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New Innovations in Wound Healing and Repair
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New Innovations in Wound Healing and Repair

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2018) | Viewed by 128248

Special Issue Editor

Prof. Dr. Allison Cowin

E-Mail Website
Guest Editor
Regenerative Medicine, Future Industries Institute, Mawson Lakes, University of South Australia, Adelaide, SA 5095, Australia
Interests: wound healing; cytoskeleton; inflammation; stem cell therapy; immunotherapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Wounds are a largely unrecognized, spiraling epidemic that affect millions of people world-wide. They are complex and involve temporal and spatial involvement of many different cell types and tissue processes. Recent advances in our understanding of wound repair and regeneration, as well as the many novel and exciting approaches aimed at healing chronic/acute wounds and reducing scar formation, make this a pertinent time for a Special Issue aimed at overviewing this important field.

The goal of this Special Issue is to provide a summary of the field, describe its impact, as well as introduce the recent advances in understanding the mechanisms that underpin wound healing and scar formation. This Special Issue will highlight new developments in therapeutic approaches for wound repair including the use of nanomedicine and biomaterials to deliver cells and/or drugs to promote healing. Cellular responses that underpin angiogenesis, inflammation, proliferation and remodeling will be addressed, as will advances in cytoskeletal interactions in keratinocytes and fibroblast cell functions. Wound remodeling and scar formation including the roles of growth factors, cytokines and stem cells will be included.

Prof. Dr. Allison Cowin
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Wound healing
  • Inflammation
  • Scarring
  • Extracellular matrix
  • Regeneration
  • Biomaterials
  • Chronic wounds
  • Remodeling
  • Stem cells
  • Growth factors

Related Special Issues

Published Papers (20 papers)

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Editorial

Jump to: Research, Review

2 pages, 149 KiB  
Editorial
New Innovations in Wound Healing and Repair
by Allison J. Cowin
Int. J. Mol. Sci. 2019, 20(7), 1724; https://doi.org/10.3390/ijms20071724 - 08 Apr 2019
Cited by 1 | Viewed by 2611
Abstract
Wounds are a largely unrecognized, spiraling epidemic that affect millions of people world-wide [...] Full article
(This article belongs to the Special Issue New Innovations in Wound Healing and Repair)

