Rabbit Ear Model Research Articles

The effectiveness of antimicrobial photodynamic therapy on catheter infection model

Background/AimThis experimental study aimed to examine the effectiveness of transdermal antimicrobial photodynamic therapy (APDT) with and without antimicrobial lock therapy (ALT), on catheter biofilms. MethodsS. epidermidis and C. orthopsilosis biofilms were formed within peripheral venous catheters positioned in the marginal ear veins of New Zealand white rabbits. Biofilm formation was confirmed with scanning electron microscopy in two catheters. 24 catheters with staphylococcal biofilms and 24 with fungal biofilms were treated with APDT, ALT or “APDT plus ALT” for five days. Six catheters were separated as controls. APDT was applied with a red colored LED lamp and methylene blue as the photosensitizer. Vancomycin lock solutions were used as ALT for staphylococcal biofilms and amphotericin B for fungal biofilms. The effect of treatment procedures was evaluated by intraluminal biofilm viability testing based on spectrophotometric evaluation, and a quantitative (OD) value was obtained for each catheter. ResultsThe mean OD values obtained by 600 nm spectrophotometric reading at 24 h (biofilm viability) after “ALT”, “APDT” and “ALT plus APDT” procedures were 0.363, 0.151 and 0.128 for S. epidermidis and 0.092, 0.104 and 0.227 for C. orthopsilosis, respectively. All these OD values obtained after treatment procedures were lower than controls for both S. epidermidis (OD: 0,802) and C. orthopsilosis (OD: 0,315), although there were large fluctuations in our results. ConclusionsOur results suggest that transdermal APDT may be an effective method for treating staphylococcal and candida biofilms formed within intravenous catheters in our rabbit ear model. The combined use of APDT and ALT might be beneficial in these staphylococcal biofilms.

Dual-Modal Optical Imaging of Tissue Perfusion in Response to Cooling Stimulation Facilitates Early Detection of Pressure Ulcer.

Pressure ulcers present a significant human and economic challenge, lacking a reliable method for early detection. To address this, we developed a system capable of early detection by using cooling stimulation and dynamic data acquisition techniques to monitor blood perfusion and skin temperature. The system consists of laser speckle perfusion imaging and thermal imaging. And we performed simulations to demonstrate that the system is capable of detect tissue damage across multiple layers, from superficial to deep. Testing on a rabbit ear model demonstrated that this approach, which combines dynamic perfusion and temperature parameters, effectively distinguishes early pressure ulcer areas from normal skin with a significant p value of 0.0015. This distinction was more precise compared to methods relying solely on static parameters or one parameter. Our study thereby offers a promising advancement in the proactive management and prevention of pressure ulcers.

Minimally invasive surgical approach to model hypertrophic scarring in the rabbit ear.

Current strategies for hypertrophic scar prevention and treatment are limited. To facilitate these efforts, a minimally invasive hypertrophic scar model was created in a rabbit ear for the first time based on previous methods used to induce ischemia. Six New Zealand white rabbits (12 ears total) were studied. First, ischemia was achieved by ligating the cranial artery, cranial vein and central artery, while preserving the caudal artery, caudal vein and central vein, respectively. The relative level of ischemia induced at time of surgery, both baseline and maximum perfusion, was assessed with a fluorescent light-assisted angiography and demonstrated lower rates of perfusion in the ischemic ears. Following vascular injury, a 2-cm full thickness linear wound was created on the ventral ear and closed with 4 - 0 Nylon sutures under high tension. For each rabbit, one ear received a combination of ischemia and wounding with suture tension (n = 6), while the other ear was non-ischemic with wounding and suture tension alone (n = 6). Four weeks post-operatively, ischemic ears developed scar hypertrophy (histological scar thickness: 1.1 ± 0.2mm versus 0.5 ± 0.1mm, p < 0.05). Herein, we describe a novel, prototypical minimally invasive rabbit ear model of hypertrophic scar formation that can allow investigation of new drugs for scar prevention.

