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15 pages, 2775 KiB

Open AccessArticle

Therapeutic Potential in Wound Healing of Allogeneic Use of Equine Umbilical Cord Mesenchymal Stem Cells

by Ailén Iribarne, María Belén Palma, Laura Andrini, Fernando Riccillo, Delfina Rodriguez, Martín Casella, Felipe Garay, Julieta Spoto Zabala, Leandro Mazza, Adriana Muro, Guillermo Buero, Santiago G. Miriuka, Edgardo Carosella and Marcela N. García

Int. J. Mol. Sci. 2024, 25(4), 2350; https://doi.org/10.3390/ijms25042350 - 16 Feb 2024

Cited by 2 | Viewed by 1609

Abstract

Wound healing after skin injury is a complex process, particularly in equines where leg wounds are prevalent and their repair is complicated due to the anatomical characteristics. Conventional treatments are not effective enough. The umbilical cord offers an unlimited source of adult mesenchymal [...] Read more.

Wound healing after skin injury is a complex process, particularly in equines where leg wounds are prevalent and their repair is complicated due to the anatomical characteristics. Conventional treatments are not effective enough. The umbilical cord offers an unlimited source of adult mesenchymal stem cells (ucMSCs) from Wharton’s jelly tissue. The present study aims to demonstrate the safety and therapeutic potential of the allogeneic use of equine ucMSCs (e-ucMSCs) in the healing of severe equine leg wounds. The methods employed were the isolation, culture and expansion of e-ucMSCs. Flow cytometry and a PCR assay were used for cell characterization. This study included an immunomodulation assay, a murine pre-clinical trial and the first phase of an equine clinical trial. Our results showed that e-ucMSCs express a functional HLA-G homolog, EQMHCB2. In the immunomodulation assay, the e-ucMSCs inhibited the proliferation of activated equine peripheral blood mononuclear cells (e-PBMCs). In the murine pre-clinical trial, e-ucMSCs reduced healing time by 50%. In the equine clinical trial, the injection of e-ucMSCs into severe leg lesions improved the closure time and quality of the tissues involved, regenerating them without fibrous tissue scar formation. In conclusion, the results of this study suggest that e-ucMSCs can be used allogeneically for wound healing by creating a tolerogenic environment. Full article

(This article belongs to the Special Issue Advanced Therapies and Functional Materials for Wound Healing)

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22 pages, 2658 KiB

Open AccessArticle

Chitosan-Based Dressing as a Sustained Delivery System for Bioactive Cytokines

by Sławomir Lewicki, Michał Zwoliński, Adrian Hovagimyan, Marta Stelmasiak, Łukasz Szarpak, Aneta Lewicka, Zygmunt Pojda and Łukasz Szymański

Int. J. Mol. Sci. 2024, 25(1), 30; https://doi.org/10.3390/ijms25010030 - 19 Dec 2023

Viewed by 1567

Abstract

Wounds represent a common occurrence in human life. Consequently, scientific investigations are underway to advance wound healing methodologies, with a notable focus on dressings imbued with biologically active compounds capable of orchestrating the wound microenvironment through meticulously regulated release mechanisms. Among these bioactive [...] Read more.

Wounds represent a common occurrence in human life. Consequently, scientific investigations are underway to advance wound healing methodologies, with a notable focus on dressings imbued with biologically active compounds capable of orchestrating the wound microenvironment through meticulously regulated release mechanisms. Among these bioactive agents are cytokines, which, when administered to the wound milieu without appropriate protection, undergo rapid loss of their functional attributes. Within the context of this research, we present a method for fabricating dressings enriched with G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte-macrophage colony-stimulating factor), showcasing both biological activity and protracted release dynamics. Based on Ligasano, a commercial polyurethane foam dressing, and chitosan crosslinked with TPP (sodium tripolyphosphate), these dressings are noncytotoxic and enable cytokine incorporation. The recovery of cytokines from dressings varied based on the dressing preparation and storage techniques (without modification, drying, freeze-drying followed by storage at 4 °C or freeze-drying followed by storage at 24 °C) and cytokine type. Generally, drying reduced cytokine levels and their bioactivity, especially with G-CSF. The recovery of G-CSF from unmodified dressings was lower compared to GM-CSF (60% vs. 80%). In summary, our freeze-drying approach enables the storage of G-CSF or GM-CSF enriched dressings at 24 °C with minimal cytokine loss, preserving their biological activity and thus enhancing future clinical availability. Full article

