Hypertrophic scars (HS) represent a significant clinical challenge due to their complex pathophysiology and resistance to conventional therapies, often resulting in persistent symptoms such as itching, pain, and impaired joint mobility that compromise patients' quality of life. Current treatment modalities, including compression therapy, pharmacological agents, radiation, silicone gel, and laser therapies, have faced limitations primarily due to inadequate drug penetration into the dense fibrotic scar tissue. In this context, microneedle-mediated controlled delivery systems have emerged as a promising pharmaceutical platform to enhance localized and sustained delivery of therapeutic agents, including small-molecule drugs, biologic proteins, small interfering RNA, and living cells, directly into HS. This article critically reviews the biological and formulation-related challenges associated with transdermal delivery in scar tissue and highlights recent innovations in microneedle design, material selection, and drug-loading techniques tailored for controlled release applications. Furthermore, it discusses the integration of proteins and cell-based therapies within microneedle platforms and their potential to modulate scar remodeling and inflammation. By addressing current limitations and exploring cutting-edge technologies, this review article aims to guide the development of effective microneedle-mediated strategies for pharmaceutical intervention in hypertrophic scar management.

The wound microbiome has been shown to play a significant role in influencing the wound healing process. Coptis chinensis, a traditional Chinese medicine (TCM) known for its heat-clearing properties, contains berberine (BER) as major active ingredient, which exhibits notable antibacterial activity. In this study, we investigated the effect of BER on wound healing and wound microbiome through three distinct delivery strategies, including solution form, burst-release scaffolds (PCL/BER), and sustained-release scaffolds (PCL/PLGA/BER), compared with an untreated negative control (NC) group. Drug release studies confirmed that PCL/BER caused a pronounced burst release, while the incorporation of PLGA enabled sustained release of BER for up to 120 h. Further in vivo studies showed that the sustained BER release from the PCL/PLGA/BER resulted in the most effective improvement in wound healing. Microbiome analysis using 16S rRNA sequencing identified Staphylococcus xylosus (S. xylosus) as the key species influencing wound healing outcomes in response to BER delivery. S. xylosus overabundance in the NC group and its depletion in the BER solution and burst BER release groups impaired wound healing. In contrast, sustained BER delivery maintained an optimal S. xylosus abundance that promoted a favorable immune microenvironment by modulating CXCL10 and (IFN-α) expression. Our findings emphasize the importance of coordinating drug release kinetics with microbiome dynamics for optimal wound healing outcomes and provide valuable insights for developing future delivery systems for heat-clearing TCMs, with a focus on microbiome-modulation therapeutic strategies.

In current clinical practice, various dermal templates and skin substitutes are used to enhance wound healing. However, the role of wound commensal microbiome in regulating scaffold performance and the healing process remains unclear. In this study, we investigated the influence of both natural and synthetic scaffolds on the wound commensal microbiome and wound repair in three distinct models including diabetic wounds, burn injuries, and germ-free (GF) wounds. Remarkably, synthetic electrospun polycaprolactone (PCL) scaffolds were observed to positively promote microbiome diversity, leading to enhanced diabetic wound healing compared to the natural scaffolds Integra® (INT) and MatriDerm® (MAD). In contrast, both natural and synthetic scaffolds exhibited comparable effects on the diversity of the microbiome and the healing of burn injuries. In GF wounds with no detectable microorganisms, a reversed healing rate was noted showing natural scaffold (MAD) accelerated wound repair compared to the open or the synthetic scaffold (PCL) treatment. Furthermore, the response of the wound commensal microbiome to PCL scaffolds appears pivotal in promoting anti-inflammatory factors during diabetic wound healing. Our results emphasize that the wound commensal microbiome, mediated by different scaffolds plays an important role in the wound healing process.

Chronic diabetic wounds are characterized by persistent inflammation and impaired angiogenesis, presenting a major therapeutic challenge. Here, we report a three-dimensional (3D)-printed polycaprolactone (PCL) scaffold integrating shikonin (SK), a bioactive compound derived from Lithospermum erythrorhizon, to achieve controlled drug release and multifunctional wound repair. The PCL/SK scaffold exhibited a porous, breathable architecture with high mechanical integrity and biocompatibility, enabling sustained SK release over 72 h. In a diabetic mouse wound model, the PCL/SK scaffold significantly accelerated wound closure, enhanced collagen deposition, and increased the density of anti-inflammatory CD206+ macrophages compared to free SK or PCL controls. Transcriptomic and immunohistochemical analyses revealed that PCL/SK treatment upregulated angiogenesis-related genes, including vascular endothelial growth factor (Vegf), platelet endothelial cell adhesion molecule 1 (Pecam1) and TEK receptor tyrosine kinase (Tek), meanwhile elevated CD31+ and VEGF+ endothelial markers, concomitant with improved blood perfusion. Mechanistically, this effect was attributed to synergistic anti-inflammatory and pro-angiogenic modulation by sustained SK delivery and the supportive PCL microenvironment. These findings establish a bioactive drug-biomaterial hybrid platform that leverages controlled release to coordinate immune resolution and vascular regeneration, offering a promising strategy for chronic diabetic wound management and broader regenerative applications.

