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Wound Repair and Regeneration 2022

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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 (30 April 2023) | Viewed by 28793

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Prof. Dr. Sadanori Akita

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Guest Editor

Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 9601247, Japan
Interests: wound healing; inflammation; scarring; extracellular matrix; regeneration; biomaterials; chronic wounds; remodeling; stem cells; growth factors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our 2019 Special Issue “Wound Repair and Regeneration: Mechanisms, Signaling” and 2020 Special Issue "Wound Repair and Regeneration 2.0".

Wound healing plays an integral part in cellular and molecular events. This process is implicated in regeneration. Regeneration is also a process of restoring defects and disfigurement towards the original or more ideal states by cells, molecules, and environmental factors. Cellular and molecular events are orchestrated both spatially and temporally. When targeting each disease, understanding wound healing and the process of regeneration, as well as the findings of pathophysiology, will deliver new insights into realistic novel therapeutic options.

This Special Issue ‘’Wound Repair and Regeneration 2.0’’ calls for original articles, reviews, and perspectives that address the current knowledge and progress in the field of wound healing and regeneration by using conventional approaches as well as highly technologically advanced approaches. These include but are not limited to the fields that are mentioned in the keywords.

Prof. Dr. Sadanori Akita
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
disease
pathophysiology
therapy
tissue engineering

Published Papers (11 papers)

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Research

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14 pages, 6711 KiB

Open AccessArticle

Effective Healing of Staphylococcus aureus-Infected Wounds in Pig Cathelicidin Protegrin-1-Overexpressing Transgenic Mice

by Nagasundarapandian Soundrarajan, Prathap Somasundaram, Dohun Kim, Hye-Sun Cho, Hyoim Jeon, Byeonyong Ahn, Mingue Kang, Hyuk Song and Chankyu Park

Int. J. Mol. Sci. 2023, 24(14), 11658; https://doi.org/10.3390/ijms241411658 - 19 Jul 2023

Cited by 1 | Viewed by 1157

Abstract

Antimicrobial peptides (AMPs) are promising alternatives to existing treatments for multidrug-resistant bacteria-infected wounds. Therefore, the effect of protegrin-1 (PG1), a potent porcine AMP with broad-spectrum activity, on wound healing was evaluated. PG1-overexpressing transgenic mice were used as an in vivo model to evaluate its healing efficiency against Staphylococcus aureus-infected (10⁶ colony forming units) wounds. We analyzed the wounds under four specific conditions in the presence or absence of antibiotic treatment. We observed the resolution of bacterial infection and formation of neo-epithelium in S. aureus-infected wounds of the mice, even without antibiotic treatment, whereas all wild-type mice with bacterial infection died within 8 to 10 days due to uncontrolled bacterial proliferation. Interestingly, the wound area on day 7 was smaller (p < 0.01) in PG1 transgenic mice than that in the other groups, including antibiotic-treated mice, suggesting that PG1 exerts biological effects other than bactericidal effect. Additionally, we observed that the treatment of primary epidermal keratinocytes with recombinant PG1 enhanced cell migration in in vitro scratch and cell migration assays. This study contributes to the understanding of broad-spectrum endogenous cathelicidins with potent antimicrobial activities, such as PG1, on wound healing. Furthermore, our findings suggest that PG1 is a potent therapeutic candidate for wound healing. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration 2022)

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11 pages, 2248 KiB

Open AccessArticle

Enzymatic Deglycation of Damaged Skin by Means of Combined Treatment of Fructosamine-3-Kinase and Fructosyl-Amino Acid Oxidase

by Ignace De Decker, Margo Notebaert, Marijn M. Speeckaert, Karel E. Y. Claes, Phillip Blondeel, Elisabeth Van Aken, Jo Van Dorpe, Filip De Somer, Margaux Heintz, Stan Monstrey and Joris R. Delanghe

Int. J. Mol. Sci. 2023, 24(10), 8981; https://doi.org/10.3390/ijms24108981 - 19 May 2023