Research

Jump to: Editorial, Review

17 pages, 3142 KiB  
Article
Honey-Mediated Wound Healing: H2O2 Entry through AQP3 Determines Extracellular Ca2+ Influx
by Simona Martinotti, Umberto Laforenza, Mauro Patrone, Francesco Moccia and Elia Ranzato
Int. J. Mol. Sci. 2019, 20(3), 764; https://doi.org/10.3390/ijms20030764 - 11 Feb 2019
Cited by 43 | Viewed by 7154
Abstract
Since Biblical times, honey has been utilized in “folk medicine”, and in recent decades the positive qualities of honey have been re-discovered and are gaining acceptance. Scientific literature states that honey has been successfully utilized on infections not responding to classic antiseptic and [...] Read more.
Since Biblical times, honey has been utilized in “folk medicine”, and in recent decades the positive qualities of honey have been re-discovered and are gaining acceptance. Scientific literature states that honey has been successfully utilized on infections not responding to classic antiseptic and antibiotic therapy, because of its intrinsic H2O2 production. In our study, we demonstrated the involvement of H2O2 as a main mediator of honey regenerative effects on an immortalized human keratinocyte cell line. We observed that this extracellularly released H2O2 could pass across the plasma membrane through a specific aquaporin (i.e., AQP3). Once in the cytoplasm H2O2, in turn, induces the entry of extracellular Ca2+ through Melastatin Transient Receptor Potential 2 (TRPM2) and Orai1 channels. Honey-induced extracellular Ca2+ entry results in wound healing, which is consistent with the role played by Ca2+ signaling in tissue regeneration. This is the first report showing that honey exposure increases intracellular Ca2+ concentration ([Ca2+]i), due to H2O2 production and redox regulation of Ca2+-permeable ion channels, opening up a new horizon for the utilization of the honey as a beneficial tool. Full article
(This article belongs to the Special Issue New Innovations in Wound Healing and Repair)
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14 pages, 2916 KiB  
Article
Fatty Acid Potassium Had Beneficial Bactericidal Effects and Removed Staphylococcus aureus Biofilms while Exhibiting Reduced Cytotoxicity towards Mouse Fibroblasts and Human Keratinocytes
by Takayoshi Kawahara, Miki Takita, Akihiro Masunaga, Hayato Morita, Tadayuki Tsukatani, Kohji Nakazawa, Daisuke Go and Sadanori Akita
Int. J. Mol. Sci. 2019, 20(2), 312; https://doi.org/10.3390/ijms20020312 - 14 Jan 2019
Cited by 11 | Viewed by 3720
Abstract
Wounds frequently become infected or contaminated with bacteria. Potassium oleate (C18:1K), a type of fatty acid potassium, caused >4 log colony-forming unit (CFU)/mL reductions in the numbers of Staphylococcus aureus and Escherichia coli within 10 min and a >2 log CFU/mL reduction in [...] Read more.
Wounds frequently become infected or contaminated with bacteria. Potassium oleate (C18:1K), a type of fatty acid potassium, caused >4 log colony-forming unit (CFU)/mL reductions in the numbers of Staphylococcus aureus and Escherichia coli within 10 min and a >2 log CFU/mL reduction in the number of Clostridium difficile within 1 min. C18:1K (proportion removed: 90.3%) was significantly more effective at removing Staphylococcus aureus biofilms than the synthetic surfactant detergents sodium lauryl ether sulfate (SLES) (74.8%, p < 0.01) and sodium lauryl sulfate (SLS) (78.0%, p < 0.05). In the WST (water-soluble tetrazolium) assay, mouse fibroblasts (BALB/3T3 clone A31) in C18:1K (relative viability vs. control: 102.8%) demonstrated a significantly higher viability than those in SLES (30.1%) or SLS (18.1%, p < 0.05). In a lactate dehydrogenase (LDH) leakage assay, C18:1K (relative leakage vs. control: 108.9%) was found to be associated with a significantly lower LDH leakage from mouse fibroblasts than SLES or SLS (720.6% and 523.4%, respectively; p < 0.05). Potassium oleate demonstrated bactericidal effects against various species including Staphylococcus aureus, Escherichia coli, Bacillus cereus, and Clostridium difficile; removed significantly greater amounts of Staphylococcus aureus biofilm material than SLES and SLS; and maintained fibroblast viability; therefore, it might be useful for wound cleaning and peri-wound skin. Full article
(This article belongs to the Special Issue New Innovations in Wound Healing and Repair)
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13 pages, 2794 KiB  
Article
Beneficial Effects of Deoxyshikonin on Delayed Wound Healing in Diabetic Mice
by Jun Yeon Park, Myoung-Sook Shin, Gwi Seo Hwang, Noriko Yamabe, Jeong-Eun Yoo, Ki Sung Kang, Jin-Chul Kim, Jeong Gun Lee, Jungyeob Ham and Hye Lim Lee
Int. J. Mol. Sci. 2018, 19(11), 3660; https://doi.org/10.3390/ijms19113660 - 20 Nov 2018
Cited by 19 | Viewed by 4414
Abstract
Shiunko ointment is composed of five ingredients including Lithospermi Radix (LR), Angelicae Gigantis Radix, sesame seed oil, beeswax, and swine oil. It is externally applied as a treatment for a wide range of skin conditions such as eczema, psoriasis, hair loss, burns, topical [...] Read more.
Shiunko ointment is composed of five ingredients including Lithospermi Radix (LR), Angelicae Gigantis Radix, sesame seed oil, beeswax, and swine oil. It is externally applied as a treatment for a wide range of skin conditions such as eczema, psoriasis, hair loss, burns, topical wounds, and atopic dermatitis. Deoxyshikonin is the major angiogenic compound extracted from LR. In this study, we investigated the efficacy of LR extract and deoxyshikonin on impaired wound healing in streptozotocin (STZ)-induced diabetic mice. Treatment with LR extract elevated tube formation in human umbilical vein endothelial cells (HUVECs) and exerted antioxidant activity. An open skin wound was produced on the backs of diabetic mice and was then topically treated with deoxyshikonin or vehicle. In addition, deoxyshikonin promoted tube formation in high glucose conditions exposed to HUVECs, and which may be regulated by increased VEGFR2 expression and phosphorylation of Akt and p38. Our results demonstrate that deoxyshikonin application promoted wound repair in STZ-induced diabetic mice. Collectively, these data suggest that deoxyshikonin is an active ingredient of LR, thereby contributing to wound healing in patients with diabetes. Full article