(This article belongs to the Special Issue Advanced Therapies and Functional Materials for Wound Healing)

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20 pages, 7157 KiB

Open AccessArticle

Corneal Wound Healing in the Presence of Antifibrotic Antibody Targeting Collagen Fibrillogenesis: A Pilot Study

by Zeba A. Syed, Tatyana Milman, Jolanta Fertala, Andrzej Steplewski and Andrzej Fertala

Int. J. Mol. Sci. 2023, 24(17), 13438; https://doi.org/10.3390/ijms241713438 - 30 Aug 2023

Viewed by 1573

Abstract

Highly organized collagen fibrils interlacing with proteoglycans form the crucial architecture of the cornea and facilitate its transparency. Corneal scarring from accidental injury, surgery, or infection alters this highly organized tissue, causing severe consequences, including blindness. There are no pharmacological or surgical methods [...] Read more.

Highly organized collagen fibrils interlacing with proteoglycans form the crucial architecture of the cornea and facilitate its transparency. Corneal scarring from accidental injury, surgery, or infection alters this highly organized tissue, causing severe consequences, including blindness. There are no pharmacological or surgical methods to effectively and safely treat excessive corneal scarring. Thus, we tested the anticorneal scarring utility of a rationally designed anticollagen antibody (ACA) whose antifibrotic effects have already been demonstrated in nonocular models. Utilizing a rabbit model with an incisional corneal wound, we analyzed ACA’s effects on forming collagen and proteoglycan-rich extracellular matrices in scar neotissue. We used microscopic and spectroscopic techniques to quantify these components and measure crucial parameters characterizing the structure and organization of collagen fibrils. Moreover, we analyzed the spatial distribution of collagen and proteoglycans in normal and healing corneas. Our study demonstrated significant changes in the quality and quantity of the analyzed molecules synthesized in scar neotissue. It showed that these changes extend beyond incision margins. It also showed ACA’s positive impact on some crucial parameters defining proper cornea structure. This pilot study provides a stepping stone for future tests of therapeutic approaches that target corneal extracellular scar matrix assembly. Full article

(This article belongs to the Special Issue Advanced Therapies and Functional Materials for Wound Healing)

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16 pages, 45965 KiB

Open AccessArticle

Combination of Pinocembrin and Epidermal Growth Factor Enhances the Proliferation and Survival of Human Keratinocytes

by Jirapak Ruttanapattanakul, Nitwara Wikan, Saranyapin Potikanond and Wutigri Nimlamool

Int. J. Mol. Sci. 2023, 24(15), 12450; https://doi.org/10.3390/ijms241512450 - 5 Aug 2023

Viewed by 1564

Abstract

Re-epithelialization is delayed in aged skin due to a slow rate of keratinocyte proliferation, and this may cause complications. Thus, there has been development of new therapies that increase treatment efficacy for skin wounds. Epidermal growth factor (EGF) has been clinically used, but [...] Read more.

