Effect of Combining Low Temperature Plasma, Negative Pressure Wound Therapy, and Bone Marrow Mesenchymal Stem Cells on an Acute Skin Wound Healing Mouse Model

Low-temperature plasma (LTP; 3 min/day), negative pressure wound therapy (NPWT; 4 h/day), and bone marrow mesenchymal stem cells (MSCs; 1 × 106 cells/day) were used as mono- and combination therapy in an acute excisional skin wound-healing ICR mouse model. These therapies have been beneficial in treating wounds. We investigated the effectiveness of monotherapy with LTP, NPWT, and MSC and combination therapy with LTP + MSC, LTP + NPWT, NPWT + MSC, and LTP + NPWT + MSC on skin wounds in mice for seven consecutive days. Gene expression, protein expression, and epithelial thickness were analyzed using real time polymerase chain reaction (RT-qPCR), western blotting, and hematoxylin and eosin staining (H&E), respectively. Wound closure was also evaluated. Wound closure was significantly accelerated in monotherapy groups, whereas more accelerated in combination therapy groups. Tumor necrosis factor-α (TNF-α) expression was increased in the LTP monotherapy group but decreased in the NPWT, MSC, and combination therapy groups. Expressions of vascular endothelial growth factor (VEGF), α-smooth muscle actin (α-SMA), and type I collagen were increased in the combination therapy groups. Re-epithelialization was also considerably accelerated in combination therapy groups. Our findings suggest that combination therapy with LPT, NPWT, and MSC exert a synergistic effect on wound healing, representing a promising strategy for the treatment of acute wounds.

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Overexpression of the Oral Mucosa-Specific microRNA-31 Promotes Skin Wound Closure

International Journal of Molecular Sciences ◽

10.3390/ijms20153679 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3679 ◽

Cited By ~ 3

Author(s):

Lin Chen ◽

Alyne Simões ◽

Zujian Chen ◽

Yan Zhao ◽

Xinming Wu ◽

...

Keyword(s):

Wound Healing ◽

Oral Mucosa ◽

Wound Closure ◽

Expression Patterns ◽

Skin Wound ◽

Skin Wound Healing ◽

Specific Expression ◽

Keratinocyte Proliferation

Wounds within the oral mucosa are known to heal more rapidly than skin wounds. Recent studies suggest that differences in the microRNAome profiles may underlie the exceptional healing that occurs in oral mucosa. Here, we test whether skin wound-healing can be accelerating by increasing the levels of oral mucosa-specific microRNAs. A panel of 57 differentially expressed high expresser microRNAs were identified based on our previously published miR-seq dataset of paired skin and oral mucosal wound-healing [Sci. Rep. (2019) 9:7160]. These microRNAs were further grouped into 5 clusters based on their expression patterns, and their differential expression was confirmed by TaqMan-based quantification of LCM-captured epithelial cells from the wound edges. Of these 5 clusters, Cluster IV (consisting of 8 microRNAs, including miR-31) is most intriguing due to its tissue-specific expression pattern and temporal changes during wound-healing. The in vitro functional assays show that ectopic transfection of miR-31 consistently enhanced keratinocyte proliferation and migration. In vivo, miR-31 mimic treatment led to a statistically significant acceleration of wound closure. Our results demonstrate that wound-healing can be enhanced in skin through the overexpression of microRNAs that are highly expressed in the privileged healing response of the oral mucosa.

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Carbonic Anhydrase VI in Skin Wound Healing Study on Car6 Knockout Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21145092 ◽

2020 ◽

Vol 21 (14) ◽

pp. 5092

Author(s):

Toini Pemmari ◽

Jaakko Laakso ◽

Maarit S. Patrikainen ◽

Seppo Parkkila ◽

Tero A. H. Järvinen

Keyword(s):

Wound Healing ◽

Knockout Mice ◽

Wound Closure ◽

Skin Wound ◽

Carbonic Anhydrases ◽

Skin Wound Healing ◽

Tumor Cell Migration ◽

Treatment Groups ◽

Thickness Skin ◽

Carbonic Anhydrase Vi

Carbonic anhydrases (CAs) contribute to tumor cell migration by generating an acidic environment through the conversion of carbon dioxide to bicarbonate and a proton. CA VI is secreted to milk and saliva, and it could contribute to wound closure, as a potential trophic factor, in animals that typically lick their wounds. Our aim was to investigate whether human CA VI improves skin-wound healing in full-thickness skin-wound models. The effect was studied in Car6 −/− knockout mice and wild type littermates. Half of both mice strains were given topically administered, milk-derived CA VI after wounding and eight hours later. The amount of topically given CA VI exceeded the predicted amount of natural saliva-delivered CA VI. The healing was followed for seven days and studied from photographs and histological sections. Our results showed no significant differences between the treatment groups in wound closure, re-epithelization, or granulation tissue formation, nor did the Car6 genotype affect the healing. Our results demonstrate that CA VI does not play a major role in skin-wound healing and also suggest that saliva-derived CA VI is not responsible for the licking-associated improved wound healing in animals.

