Intermittent lysis on a single paper-based device to extract exosomal nucleic acid biomarkers from biological samples for downstream analysis.

As the role of exosomes in physiological and pathological processes has been properly perceived, harvesting them and their internal components is critical for subsequent applications. This study is a debut of intermittent lysis, which has been integrated into a simple and easy-to-operate procedure on a single paper-based device to extract exosomal nucleic acid biomarkers for downstream analysis. Exosomes from biological samples were captured by anti-CD63-modified papers before being intermittently lysed by high-temperature, short-time treatment with double-distilled water to release their internal components. Exosomal nucleic acids were finally adsorbed by sol-gel silica for downstream analysis. Empirical trials not only revealed that sporadically dropping 95 °C ddH2O onto the anti-CD63-modified papers every 5 min for 6 times optimized the exosomal nucleic acids extracted by the anti-CD63 paper but also verified that the whole deployed procedure is applicable for point-of-care testing (POCT) in low-resource areas and for both in vitro (culture media) and in vivo (plasma and chronic lesion) samples. Importantly, downstream analysis of exosomal miR-21 extracted by the paper-based procedure integrated with this novel technique discovered that the content of exosomal miR-21 in chronic lesions related to their stages and the levels of exosomal carcinoembryonic antigen originated from colorectal cancer cells correlated to their exosomal miR-21.

Monocyte chemoattractant protein-1 detection in wound tissue fluids for the assisted diagnosis of wound infection.

BACKGROUND: Infections are commonly seen in wounds. The overall infection rate is 1.8% to 4.2%. Improper infection management can lead to serious conditions and may progress to life-threatening sepsis. Because there is a need for assistance in predicting wound infection before obvious clinical symptoms, the measurement of cytokines in wound tissue fluids has attracted our attention for determining the overall status of wound infection. Our intent was to assess the potential biomarkers in the diagnosis of wound infection. METHODS: We collected 146 tissue fluids (acute: 59, chronic: 61, and normal: 26) for analysis of biomarkers using a human cytokine array. Serum C-reactive protein was also measured from 104 patients. The sensitivity and specificity of significant wound cytokines and serum C-reactive protein for the diagnosis of wound infection were evaluated. RESULTS: Among biomarkers examined, serum C-reactive protein and tissue C-reactive protein were highly expressed in acute infection wounds, whereas monocyte chemoattractant protein-1 was significantly expressed in chronic infection wounds. Because the expression of wound biomarkers varied in different types of wounds, relationships among them were studied. A high correlation between tissue C-reactive protein and interleukin-8 (R2 = 0.7) and a moderate correlation between systemic and local C-reactive protein (R2 = 0.47) were observed. In addition, tissue monocyte chemoattractant protein-1 had better sensitivity (74%) and specificity (65%) in the diagnosis of wound infection. Moreover, combined serum C-reactive protein with monocyte chemoattractant protein-1 examination provided a higher area under the curve in the receiver operator characteristic curve (0.75). CONCLUSION: We found that tissue monocyte chemoattractant protein-1 is a superior diagnostic marker for assistance with the diagnosis of wound infection.

Point-of-care detection devices for wound care and monitoring.

Healthcare resources are heavily burdened by infections that impede the wound-healing process. A wide range of advanced technologies have been developed for detecting and quantifying infection biomarkers. Finding a timely, accurate, non-invasive diagnostic alternative that does not require a high level of training is a critical step toward arresting common clinical patterns of wound health decline. There is growing interest in the development of innovative diagnostics utilizing a variety of emerging technologies, and new biomarkers have been investigated as potential indicators of wound infection. In this review, we summarize diagnostics available for wound infection, including those used in clinics and still under development.

Paper/PMMA hybrid device with a microvalve-controlled design for exosome isolation and analysis.