BackgroundRice bran is the outer layer of rice grains (Oryza sativa). Due to its rich bioactive components, it has long been used in cosmetics. However, the mechanism by which it delays skin aging remains unclear.MethodsIn this study, volatile polar solvents combined with microbial fermentation were utilized to enhance the yield and bioavailability of functional components in rice bran extract (RBE). The crude RBE was fermented with Aspergillus oryzae for 14 days to promote enzymatic decomposition into smaller and more bioavailable molecules. The components in the fermented RBE were qualitatively analyzed by UPLC-QTOF-MS/MS. The expression of collagen in two-dimensional and three-dimensional cell cultures was evaluated by qPCR technology. The expressions of collagen and elastin and the changes in water content and elastic modulus in the skin of mice were evaluated by histopathology, immunofluorescence staining, and transepidermal water loss (TEWL).ResultsThrough UPLC-QTOF-MS/MS analysis, eight key compounds, including azelaic acid, ferulic acid, γ-tocotrienols, and squalene, were identified in RBE, mainly lipids and polyphenols. The treatment of RBE significantly upregulated the expression of type I collagen in MSF cells and the expression of type III collagen in MSF 3D cell spheres (by approximately 12 times). The results of tissue staining showed that the content of collagen in the skin after RBE treatment increased by 10% compared with the control group. The results of immunofluorescence staining confirmed that RBE could increase the content of elastin in the skin. The TEWL results showed that the skin moisture content and elastic coefficient of mice treated with RBE increased by more than 10% compared with those of the untreated group.ConclusionBoth in vitro and in vivo studies have shown that RBE can significantly improve the synthesis of collagen and elastin in the skin, reduce water loss in mouse skin, increase collagen deposition in the skin, and ultimately improve skin elasticity and overall quality. This green, solvent-efficient, and fermentation-enhanced approach offers a sustainable strategy for utilizing rice bran as a high-value cosmetic ingredient with strong potential for skincare applications.

Sanguisorbae Radix (SR) has been employed as an herbal medicine over centuries. Charred SR (CSR), acquired via carbonization after the charred stir-frying of SR, demonstrates superior antimicrobial activity compared to SR. The aim of the study was to identify how carbonizing technology enhanced the ability of SR to inhibit the transformation from yeast to hypha and biofilm formation in C. albicans. In this paper, a vulvovaginal candidiasis (VVC) mouse model was used to evaluate the therapeutic effects. After CSR treatment, VVC mouse models nearly eliminated hyphal C. albicans adhering to the vaginal mucosa. The inhibitory activities of CSR on C. albicans biofilm formation and hyphal growth were assessed through quantitative biofilm analysis, morphological observations, and gene expression studies in vitro. Since the hyphal form signifies the initiation of biofilm development, this study confirmed CSR's remarkable inhibitory effect on C. albicans biofilm formation and hyphal growth. These effects were significantly weaker with SR. Additionally, the impact of carbonization on the composition of active compounds was analyzed. Carbonization significantly increased the content of ellagic acid (EA) and pyrogallic acid (PYG) by 7.44-fold and 28.09-fold, respectively. Both EA and PYG inhibited C. albicans biofilms and hyphal growth, with EA showing a more pronounced inhibitory effect. Finally, we concluded that carbonization technology enables SR to inhibit the yeast-to-hypha transition and biofilm formation in C. albicans by increase the levels of EA and PYG. EA was identified as the primary bioactive compound responsible for CSR's anti-biofilm effects.

Starch gels with precisely controlled viscosity show considerable potential as topical carriers for personalized therapeutic applications. However, conventional gelation processes are often inefficient and difficult to regulate, thereby limiting the effective utilization of the favorable properties of starch gels. To address these limitations, an ultrasound-assisted dimethyl sulfoxide (DMSO) solvent method was developed to enable one-step gelation of starch derived from medicinal plant sources. This innovative approach produces gels with a wide viscosity range and can stably encapsulate diverse components, including methotrexate, molybdenum disulfide, and composite molybdenum disulfide. In this study, the properties of the starch gel were comprehensively analyzed, and its gelation mechanism was elucidated using grey prediction modeling and molecular dynamics simulations. The results indicate that the combination of DMSO and water enables rapid starch gel formation, with the process exhibiting a positive correlation with the degree of starch substitution. Furthermore, the gel demonstrated high loading capacity and excellent biocompatibility, making it suitable for applications such as psoriasis treatment and modification of hemodialysis membranes. This method not only expands the techniques available for starch gel preparation but also enhances clinical applications and the development of advanced drug delivery systems.