(This article belongs to the Special Issue New Innovations in Wound Healing and Repair)
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15 pages, 5547 KiB  
Article
Visfatin Promotes Wound Healing through the Activation of ERK1/2 and JNK1/2 Pathway
by Byung-Cheol Lee, Jisun Song, Arim Lee, Daeho Cho and Tae Sung Kim
Int. J. Mol. Sci. 2018, 19(11), 3642; https://doi.org/10.3390/ijms19113642 - 19 Nov 2018
Cited by 25 | Viewed by 3496
Abstract
Visfatin, a member of the adipokine family, plays an important role in many metabolic and stress responses. The mechanisms underlying the direct therapeutic effects of visfatin on wound healing have not been reported yet. In this study, we examined the effects of visfatin [...] Read more.
Visfatin, a member of the adipokine family, plays an important role in many metabolic and stress responses. The mechanisms underlying the direct therapeutic effects of visfatin on wound healing have not been reported yet. In this study, we examined the effects of visfatin on wound healing in vitro and in vivo. Visfatin enhanced the proliferation and migration of human dermal fibroblasts (HDFs) and keratinocytes the expression of wound healing-related vascular endothelial growth factor (VEGF) in vitro and in vivo. Treatment of HDFs with visfatin induced activation of both extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinases 1 and 2 (JNK1/2) in a time-dependent manner. Inhibition of ERK1/2 and JNK1/2 led to a significant decrease in visfatin-induced proliferation and migration of HDFs. Importantly, blocking VEGF with its neutralizing antibodies suppressed the visfatin-induced proliferation and migration of HDFs and human keratinocytes, indicating that visfatin induces the proliferation and migration of HDFs and human keratinocytes via increased VEGF expression. Moreover, visfatin effectively improved wound repair in vivo, which was comparable to the wound healing activity of epidermal growth factor (EGF). Taken together, we demonstrate that visfatin promotes the proliferation and migration of HDFs and human keratinocytes by inducing VEGF expression and can be used as a potential novel therapeutic agent for wound healing. Full article
(This article belongs to the Special Issue New Innovations in Wound Healing and Repair)
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9 pages, 1121 KiB  
Communication
The Small Molecule NLRP3 Inflammasome Inhibitor MCC950 Does Not Alter Wound Healing in Obese Mice
by James S. Lee, Avril A. B. Robertson, Matthew A. Cooper and Kiarash Khosrotehrani
Int. J. Mol. Sci. 2018, 19(11), 3289; https://doi.org/10.3390/ijms19113289 - 23 Oct 2018
Cited by 10 | Viewed by 3791
Abstract
The incidence of chronic wounds is escalating, and the associated healing process is especially problematic in an aging population with increased morbidity. Targeting increased inflammation in chronic wounds is a promising but challenging therapeutic strategy. Indeed, inflammation and especially macrophages are required for [...] Read more.
The incidence of chronic wounds is escalating, and the associated healing process is especially problematic in an aging population with increased morbidity. Targeting increased inflammation in chronic wounds is a promising but challenging therapeutic strategy. Indeed, inflammation and especially macrophages are required for wound healing. As the NLRP3 inflammasome has been implicated with various other inflammatory diseases, in this study, we used MCC950—a selective NLRP3 small molecule inhibitor—on murine models of both acute and chronic wounds. This molecule, while tested for other inflammatory conditions, has never been investigated to reduce topical inflammation driving chronic wounds. We found that there were no significant differences when the treatment was applied either topically or orally in wild-type C57Bl/6 mice and that it even impaired wound healing in obese mice. The treatment was also unable to improve re-epithelialisation or angiogenesis, which are both required for the closure of wounds. We are inclined to believe that MCC950 may inhibit the closure of chronic wounds and that it does not alter wound-associated macrophage polarisation. Full article
(This article belongs to the Special Issue New Innovations in Wound Healing and Repair)
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18 pages, 2417 KiB  
Article
Anthocyanins Extracted from Oryza sativa L. Prevent Fluorouracil-Induced Nuclear Factor-κB Activation in Oral Mucositis: In Vitro and In Vivo Studies
by Salunya Tancharoen, Prana Shakya, Somphong Narkpinit, Pornpen Dararat and Kiyoshi Kikuchi
Int. J. Mol. Sci. 2018, 19(10), 2981; https://doi.org/10.3390/ijms19102981 - 29 Sep 2018
Cited by 21 | Viewed by 4327
Abstract
This study aims to investigate the immunomodulatory effect of anthocyanins (ANTs) from Oryza sativa L. extracts on 5-fluorouracil (5-FU)-induced oral mucositis, using a rat model and oral keratinocytes. ANTs were detected by high-performance liquid chromatography (HPLC)-electrospray ionization mass spectrometry. Animals were randomly given [...] Read more.
This study aims to investigate the immunomodulatory effect of anthocyanins (ANTs) from Oryza sativa L. extracts on 5-fluorouracil (5-FU)-induced oral mucositis, using a rat model and oral keratinocytes. ANTs were detected by high-performance liquid chromatography (HPLC)-electrospray ionization mass spectrometry. Animals were randomly given varying doses of ANT-rich extract treatment (500 mg/kg and 1000 mg/kg) in the absence or presence of 5-FU-induced mucositis. Buccal mucosae were photographed and scored for macroscopic analysis and incisional biopsies of cheek pouches were collected for microscopic examination of oral mucositis. 5-FU caused marked hemorrhage, extensive ulcerations and abscesses compared to non-treated animals with slight erythema. Histologically, a loss of collagen bundles and inflammatory cell infiltrates was observed. After 29 days of ANT treatment, lesions resolved, and abundant collagen fibers were evident in the lamina propria. Buccal mucosa of 5-FU-injected rats showed increased Nuclear factor-kappa B (NF-κB) p50 and p65 in oral keratinocytes. The administration of ANT reduced NF-κB-positive cells in 5-FU rats (p < 0.001) compared to the non-treatment group. In oral keratinocytes, ANT treatment significantly restored 5-FU-induced growth inhibition and impaired the nuclear accumulation of NF-κB p50 and p65. Our study demonstrated that ANT from Oryza sativa L. exhibited effective anti-inflammatory properties against 5-FU-induced oral mucositis by inhibiting NF-κB activation. Full article