This study proposes a paper/PMMA hybrid device designed to isolate exosomes and extract exosomal miRNA, followed by quantitative analysis. It aims to provide simplified and convenient sample preparation for potential point-of-care testing (POCT) processes. In contrast to previous work conducted by our research team, which focused on isolating exosomes and exosomal nucleic acids, this study introduces a novel approach by integrating paper and a PMMA mold with a microvalve controlled design. This innovative method enables the entire process to be performed on paper. The pressure on the paper could be adjusted by turning the screw upon the valve to change the pore size and permeability of the paper, which achieved the effect of controlling the flow rate of fluids. The paper was designed to have an immunoaffinity area for capturing exosomes and a sol-gel silica coating area for extracting miRNA. The paper-based ELISA (p-ELISA) exhibited a limit of detection and a limit of quantitation of 6 × 107 and 5.4 × 108 particles/mL, respectively, for exosome measurement. The reverse transcription quantitative polymerase chain reaction (RT-qPCR) revealed that the Ct (threshold cycle) value for quantifying the miR-21 in the miRNAs extracted by the proposed paper/PMMA hybrid device was comparable to the Ct value of the commercial extraction kit. The developed paper/PMMA hybrid device with a microvalve-controlled design should be incorporated into the POCT system to extract exosomal miRNAs.

Paper-Based Exosomal MicroRNA-21 Detection for Wound Monitoring: A Proof of Concept and Clinical Validation Trial Study.

Emerging evidence has shown that microRNAs play pivotal roles in wound healing. MicroRNA-21 (miR-21) was previously found to upregulate in order to fulfill an anti-inflammation role for wounds. Exosomal miRNAs have been identified and explored as essential markers for diagnostic medicine. However, the role of exosomal miR-21 in wounds has yet to be well studied. In order to facilitate the early management of poorly healing wounds, we developed an easy-to-use, rapid, paper-based microfluidic-exosomal miR-21 extraction device to determine wound prognosis in a timely manner. We isolated and then quantitatively examined exosomal miR-21 in wound fluids from normal tissues and acute and chronic wounds. Eight improving wounds displayed lower levels of exosomal miR-21 expression after wound debridement. However, four instances of increased exosomal miR-21 expression levels were notably associated with patients with poor healing wounds despite aggressive wound debridement, indicating a predictive role of tissue exosomal miR-21 for wound outcome. Paper-based nucleic acid extraction device provides a rapid and user-friendly approach for evaluating exosomal miR-21 in wound fluids as a means of monitoring wounds. Our data suggest that tissue exosomal miR-21 is a reliable marker for determining current wound status.

Plate-related complication and health-related quality of life after mandibular reconstruction by fibula flap with reconstruction plate or miniplate versus anterolateral thigh flap with reconstruction plate.

BACKGROUND: Plate-related complications are major long-term complications in mandible reconstruction. There are controversies regarding the use of a reconstruction plate versus miniplates and a bone flap versus a soft tissue flap with a bridging plate. Direct comparisons of a fibula flap and an anterolateral thigh flap, the applicability between a reconstruction plate and miniplate, and the correlation between plate-related complications and quality of life remain unclarified. Therefore, this study aimed to the explore complications of different flaps and plates and how they impact the patients' quality of life. METHODS: We retrospectively reviewed the medical records of a total of 205 patients aged >18 years who underwent segmental mandibulectomy and reconstruction using fibula flap with reconstruction plate (FR; n = 86), fibula flap with miniplate (FM; n = 61), and anterolateral thigh flap with reconstruction plate (AR; n = 58) due to cancer ablation, osteoradionecrosis, or benign tumor excision between August 2010 and December 2019. Data on characteristics, complications, and health-related quality of life were collected and analyzed. RESULTS: The plate-related complication rate was the highest in the AR group (37.9%), then in the FR group (25.6%), and was the lowest in the FM group (13.1%; p = 0.0079). The plate exposure rate was the highest in the AR group (24.1%), then in the FR group (15.7%), and was the lowest in the FM group (4.9%; p = 0.0128). The plate fracture and dislodge rates for the AR group were both higher than those for the FR and FM groups (24.1% versus 9.3% versus 9.8%, respectively; p = 0.023). The AR group had worse complication-free survival (hazard ratio [HR]: 3.61, 95% CI: 1.99-6.56, and p < 0.0001) than the FR and FM groups. Osteoradionecrosis (HR: 6.19, 95% CI: 2.11-18.21, and p = 0.0009) and postoperative radiotherapy (HR: 2.87, 95% CI: 1.34-6.12, and p = 0.0402) were both independent adverse factors for complication-free survival, whereas patient treated primarily (HR: 0.35, 95% CI: 0.17-0.73, and p = 0.0048) was an independent protective factor. Plate-related complication negatively impacted the quality of life based on pain scores (ß: -0.56, SE: 0.26, and p = 0.034). CONCLUSIONS: Using a fibular flap fixed with miniplates and avoiding the use of a reconstruction plate may yield a reduced plate exposure rate and better health-related quality of life, particularly for patients with osteoradionecrosis or those who need postoperative radiotherapy.