Re-epithelialization is delayed in aged skin due to a slow rate of keratinocyte proliferation, and this may cause complications. Thus, there has been development of new therapies that increase treatment efficacy for skin wounds. Epidermal growth factor (EGF) has been clinically used, but this agent is expensive, and its activity is less stable. Therefore, a stable compound possessing EGF-like properties may be an effective therapy, especially when combined with EGF. The current study discovered that pinocembrin (PC) effectively synergized with EGF in increasing keratinocyte viability. The combination of PC and EGF significantly enhanced the proliferation and wound closure rate of the keratinocyte monolayer through activating the phosphorylation of ERK and Akt. Although these effects of PC were like those of EGF, we clearly proved that PC did not transactivate EGFR. Recent data from a previous study revealed that PC activates G-protein-coupled receptor 120 which further activates ERK1/2 and Akt phosphorylation. Therefore, this clearly indicates that PC possesses a unique property to stimulate the growth and survival of keratinocytes through activating a different receptor, which subsequently conveys the signal to cross-talk with the effector kinases downstream of the EGFR, suggesting that PC is a potential compound to be combined with EGF. Full article

(This article belongs to the Special Issue Advanced Therapies and Functional Materials for Wound Healing)

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14 pages, 3805 KiB

Open AccessArticle

Topical Probiotic Formulation Promotes Rapid Healing in Dog Keratinocyte Cells: A Promising Approach for Wound Management

by Manon Barthe, Lionel Gillot, Laurie Perdigon, Aline Jacobs, Gregory Schoonbroodt, Paul Mauhin, Emna Bouhajja and Hanan Osman-Ponchet

Int. J. Mol. Sci. 2023, 24(15), 12360; https://doi.org/10.3390/ijms241512360 - 2 Aug 2023

Cited by 1 | Viewed by 3988

Abstract

The use of probiotics has gained increasing attention as a strategy for wound healing to decrease microbial resistance to disinfectants and antibiotics. This study aimed to investigate the potential of a non-medicinal topical cocktail of probiotic bacteria (CPB) in promoting wound healing in [...] Read more.

The use of probiotics has gained increasing attention as a strategy for wound healing to decrease microbial resistance to disinfectants and antibiotics. This study aimed to investigate the potential of a non-medicinal topical cocktail of probiotic bacteria (CPB) in promoting wound healing in dogs using in vitro scratch assay. Canine Progenitors Epidermal Keratinocytes (CPEK) were exposed to a prototype product formulated with CPB (PPP), non-formulated CPB, and the vehicle. The viability of CPB and CPEK cells was first evaluated in the co-culture model. Then, wound closure was analyzed over time. The CPB required a minimum concentration of 75 CFU/mL for better viability with CPEK. While the CPEK preserved 100% of their viability when PPP was diluted to up to 75,000 CFU/mL. At higher concentrations, the viability of CPEK was reduced by the concomitant effect of the non-formulated CPB and the vehicle. The formulated and non-formulated CPB and the vehicle seem to lead to a dose-dependent increase in cell migration compared to the control. Importantly, at the concentration of 750,000 CFU/mL, the PPP showed a 20% increase in wound closure. Taken together, our findings suggest the potential beneficial effects of the probiotic-based topical cocktail (PPP) on wound healing. However, to confirm and validate these effects, further experiments are necessary to provide more robust evidence and allow us to confidently establish the potential beneficial effects of the probiotic bacteria (CPB) in promoting wound healing. Full article

(This article belongs to the Special Issue Advanced Therapies and Functional Materials for Wound Healing)

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21 pages, 8046 KiB

Open AccessArticle

Novel Molecular Vehicle-Based Approach for Cardiac Cell Transplantation Leads to Rapid Electromechanical Graft–Host Coupling

by Aleria Aitova, Serafima Scherbina, Andrey Berezhnoy, Mikhail Slotvitsky, Valeriya Tsvelaya, Tatyana Sergeeva, Elena Turchaninova, Elizaveta Rybkina, Sergey Bakumenko, Ilya Sidorov, Mikhail A. Popov, Vladislav Dontsov, Evgeniy G. Agafonov, Anton E. Efimov, Igor Agapov, Dmitriy Zybin, Dmitriy Shumakov and Konstantin Agladze

Int. J. Mol. Sci. 2023, 24(12), 10406; https://doi.org/10.3390/ijms241210406 - 20 Jun 2023

Cited by 2 | Viewed by 3004

Abstract

Myocardial remodeling is an inevitable risk factor for cardiac arrhythmias and can potentially be corrected with cell therapy. Although the generation of cardiac cells ex vivo is possible, specific approaches to cell replacement therapy remain unclear. On the one hand, adhesive myocyte cells [...] Read more.