(This article belongs to the Special Issue New Innovations in Wound Healing and Repair)
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18 pages, 2670 KiB  
Article
Toll-Like Receptor Agonists Modulate Wound Regeneration in Airway Epithelial Cells
by Anna Lewandowska-Polak, Małgorzata Brauncajs, Marzanna Jarzębska, Małgorzata Pawełczyk, Marcin Kurowski, Maciej Chałubiński, Joanna Makowska and Marek L. Kowalski
Int. J. Mol. Sci. 2018, 19(8), 2456; https://doi.org/10.3390/ijms19082456 - 20 Aug 2018
Cited by 11 | Viewed by 4581
Abstract
Background: Impaired regeneration of airway epithelium may lead to persistence of inflammation and remodelling. Regeneration of injured epithelium is a complex phenomenon and the role of toll-like receptors (TLRs) in the stimulation of respiratory virus products in this process has not been established. [...] Read more.
Background: Impaired regeneration of airway epithelium may lead to persistence of inflammation and remodelling. Regeneration of injured epithelium is a complex phenomenon and the role of toll-like receptors (TLRs) in the stimulation of respiratory virus products in this process has not been established. Objective: This study was undertaken to test the hypothesis that the wound repair process in airway epithelium is modulated by microbial products via toll-like receptors. Methods: Injured and not-injured bronchial epithelial cells (ECs) (BEAS-2B line) were incubated with the TLR agonists poly(I:C), lipopolisacharide (LPS), allergen Der p1, and supernatants from virus-infected epithelial cells, either alone or in combination with TLR inhibitors. Regeneration and immune response in injured and not-injured cells were studied. Results: Addition of either poly(I:C) or LPS to ECs induced a marked inhibition of wound repair. Supernatants from RV1b-infected cells also decreased regeneration. Preincubation of injured and not-injured ECs with TLR inhibitors decreased LPS and poly(I:C)-induced repair inhibition. TGF-β and RANTES mRNA expression was higher in injured ECs and IFN-α, IFN-β, IL-8, and VEGF mRNA expression was lower in damaged epithelium as compared to not-injured. Stimulation with poly(I:C) increased IFN-α and IFN-β mRNA expression in injured cells, and LPS stimulation decreased interferons mRNA expression both in not-injured and injured ECs. Conclusion: Regeneration of the airway epithelium is modulated by microbial products via toll-like receptors. Full article
(This article belongs to the Special Issue New Innovations in Wound Healing and Repair)
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12 pages, 2263 KiB  
Article
Recombinant Leucine-Rich Repeat Flightless-Interacting Protein-1 Improves Healing of Acute Wounds through Its Effects on Proliferation Inflammation and Collagen Deposition
by Zlatko Kopecki, Natalie E. Stevens, Gink N. Yang, Elizabeth Melville and Allison J. Cowin
Int. J. Mol. Sci. 2018, 19(7), 2014; https://doi.org/10.3390/ijms19072014 - 10 Jul 2018
Cited by 10 | Viewed by 3736
Abstract
Wound healing is an increasing clinical problem involving substantial morbidity, mortality, and rising health care costs. Leucine-rich repeat flightless-interacting protein-1 (LRRFIP-1) regulates toll-like receptor (TLR)-mediated inflammation, suggesting a potential role in the healing of wounds. We sought to determine the role of LRRFIP-1 [...] Read more.
Wound healing is an increasing clinical problem involving substantial morbidity, mortality, and rising health care costs. Leucine-rich repeat flightless-interacting protein-1 (LRRFIP-1) regulates toll-like receptor (TLR)-mediated inflammation, suggesting a potential role in the healing of wounds. We sought to determine the role of LRRFIP-1 in wound repair and whether the exogenous addition of recombinant LRRFIP-1 (rLRRFIP-1) affected healing responses. Using a model of full-thickness incisional acute wounds in BALB/c mice, we investigated the effect of wounding on LRRFIP-1 expression. The effect of rLRRFIP-1 on cellular proliferation, inflammation, and collagen deposition was also investigated. LRRFIP-1 was upregulated in response to wounding, was found to directly associate with flightless I (Flii), and significantly increased cellular proliferation both in vitro and in vivo. rLRRFIP-1 reduced Flii expression in wounds in vivo and resulted in significantly improved healing with a concurrent dampening of TLR4-mediated inflammation and improved collagen deposition. Additionally, decreased levels of TGF-β1 and increased levels of TGF-β3 were observed in rLRRFIP-1-treated wounds suggesting a possible antiscarring effect of rLRRFIP-1. Further studies are required to elucidate if the mechanisms behind LRRFIP-1 action in wound repair are independent of Flii. However, these results identify rLRRFIP-1 as a possible treatment modality for improved healing of acute wounds. Full article
(This article belongs to the Special Issue New Innovations in Wound Healing and Repair)
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26 pages, 15470 KiB  
Article
Role of Bone Morphogenetic Protein 7 (BMP7) in the Modulation of Corneal Stromal and Epithelial Cell Functions
by Bhavani S. Kowtharapu, Ruby Kala Prakasam, Radovan Murín, Dirk Koczan, Thomas Stahnke, Andreas Wree, Anselm G. M. Jünemann and Oliver Stachs
Int. J. Mol. Sci. 2018, 19(5), 1415; https://doi.org/10.3390/ijms19051415 - 09 May 2018
Cited by 13 | Viewed by 5818
Abstract
In the cornea, healing of the wounded avascular surface is an intricate process comprising the involvement of epithelial, stromal and neuronal cell interactions. These interactions result to the release of various growth factors that play prominent roles during corneal wound healing response. Bone [...] Read more.