CD248 interacts with ECM to promote hypertrophic scar formation and development

Hypertrophic scar (HS) presents a significant clinical challenge, frequently arising as a fibrotic sequela of burn injuries and trauma. Characterized by the aberrant activation and proliferation of myofibroblasts, HS lacks a targeted therapeutic approach to effectively reduce this dysregulation. This study offers novel evidence of upregulated expression of CD248 in HS tissues compared to normal skin (NS) tissues. Specifically, the expression of CD248 was predominantly localized to α-SMA+-myofibroblasts in the dermis. To explain the functional role of CD248 in dermal myofibroblast activity, we employed a targeted anti-CD248 antibody, IgG78. Both CD248 intervention and IgG78 treatment effectively suppressed the proliferative, migratory, and ECM-synthesizing activities of myofibroblasts isolated from HS dermis. In addition, IgG78 administration significantly attenuated HS formation in an in vivo rabbit ear model. The LC/MS analysis coupled with co-immunoprecipitation of HS tissues indicated a direct interaction between CD248 and the ECM components Fibronectin (FN) and Collagen I (COL I). These findings collectively suggest that CD248 may function as a pro-fibrotic factor in HS development through its interaction with ECM constituents. The utilization of an anti-CD248 antibody, such as IgG78, represents a promising novel therapeutic strategy for the treatment of HS.

Catechin Hydrate Improves Hypertrophic Scar in Rabbit Ear Model via Reduction of Collagen Synthesis

Catechin Hydrate Improves Hypertrophic Scar in Rabbit Ear Model via Reduction of Collagen Synthesis

Layered dissolving microneedle containing a three-drug combination on the treatment of hypertrophic scar

Hypertrophic scars (HS), mainly caused by burns, trauma, and surgery, are associated with erythema, bumps, itching, and pain. The oral administration of Asiaticoside (AS) is a prevalent treatment for HS in clinical settings; however, its effectiveness is constrained due to its low bioavailability, necessitating high dosages for therapeutic impact. To mitigate this issue, we developed a layered dissolving microneedle (DMN) incorporating AS–ginsenoside Rb1–L–carnosine (A–G–C) at the tip for HS treatment. The tip layer of the DMNs comprised sodium carboxymethyl cellulose (CMC), while the base layer consisted of low-viscosity CMC to enhance mechanical strength. We examined its puncture performance, in vitro dissolution ability, and therapeutic effect on a rabbit ear model of HS. Histological analysis was performed by Hematoxylin and Eosin (H&E), Masson staining and Sirius red staining. The results demonstrated that the DMNs exhibited excellent puncture performance and dissolution rates. A-G-C DMNs were found to be effective in reducing scar thickness by measuring scar thickness changes. Histological analysis revealed that the A–G–C DMNs significantly reduced inflammation and collagen fiber deposition in scar tissue. Importantly, the therapeutic effect achieved with A–G–C DMNs was comparable to that of triamcinolone acetonide injection. These findings highlight the potential of DMNs loaded with A–G–C as a promising treatment modality for HS, offering improved bioavailability and therapeutic outcomes.

Cellulose nanocrystals-reinforced dual crosslinked double network GelMA/hyaluronic acid injectable nanocomposite cryogels with improved mechanical properties for cartilage tissue regeneration.