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Bioinspired mechanically active adhesive dressings to accelerate wound closure

Science Advances ◽

10.1126/sciadv.aaw3963 ◽

2019 ◽

Vol 5 (7) ◽

pp. eaaw3963 ◽

Cited By ~ 61

Author(s):

S. O. Blacklow ◽

J. Li ◽

B. R. Freedman ◽

M. Zeidi ◽

C. Chen ◽

...

Keyword(s):

Wound Healing ◽

Wound Closure ◽

Healing Process ◽

Skin Wound ◽

Wound Management ◽

In Vivo Studies ◽

Skin Wound Healing ◽

Accelerate Wound Healing

Inspired by embryonic wound closure, we present mechanically active dressings to accelerate wound healing. Conventional dressings passively aid healing by maintaining moisture at wound sites. Recent developments have focused on drug and cell delivery to drive a healing process, but these methods are often complicated by drug side effects, sophisticated fabrication, and high cost. Here, we present novel active adhesive dressings consisting of thermoresponsive tough adhesive hydrogels that combine high stretchability, toughness, tissue adhesion, and antimicrobial function. They adhere strongly to the skin and actively contract wounds, in response to exposure to the skin temperature. In vitro and in vivo studies demonstrate their efficacy in accelerating and supporting skin wound healing. Finite element models validate and refine the wound contraction process enabled by these active adhesive dressings. This mechanobiological approach opens new avenues for wound management and may find broad utility in applications ranging from regenerative medicine to soft robotics.

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Sphingosine-1-Phosphate Facilitates Skin Wound Healing by Increasing Angiogenesis and Inflammatory Cell Recruitment with Less Scar Formation

International Journal of Molecular Sciences ◽

10.3390/ijms20143381 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3381 ◽

Cited By ~ 10

Author(s):

Masayo Aoki ◽

Hiroaki Aoki ◽

Partha Mukhopadhyay ◽

Takuya Tsuge ◽

Hirofumi Yamamoto ◽

...

Keyword(s):

Wound Healing ◽

Wound Closure ◽

Inflammatory Cell ◽

Skin Wound ◽

Sphingosine Kinase 1 ◽

Related Factors ◽

Skin Wound Healing ◽

Cell Recruitment ◽

Sphingosine 1 Phosphate ◽

Inflammatory Cell Recruitment

Wound healing starts with the recruitment of inflammatory cells that secrete wound-related factors. This step is followed by fibroblast activation and tissue construction. Sphingosine-1-phosphate (S1P) is a lipid mediator that promotes angiogenesis, cell proliferation, and attracts immune cells. We investigated the roles of S1P in skin wound healing by altering the expression of its biogenic enzyme, sphingosine kinase-1 (SphK1). The murine excisional wound splinting model was used. Sphingosine kinase-1 (SphK1) was highly expressed in murine wounds and that SphK1−/− mice exhibit delayed wound closure along with less angiogenesis and inflammatory cell recruitment. Nanoparticle-mediated topical SphK1 overexpression accelerated wound closure, which associated with increased angiogenesis, inflammatory cell recruitment, and various wound-related factors. The SphK1 overexpression also led to less scarring, and the interaction between transforming growth factor (TGF)-β1 and S1P receptor-2 (S1PR2) signaling is likely to play a key role. In summary, SphK1 play important roles to strengthen immunity, and contributes early wound healing with suppressed scarring. S1P can be a novel therapeutic molecule with anti-scarring effect in surgical, trauma, and chronic wound management.

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Novel home use of mechanical negative pressure wound therapy in diabetic foot ulcers

Journal of Wound Care ◽

10.12968/jowc.2021.30.12.1006 ◽

2021 ◽

Vol 30 (12) ◽

pp. 1006-1010

Author(s):

Xuxin Lim ◽

Li Zhang ◽

Qiantai Hong ◽

Enming Yong ◽

Shufen Neo ◽

...