In the cornea, healing of the wounded avascular surface is an intricate process comprising the involvement of epithelial, stromal and neuronal cell interactions. These interactions result to the release of various growth factors that play prominent roles during corneal wound healing response. Bone morphogenetic proteins (BMPs) are unique multi-functional potent growth factors of the transforming growth factor-beta (TGF-β) superfamily. Treatment of corneal epithelial cells with substance P and nerve growth factor resulted to an increase in the expression of BMP7 mRNA. Since BMP7 is known to modulate the process of corneal wound healing, in this present study, we investigated the influence of exogenous rhBMP7 on human corneal epithelial cell and stromal cell (SFs) function. To obtain a high-fidelity expression profiling of activated biomarkers and pathways, transcriptome-wide gene-level expression profiling of epithelial cells in the presence of BMP7 was performed. Gene ontology analysis shows BMP7 stimulation activated TGF-β signaling and cell cycle pathways, whereas biological processes related to cell cycle, microtubule and intermediate filament cytoskeleton organization were significantly impacted in corneal epithelial cells. Scratch wound healing assay showed increased motility and migration of BMP7 treated epithelial cells. BMP7 stimulation studies show activation of MAPK cascade proteins in epithelial cells and SFs. Similarly, a difference in the expression of claudin, Zink finger E-box-binding homeobox 1 was observed along with phosphorylation levels of cofilin in epithelial cells. Stimulation of SFs with BMP7 activated them with increased expression of α-smooth muscle actin. In addition, an elevated phosphorylation of epidermal growth factor receptor following BMP7 stimulation was also observed both in corneal epithelial cells and SFs. Based on our transcriptome analysis data on epithelial cells and the results obtained in SFs, we conclude that BMP7 contributes to epithelial-to-mesenchymal transition-like responses and plays a role equivalent to TGF-β in the course of corneal wound healing. Full article
(This article belongs to the Special Issue New Innovations in Wound Healing and Repair)
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11 pages, 9302 KiB  
Article
Instillation of Sericin Enhances Corneal Wound Healing through the ERK Pathway in Rat Debrided Corneal Epithelium
by Noriaki Nagai, Yuya Fukuoka, Miyu Ishii, Hiroko Otake, Tetsushi Yamamoto, Atsushi Taga, Norio Okamoto and Yoshikazu Shimomura
Int. J. Mol. Sci. 2018, 19(4), 1123; https://doi.org/10.3390/ijms19041123 - 09 Apr 2018
Cited by 22 | Viewed by 5964
Abstract
Sericin is a major constituent of silk produced by silkworms. We previously found that the instillation of sericin enhanced the proliferation of corneal epithelial cells, and acted to promote corneal wound healing in both normal and diabetic model rats. However, the mechanisms by [...] Read more.
Sericin is a major constituent of silk produced by silkworms. We previously found that the instillation of sericin enhanced the proliferation of corneal epithelial cells, and acted to promote corneal wound healing in both normal and diabetic model rats. However, the mechanisms by which sericin promotes the proliferation of corneal cells have not been established. In this study, we investigated the effects of sericin on Akt and ERK activation in a human corneal epithelial cell line (HCE-T cells) and rat debrided corneal epithelium. Although Akt phosphorylation was not detected following the treatment of HCE-T cells with sericin, ERK1/2 phosphorylation was enhanced. The growth of HCE-T cells treated with sericin was significantly increased, with the cell growth of sericin-treated HCE-T cells being 1.7-fold higher in comparison with vehicle-treated HCE-T cells. On the other hand, both of an ERK inhibitor U0126 (non-specific specific inhibitor) and SCH772984 (specific inhibitor) attenuated the enhanced cell growth by sericin, and the growth level in the case of co-treatment with sericin and ERK1/2 inhibitor was similar to that of cells treated with ERK1/2 inhibitor alone. In an in vivo study using rat debrided corneal epithelium, the corneal wound healing rate was enhanced by the instillation of sericin, and this enhancement was also attenuated by the instillation of U0126. In addition, the corneal wound healing rate in rats co-instilled with sericin and U0126 was similar to that following the instillation of U0126 alone. In conclusion, we found that the instillation of sericin enhanced cell proliferation via the activation of the MAPK/ERK pathway, resulting in the promotion of corneal wound healing in rat eyes. These findings provide significant information for designing further studies to develop potent corneal wound-healing drugs. Full article
(This article belongs to the Special Issue New Innovations in Wound Healing and Repair)
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15 pages, 8414 KiB  
Article
Development and Characterisation of a Human Chronic Skin Wound Cell Line—Towards an Alternative for Animal Experimentation
by Matthew Caley, Ivan B. Wall, Matthew Peake, David Kipling, Peter Giles, David W. Thomas and Phil Stephens
Int. J. Mol. Sci. 2018, 19(4), 1001; https://doi.org/10.3390/ijms19041001 - 27 Mar 2018
Cited by 10 | Viewed by 4541
Abstract
Background: Chronic skin wounds are a growing financial burden for healthcare providers, causing discomfort/immobility to patients. Whilst animal chronic wound models have been developed to allow for mechanistic studies and to develop/test potential therapies, such systems are not good representations of the [...] Read more.