Cited by 1 | Viewed by 1332

Abstract

The consensus in aging is that inflammation, cellular senescence, free radicals, and epigenetics are contributing factors. Skin glycation through advanced glycation end products (AGEs) has a crucial role in aging. Additionally, it has been suggested that their presence in scars leads to elasticity loss. This manuscript reports fructosamine-3-kinase (FN3K) and fructosyl-amino acid oxidase (FAOD) in counteracting skin glycation by AGEs. Skin specimens were obtained (n = 19) and incubated with glycolaldehyde (GA) for AGE induction. FN3K and FAOD were used as monotherapy or combination therapy. Negative and positive controls were treated with phosphate-buffered saline and aminoguanidine, respectively. Autofluorescence (AF) was used to measure deglycation. An excised hypertrophic scar tissue (HTS) (n = 1) was treated. Changes in chemical bonds and elasticity were evaluated using mid-infrared spectroscopy (MIR) and skin elongation, respectively. Specimens treated with FN3K and FAOD in monotherapy achieved an average decrease of 31% and 33% in AF values, respectively. When treatments were combined, a decrease of 43% was achieved. The positive control decreased by 28%, whilst the negative control showed no difference. Elongation testing of HTS showed a significant elasticity improvement after FN3K treatment. ATR-IR spectra demonstrated differences in chemical bounds pre- versus post-treatment. FN3K and FAOD can achieve deglycation and the effects are most optimal when combined in one treatment. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration 2022)

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25 pages, 4351 KiB

Open AccessArticle

Purification of PaTx-II from the Venom of the Australian King Brown Snake and Characterization of Its Antimicrobial and Wound Healing Activities

by Ramar Perumal Samy, Stephen P. Mackessy, Alagarmalai Jeyasankar, Mano Ranjana Ponraj, Octavio Luiz Franco, Matthew A. Cooper, Matheswaran Kandasamy, Tapan Kumar Mohanta, Jebasingh Bhagavathsingh and Sakthivel Vaiyapuri

Int. J. Mol. Sci. 2023, 24(5), 4359; https://doi.org/10.3390/ijms24054359 - 22 Feb 2023

Viewed by 1957

Abstract

Infections caused by multi-drug-resistant (MDR) bacteria are a global threat to human health. As venoms are the source of biochemically diverse bioactive proteins and peptides, we investigated the antimicrobial activity and murine skin infection model-based wound healing efficacy of a 13 kDa protein. The active component PaTx-II was isolated from the venom of Pseudechis australis (Australian King Brown or Mulga Snake). PaTx-II inhibited the growth of Gram-positive bacteria in vitro, with moderate potency (MICs of 25 µM) observed against S. aureus, E. aerogenes, and P. vulgaris. The antibiotic activity of PaTx-II was associated with the disruption of membrane integrity, pore formation, and lysis of bacterial cells, as evidenced by scanning and transmission microscopy. However, these effects were not observed with mammalian cells, and PaTx-II exhibited minimal cytotoxicity (CC₅₀ > 1000 µM) toward skin/lung cells. Antimicrobial efficacy was then determined using a murine model of S. aureus skin infection. Topical application of PaTx-II (0.5 mg/kg) cleared S. aureus with concomitant increased vascularization and re-epithelialization, promoting wound healing. As small proteins and peptides can possess immunomodulatory effects to enhance microbial clearance, cytokines and collagen from the wound tissue samples were analyzed by immunoblots and immunoassays. The amounts of type I collagen in PaTx-II-treated sites were elevated compared to the vehicle controls, suggesting a potential role for collagen in facilitating the maturation of the dermal matrix during wound healing. Levels of the proinflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2) and interleukin-10 (IL-10), factors known to promote neovascularization, were substantially reduced by PaTx-II treatment. Further studies that characterize the contributions towards efficacy imparted by in vitro antimicrobial and immunomodulatory activity with PaTx-II are warranted. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration 2022)

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15 pages, 3367 KiB

Open AccessArticle

Evaluating Thera-101 as a Low-Volume Resuscitation Fluid in a Model of Polytrauma

by Jessica Stukel Shah, Joseph Macaitis, Bridney Lundquist, Brian Johnstone, Michael Coleman, Michelle A. Jefferson, Jacob Glaser, Annette R. Rodriguez, Sylvain Cardin, Heuy-Ching Wang and Alexander Burdette