Improvement of mechanical properties of injectable tissue engineering scaffolds is a current challenge. The objective of the current study is to produce a highly porous injectable scaffold with improved mechanical properties. For this aim, cellulose nanocrystals-reinforced dual crosslinked porous nanocomposite cryogels were prepared using chemically crosslinked methacrylated gelatin (GelMA) and ionically crosslinked hyaluronic acid (HA) through the cryogelation process. The resulting nanocomposites showed highly porous structures with interconnected porosity (>90%) and mean pore size in the range of 130-296 μm. The prepared nanocomposite containing 3%w/v of GelMA, 20 w/w% of HA, and 1%w/v of CNC showed the highest Young's modulus (10 kPa) and excellent reversibility after 90% compression and could regain its initial shape after injection by a 16-gauge needle in the aqueous media. The in vitro results demonstrated acceptable viability (>90%) and migration of the human chondrocyte cell line (C28/I2), and chondrogenic differentiation of human adipose stem cells. A two-month in vivo assay on a rabbit's ear model confirmed that the regeneration potential of the prepared cryogel is comparable to the natural autologous cartilage graft, suggesting it is a promising alternative for autografts in the treatment of cartilage defects.

Suture-anchored cutaneous tension induces persistent hypertrophic scarring in a novel murine model.

Hypertrophic scars cause impaired skin appearance and function, seriously affecting physical and mental health. Due to medical ethics and clinical accessibility, the collection of human scar specimens is frequently restricted, and the establishment of scar experimental animal models for scientific research is urgently needed. The four most commonly used animal models of hypertrophic scars have the following drawbacks: the rabbit ear model takes a long time to construct; the immunodeficient mouse hypertrophic scar model necessitates careful feeding and experimental operations; female Duroc pigs are expensive to purchase and maintain, and their large size makes it difficult to produce a significant number of models; and mouse scar models that rely on tension require special skin stretch devices, which are often damaged and shed, resulting in unstable model establishment. Our group overcame the shortcomings of previous scar animal models and created a new mouse model of hypertrophic scarring induced by suture anchoring at the wound edge. We utilized suture anchoring of incisional wounds to impose directional tension throughout the healing process, restrain wound contraction, and generate granulation tissue, thus inducing scar formation. Dorsal paired incisions were generated in mice, with wound edges on the upper back sutured to the rib cage and the wound edges on the lower back relaxed as a control. Macroscopic manifestation, microscopic histological analysis, mRNA sequencing, bioinformatics, and in vitro cell assays were also conducted to verify the reliability of this method. Compared with those in relaxed controls, the fibrotic changes in stretched wounds were more profound. Histologically, the stretched scars were hypercellular, hypervascular, and hyperproliferative with disorganized extracellular matrix deposition, and displayed molecular hallmarks of hypertrophic fibrosis. In addition, the stretched scars exhibited transcriptional overlap with mechanically stretched scars, and human hypertrophic and keloid scars. Phosphatidylinositol 3-kinase-serine/threonine-protein kinase B signaling was implicated as a profibrotic mediator of apoptosis resistance under suture-induced tension. This straightforward murine model successfully induces cardinal molecular and histological features of pathological hypertrophic scarring through localized suture tension to inhibit wound contraction. The model enables us to interrogate the mechanisms of tension-induced fibrosis and evaluate anti-scarring therapies.

Effect of Silicone Patch Containing Metal-organic Framework on Hypertrophic Scar Suppression.

Hypertrophic scars (HS) are an abnormal cutaneous condition of wound healing characterized by excessive fibrosis and disrupted collagen deposition. This study assessed the potential of a silicone patch embedded with chemically stable zirconium-based metal-organic frameworks (MOF)-808 structures to mitigate HS formation using a rabbit ear model. A silicone patch was strategically engineered by incorporating Zr-MOF-808, a composite structure comprising metal ions and organic ligands. Structural integrity of the Zr-MOF-808 silicone patch was validated using scanning electron microscopy and X-ray diffraction analysis. The animals were divided into three groups: a control, no treatment group (Group 1), a silicone patch treatment group (Group 2), and a group treated with a 0.2% loaded Zr-MOF-808 silicone patch (Group 3). HS suppression effects were quantified using scar elevation index (SEI), dorsal skin thickness measurements, and myofibroblast protein expression. Histopathological examination of post-treatment HS samples revealed substantial reductions in SEI (34.6%) and epidermal thickness (49.5%) in Group 3. Scar hyperplasia was significantly diminished by 53.5% (p<0.05), while collagen density declined by 15.7% in Group 3 compared to Group 1. Western blot analysis of protein markers, including TGF-β1, collagen-1, and α-SMA, exhibited diminished levels by 8.8%, 12%, and 21.3%, respectively, in Group 3, and substantially higher levels by 21.9%, 27%, and 39.9%, respectively, in Group 2. On the 35th day post-wound generation, Zr-MOF-808-treated models exhibited smoother, less conspicuous, and flatter scars. Zr-MOF-808-loaded silicone patch reduced HS formation in rabbit ear models by inducing the proliferation and remodeling of the wound healing process.