IntroductionDelayed wound healing is a major complication of diabetes, often associated with chronic inflammation and microbial dysbiosis. Although androgens are known to impair wound repair, their role in diabetic wound healing, particularly in regulating the local wound microbiome and associated immune response, remains poorly understood. In this study, we investigated whether androgen deprivation via surgical castration could enhance diabetic wound healing by modulating local microbial communities and inflammation.MethodsA full-thickness wound model was established in db/db mice. Surgical castration was used to achieve androgen deprivation. Wound closure and histology were assessed longitudinally. Blood glucose and body weight were monitored. The local immune microenvironment was profiled, focusing on pro-inflammatory factors and macrophage polarization. 16S rRNA sequencing characterized α-diversity and community composition over time. Functional prediction analyses inferred microbial metabolic potential, and machine-learning models evaluated taxa associated with healing dynamics.ResultsAndrogen deprivation significantly accelerated wound closure and improved histological outcomes without altering blood glucose or body weight. The wound microenvironment showed reduced pro-inflammatory factors and enhanced M2 macrophage polarization. 16S rRNA sequencing revealed increased microbial α-diversity and durable shifts in community composition, most prominently during early healing. Escherichia-Shigella, Rhodococcus, and Ochrobactrum were enriched, while Staphylococcus abundance decreased. Functional prediction indicated elevated microbial metabolic activity after castration. Machine-learning analysis identified Escherichia-Shigella as a key genus associated with accelerated healing.DiscussionLow androgen levels were associated with improved diabetic wound repair, potentially by attenuating local inflammation and fostering a more diverse, metabolically active microbiota. These data support a mechanistic link among androgens, wound inflammation, and the microbiome, and suggest host-directed therapeutic strategies for chronic diabetic wounds.

Hypertrophic scars (HS) are pathological cutaneous scars characterized by excessive collagen deposition and fibrosis. Intralesional glucocorticoid injections remain the standard treatment for HS, but it is often associated with side effects. In this study, we developed a novel silk fibroin microneedle (SF-MN) loaded with prednisone for localized delivery and glucocorticoid metabolism. The SF-MNs were fabricated using 10 % (w/v) silk fibroin. Prednisone-loaded SF-MNs were characterized by SEM and evaluated for biocompatibility, mechanical strength, and preclinical efficacy. Overall, the results demonstrated that the SF-MN enhanced local expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a specific enzyme that converting inactive glucocorticoids to its active form. SF-MN also achieved sustained in vitro release of prednisone over 7 days. Once released into local tissue, prednisone was rapidly converted to its active form, prednisolone. In the animal study, prednisone-SF-MNs effectively prevented scar formation during wound healing. Moreover, in the HS model, the prednisone-SF-MN accelerated scar remodelling, resulting in smaller scar size and decreased fibrosis. This targeted delivery strategy optimizes local glucocorticoid metabolism, enhance drug penetration, and minimize side effects associated with active glucocorticoid administration. These findings highlight the potential of SF microneedle-based drug delivery for improving HS treatment and support its future clinical translation.

Objectives To develop and evaluate a novel human stratum corneum (SC) mimetic phospholipid vesicle-based permeation assay (PVPA(SC)) model for in vitro permeation studies. Significance Due to the increasing restrictions on the use of human and animal skins, artificial skin models have attracted substantial interest in pharmaceuticals and cosmetic industries. In this study, a modified PVPA(SC) model containing both SC lipids and proteins was developed. Methods The PVPASC model was optimized by altering the lipid composition and adding keratin in the formulation of large liposomes. The barrier properties were monitored by measuring the electrical resistance (ER) and permeability of Rhodamine B (RB). The modified PVPA(SC) model was characterized in terms of the surface topography, solvent influence and storage stability. The permeation studies of the active components in Compound Nanxing Zhitong Plaster (CNZP) were performed to examine the capability of PVPA(SC) in the application of skin penetration. Results The ER and P-app values of RB obtained from the optimized PVPASC model indicated a similar barrier property to porcine ear skin. Scanning electron microscope analysis demonstrated a mimic 'brick-and-mortar' structure. The PVPA(SC) model can be stored for three weeks at -20 degree celsius, and withstand the presence of different receptor medium for 24 h. The permeation studies of the active components demonstrated a good correlation (r(2) = 0.9136) of P-app values between the drugs' permeation through the PVPA(SC) model and porcine ear skin. Conclusion Keratin contained composite phospholipid vesicle-based permeation assay models have been proven to be potential skin tools in topical/transdermal permeation studies.