Int. J. Mol. Sci. 2022, 23(20), 12664; https://doi.org/10.3390/ijms232012664 - 21 Oct 2022

Viewed by 1303

Abstract

Traumatic brain injury (TBI) and hemorrhage remain challenging to treat in austere conditions. Developing a therapeutic to mitigate the associated pathophysiology is critical to meet this treatment gap, especially as these injuries and associated high mortality are possibly preventable. Here, Thera-101 (T-101) was evaluated as low-volume resuscitative fluid in a rat model of TBI and hemorrhage. The therapeutic, T-101, is uniquely situated as a TBI and hemorrhage intervention. It contains a cocktail of proteins and microvesicles from the secretome of adipose-derived mesenchymal stromal cells that can act on repair and regenerative mechanisms associated with poly-trauma. T-101 efficacy was determined at 4, 24, 48, and 72 h post-injury by evaluating blood chemistry, inflammatory chemo/cytokines, histology, and diffusion tensor imaging. Blood chemistry indicated that T-101 reduced the markers of liver damage to Sham levels while the levels remained elevated with the control (saline) resuscitative fluid. Histology supports the potential protective effects of T-101 on the kidneys. Diffusion tensor imaging showed that the injury caused the most damage to the corpus callosum and the fimbria. Immunohistochemistry suggests that T-101 may mitigate astrocyte activation at 72 h. Together, these data suggest that T-101 may serve as a potential field deployable low-volume resuscitation therapeutic. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration 2022)

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12 pages, 2522 KiB

Open AccessArticle

Impact of Freeze-Drying on Cord Blood (CB), Serum (S), and Platelet-Rich Plasma (CB-PRP) Preparations on Growth Factor Content and In Vitro Cell Wound Healing

by Sabrina Valente, Carmen Ciavarella, Gloria Astolfi, Elisa Bergantin, Nico Curti, Marina Buzzi, Luigi Fontana and Piera Versura

Int. J. Mol. Sci. 2022, 23(18), 10701; https://doi.org/10.3390/ijms231810701 - 14 Sep 2022

Cited by 2 | Viewed by 1787

Abstract

Blood-based preparations are used in clinical practice for the treatment of several eye disorders. The aim of this study is to analyze the effect of freeze-drying blood-based preparations on the levels of growth factors and wound healing behaviors in an in vitro model. Platelet-rich plasma (PRP) and serum (S) preparations from the same Cord Blood (CB) sample, prepared in both fresh frozen (FF) and freeze-dried (FD) forms (and then reconstituted), were analyzed for EGF and BDNF content (ELISA Quantikine kit). The human MIO-M1 glial cell line (Moorfield/Institute of Ophthalmology, London, UK) was incubated with FF and FD products and evaluated for cell migration with scratch-induced wounding (IncuCyte S3 Essen BioScience), proliferation with cyclin A2 and D1 gene expression, and activation with vimentin and GFAP gene expression. The FF and FD forms showed similar concentrations of EGF and BDNF in both the S and PRP preparations. The wound healing assay showed no significant difference between the FF and FD forms for both S and PRP. Additionally, cell migration, proliferation, and activation did not appear to change in the FD forms compared to the FF ones. Our study showed that reconstituted FD products maintained the growth factor concentrations and biological properties of FF products and could be used as a functional treatment option. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration 2022)

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12 pages, 2338 KiB

Open AccessArticle

Accelerated Wound Border Closure Using a Microemulsion Containing Non-Inhibitory Recombinant α1-Antitrypsin

by Alon Gimmon, Lior Sherker, Lena Kojukarov, Melodie Zaknoun, Yotam Lior, Tova Fadel, Ronen Schuster, Eli C. Lewis and Eldad Silberstein

Int. J. Mol. Sci. 2022, 23(13), 7364; https://doi.org/10.3390/ijms23137364 - 01 Jul 2022