Paper-Based Interleukin-6 Test Strip for Early Detection of Wound Infection.

The early stage of wound infection is always non-specific. Prompt intervention may help to prevent the wound from worsening. We developed a new protocol, based on previous research, that employs a paper-based IL-6 test strip used in combination with a spectrum-based optical reader to detect IL-6 in normal tissue (n = 19), acute wounds (n = 31), and chronic wounds (n = 32). Our data indicated the presence of significantly higher levels of IL-6 in acute wound tissues, but no significant difference in serum CRP. Receiver operating characteristics were used to determine clinical sensitivity and specificity of tissue IL-6 and systemic CRP. The area under the curve values were 0.87 and 0.63, respectively. The cut-off value of 30 pg/mL for IL-6 provided good sensitivity (75.0%) and superior specificity (88.9%). We found a high correlation between the IL-6 test strip and conventional ELISA results (R2 = 0.85, p < 0.001), and good agreement was also observed according to Bland-Altman analysis. We showed a promising role of tissue IL-6 to help early diagnosis of wound infection when clinical symptoms were non-specific. The advantages of this wound detection protocol included minimal invasiveness, small sample requirements, speed, sample preparation ease, and user-friendliness. This methodology could help care providers quickly clarify wound infection status and implement timely, optimal management.

Body Image as a Mediator Between Gender and Quality of Life Among Patients With Diabetic Foot Ulcers in Indonesia.

INTRODUCTION: Foot ulcers cause women in Indonesia to lose opportunities to participate in religious and cultural activities due to the inability to wear certain footwear. This study examined body image as a mediator in the relationship between gender and quality of life (QoL) among patients with diabetic foot ulcer (DFU) in Indonesia. METHOD: A cross-sectional design with convenience sampling was used to recruit participants at the Surgical Outpatient Department and Wound Care Clinic in Bali, Indonesia. The Diabetic Foot Ulcer Scale-Short Form and the body image domain of the Body Investment Scale were administered. RESULTS: We found gender differences in participants' (n = 201) QoL and body image (p < .05). Body image fully mediated the effect of the relationship between gender and QoL (B = 6.68; 95% confidence interval [3.14, 10.52]) and explained 39.13% of the variance. DISCUSSION: Health care providers should consider patients' religious beliefs in DFU education and consider women's body image issues. Diabetes foot ulcer may prevent women from performing religious rituals, thus, influencing their QoL. Protective strategies to prevent DFU among women in Indonesia warrant further development.

Dynamic Traction Splint as an Alternative Surgical Treatment for Comminuted Intraarticular Fracture of Metacarpophalangeal Joint.

BACKGROUND: Comminuted intraarticular fractures of the metacarpophalangeal joint (MPJ) are difficult to treat. We evaluated the clinical outcomes of using a dynamic traction splint to treat comminuted intraarticular fracture of MPJ. PATIENTS AND METHODS: We conducted a retrospective chart review on patients with comminuted intraarticular fracture of the MPJ treated with a dynamic traction splint at National Cheng Kung University Hospital between March 2014 and February 2018. The surgical procedures consisted of a transverse Kirschner wire insertion and treatment for concomitant injuries. The patients then received staged regular rehabilitation programs under a hand therapists' supervision for 14 weeks. Active range of motion (ROM) of injured digits, Visual Analog Scale score for pain, and return-to-work status were recorded to evaluate functional outcomes. RESULTS: A total of 10 patients were included. All were male patients and aged 8 to 66 years. The most common injury mechanism was motor vehicle accident (70%). The locations of fractures were 1 at the metacarpal head and 9 at the proximal phalangeal bases. Half of the fractures were open. Concomitant injuries were 1 digital nerve severance, 1 extensor tendon rupture, and 3 dorsal skin avulsions. There were no postoperative complications. The active ROM of the MPJ ranged from 40° to 90° with a median ROM of 80°. The Visual Analog Scale score for pain was 0 in 8 patients and 1 in the other 2 patients. All patients returned to their original workplace after rehabilitation. CONCLUSIONS: Dynamic traction splints and postoperative rehabilitation programs could be an alternative treatment for comminuted intraarticular fracture of the MPJ.