Background: Chronic skin wounds are a growing financial burden for healthcare providers, causing discomfort/immobility to patients. Whilst animal chronic wound models have been developed to allow for mechanistic studies and to develop/test potential therapies, such systems are not good representations of the human chronic wound state. As an alternative, human chronic wound fibroblasts (CWFs) have permitted an insight into the dysfunctional cellular mechanisms that are associated with these wounds. However, such cells strains have a limited replicative lifespan and therefore a limited reproducibility/usefulness. Objectives: To develop/characterise immortalised cell lines of CWF and patient-matched normal fibroblasts (NFs). Methods and Results: Immortalisation with human telomerase resulted in both CWF and NF proliferating well beyond their replicative senescence end-point (respective cell strains senesced as normal). Gene expression analysis demonstrated that, whilst proliferation-associated genes were up-regulated in the cell lines (as would be expected), the immortalisation process did not significantly affect the disease-specific genotype. Immortalised CWF (as compared to NF) also retained a distinct impairment in their wound repopulation potential (in line with CWF cell strains). Conclusions: These novel CWF cell lines are a credible animal alternative and could be a valuable research tool for understanding both the aetiology of chronic skin wounds and for therapeutic pre-screening. Full article
(This article belongs to the Special Issue New Innovations in Wound Healing and Repair)
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23 pages, 2685 KiB  
Article
A Neutrophil Proteomic Signature in Surgical Trauma Wounds
by Sander Bekeschus, Jan-Wilm Lackmann, Denis Gümbel, Matthias Napp, Anke Schmidt and Kristian Wende
Int. J. Mol. Sci. 2018, 19(3), 761; https://doi.org/10.3390/ijms19030761 - 07 Mar 2018
Cited by 18 | Viewed by 4763
Abstract
Non-healing wounds continue to be a clinical challenge for patients and medical staff. These wounds have a heterogeneous etiology, including diabetes and surgical trauma wounds. It is therefore important to decipher molecular signatures that reflect the macroscopic process of wound healing. To this [...] Read more.
Non-healing wounds continue to be a clinical challenge for patients and medical staff. These wounds have a heterogeneous etiology, including diabetes and surgical trauma wounds. It is therefore important to decipher molecular signatures that reflect the macroscopic process of wound healing. To this end, we collected wound sponge dressings routinely used in vacuum assisted therapy after surgical trauma to generate wound-derived protein profiles via global mass spectrometry. We confidently identified 311 proteins in exudates. Among them were expected targets belonging to the immunoglobulin superfamily, complement, and skin-derived proteins, such as keratins. Next to several S100 proteins, chaperones, heat shock proteins, and immune modulators, the exudates presented a number of redox proteins as well as a discrete neutrophil proteomic signature, including for example cathepsin G, elastase, myeloperoxidase, CD66c, and lipocalin 2. We mapped over 200 post-translational modifications (PTMs; cysteine/methionine oxidation, tyrosine nitration, cysteine trioxidation) to the proteomic profile, for example, in peroxiredoxin 1. Investigating manually collected exudates, we confirmed presence of neutrophils and their products, such as microparticles and fragments containing myeloperoxidase and DNA. These data confirmed known and identified less known wound proteins and their PTMs, which may serve as resource for future studies on human wound healing. Full article
(This article belongs to the Special Issue New Innovations in Wound Healing and Repair)
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24 pages, 6493 KiB  
Article
Role of Corneal Stromal Cells on Epithelial Cell Function during Wound Healing
by Bhavani S. Kowtharapu, Radovan Murín, Anselm G. M. Jünemann and Oliver Stachs
Int. J. Mol. Sci. 2018, 19(2), 464; https://doi.org/10.3390/ijms19020464 - 04 Feb 2018
Cited by 20 | Viewed by 7260
Abstract
Following injury, corneal stromal keratocytes transform into repair-phenotype of activated stromal fibroblasts (SFs) and participate in wound repair. Simultaneously, ongoing bi-directional communications between corneal stromal-epithelial cells also play a vital role in mediating the process of wound healing. Factors produced by stromal cells [...] Read more.
Following injury, corneal stromal keratocytes transform into repair-phenotype of activated stromal fibroblasts (SFs) and participate in wound repair. Simultaneously, ongoing bi-directional communications between corneal stromal-epithelial cells also play a vital role in mediating the process of wound healing. Factors produced by stromal cells are known to induce proliferation, differentiation, and motility of corneal epithelial cells, which are also subsequently the main processes that occur during wound healing. In this context, the present study aims to investigate the effect of SFs conditioned medium (SFCM) on corneal epithelial cell function along with substance P (SP). Antibody microarrays were employed to profile differentially expressed cell surface markers and cytokines in the presence of SFCM and SP. Antibody microarray data revealed enhanced expression of the ITGB1 in corneal epithelial cells following stimulation with SP whereas SFCM induced abundant expression of IL-8, ITGB1, PD1L1, PECA1, IL-15, BDNF, ICAM1, CD8A, CD44 and NTF4. All these proteins have either direct or indirect roles in epithelial cell growth, movement and adhesion related signaling cascades during tissue regeneration. We also observed activation of MAPK signaling pathway along with increased expression of focal adhesion kinase (FAK), paxillin, vimentin, β-catenin and vasodilator-stimulated phosphoprotein (VASP) phosphorylation. Additionally, epithelial-to-mesenchymal transition (EMT) regulating transcription factors Slug and ZEB1 expression were enhanced in the presence of SFCM. SP enriched the expression of integrin subunits α4, α5, αV, β1 and β3 whereas SFCM increased α4, α5, αV, β1 and β5 integrin subunits. We also observed increased expression of Serpin E1 following SP and SFCM treatment. Wound healing scratch assay revealed enhanced migration of epithelial cells following the addition of SFCM. Taken together, we conclude that SFCM-mediated sustained activation of ZEB1, Slug in combination with upregulated migration-associated integrins and ERK (Extracellular signal-regulated kinase)-FAK-paxillin axis, may lead to induce type 2 EMT-like changes during corneal epithelial wound healing. Full article
(This article belongs to the Special Issue New Innovations in Wound Healing and Repair)
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Review

