wound healing in patients with diabetes. Scavenging ROS and reducing inflammation are crucial for rapid healing. In this work, a multi-responsive sodium hyaluronate (HA)/tannic acid (TA) hydrogel was developed based on boronate ester bonds. Sodium hyaluronate with 3-aminophenyl boronic acid modification (HA-APBA) was mixed and crosslinked with TA to form HA-APBA/TA hydrogels. These hydrogels are injectable, self-healing, and biocompatible. The HA-APBA/TA hydrogels could release free TA through the collapse of the structure at low pH, high H2O2 concentration, and high glucose concentration, thus possessing good ROS scavenging ability. In full-thickness skin wounds of db/db mice, the HA-APBA/TA hydrogels promoted wound healing, collagen deposition, and significant angiogenesis. Furthermore, they have been shown to effectively reduce the levels of inflammatory factors in wounds and lower the expression of CD86, a pro-inflammatory macrophage surface marker. This resulted in a more effective transition of wound healing from the inflammatory phase to the proliferative phase. This study provides an optional strategy for alleviating oxidative stress and controlling excessive inflammation, thereby promoting diabetic wound healing.

Bioactive glasses (BG) play a vital role in angiogenesis and osteogenesis through releasing functional ions. However, the rapid ion release in the early stage will cause excessive accumulation of metal ions, which in turn leads to obvious cytotoxicity, long-term inflammation, and bone repair failure. Inspired by the vibration exciter, small extracellular vesicles (sEVs) obtained by treating mesenchymal stem cells with copper-doped bioactive glass (CuBG-sEVs), is prepared as a nano-vibration exciter. The nano-vibration exciter can convert the ion signals of CuBG into biochemical factor signals through hypoxia-inducible factor 1 (HIF-1) signaling pathway and its activated autophagy, so as to better exert the osteogenic activity of BG. The results showed that CuBG extracts could significantly improve the enrichment of key miRNAs and increase the yield of CuBG-sEVs by activating HIF-1 signaling pathway and its activated autophagy. Cell experiments showed that CuBG-sEVs are favor to cell recruitment, vascularization and osteogenesis as the enrichment of key miRNAs. The animal experiments results showed that CuBG-sEVs stimulated angiogenesis mediated by CD31 and promoted bone regeneration by activating signaling pathways related to osteogenesis. These findings underscored the significant potential of sEVs as alternative strategies to better roles of BG.

Osteoarthritis (OA) is a prevalent and disabling disease that affects a significant proportion of the global population. Urine-derived stem cells (USCs) have shown great prospects in the treatment of OA, but there is no study that has compared them with traditional stem cells.

This study aimed to compare the therapeutic efficacy and mechanisms of USCs and adipose-derived stem cells (ADSCs) for OA treatment.

Controlled laboratory study.

We compared the biological properties of USCs and ADSCs using CCK-8, colony formation, EdU, adhesion, and apoptosis assays. We evaluated the protective effects of USCs and ADSCs on IL-1β-treated OA chondrocytes by chemical staining, immunofluorescence, and Western blotting. We assessed the effects of USCs and ADSCs on chondrocyte autophagy by transmission electron microscopy, immunofluorescence, and Western blotting. We also compared the therapeutic efficacy of intra-articular injections of USCs and ADSCs by gross, histological, micro-computed tomography, and immunohistochemical analyses in an OA rat model induced by anterior cruciate ligament transection.

USCs showed higher proliferation, colony formation, DNA synthesis, adhesion, and anti-apoptotic abilities than ADSCs. Both USCs and ADSCs increased the expression of cartilage-specific proteins and decreased the expression of matrix degradation-related proteins and inflammatory factors in OA chondrocytes. USCs had a greater advantage in suppressing MMP-13 and inflammatory factors than ADSCs. Both USCs and ADSCs enhanced autophagy in OA chondrocytes, with USCs being more effective than ADSCs. The autophagy inhibitor 3-MA reduced the enhanced autophagy and protective effects of USCs and ADSCs on OA chondrocytes.