Hydroxy-α-sanshool has anti-inflammatory and antioxidant effects and affects the NF-κB/STAT3 pathway via TRPV1 in acne

Hydroxy- α-sanshool (HAS), an extract derived from Zanthoxylum plants, possesses anti-inflammatory and antioxidant effects. However, its potential effects on acne have not been reported. In this study, 2% absolute ethanol formulation of HAS was effective in inflammatory rashes in a rabbit ear model of acne, surpassing the performance of 0.1% adapalene and matching the effectiveness of 10% benzoyl peroxide, but with a faster onset of action. HAS effectively inhibited Cutibacterium acnes (C. acnes) growth with a minimum inhibitory concentration of 1.25 mg/mL. HAS could effectively inhibit the expression of reactive oxygen species (ROS), various inflammatory factors, and the activation of NF-κB and STAT3 pathways induced by C. acnes in HaCat and THP-1 cells. HAS's antioxidant and anti-inflammatory effects in acne may be mediated through TRPV1. Notably, 2% HAS lotion alone display efficacy in reducing inflammatory rashes in patients with mild to moderate acne, but studies with large samples are needed.

Intralesional Axitinib Injection Mitigates Hypertrophic Scar by Inhibiting Angiogenesis Pathway: A Preliminary Study in a Rabbit Ear Model.

High levels of VEGF and excessive angiogenesis contribute significantly to hypertrophic scar (HS) formation. Our study aimed to preliminarily investigate the effect of axitinib, a selective VEGF receptor tyrosine kinase inhibitor, on angiogenesis of HS and to explore its possible mechanism in a rabbit ear model. Ten male New Zealand white rabbits were used to establish HS models and then randomised to the control and axitinib groups. The scar tissues in the two groups were injected with axitinib or normal saline, and they were evaluated after one month of treatment. Macroscopic scar thickness, vascularity and pliability, as well as histopathological analysis including HE staining and Masson staining and scar elevation index (SEI) between two groups were compared. Immunohistochemical staining of CD31 in two groups was conducted to assess the degree of angiogenesis in HS tissue. The protein expression of protein kinase B (AKT) and ribosomal protein S6 kinase (p70S6K) and their phosphorylation levels in both groups were examined by Western blot analysis. The macroscopic and histological observation showed intralesional axitinib injection significantly reduced scar thickness, vascularity and pliability of HS in the rabbit ear model. The value of SEI in HE assessment was also significantly declined in the axitinib group. Furthermore, immunohistochemical analysis revealed that axitinib suppressed the expression of CD31 in HS tissue, and the mean IOD for blood vessels was significantly lower in the axitinib-treated group. Additionally, axitinib effectively attenuated the protein expression of p70S6K, p-AKT and p-p70S6K by Western blot analysis. Our study suggests that intralesional injection of axitinib can effectively attenuate HS by reducing angiogenesis in the rabbit ear model, and this inhibitory effect may be mediated by suppression of AKT/p70S6K signaling pathway. It indicates that axitinib may be a promising option for the treatment of HS in the future.

Exploring the Potential of Hesperidin in Preventing Hypertrophic Scars: Insights from a Rabbit Ear Model.