Cited by 1 | Viewed by 1445

Abstract

Wound healing requires a non-compromising combination of inflammatory and anti-inflammatory processes. Human α1-antitrypsin (hAAT), a circulating glycoprotein that rises during acute-phase responses and during healthy pregnancies, is tissue-protective and tolerance-inducing; although anti-inflammatory, hAAT enhances revascularization. hAAT blocks tissue-degrading enzymes, including neutrophil elastase; it is, therefore, unclear how wound healing might improve under hAAT-rich conditions. Here, wound healing was examined in the presence of recombinant hAAT (hAAT^WT) and protease-inhibition-lacking hAAT (hAAT^CP). The impact of both hAAT forms was determined by an epithelial cell gap closure assay, and by excisional skin injuries via a microemulsion optimized for open wounds. Neutrophilic infiltration was examined after 8 h. According to results, both hAAT forms accelerated epithelial gap closure and excisional wound closure, particularly at early time points. Unlike dexamethasone-treated wounds, both resulted in closed borders at the 8-h time point. In untreated and hAAT^CP-treated wounds, leukocytic infiltrates were widespread, in hAAT^WT-treated wounds compartmentalized and in dexamethasone-treated wounds, scarce. Both hAAT forms decreased interleukin-1β and increased VEGF gene expression. In conclusion hAAT improves epithelial cell migration and outcomes of in vivo wounds irrespective of protease inhibition. While both forms of hAAT allow neutrophils to infiltrate, only native hAAT created discrete neutrophilic tissue clusters. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration 2022)

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12 pages, 4015 KiB

Open AccessArticle

MicroRNA-365a/b-3p as a Potential Biomarker for Hypertrophic Scars

by Joon Seok Lee, Gyeonghwa Kim, Jong Ho Lee, Jeong Yeop Ryu, Eun Jung Oh, Hyun Mi Kim, Suin Kwak, Keun Hur and Ho Yun Chung

Int. J. Mol. Sci. 2022, 23(11), 6117; https://doi.org/10.3390/ijms23116117 - 30 May 2022

Cited by 2 | Viewed by 1651

Abstract

The clinical aspects of hypertrophic scarring vary according to personal constitution and body part. However, the mechanism of hypertrophic scar (HS) formation remains unclear. MicroRNAs (miRNAs) are known to contribute to HS formation, however, their detailed role remains unknown. In this study, candidate miRNAs were identified and analyzed as biomarkers of hypertrophic scarring for future clinical applications. HSfibroblasts and normal skin fibroblasts from patients were used for profiling and validation of miRNAs. An HS mouse model with xenografted human skin on nude mice was established. The miRNA expression between normal human, normal mouse, and mouse HS skin tissues was compared. Circulating miRNA expression levels in the serum of normal mice and mice with HSs were also analyzed. Ten upregulated and twenty-one downregulated miRNAs were detected. Among these, miR-365a/b-3p and miR-16-5p were identified as candidate miRNAs with statistically significant differences; miR-365a/b-3p was significantly upregulated (p = 0.0244). In mouse studies, miR-365a/b-3p expression levels in skin tissue and serum were higher in mice with HSs than in the control group. These results indicate that miRNAs contribute to hypertrophic scarring and that miR-365a/b-3p may be considered a potential biomarker for HS formation. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration 2022)

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Review

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30 pages, 5926 KiB

Open AccessReview

Innovative Functional Biomaterials as Therapeutic Wound Dressings for Chronic Diabetic Foot Ulcers

by Jessica Da Silva, Ermelindo C. Leal, Eugénia Carvalho and Eduardo A. Silva

Int. J. Mol. Sci. 2023, 24(12), 9900; https://doi.org/10.3390/ijms24129900 - 08 Jun 2023