The excessive inflammatory response is known to be a major challenge for diabetic wound healing, while bacteria secreted toxin, α-hemolysin (Hlα), was recently reported to prolong inflammation and delay diabetic wound healing. In this study, we designed a red blood cell membrane (RBCM)-mimicking liposome containing curcumin (named RC-Lip) for the treatment of diabetic wounds. RC-Lips were successfully fabricated using the thin film dispersion method, and the fusion of RBC membrane with the liposomal membrane was confirmed via surface protein analysis. RC-Lips efficiently adsorbed Hlα, thereby reducing the damage and pro-apoptotic effects of Hlα on keratinocytes. Furthermore, they remarkably facilitated liposome uptake into macrophages with advanced curcumin release and regulation of M2 macrophage polarization. In a diabetic mouse and infected wound model, RC-Lips treatment significantly promoted wound healing and re-epithelialization while downregulating interleukin-1β (IL-1β) and upregulating interleukin-10 (IL-10). In summary, the results showed that the spongiform RC-Lips effectively modulate the inflammatory response after adsorbing Hlα and regulating M2 macrophage polarization, leading to a significant promotion of wound healing in diabetic mice. Hence, this study provides a prospective strategy of efficiently mediating inflammatory response for diabetic wounds.

Background and Purpose: Three-dimensional printing (3DP) selective laser melting (SLM) and electron beam melting (EBM) technique can construct porous Ti-6Aluminum-4Vanadium (Ti-6Al-4V) scaffolds with special microstructural and biomechanical properties. However, it is still needed to be tested for bone tissue engineering. Materials and Methods: To investigate the microstructure and surface modification of a porous titanium scaffold, 3DP-SLM technique was used, and the mechanical and biological performance of the scaffolds was compared with that fabricated by EBM technique. Ti-6Al-4V scaffolds were computer-designed and fabricated using low-power SLM (L-SLM). The microstructure morphologies of L-SLM Ti-6Al-4V (L-SLM-Ti) scaffolds were determined and compared with EBM-fabricated Ti-6Al-4V (EBM-Ti) scaffolds. Each scaffold was immersed with marrow clot for 1 h until fully combined with bone mesenchymal stem cells in clots. The biomechanical and cellular response of these two kinds of Ti-6Al-4V scaffolds were compared. Results: The L-SLM-Ti scaffolds showed a microstructure closer to the designed parameters than that of the EBM-Ti scaffolds. The L-SLM-Ti scaffold fibers had a rougher surface than the EBM-Ti scaffolds. Meanwhile, L-SLM-Ti scaffolds had a lower elasticity modulus and lower bearing force than EBM-Ti scaffold. Cell proliferation and the relative expression levels of OPN, COL1, and RUNX2 in L-SLM-Ti scaffolds was apparently higher than in the EBM-Ti scaffolds, with no significant difference found between the percentage of live cells found in L-SLM-Ti and EBM-Ti scaffolds. Conclusion: 3DP-Ti-6Al-4V scaffolds fabricated by L-SLM and designed with rougher surfaces and larger pore sizes may have more reasonable biomechanical properties and increased biological performance than traditional EBM-Ti scaffolds. These L-SLM-Ti scaffolds might be suitable candidates for bone defect repair.

Diabetic wounds have been a serious concern for human health owing to their long chronic inflammation and reduced vascularization. Herein, we report novel oil-in-water (o/w) nanoemulsions (NEs) containing Poria cocos triterpenes extract (PTE) to fabricate hyaluronic acid hydrogels (PTE-NEs) for the treatment of diabetic wounds. The size and morphology of NEs are analyzed by transmission electron microscope (TEM) and Zeta potential, respectively. Furthermore, the rheological behavior and morphology of synthesized hydrogels are also determined. It is found that PTE-NEs gel has a homogeneous and porous structure with good elastic properties. In addition, in vitro experiments show that the cell viability of PTE-NEs gel is >85 % without cytotoxicity. In vivo experiments of diabetic rats demonstrate that the PTE-NEs gel can not only significantly accelerate diabetic wound healing, collagen deposition, M2 macrophage polarization, and angiogenesis, but also inhibit inflammation. In conclusion, PTE plays a significant role in wound healing and exhibits anti-inflammatory effects, demonstrating its great potential in treating diabetic wounds.