Big Carotid Body Paraganglioma: A Case Report With Successful Surgical Excision and Literature Review.

BACKGROUND: Carotid body paragangliomas are rare and therapeutically challenging. Shamblin I or II carotid body paraganglioma can be removed en bloc. This operation is sometimes combined with preoperative transarterial embolization to control bleeding. However, Shamblin III carotid body paraganglioma, which is encased with carotid vessels, is difficult to remove without carotid artery ligation for excision. Sometimes, not all tumor tissues are removed during operation and residual tumor tissues remain. Here, we review a case of Shamblin III carotid body paraganglioma removal without preoperative transarterial embolization or ligation of the carotid artery. We present a successful technique for Shamblin III carotid body paraganglioma resection that reduces bleeding during the operation. MATERIAL AND METHODS: A 74-year-old male patient who had an enlarged left neck mass for more than 20 years underwent tumor excision. The final pathology was carotid body paraganglioma. During the operation, the tumor was discovered to be encased in the bifurcation of the common carotid artery. We carefully isolated and temporarily clamped the common carotid artery to enable application of the finger dissection method to completely free the tumor from the carotid artery in a safe and bloodless plane. RESULTS: Neither intraoperative massive bleeding nor postoperative cranial nerve deficit occurred. Favorable wound status was noted during outpatient department follow-up. CONCLUSIONS: We describe a successful case of Shamblin III carotid body paraganglioma removal using temporary clamping of the common carotid artery and the finger dissection method.

Enhancing wound healing in recalcitrant leg ulcers with aminolevulinic acid-mediated antimicrobial photodynamic therapy.

Chronic leg ulcers effect millions of people around the world. It is imperative to search for effective treatments for such challenging ulcers. We report the success of aminolevulinic acid-mediated antimicrobial photodynamic therapy (A-PDT) to enhance wound healing of chronic ulcers for 3 patients who were refractory to conventional treatments. These ulcers healed after one to three sessions of A-PDT and there was no recurrence for more than 29 months. Interestingly, no bacteria were isolated from the ulcers after A-PDT treatment. In vitro, A-PDT also inactivated all bacteria isolated from the patients. A-PDT conditioned medium containing IL-6 enhanced keratinocyte migration. The results suggest in addition to bactericidal effects, A-PDT also alters the wound microenvironment. A-PDT may be an effective treatment for patients with recalcitrant infected ulcers.

Paper-based human neutrophil elastase detection device for clinical wound monitoring.

Paper-based diagnostic devices have been widely applied to assess the presence and status of a variety of clinical diseases by analyzing samples such as urine or blood. Due to their low cost, user-friendliness, and convenience, they have been used as point-of-care (POC) devices in countries lacking resources or energy. Despite wide-ranging research and implementation, paper-based devices have not previously been developed for wound analysis. Here, we discuss the successful development of such a tool to facilitate simple and rapid wound status assessment. The purpose of this study was to develop a paper-based elastase detection device (PEDD) for clinical wound assessment that specifically examines human neutrophil elastase (HNE), one of the most abundant serine proteases found in chronic wounds. The first step in this study was an examination of different paper substrate types (i.e., chromatography paper and filter paper) to determine which provided the best protease immobilization and colorimetric response. We then used a wax printing approach to create hydrophobic and hydrophilic regions and designated test zones created on both chromatography and filter papers. This allowed us to physically immobilize both substrate and protease within the desired test zone regions. This PEDD which demonstrated good sensitivity (0.631 µg mL-1, in a wound fluid system) can be used to monitor protease activity expressed in wounds. After developing this device, we examined samples from 9 patients presenting a total of 7 acute and 4 chronic wounds to determine wound HNE concentration. We believe that this study may be widely applicable in both academic and commercial sciences, including the development of practical POC detection devices.

Preliminary Assessment of Burn Depth by Paper-Based ELISA for the Detection of Angiogenin in Burn Blister Fluid-A Proof of Concept.