Hypertrophic scars, commonly occurring after trauma or surgery in critical areas like the head and joints, pose significant challenges to both physical and mental health due to their impact on skin function and aesthetics. While the complex pathogenesis involves fibroblast activation and collagen deposition, effective treatments are lacking, underscoring the importance of exploring pathogenesis and targeted therapies. Hesperidin, a bioactive compound in citrus fruits with diverse health benefits, including anti-fibrotic and anti-angiogenic effects, is the focus of this study with the aim of investigating its impact on hypertrophic scar formation, given its potential to promote blood flow and improve skin microcirculation. This study aimed to observe the inhibitory effect of topical hesperidin on hypertrophic scars in rabbits. A total of 8 healthy adult New Zealand white rabbits were used to establish a rabbit hypertrophic scarring animal model. Five wounds were created on each rabbit's two ears, with three wounds on the left ear (groups A, B, and C) and two wounds on the right ear (groups D and E). After six days of wound drying postoperatively, the wounds were locally treated with medication as followed: group A, 0.1% hesperidin; group B, 1% hesperidin; group C, 1% triamcinolone acetonide; group D, Vaseline; and group E, blank control without any medication. After 28 days, the scar tissue samples were collected for histological examination. The results showed that the scar texture of groups B and C was softer and lighter in color, and the number of fibroblasts, capillaries, and inflammatory cells in the tissue was significantly less than those in the other three groups. The hypertrophic scar indices of groups B and C were significantly smaller than those of groups A, D, and E, and the difference was statistically significant (P < 0.05). There were no significant difference between groups B and C. Topical application of hesperidin demonstrated promising potential for reducing hypertrophic scar formation in rabbits.

Melatonin inhibits fibroblast cell functions and hypertrophic scar formation by enhancing autophagy through the MT2 receptor-inhibited PI3K/Akt /mTOR signaling

Hypertrophic scar (HS) is a fibrotic skin condition and characterized by abnormal proliferation of myofibroblasts and accumulation of extracellular matrix. Melatonin, an endogenous hormone, can alleviate fibrosis in multiple models of diseases. This study examined the effect of melatonin on fibrosis in primary fibroblasts from human HS (HSFs) and a rabbit ear model and potential mechanisms. Melatonin treatment significantly decreased the migration and contraction capacity, collagen and α-smooth muscle actin (α-SMA) production in HSFs. RNA-sequencing and bioinformatic analyses indicated that melatonin modulated the expression of genes involved in autophagy and oxidative stress. Mechanistically, melatonin treatment attenuated the AKT/mTOR activation through affecting the binding of MT2 receptor with PI3K to enhance autophagy, decreasing fibrogenic factor production in HSFs. Moreover, melatonin treatment inhibited HS formation in rabbit ears by enhancing autophagy. The anti-fibrotic effects of melatonin were abrogated by treatment with an autophagy inhibitor (3-methyladenine, 3-MA), an Akt activator (SC79), or an MT2 selective antagonist (4-phenyl-2propionamidotetralin, 4-P-PDOT). Therefore, melatonin may be a potential drug for prevention and treatment of HS.

Comparison research on the therapeutic effects of botulinum toxin type A and stromal vascular fraction gel on hypertrophic scars in the rabbit ear model