Myocardial remodeling is an inevitable risk factor for cardiac arrhythmias and can potentially be corrected with cell therapy. Although the generation of cardiac cells ex vivo is possible, specific approaches to cell replacement therapy remain unclear. On the one hand, adhesive myocyte cells must be viable and conjugated with the electromechanical syncytium of the recipient tissue, which is unattainable without an external scaffold substrate. On the other hand, the outer scaffold may hinder cell delivery, for example, making intramyocardial injection difficult. To resolve this contradiction, we developed molecular vehicles that combine a wrapped (rather than outer) polymer scaffold that is enveloped by the cell and provides excitability restoration (lost when cells were harvested) before engraftment. It also provides a coating with human fibronectin, which initiates the process of graft adhesion into the recipient tissue and can carry fluorescent markers for the external control of the non-invasive cell position. In this work, we used a type of scaffold that allowed us to use the advantages of a scaffold-free cell suspension for cell delivery. Fragmented nanofibers (0.85 µm ± 0.18 µm in diameter) with fluorescent labels were used, with solitary cells seeded on them. Cell implantation experiments were performed in vivo. The proposed molecular vehicles made it possible to establish rapid (30 min) electromechanical contact between excitable grafts and the recipient heart. Excitable grafts were visualized with optical mapping on a rat heart with Langendorff perfusion at a 0.72 ± 0.32 Hz heart rate. Thus, the pre-restored grafts’ excitability (with the help of a wrapped polymer scaffold) allowed rapid electromechanical coupling with the recipient tissue. This information could provide a basis for the reduction of engraftment arrhythmias in the first days after cell therapy. Full article

(This article belongs to the Special Issue Advanced Therapies and Functional Materials for Wound Healing)

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15 pages, 2705 KiB

Open AccessArticle

Effect of Achillea fragrantissima Extract on Excision Wound Biofilms of MRSA and Pseudomonas aeruginosa in Diabetic Mice

by Yasir Almuhanna, Mohammed Hussein Alqasmi, Hamood AlSudais, Mohammed Alrouji, Fahd A. Kuriri, Mohammed Alissa, Meshari A. Alsuwat, Mohammed Asad and Babu Joseph

Int. J. Mol. Sci. 2023, 24(11), 9774; https://doi.org/10.3390/ijms24119774 - 5 Jun 2023

Cited by 5 | Viewed by 1935

Abstract

Achillea fragrantissima, a desert plant commonly known as yarrow, is traditionally used as an antimicrobial agent in folklore medicine in Saudi Arabia. The current study was undertaken to determine its antibiofilm activity against methicillin-resistant Staphylococcus aureus (MRSA) and multi-drug-resistant Pseudomonas aeruginosa (MDR- [...] Read more.

Achillea fragrantissima, a desert plant commonly known as yarrow, is traditionally used as an antimicrobial agent in folklore medicine in Saudi Arabia. The current study was undertaken to determine its antibiofilm activity against methicillin-resistant Staphylococcus aureus (MRSA) and multi-drug-resistant Pseudomonas aeruginosa (MDR-P. aeruginosa) using in vitro and in vivo studies. A biofilm model induced through an excision wound in diabetic mice was used to evaluate its effect in vivo. The skin irritation and cytotoxic effects of the extract were determined using mice and HaCaT cell lines, respectively. The Achillea fragrantissima methanolic extract was analyzed with LC-MS to detect different phytoconstituents, which revealed the presence of 47 different phytoconstituents. The extract inhibited the growth of both tested pathogens in vitro. It also increased the healing of biofilm-formed excision wounds, demonstrating its antibiofilm, antimicrobial, and wound-healing action in vivo. The effect of the extract was concentration-dependent, and its activity was stronger against MRSA than MDR-P. aeruginosa. The extract formulation was devoid of a skin irritation effect in vivo and cytotoxic effect on HaCaT cell lines in vitro. Full article