Keyword(s):

Wound Healing ◽

Limb Salvage ◽

Negative Pressure ◽

Diabetic Foot ◽

Wound Closure ◽

Negative Pressure Wound Therapy ◽

Length Of Hospital Stay ◽

Wound Therapy ◽

Primary Wound Closure ◽

Mean Cost

Objective: Mechanical negative pressure wound therapy is an ultraportable, light weight and disposable single-use device that has been shown to promote wound healing. This study evaluated home use of a mechanically powered negative pressure wound therapy (NPWT) in diabetic foot wounds. Methods: Patients underwent revascularisation and/or debridement or amputation before starting mechanical NPWT. Wound outcomes and images of the wounds were recorded at each follow-up visit by the wound nurse. Patients were followed up until wound closure or end of therapy. Results: A total of 12 patients (each with one wound) were included in the study. Of the 12 wounds, 33.3% (n=4) of wounds achieved primary wound closure while the remaining 66.6% (n=8) of wounds demonstrated a mean wound size reduction of 37.5±0.13%. Of the closed wounds, mean time to healing was 4.75±2.50 weeks. There was 100% limb salvage with no further debridement or amputations, and no 30-day unplanned readmissions. Mean length of hospital stay before starting home NPWT was 9.75±6.31 days. Mean number of NPWT changes was 8.33±2.67 sessions, while mean duration of therapy was 4.0±1.54 weeks. Mean cost of home NWPT therapy was US$1904±731 per patient. Conclusion: The home use of mechanically powered NPWT in diabetic foot wounds demonstrated excellent wound healing rates and 100% limb salvage, with no complications.

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Neuropeptide Substance P Enhances Skin Wound Healing In Vitro and In Vivo under Hypoxia

Biomedicines ◽

10.3390/biomedicines9020222 ◽

2021 ◽

Vol 9 (2) ◽

pp. 222

Author(s):

Suneel Kumar ◽

Yuying Tan ◽

Francois Berthiaume

Keyword(s):

Cell Proliferation ◽

Wound Healing ◽

Substance P ◽

Wound Closure ◽

Skin Wound ◽

Skin Wound Healing ◽

Male And Female ◽

Low Serum

Pressure ulcers (PUs) or sores are a secondary complication of diabetic neuropathy and traumatic spinal cord injury (SCI). PUs tend to occur in soft tissues located around bony prominences and may heal slowly or not at all. A common mechanism underlying impaired healing of PUs may be dysfunction of the local neurovascular system including deficiency of essential neuropeptides, such as substance P (SP). Previous studies indicate that disturbance in cutaneous sensory innervation leads to a defect in all stages of wound healing, as is the case after SCI. It is hypothesized that nerve fibers enhance wound healing by promoting initial inflammation via the releasing of neuropeptides such as SP. Therefore, we investigated whether exogenous SP improves skin wound healing using in vitro and in vivo models. For in vitro studies, the effects of SP on keratinocyte proliferation and wound closure after a scratch injury were studied under normoxia (pO2 ~21%) or hypoxia (pO2 ~1%) and in presence of normal serum (10% v/v) or low serum (1% v/v) concentrations. Hypoxia and low serum both significantly slowed cell proliferation and wound closure. Under combined low serum and hypoxia, used to mimic the nutrient- and oxygen-poor environment of chronic wounds, SP (10−7 M) significantly enhanced cell proliferation and wound closure rate. For in vivo studies, two full-thickness excisional wounds were created with a 5 mm biopsy punch on the dorsum on either side of the midline of 15-week-old C57BL/6J male and female mice. Immediately, wounds were treated topically with one dose of 0.5 μg SP or PBS vehicle. The data suggest a beneficial role in wound closure and reepithelization, and thus enhanced wound healing, in male and female mice. Taken together, exogenously applied neuropeptide SP enhanced wound healing via cell proliferation and migration in vitro and in vivo. Thus, exogenous SP may be a useful strategy to explore further for treating PUs in SCI and diabetic patients.

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A Case of a Patient Who Successfully Achieved Early Wound Closure by Local Negative Pressure Wound Therapy (NPWT) against Compromised Wound Healing after Arterio-Venous Graft Infection

Kidney and Dialysis ◽

10.3390/kidneydial1010003 ◽

2021 ◽

Vol 1 (1) ◽

pp. 14-19

Author(s):

Risa Kusuta ◽

Keiji Shimazu ◽

Kazuhiro Mizoguchi ◽

Kazumasa Komura ◽

Atsuo Tanaka

Keyword(s):

Wound Healing ◽

Negative Pressure ◽

Wound Closure ◽

Negative Pressure Wound Therapy ◽

Present Report ◽

Graft Infection ◽

Severe Bleeding ◽

Wound Therapy ◽

Venous Graft ◽

Early Wound

The primary treatment strategy for arterio-venous graft (AVG) infection includes appropriate antibiotic use and removal of the infected graft. It is well known that patients with hemodialysis are likely to experience compromised wound healing, which often leads to various postoperative complications. Negative pressure wound therapy (NPWT) is a non-invasive procedure that promotes wound healing by sealing the wound under negative pressure. Although NPWT is practically accepted in general surgery, there are only a few reports of this strategy to the vascular access operation for patients with hemodialysis due to the possibility of severe bleeding. In the present report, we report a case of a patient who successfully achieved safe and early wound closure by NPWT against compromised wound healing after AVG infection.