Background and objectivesBotulinum toxin type A (BTA) is often used for wrinkles and muscle convulsive diseases due to its blocking of the transmission of nerve impulses. Stromal vascular fraction gel (SVF-gel) prepared from adipose tissue has novel effects on skin depression and poor texture. Both BTA and SVF-gel are proved to possess anti-scar potential. This study aimed to assess and compare their therapeutic effects on hypertrophic scars. Materials and methodsThe rabbit ear scar model was established and treated with BTA and SVF-gel, alone or in combination. Gross evaluation using Manchester Scar Scale (MSS) was conducted immediately, 4 and 8 weeks after initial treatment. After tissue sample harvest, histological and Western blot analyses were performed. ResultsAll the treatments alleviated scar hyperplasia in different degrees by inhibiting fibroblast activation (Ki-67, α-SMA), tissue inflammation (CD45, IL-1β) and the transforming growth factor-β1 (TGF-β1)/Smad3 pathway. Despite an excellent anti-inflammatory effect, improvement of scar appearance and pathological characteristics in SVF-gel-contained groups was not as good as that in BTA-only group, which might be related to the retention of M2-type macrophages (CD163 +) and partial maintenance of TGF-β1 expression. ConclusionOur data suggest that BTA has better anti-scar efficacy than SVF-gel, and the combination of these two treatments shows no obvious combinatorial effect.

Human Umbilical Mesenchymal Stem Cells-Derived Microvesicles Attenuate Formation of Hypertrophic Scar through Multiple Mechanisms

Mesenchymal stem cells and the derived extracellular microvesicles are potential promising therapy for many disease conditions, including wound healing. Since current therapeutic approaches do not satisfactorily attenuate or ameliorate formation of hypertrophic scars, it is necessary to develop novel drugs to achieve better outcomes. In this study, we investigated the effects and the underlying mechanisms of human umbilical mesenchymal stem cells (HUMSCs)-derived microvesicles (HUMSCs-MVs) on hypertrophic scar formation using a rabbit ear model and a human foreskin fibroblasts (HFF) culture model. The results showed that HUMSCs-MVs reduced formation of hypertrophic scar tissues in the rabbit model based on appearance observation, and hematoxylin and eosin (H&amp;E), Masson, and immunohistochemical stainings. HUMSCs-MVs inhibited invasion of HFF cells and decreased the levels of the α-SMA, N-WASP, and cortacin proteins. HUMSCs-MVs also inhibited cell proliferation of HFF cells. The MMP-1, MMP-3, and TIMP-3 mRNA levels were significantly increased, and the TIMP-4 mRNA level and the NF-kB p65/β-catenin protein levels were significantly decreased in HFF cells after HUMSCs-MVs treatment. The p-SMAD2/3 levels and the ratios of p-SMAD2/3/SMAD2/3 were significantly decreased in both the wound healing tissues and HFF cells after HUMSCs-MVs treatment. CD34 levels were significantly decreased in both wound healing scar tissues and HFF cells after HUMSCs-MVs treatment. The VEGF-A level was also significantly decreased in HFF cells after HUMSCs-MVs treatment. The magnitudes of changes in these markers by HUMSCs-MVs were mostly higher than those by dexamethasone. These results suggested that HUMSCs-MVs attenuated formation of hypertrophic scar during wound healing through inhibiting proliferation and invasion of fibrotic cells, inflammation and oxidative stress, Smad2/3 activation, and angiogenesis. HUMSCs-MVs is a potential promising drug to attenuate formation of hypertrophic scar during wound healing.

Curcumin alleviates hypertrophic scarring by inhibiting fibroblast activation and regulating tissue inflammation.