Cited by 6 | Viewed by 3705

Abstract

The imbalance of local and systemic factors in individuals with diabetes mellitus (DM) delays, or even interrupts, the highly complex and dynamic process of wound healing, leading to diabetic foot ulceration (DFU) in 15 to 25% of cases. DFU is the leading cause of non-traumatic amputations worldwide, posing a huge threat to the well-being of individuals with DM and the healthcare system. Moreover, despite all the latest efforts, the efficient management of DFUs still remains a clinical challenge, with limited success rates in treating severe infections. Biomaterial-based wound dressings have emerged as a therapeutic strategy with rising potential to handle the tricky macro and micro wound environments of individuals with DM. Indeed, biomaterials have long been related to unique versatility, biocompatibility, biodegradability, hydrophilicity, and wound healing properties, features that make them ideal candidates for therapeutic applications. Furthermore, biomaterials may be used as a local depot of biomolecules with anti-inflammatory, pro-angiogenic, and antimicrobial properties, further promoting adequate wound healing. Accordingly, this review aims to unravel the multiple functional properties of biomaterials as promising wound dressings for chronic wound healing, and to examine how these are currently being evaluated in research and clinical settings as cutting-edge wound dressings for DFU management. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration 2022)

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16 pages, 1159 KiB

Open AccessReview

The Epidermal Keratinocyte as a Therapeutic Target for Management of Diabetic Wounds

by Wei-Cheng Fang and Cheng-Che E. Lan

Int. J. Mol. Sci. 2023, 24(5), 4290; https://doi.org/10.3390/ijms24054290 - 21 Feb 2023

Cited by 7 | Viewed by 2490

Abstract

Diabetes mellitus (DM) is an important cause of chronic wounds and non-traumatic amputation. The prevalence and number of cases of diabetic mellitus are increasing worldwide. Keratinocytes, the outermost layer of the epidermis, play an important role in wound healing. A high glucose environment may disrupt the physiologic functions of keratinocytes, resulting in prolonged inflammation, impaired proliferation, and the migration of keratinocytes and impaired angiogenesis. This review provides an overview of keratinocyte dysfunctions in a high glucose environment. Effective and safe therapeutic approaches for promoting diabetic wound healing can be developed if molecular mechanisms responsible for keratinocyte dysfunction in high glucose environments are elucidated. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration 2022)

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26 pages, 1844 KiB

Open AccessReview

Acute Inflammation in Tissue Healing

by Amro M. Soliman and Daniel R. Barreda

Int. J. Mol. Sci. 2023, 24(1), 641; https://doi.org/10.3390/ijms24010641 - 30 Dec 2022

Cited by 17 | Viewed by 6981

Abstract

There are well-established links between acute inflammation and successful tissue repair across evolution. Innate immune reactions contribute significantly to pathogen clearance and activation of subsequent reparative events. A network of molecular and cellular regulators supports antimicrobial and tissue repair functions throughout the healing process. A delicate balance must be achieved between protection and the potential for collateral tissue damage associated with overt inflammation. In this review, we summarize the contributions of key cellular and molecular components to the acute inflammatory process and the effective and timely transition toward activation of tissue repair mechanisms. We further discuss how the disruption of inflammatory responses ultimately results in chronic non-healing injuries. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration 2022)

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34 pages, 1847 KiB

Open AccessReview

State-of-the-Art on Wound Vitality Evaluation: A Systematic Review

by Aniello Maiese, Alice Chiara Manetti, Naomi Iacoponi, Eleonora Mezzetti, Emanuela Turillazzi, Marco Di Paolo, Raffaele La Russa, Paola Frati and Vittorio Fineschi

Int. J. Mol. Sci. 2022, 23(13), 6881; https://doi.org/10.3390/ijms23136881 - 21 Jun 2022

Cited by 7 | Viewed by 2263

Abstract

The vitality demonstration refers to determining if an injury has been caused ante- or post-mortem, while wound age means to evaluate how long a subject has survived after the infliction of an injury. Histology alone is not enough to prove the vitality of a lesion. Recently, immunohistochemistry, biochemistry, and molecular biology have been introduced in the field of lesions vitality and age demonstration. The study was conducted according to the preferred reporting items for systematic review (PRISMA) protocol. The search terms were “wound”, “lesion”, “vitality”, “evaluation”, “immunohistochemistry”, “proteins”, “electrolytes”, “mRNAs”, and “miRNAs” in the title, abstract, and keywords. This evaluation left 137 scientific papers. This review aimed to collect all the knowledge on vital wound demonstration and provide a temporal distribution of the methods currently available, in order to determine the age of lesions, thus helping forensic pathologists in finding a way through the tangled jungle of wound vitality evaluation. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration 2022)

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