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38 pages, 788 KiB  
Review
Efficacy of Biophysical Energies on Healing of Diabetic Skin Wounds in Cell Studies and Animal Experimental Models: A Systematic Review
by Rachel Lai-Chu Kwan, Song Lu, Harry Ming-Chun Choi, Luther C. Kloth and Gladys Lai-Ying Cheing
Int. J. Mol. Sci. 2019, 20(2), 368; https://doi.org/10.3390/ijms20020368 - 16 Jan 2019
Cited by 12 | Viewed by 4869
Abstract
We have systematically assessed published cell studies and animal experimental reports on the efficacy of selected biophysical energies (BPEs) in the treatment of diabetic foot ulcers. These BPEs include electrical stimulation (ES), pulsed electromagnetic field (PEMF), extracorporeal shockwave (ECSW), photo energies and ultrasound [...] Read more.
We have systematically assessed published cell studies and animal experimental reports on the efficacy of selected biophysical energies (BPEs) in the treatment of diabetic foot ulcers. These BPEs include electrical stimulation (ES), pulsed electromagnetic field (PEMF), extracorporeal shockwave (ECSW), photo energies and ultrasound (US). Databases searched included CINAHL, MEDLINE and PubMed from 1966 to 2018. Studies reviewed include animal and cell studies on treatment with BPEs compared with sham, control or other BPEs. Information regarding the objective measures of tissue healing and data was extracted. Eighty-two studies were eventually selected for the critical appraisal: five on PEMF, four each on ES and ECSW, sixty-six for photo energies, and three about US. Based on the percentage of original wound size affected by the BPEs, both PEMF and low-level laser therapy (LLL) demonstrated a significant clinical benefit compared to the control or sham treatment, whereas the effect of US did not reveal a significance. Our results indicate potential benefits of selected BPEs in diabetic wound management. However, due to the heterogeneity of the current clinical trials, comprehensive studies using well-designed trials are warranted to confirm the results. Full article
(This article belongs to the Special Issue New Innovations in Wound Healing and Repair)
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20 pages, 533 KiB  
Review
Bicellular Tight Junctions and Wound Healing
by Junhe Shi, May Barakat, Dandan Chen and Lin Chen
Int. J. Mol. Sci. 2018, 19(12), 3862; https://doi.org/10.3390/ijms19123862 - 04 Dec 2018
Cited by 43 | Viewed by 14045
Abstract
Bicellular tight junctions (TJs) are intercellular junctions comprised of a variety of transmembrane proteins including occludin, claudins, and junctional adhesion molecules (JAMs) as well as intracellular scaffold proteins such as zonula occludens (ZOs). TJs are functional, intercellular structures that form a barrier between [...] Read more.
Bicellular tight junctions (TJs) are intercellular junctions comprised of a variety of transmembrane proteins including occludin, claudins, and junctional adhesion molecules (JAMs) as well as intracellular scaffold proteins such as zonula occludens (ZOs). TJs are functional, intercellular structures that form a barrier between adjacent cells, which constantly seals and unseals to control the paracellular passage of molecules. They are primarily present in the epithelial and endothelial cells of all tissues and organs. In addition to their well-recognized roles in maintaining cell polarity and barrier functions, TJs are important regulators of signal transduction, which modulates cell proliferation, migration, and differentiation, as well as some components of the immune response and homeostasis. A vast breadth of research data is available on TJs, but little has been done to decipher their specific roles in wound healing, despite their primary distribution in epithelial and endothelial cells, which are essential contributors to the wound healing process. Some data exists to indicate that a better understanding of the functions and significance of TJs in healing wounds may prove crucial for future improvements in wound healing research and therapy. Specifically, recent studies demonstrate that occludin and claudin-1, which are two TJ component proteins, are present in migrating epithelial cells at the wound edge but are absent in chronic wounds. This indicates that functional TJs may be critical for effective wound healing. A tremendous amount of work is needed to investigate their roles in barrier function, re-epithelialization, angiogenesis, scar formation, and in the interactions between epithelial cells, endothelial cells, and immune cells both in the acute wound healing process and in non-healing wounds. A more thorough understanding of TJs in wound healing may shed new light on potential research targets and reveal novel strategies to enhance tissue regeneration and improve wound repair. Full article
(This article belongs to the Special Issue New Innovations in Wound Healing and Repair)
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20 pages, 634 KiB  
Review
The Role of Chemokines in Wound Healing
by Anisyah Ridiandries, Joanne T. M. Tan and Christina A. Bursill
Int. J. Mol. Sci. 2018, 19(10), 3217; https://doi.org/10.3390/ijms19103217 - 18 Oct 2018
Cited by 265 | Viewed by 12844
Abstract
Wound healing is a multistep process with four overlapping but distinct stages: hemostasis, inflammation, proliferation, and remodeling. An alteration at any stage may lead to the development of chronic non-healing wounds or excessive scar formation. Impaired wound healing presents a significant health and [...] Read more.
Wound healing is a multistep process with four overlapping but distinct stages: hemostasis, inflammation, proliferation, and remodeling. An alteration at any stage may lead to the development of chronic non-healing wounds or excessive scar formation. Impaired wound healing presents a significant health and economic burden to millions of individuals worldwide, with diabetes mellitus and aging being major risk factors. Ongoing understanding of the mechanisms that underly wound healing is required for the development of new and improved therapies that increase repair. Chemokines are key regulators of the wound healing process. They are involved in the promotion and inhibition of angiogenesis and the recruitment of inflammatory cells, which release growth factors and cytokines to facilitate the wound healing process. Preclinical research studies in mice show that the administration of CCL2, CCL21, CXCL12, and a CXCR4 antagonist as well as broad-spectrum inhibition of the CC-chemokine class improve the wound healing process. The focus of this review is to highlight the contributions of chemokines during each stage of wound healing and to discuss the related molecular pathologies in complex and chronic non-healing wounds. We explore the therapeutic potential of targeting chemokines as a novel approach to overcome the debilitating effects of impaired wound healing. Full article