(This article belongs to the Special Issue Advanced Therapies and Functional Materials for Wound Healing)

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18 pages, 5955 KiB

Open AccessArticle

Salvianolic-Acid-B-Loaded HA Self-Healing Hydrogel Promotes Diabetic Wound Healing through Promotion of Anti-Inflammation and Angiogenesis

by Guoying Zhou, Jiayan Zhu, Liang Jin, Jing Chen, Ruojiao Xu, Yali Zhao, Tingzi Yan and Haitong Wan

Int. J. Mol. Sci. 2023, 24(7), 6844; https://doi.org/10.3390/ijms24076844 - 6 Apr 2023

Cited by 15 | Viewed by 3689

Abstract

Inflammatory dysfunction and angiogenesis inhibition are two main factors leading to the delayed healing of diabetic wounds. Hydrogels with anti-inflammatory and angiogenesis-promoting effects have been considered as promising wound care materials. Herein, a salvianolic acid B (SAB)-loaded hyaluronic acid (HA) self-healing hydrogel (HA/SAB) [...] Read more.

Inflammatory dysfunction and angiogenesis inhibition are two main factors leading to the delayed healing of diabetic wounds. Hydrogels with anti-inflammatory and angiogenesis-promoting effects have been considered as promising wound care materials. Herein, a salvianolic acid B (SAB)-loaded hyaluronic acid (HA) self-healing hydrogel (HA/SAB) with anti-inflammatory and pro-angiogenesis capacities for diabetic wound healing is reported. The HA hydrogel was prepared via the covalent cross-linking of aldehyde groups in oxidized HA (OHA) and hydrazide groups in adipic dihydrazide (ADH)-modified HA (HA-ADH) with the formation of reversible acylhydrazone bonds. The obtained HA hydrogel exhibited multiple favorable properties such as porous structures, excellent self-healing properties, a sustainable release capacity of SAB, as well as excellent cytocompatibility. In addition, the effects of the SAB-loaded HA self-healing hydrogel were investigated via a full-thickness skin defect model using diabetic rats. The HA/SAB hydrogel showed enhanced skin regeneration effects with accelerated wound closure, shorter remaining dermal space length, thicker granulation tissue formation, and more collagen deposition. Furthermore, reduced inflammatory response and enhanced vascularization were found with HA/SAB2.5 hydrogel-treated wounds, indicating that the hydrogel promotes diabetic wound healing through the promotion of anti-inflammation and angiogenesis. Our results suggest that the fabricated SAB-loaded HA self-healing hydrogel is promising as a wound dressing for the treatment of diabetic wounds. Full article

(This article belongs to the Special Issue Advanced Therapies and Functional Materials for Wound Healing)

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Review

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18 pages, 7716 KiB

Open AccessReview

Kick-Starting Wound Healing: A Review of Pro-Healing Drugs

by Bethany L. Patenall, Kristyn A. Carter and Matthew R. Ramsey

Int. J. Mol. Sci. 2024, 25(2), 1304; https://doi.org/10.3390/ijms25021304 - 21 Jan 2024

Cited by 6 | Viewed by 4520

Abstract

Cutaneous wound healing consists of four stages: hemostasis, inflammation, proliferation/repair, and remodeling. While healthy wounds normally heal in four to six weeks, a variety of underlying medical conditions can impair the progression through the stages of wound healing, resulting in the development of [...] Read more.