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4-aminopyridine promotes accelerated skin wound healing

10.21203/rs.3.rs-1037729/v1 ◽

2021 ◽

Author(s):

Jagadeeshaprasad Mashanipalya ◽

Prem Kumar Govindappa ◽

Amanda Nelson ◽

Mark Noble ◽

John Elfar

Keyword(s):

Wound Healing ◽

Growth Factor ◽

Wound Closure ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Transforming Growth Factor Β ◽

Skin Wound ◽

Skin Wound Healing ◽

S 100 ◽

Skin Healing

Abstract The discovery of ways to enhance skin healing is of great importance due to the frequency and severity of skin wounds. We discovered that 4-aminopyridine (4-AP), a potassium channel blocker, greatly enhances skin wound healing. Benefits include faster wound closure, restoration of normal-appearing skin architecture and epidermal thickness, increased vascularization and increases in K14+ keratinocytes. Hair follicle number was increased, both histologically and by analysis of K15 and K17 expression. Levels of vimentin (which marks fibroblasts) and α-smooth muscle actin (α-SMA, which marks collagen-producing myofibroblasts) increased, as did α-SMA+ cell numbers. 4-AP also increased numbers of axons and S-100+ Schwann cells, and increased expression of p75-NTR and SOX10. Treatment also increased levels of nerve growth factor, transforming growth factor-β, Substance P and PGP9.5, important modulators of wound healing. As 4-AP is already used for treatment of multiple sclerosis and other chronic neurological syndromes, it has strong potential for rapid translational development.

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Autophagy inhibition facilitates wound closure partially dependent on the YAP/IL‐33 signaling in a mouse model of skin wound healing

The FASEB Journal ◽

10.1096/fj.202002623rrr ◽

2021 ◽

Vol 35 (10) ◽

Author(s):

Yuan Gao ◽

Chengliang Luo ◽

Tongyu Rui ◽

Yanyan Fan ◽

Yi Yao ◽

...

Keyword(s):

Wound Healing ◽

Mouse Model ◽

Wound Closure ◽

Skin Wound ◽

Skin Wound Healing ◽

Autophagy Inhibition

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Indirubin-pregnane X receptor-JNK axis accelerates skin wound healing

Scientific Reports ◽

10.1038/s41598-019-54754-2 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Yuka Tanaka ◽

Hiroshi Uchi ◽

Takamichi Ito ◽

Masutaka Furue

Keyword(s):

Wound Healing ◽

Wound Closure ◽

Mouse Skin ◽

Pregnane X Receptor ◽

Skin Wound ◽

Skin Ulcer ◽

Luciferase Reporter ◽

Skin Wound Healing ◽

Jnk Pathway ◽

Ulcer Model

AbstractIndirubin is a potent anti-inflammatory phytochemical derived from indigo naturalis. It is also endogenously produced in the intestine and detected in the circulation in mammals. Indirubin exerts its biological functions via two xenobiotic receptor systems: aryl hydrocarbon receptor (AHR) and pregnane X receptor (PXR); however, its effects on wound healing remain elusive. To investigate whether indirubin promotes wound healing, we utilized an in vitro scratch injury assay and in vivo full-thickness mouse skin ulcer model and assessed wound closure. Indirubin significantly accelerated wound closure in both the scratch assay and the skin ulcer model. Using inhibitors of cell proliferation or migration, indirubin was found to upregulate the migratory but not the proliferative capacity of keratinocytes. Activation of AHR/PXR by indirubin was confirmed by their nuclear translocation and subsequent upregulation of CYP1A1 (AHR), or UGT1A1 mRNA (PXR) and also by luciferase reporter assay (PXR). Although both AHR and PXR were activated by indirubin, its pro-migratory capacity was canceled by PXR inhibition but not by AHR inhibition and was dependent on the JNK pathway. Moreover, activated PXR was detected in the nuclei of re-epithelialized keratinocytes in human skin ulcers. In conclusion, this study shows that the indirubin-PXR-JNK pathway promotes skin wound healing.

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