Rapid assessment of burn depth is important for burn wound management. Superficial partial-thickness burn (SPTB) wounds heal without scars, but deep partial-thickness burn (DPTB) wounds require a longer healing time and have a higher risk of scar formation. We previously found that DPTB blister fluid displayed a higher angiogenin level than SPTB blister fluid by conventional ELISA. In this study, we developed a paper-based ELISA (P-ELISA) technique for rapid assessment of angiogenin concentration in burn blister fluid. We collected six samples of SPTB blister fluid, six samples of DPTB blister fluid, and seven normal healthy serum samples for analysis. We again chose ELISA to measure and compare angiogenin levels across all of our samples, but we developed a P-ELISA tool and compared sample results from that tool to the results from conventional ELISA. As with conventional ELISA, DPTB blister fluid displayed higher angiogenin levels than SPTB in P-ELISA. Furthermore, our P-ELISA results showed a moderate correlation with conventional ELISA results. This new diagnostic technique facilitates rapid and convenient assessment of burn depth by evaluating a key molecule in burn blister fluid. It presents a novel and easy-to-learn approach that may be suitable for clinically determining burn depth with diagnostic precision.

The anti-TH17 polarization effect of Indigo naturalis and tryptanthrin by differentially inhibiting cytokine expression.

ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese herbal medicine Qing-Dai (also known as Indigo naturalis) extracted from indigo-bearing plants including Baphicacanthus cusia (Ness) Bremek was previously reported to exhibit anti-psoriatic effects in topical treatment. TH17 was later established as a key player in the pathogenesis of psoriasis. We investigated the anti-TH17 effect of Indigo naturalis and its active compounds. The aim of this study is to evaluate the toxicity of Indigo naturalis (IN) and its derivatives on five cell types involved in psoriasis, and to study the anti-inflammatory mechanism for the toxicity. MATERIALS AND METHODS: Following the fingerprint and quantity analysis of indirubin, indigo, and tryptanthrin in IN extract, we used MTS kits to measure the anti-proliferative effect of IN and three active compounds on five different cell types identified in psoriatic lesions. Quantitative RT-PCR analysis was used to measure the expression of various genes identified in the activated keratinocytes and TH17 polarized gene expression in RORγt-expressing T cells. RESULTS: We showed that IN differentially inhibited the proliferation of keratinocytes and endothelial cells but not monocytes, fibroblasts nor Jurkat T cells. Among three active compounds identified in IN, tryptanthrin was the most potent compound to reduce their proliferation. In addition to differentially reducing IL6 and IL8 expression, both IN and tryptanthrin also potently decreased the expression of anti-microbial S100A9 peptide, CCL20 chemokine, IL1B and TNFA cytokines, independent of NF-κB-p65-activation. Their attenuating effect was also detected on the expression of signature cytokines or chemokines induced during RORγT-induced TH17 polarization. CONCLUSIONS: We were the first to confirm a direct anti-TH17 effect of both IN herbal extract and tryptanthrin.

Cystic Fibrosis Transmembrane Conductance Regulator: A Possible New Target for Photodynamic Therapy Enhances Wound Healing.

Objective: Cell migration is an essential process in skin wound healing. Photodynamic therapy (PDT) enhances wound healing by photoactivating a photosensitizer with a specific wavelength of light. Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel expressed in multiple layers of keratinocytes. Recent studies showed that the activation of CFTR-related downstream signaling affects skin wound healing. We examined whether indocyanine green (ICG)-mediated PDT-enhanced cell migration is related to CFTR activation. Approach: The spatial and temporal expression levels of CFTR and proteins involved in focal adhesion, including focal adhesion kinase (FAK) and paxillin, were evaluated during cell migration in vitro and in vivo for wound healing. Results: ICG-PDT-conditioned medium collected from cells exposed to 5 J/cm2 near-infrared light in the presence of 100 µg/mL ICG activated CFTR and enhanced HaCaT cell migration. The expression of phosphorylated FAK Tyr861 and phosphorylated paxillin in focal adhesions was spatially and temporally regulated in parallel by ICG-PDT-conditioned medium. Curcumin, a nonspecific activator of CFTR, further increased PDT-enhanced cell migration, whereas inhibition of CFTR and FAK delayed cell migration. The involvement of CFTR in ICG-PDT-enhanced skin wound healing was confirmed in a mouse back skin wound model. Innovation: CFTR is a potential new therapeutic target in ICG-PDT to enhance wound healing. Conclusion: ICG-PDT-enhanced cell migration may be related to activation of the CFTR and FAK pathway. Conditioned medium collected from ICG-PDT may be useful for treating patients with chronic skin ulcer by regulating CFTR expression in keratinocytes.

Esophageal reconstruction after oncological total laryngopharyngoesophagectomy: Algorithmic approach.