(This article belongs to the Special Issue New Innovations in Wound Healing and Repair)
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19 pages, 760 KiB  
Review
The Cutaneous Microbiome and Wounds: New Molecular Targets to Promote Wound Healing
by Taylor R. Johnson, Belinda I. Gómez, Matthew K. McIntyre, Michael A. Dubick, Robert J. Christy, Susannah E. Nicholson and David M. Burmeister
Int. J. Mol. Sci. 2018, 19(9), 2699; https://doi.org/10.3390/ijms19092699 - 11 Sep 2018
Cited by 124 | Viewed by 15500
Abstract
The ecological community of microorganisms in/on humans, termed the microbiome, is vital for sustaining homeostasis. While culture-independent techniques have revealed the role of the gut microbiome in human health and disease, the role of the cutaneous microbiome in wound healing is less defined. [...] Read more.
The ecological community of microorganisms in/on humans, termed the microbiome, is vital for sustaining homeostasis. While culture-independent techniques have revealed the role of the gut microbiome in human health and disease, the role of the cutaneous microbiome in wound healing is less defined. Skin commensals are essential in the maintenance of the epithelial barrier function, regulation of the host immune system, and protection from invading pathogenic microorganisms. In this review, we summarize the literature derived from pre-clinical and clinical studies on how changes in the microbiome of various acute and chronic skin wounds impact wound healing tissue regeneration. Furthermore, we review the mechanistic insights garnered from model wound healing systems. Finally, in the face of growing concern about antibiotic-resistance, we will discuss alternative strategies for the treatment of infected wounds to improve wound healing and outcomes. Taken together, it has become apparent that commensals, symbionts, and pathogens on human skin have an intimate role in the inflammatory response that highlights several potential strategies to treat infected, non-healing wounds. Despite these promising results, there are some contradictory and controversial findings from existing studies and more research is needed to define the role of the human skin microbiome in acute and chronic wound healing. Full article
(This article belongs to the Special Issue New Innovations in Wound Healing and Repair)
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28 pages, 1402 KiB  
Review
Foxn1 in Skin Development, Homeostasis and Wound Healing
by Joanna Bukowska, Marta Kopcewicz, Katarzyna Walendzik and Barbara Gawronska-Kozak
Int. J. Mol. Sci. 2018, 19(7), 1956; https://doi.org/10.3390/ijms19071956 - 04 Jul 2018
Cited by 14 | Viewed by 6868
Abstract
Intensive research effort has focused on cellular and molecular mechanisms that regulate skin biology, including the phenomenon of scar-free skin healing during foetal life. Transcription factors are the key molecules that tune gene expression and either promote or suppress gene transcription. The epidermis [...] Read more.
Intensive research effort has focused on cellular and molecular mechanisms that regulate skin biology, including the phenomenon of scar-free skin healing during foetal life. Transcription factors are the key molecules that tune gene expression and either promote or suppress gene transcription. The epidermis is the source of transcription factors that regulate many functions of epidermal cells such as proliferation, differentiation, apoptosis, and migration. Furthermore, the activation of epidermal transcription factors also causes changes in the dermal compartment of the skin. This review focuses on the transcription factor Foxn1 and its role in skin biology. The regulatory function of Foxn1 in the skin relates to physiological (development and homeostasis) and pathological (skin wound healing) conditions. In particular, the pivotal role of Foxn1 in skin development and the acquisition of the adult skin phenotype, which coincides with losing the ability of scar-free healing, is discussed. Thus, genetic manipulations with Foxn1 expression, specifically those introducing conditional Foxn1 silencing in a Foxn1+/+ organism or its knock-in in a Foxn1−/− model, may provide future perspectives for regenerative medicine. Full article
(This article belongs to the Special Issue New Innovations in Wound Healing and Repair)
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11 pages, 954 KiB  
Review
Interferon Crevicular Fluid Profile and Correlation with Periodontal Disease and Wound Healing: A Systemic Review of Recent Data
by Luca Fiorillo, Gabriele Cervino, Alan Scott Herford, Floriana Lauritano, Cesare D’Amico, Roberto Lo Giudice, Luigi Laino, Giuseppe Troiano, Salvatore Crimi and Marco Cicciù
Int. J. Mol. Sci. 2018, 19(7), 1908; https://doi.org/10.3390/ijms19071908 - 29 Jun 2018
Cited by 71 | Viewed by 6785
Abstract
The purpose of the present study was to see if there is a correlation between the effect of interferons in crevicular fluid and periodontitis, evaluating literature. Interferon gamma (IFN-γ) is an immunoregulatory cytokine that, when activated by its receptor, plays an [...] Read more.
The purpose of the present study was to see if there is a correlation between the effect of interferons in crevicular fluid and periodontitis, evaluating literature. Interferon gamma (IFN-γ) is an immunoregulatory cytokine that, when activated by its receptor, plays an important role in the activation of inflammatory processes, which are the basis of periodontal disease. Stem cells in the periodontal ligament, like stem cells from other tissues, have immunomodulatory capacity and are regulated by some cytokines such as interferon-γ (IFN-γ). The study searched MEDLINE databases from 2008 to 2018. Clinical human in vitro and in vivo studies had reported a correlation between interferon and periodontitis. The initial search obtained 359 citations. After screening and determination of eligibility, nine articles were included in the review. Significant (p < 0.05) increases in IFN-γ gene expression were observed in some studies in the chronic periodontitis group. In some cases it was suggested that molecular mechanisms underlie the possible roles of IFN-γ in the inhibition of osteoclastogenesis. Neopterin belongs to the chemical group known as pteridines. It is synthesised by human macrophages upon stimulation with the interferon-gamma. Neopterin concentrations in body fluids are high in the case of infections, immune diseases or graft rejection. In the chronic periodontitis group, this marker is significantly higher. These studies underlined the clinical evidence between interferons in the crevicular fluid and inflammatory response of periodontitis. However, there is a lack of scientific evidence that could lead the clinician to an interferon-modulated therapy because of periodontitis. Full article
(This article belongs to the Special Issue New Innovations in Wound Healing and Repair)
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