Cutaneous wound healing consists of four stages: hemostasis, inflammation, proliferation/repair, and remodeling. While healthy wounds normally heal in four to six weeks, a variety of underlying medical conditions can impair the progression through the stages of wound healing, resulting in the development of chronic, non-healing wounds. Great progress has been made in developing wound dressings and improving surgical techniques, yet challenges remain in finding effective therapeutics that directly promote healing. This review examines the current understanding of the pro-healing effects of targeted pharmaceuticals, re-purposed drugs, natural products, and cell-based therapies on the various cell types present in normal and chronic wounds. Overall, despite several promising studies, there remains only one therapeutic approved by the United States Food and Drug Administration (FDA), Becaplermin, shown to significantly improve wound closure in the clinic. This highlights the need for new approaches aimed at understanding and targeting the underlying mechanisms impeding wound closure and moving the field from the management of chronic wounds towards resolving wounds. Full article

(This article belongs to the Special Issue Advanced Therapies and Functional Materials for Wound Healing)

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18 pages, 1580 KiB

Open AccessReview

Potential Role of AGR2 for Mammalian Skin Wound Healing

by Anastasiya V. Kosykh, Maria B. Tereshina and Nadya G. Gurskaya

Int. J. Mol. Sci. 2023, 24(9), 7895; https://doi.org/10.3390/ijms24097895 - 26 Apr 2023

Cited by 3 | Viewed by 2237

Abstract

The limited ability of mammals to regenerate has garnered significant attention, particularly in regard to skin wound healing (WH), which is a critical step for regeneration. In human adults, skin WH results in the formation of scars following injury or trauma, regardless of [...] Read more.

The limited ability of mammals to regenerate has garnered significant attention, particularly in regard to skin wound healing (WH), which is a critical step for regeneration. In human adults, skin WH results in the formation of scars following injury or trauma, regardless of severity. This differs significantly from the scarless WH observed in the fetal skin of mammals or anamniotes. This review investigates the role of molecular players involved in scarless WH, which are lost or repressed in adult mammalian WH systems. Specifically, we analyze the physiological role of Anterior Gradient (AGR) family proteins at different stages of the WH regulatory network. AGR is activated in the regeneration of lower vertebrates at the stage of wound closure and, accordingly, is important for WH. Mammalian AGR2 is expressed during scarless WH in embryonic skin, while in adults, the activity of this gene is normally inhibited and is observed only in the mucous epithelium of the digestive tract, which is capable of full regeneration. The combination of AGR2 unique potencies in postnatal mammals makes it possible to consider it as a promising candidate for enhancing WH processes. Full article

(This article belongs to the Special Issue Advanced Therapies and Functional Materials for Wound Healing)

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16 pages, 1181 KiB

Open AccessReview

Extracellular Vesicle-Based Hydrogels for Wound Healing Applications

by Andreu Miquel Amengual-Tugores, Carmen Ráez-Meseguer, Maria Antònia Forteza-Genestra, Marta Monjo and Joana M. Ramis

Int. J. Mol. Sci. 2023, 24(4), 4104; https://doi.org/10.3390/ijms24044104 - 18 Feb 2023

Cited by 13 | Viewed by 4358

Abstract

Hydrogels and extracellular vesicle-based therapies have been proposed as emerging therapeutic assets in wound closure. The combination of these elements has given good results in managing chronic and acute wounds. The intrinsic characteristics of the hydrogels in which the extracellular vesicles (EVs) are [...] Read more.

Hydrogels and extracellular vesicle-based therapies have been proposed as emerging therapeutic assets in wound closure. The combination of these elements has given good results in managing chronic and acute wounds. The intrinsic characteristics of the hydrogels in which the extracellular vesicles (EVs) are loaded allow for overcoming barriers, such as the sustained and controlled release of EVs and the maintenance of the pH for their conservation. In addition, EVs can be obtained from different sources and through several isolation methods. However, some barriers must be overcome to transfer this type of therapy to the clinic, for example, the production of hydrogels containing functional EVs and identifying long-term storage conditions for EVs. The aim of this review is to describe the reported EV-based hydrogel combinations, along with the obtained results, and analyze future perspectives. Full article

(This article belongs to the Special Issue Advanced Therapies and Functional Materials for Wound Healing)

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