BACKGROUND: Reconstruction for total laryngopharyngoesophagectomy is accomplished mainly by gastrointestinal transposition but can be complicated by anastomotic tension or associated neck-skin defect. Here, we present the results of total esophageal reconstruction by gastrointestinal transposition alone or with additional free tissue transfer and propose an algorithm accordingly. METHODS: We reviewed patients who had oncologic total laryngopharyngoesophagectomy between January 2012 and January 2016. Twenty-four men and one woman were included with a mean age of 54 (range, 41-72) years. Patients were grouped by reconstruction into the gastric pull-up (GP, n = 15), colon interposition (CI, n = 2), GP combined with free jejunal flap (GPFJ, n = 6), or GP combined with anterolateral thigh flap (GPALT, n = 2) group to compare clinical outcomes. RESULTS: The mean operation time was 1037.3 minutes and was significantly longer in the GPALT group than in the GP group (1235.0 ± 50.0 minutes vs. 929.7 ± 137.7 minutes, p =.009). All flaps survived. After a mean follow-up of 18 months, the overall leakage, stricture, and successful swallowing rates were 44%, 4%, and 76%, respectively. There was no significant difference in the leakage (53.3%, 50.0%, 16.7%, and 50.0%, p =.581), stricture (6.7%, 0%, 0%, and 0%, p = 1.000), or successful swallowing (73.3%, 50.0%, 83.3%, and 100%, p =.783) rates between GP, CI, GPFJ, and GPALT groups, respectively. CONCLUSIONS: The proposed algorithm that ranks gastric pull-up as a priority and uses additional free tissue transfer to overcome the anastomotic tension or associated neck-skin defect is feasible.

The p53-S100A2 Positive Feedback Loop Negatively Regulates Epithelialization in Cutaneous Wound Healing.

The S100A2 protein is an important regulator of keratinocyte differentiation, but its role in wound healing remains unknown. We establish epithelial-specific S100A2 transgenic (TG) mice and study its role in wound repair using punch biopsy wounding assays. In line with the observed increase in proliferation and migration of S100A2-depleted human keratinocytes, mice expressing human S100A2 exhibit delayed cutaneous wound repair. This was accompanied by the reduction of re-epithelialization as well as a slow, attenuated response of Mcp1, Il6, Il1ß, Cox2, and Tnf mRNA expression in the early phase. We also observed delayed Vegfa mRNA induction, a delayed enhancement of the Tgfß1-mediated alpha smooth muscle actin (α-Sma) axis and a differential expression of collagen type 1 and 3. The stress-activated p53 tumor suppressor protein plays an important role in cutaneous wound healing and is an S100A2 inducer. Notably, S100A2 complexes with p53, potentiates p53-mediated transcription and increases p53 expression both transcriptionally and posttranscriptionally. Consistent with a role of p53 in repressing NF-κB-mediated transcriptional activation, S100A2 enhanced p53-mediated promoter suppression of Cox2, an early inducible NF-κB target gene upon wound injury. Our study thus supports a model in which the p53-S100A2 positive feedback loop regulates wound repair process.

Angiogenin Attenuates Scar Formation in Burn Patients by Reducing Fibroblast Proliferation and Transforming Growth Factor ß1 Secretion.

BACKGROUND: Deep burn wounds have a high tendency to form hypertrophic scars. Previously, we found that angiogenin promoted neovascularization during deep burn wound healing. However, the association between angiogenin and scar formation is unclear. METHODS: We obtained human burn scar tissues from patients who underwent scar surgery and examined the role of angiogenin in scar tissues and determined its effects in scar fibroblasts and on transforming growth factor ß1 (TGF-ß1) secretion. RESULTS: Our results showed an inverse correlation between angiogenin expression and scar severity. Next, we examined the effects of angiogenin in scar fibroblasts. We found that angiogenin was persistently expressed in human scar fibroblasts and that angiogenin expression significantly increased with time in the culture medium of scar fibroblasts. Treatment of scar fibroblasts with recombinant angiogenin significantly decreased their proliferation and TGF-ß1 secretion. Moreover, angiogenin inhibited TGF-ß1-mediated Smad2 signaling pathway. CONCLUSION: Our data suggest a negative role of angiogenin in fibroblast proliferation via TGF-ß1-mediated Smad2 signaling pathway.