Hypertrophic scar (HS) that can lead to defects in appearance and function is often characterized by uncontrolled fibroblast proliferation and excessive inflammation. Curcumin has been shown to have anti-inflammatory and anti-oxidative effects and to play an anti-fibrotic role by interfering transforming growth factor-β1 (TGF-β1)/Smads signaling pathways. To study the effect and mechanism of curcumin on HS from the perspective of fibroblast activity and inflammation regulation. Cell proliferation, migration and the expression of α-smooth muscle actin (α-SMA) of TGF-β1-induced human dermal fibroblasts (HDFs) treated by curcumin were evaluated using Cell Counting Kit-8 assay, 5-ethynyl-2'-deoxyuridine staining, Transwell assay, Western blotting and immunofluorescence, respectively. The expression of TGF-β1/Smad3 pathway-related molecules (TGF-β1, TGFβ-R1/2, p-Smad3, Smad4) was detected by Western blotting. In a rabbit ear model, hematoxylin and eosin and Masson's staining were conducted to assess scar elevation and collagen deposition, and immunohistochemistry was performed to detect the activation of fibroblasts and infiltration of inflammatory cells. Curcumin inhibited proliferation, migration and α-SMA expression of HDFs in a dose-dependent manner. Curcumin (25 μm mol/L) did not regulate the expression of endogenous TGF-β1, but suppressed Smad3 phosphorylation and nuclear translocation, leading to lower α-SMA expression. Curcumin also reduced hypertrophic scarring of rabbit ear, accompanied by the inhibited TGF-β1/Smad3 pathway, inflammatory infiltration and M2 macrophage polarization. Curcumin plays an anti-scar role through regulating fibroblast activation and tissue inflammation. Our findings provide scientific reference for the clinical use of curcumin in the treatment of HS.

A review on photo-mediated ultrasound therapy.

Photo-mediated ultrasound therapy (PUT) is a novel therapeutic technique based on the combination of ultrasound and laser. The underlying mechanism of PUT is the enhanced cavitation effect inside blood vessels. The enhanced cavitation activity can result in bio-effects such as reduced perfusion in microvessels. The reduced perfusion effect in microvessels in the eye has the potential to control the progression of eye diseases such as diabetic retinopathy and age-related macular degeneration. Several in vivo studies have demonstrated the feasibility of PUT in removing microvasculature in the eye using rabbit eye model and vasculature in the skin using rabbit ear model. Numerical studies using a bubble dynamics model found that cavitation is enhanced during PUT due to the dramatic increase in size of air/vapor nuclei in blood. In addition, the study conducted to model cavitation dynamics inside a blood vessel during PUT found stresses induced on the vessel wall during PUT are higher than that at normal physiological levels, which may be responsible for bio-effects. The concentration of vasodilators such as nitric oxide and prostacyclin were also found to be affected during PUT in an in vitro study, which may limit blood perfusion in vessels. The main advantage of PUT over conventional techniques is non-invasive, precise, and selective removal of microvessels with high efficiency at relatively low energy levels of ultrasound and laser, without affecting the nearby structures. However, the main limitation of vessel rupture/hemorrhage needs to be overcome through the development of real-time monitoring of treatment effects during PUT. In addition to the application in removing microvessels, PUT-based techniques were also explored in treating other diseases. Studies have found a combination of ultrasound and laser to be effective in removing blood clots inside veins, which has the potential to treat deep-vein thrombosis. The disruption of atherosclerotic plaque using combined ultrasound and laser was also tested, and the feasibility was demonstrated.

Ferroptosis‐Mediated Synergistic Therapy of Hypertrophic Scarring Based on Metal–Organic Framework Microneedle Patch

AbstractHypertrophic scarring, an abnormal fibroproliferative wound‐healing disease, has brought tremendous burden for global healthcare systems. To date, no satisfactory treatment of hypertrophic scarring is available yet. Ferroptosis, an iron‐dependent form of cell death, has attracted much attention recently for the therapy of diseases featuring iron addiction. Intriguingly, myofibroblasts derived from hypertrophic scarring are found to exhibit a high iron state which appears to be sensitive to trigger ferroptosis for scarring treatment. Accordingly, in this study, a pH responsive self‐assembly nanoplatform is designed by encapsulating silver nanoclusters (AgNCs) and Chinese herbal medicine trigonelline (TRG) into zeolitic imidazolate framework‐8 (ZIF‐8) for synergistic ferroptosis therapy against hypertrophic scarring. The fabricated AgNC/TRG/ZIF‐8 composites exhibit good biocompatibility and pH responsive‐degradation inside myofibroblasts. The ZIF‐8 precursors can increase the generation of lipid reactive oxygen species and deplete intracellular glutathione (GSH). Also, AgNCs have the capability to consume GSH, while TRG can inhibit the activity of glutathione peroxidase. Consequently, the synergistic ferroptosis anti‐scarring therapy can be effectively achieved. Furthermore, AgNC/TRG/ZIF‐8‐loaded microneedle patches made of gelatin methacrylate show remarkable therapeutic effect against hypertrophic scarring on a rabbit ear model. This study suggests the great potential of ferroptosis‐mediated strategy for treating fibrotic skin diseases in future clinical application.