To our knowledge, this is the first study to explore the efficacy of USCs in the treatment of knee OA and to compare them with ADSCs. Considering the superior properties of USCs in terms of noninvasive acquisition, a high cost-benefit ratio, and low ethical concerns, our study suggests that they may be a more promising therapeutic option than ADSCs for OA treatment under rigorous regulatory pathways.

USCs may be a superior cell source for stem cells to treat knee OA, and this study strengthens the evidence for the application of USCs.

Stem cell-derived exosomes exert comparable therapeutic effects to those of their parental stem cells without causing immunogenic, tumorigenic, and ethical disadvantages. Their therapeutic advantages are manifested in the management of a broad spectrum of diseases, and their dosing versatility are exemplified by systemic administration and local delivery. Furthermore, the activation and regulation of various signaling cascades have provided foundation for the claimed curative effects of exosomal therapy. Unlike other relevant reviews focusing on the upstream aspects (e.g., yield, isolation, modification), and downstream aspects (e.g. phenotypic changes, tissue response, cellular behavior) of stem cell-derived exosome therapy, this unique review endeavors to focus on various affected signaling pathways. After meticulous dissection of relevant literature from the past five years, we present this comprehensive, up-to-date, disease-specific, and pathway-oriented review. Exosomes sourced from various types of stem cells can regulate major signaling pathways (e.g., the PTEN/PI3K/Akt/mTOR, NF-κB, TGF-β, HIF-1α, Wnt, MAPK, JAK-STAT, Hippo, and Notch signaling cascades) and minor pathways during the treatment of numerous diseases encountered in orthopedic surgery, neurosurgery, cardiothoracic surgery, plastic surgery, general surgery, and other specialties. We provide a novel perspective in future exosome research through bridging the gap between signaling pathways and surgical indications when designing further preclinical studies and clinical trials.

Due to persistent inflammation and oxidative stress reactions, achieving drug absorption in diabetic wounds is challenging. To overcome this problem, our article presents a composite hydrogel, GelMA-GA/DMOG@GDNP, which consists of gelatin methacryloyl (GelMA) treated with gallic acid (GA) and encapsulating ginseng-derived nanoparticles (GDNPs) loaded with dimethyloxallyl glycine (DMOG). The composite hydrogel demonstrates excellent biocompatibility. In laboratory settings, the hydrogel inhibits the production of nitric oxide synthase 2 (iNOS) in mouse immune cells (RAW264.7 cells), enhances the growth and migration of mouse connective tissue cells (L929 cells) and human endothelial cells (HUVECs), and promotes tube formation in HUVECs. In a rat model of type 1 diabetes-induced wounds, the composite hydrogel attenuates inflammatory reactions, facilitates the formation of fibres and blood vessels, accelerates wound healing, and elucidates specific pathway mechanisms through transcriptome sequencing. Therefore, the GelMA-GA/DMOG@GDNP hydrogel can serve as a safe and efficient wound dressing to regulate the inflammatory response, promote collagen fiber and blood vessel formation, and accelerate wound healing. These findings suggest that utilizing this multifunctional engineered nanoparticle-loaded hydrogel in a clinical setting may be a promising strategy for diabetic wound healing.

Significance: The combination of hydrogel biomaterials with exosomes to facilitate wound healing and skin regeneration is a promising approach. Recent Advances: Recent preclinical animal studies have focused on investigating the efficacy of hydrogel-based delivery systems for exosomes in promoting wound healing and skin regeneration. Critical Issues: Despite encouraging results, critical issues remain unresolved, such as optimizing hydrogel properties to enhance the efficacy of combined therapy with exosomes for wound and bridging the translational gap between preclinical and clinical applications. Future Directions: Future research endeavors should concentrate on refining hydrogel design to enhance exosome delivery efficacy, conducting rigorous clinical trials to assess the safety and efficacy of exosome-loaded hydrogels in human wound healing and skin regeneration, and exploring innovative strategies to maximize therapeutic outcomes.