Effectiveness of fractional carbon dioxide laser combined with botulinum toxin type A in a rabbit ear model with the underlying mechanism.

Hypertrophic scar (HS) is a common disease in plastic and cosmetic surgery, with limited treatment options, and is a challenge for clinicians. This study aimed to evaluate the efficacy of fractional carbon dioxide (CO2 ) laser combined with botulinum toxin type A (BTXA) in treating HSs in rabbit ears and to provide new strategies for treating HS. Twenty-four New Zealand white rabbits with induced HSs were randomly divided into one control and three treatment groups. After 4 weeks of modeling, BTXA (2.0U) was injected into the HS of the BTXA and combination groups, whereas a fractional CO2 laser (combo mode, deep energy: 12.5mJ; super energy: 90 mJ) was used in the fractional CO2 laser and combination groups. The laser treatments were repeated after 2 weeks. The HSs in the rabbit ears were observed and photographed 5 weeks after the first treatment. The scar thickness in each group was measured and compared, and the scar elevation index (SEI) was determined using hematoxylin and eosin staining. Collagen content and alignment were observed using Masson's trichrome staining. Western blotting and immunohistochemistry were performed to analyze scar-related protein levels. Hypertrophic scars were reduced in all treatment groups compared with the control group. The combination group had lower scar thickness, SEI, and expression of scar-related proteins in HSs, with an appearance similar to that of normal rabbit ear skin. Furthermore, the fibroblast content and collagen deposition decreased significantly in the combination group (p < 0.001). Fractional CO2 laser combined with BTXA more effectively reduced HSs by inhibiting fibroblast proliferation, decreasing transforming growth factor-β1 and α- smooth muscle actin expression, and causing collagen remodeling.

Peptide deregulated in hypertrophic scar-1 alleviates hypertrophic scar fibrosis by targeting focal adhesion kinase and pyruvate kinase M2 and remodeling the metabolic landscape

Hypertrophic scarring is a fibrotic skin disease characterized by excessive deposition of collagens. Emerging evidence has suggested important roles for peptides in fibrosis-related diseases. Here, we demonstrate that a skin-derived endogenous peptide, peptide deregulated in hypertrophic scar-1 (PDHS1), with the sequence IATTTASAATAAAIGATPRAK, inhibits cell proliferation, promotes apoptosis, decreases the proportion of cells in S phase, and decreases collagen synthesis in hypertrophic scar fibroblasts. Additionally, treatment with PDHPS1 alleviates hypertrophic scarring in a rabbit ear model. PDHPS1 was found to bind to focal adhesion kinase (FAK) and to decrease its activity. PDHPS1 was also shown to bind to pyruvate kinase M2 (PKM2) and to decreased its expression. Smad2 phosphorylation is also inhibited by treatment with PDHPS1. Overexpression of FAK rescues the decreased expression of COL3A1 induced by PDHPS1 treatment. Targeted metabolomics revealed that PDHPS1 reprogramed metabolism that related to amino acid synthesis, leading to decreases of the key glycolysis intermediates glucose-6-phosphate and fructose-6-phosphate. These results demonstrated that the endogenous peptide PDHPS1 alleviates hypertrophic scar fibrosis in vitro and in vivo by targeting FAK and PKM2 and remodeling the metabolic landscape. Overall, treatment with PDHPS1 is a potential therapeutic strategy for hypertrophic scarring.