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Emerging and Innovative Approaches for Wound Healing and Skin Regeneration:...
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Emerging and Innovative Approaches for Wound Healing and Skin Regeneration: Current Status and Advances

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 53558

Special Issue Editors

Dr. Michael Mildner

E-Mail Website
Guest Editor
Department of Dermatology, Medical University of Vienna, Vienna, Austria
Interests: wound healing; hypertrophic scar formation; keloids; in vitro models; in vivo models; mechanisms of skin fibrosis
Dr. Hendrik Jan Ankersmit

E-Mail Website
Guest Editor
Division of Surgery, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
Interests: applied immunology; inflammatory processes

Special Issue Information

Dear Colleagues, 

Wound healing and tissue regeneration are complex processes that are orchestrated by a plethora of factors and cell types. Although many key mechanisms of wound healing are already well described, potent therapeutics are still scarce. Significantly, the treatment of non-healing skin ulcers in diabetic patients is still a major challenge. In addition, the formation of hypertrophic scars and keloids, as a result of disturbed skin regeneration, represents a major problem after wound healing.

In this Special Issue, we welcome basic and translational research, as well as review articles, that aim to describe novel mechanisms and innovative therapeutic approaches that can be used to improve wound healing and skin regeneration. Furthermore, manuscripts on the patho-mechanisms of hypertrophic scar and keloid formation and new potential targets for scar management are also highly appreciated.

Yours sincerely,

Dr. Michael Mildner
Dr. Hendrik Jan Ankersmit
Guest Editors

Manuscript Submission Information

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Keywords

  • wound healing
  • skin regeneration
  • drug delivery
  • tissue regeneration
  • mechanisms of skin fibrosis
  • scar

Published Papers (15 papers)

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Research

Jump to: Review, Other

24 pages, 13503 KiB  
Article
The Secretome of Irradiated Peripheral Mononuclear Cells Attenuates Hypertrophic Skin Scarring
by Vera Vorstandlechner, Dragan Copic, Katharina Klas, Martin Direder, Bahar Golabi, Christine Radtke, Hendrik J. Ankersmit and Michael Mildner
Pharmaceutics 2023, 15(4), 1065; https://doi.org/10.3390/pharmaceutics15041065 - 25 Mar 2023
Viewed by 1468
Abstract
Hypertrophic scars can cause pain, movement restrictions, and reduction in the quality of life. Despite numerous options to treat hypertrophic scarring, efficient therapies are still scarce, and cellular mechanisms are not well understood. Factors secreted by peripheral blood mononuclear cells (PBMCsec) have been [...] Read more.
Hypertrophic scars can cause pain, movement restrictions, and reduction in the quality of life. Despite numerous options to treat hypertrophic scarring, efficient therapies are still scarce, and cellular mechanisms are not well understood. Factors secreted by peripheral blood mononuclear cells (PBMCsec) have been previously described for their beneficial effects on tissue regeneration. In this study, we investigated the effects of PBMCsec on skin scarring in mouse models and human scar explant cultures at single-cell resolution (scRNAseq). Mouse wounds and scars, and human mature scars were treated with PBMCsec intradermally and topically. The topical and intradermal application of PBMCsec regulated the expression of various genes involved in pro-fibrotic processes and tissue remodeling. We identified elastin as a common linchpin of anti-fibrotic action in both mouse and human scars. In vitro, we found that PBMCsec prevents TGFβ-mediated myofibroblast differentiation and attenuates abundant elastin expression with non-canonical signaling inhibition. Furthermore, the TGFβ-induced breakdown of elastic fibers was strongly inhibited by the addition of PBMCsec. In conclusion, we conducted an extensive study with multiple experimental approaches and ample scRNAseq data demonstrating the anti-fibrotic effect of PBMCsec on cutaneous scars in mouse and human experimental settings. These findings point at PBMCsec as a novel therapeutic option to treat skin scarring. Full article
(This article belongs to the Special Issue Emerging and Innovative Approaches for Wound Healing and Skin Regeneration: Current Status and Advances)
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25 pages, 2885 KiB  
Article
Retrospectives on Three Decades of Safe Clinical Experience with Allogeneic Dermal Progenitor Fibroblasts: High Versatility in Topical Cytotherapeutic Care
by Alexis Laurent, Marina Rey, Corinne Scaletta, Philippe Abdel-Sayed, Murielle Michetti, Marjorie Flahaut, Wassim Raffoul, Anthony de Buys Roessingh, Nathalie Hirt-Burri and Lee Ann Applegate
Pharmaceutics 2023, 15(1), 184; https://doi.org/10.3390/pharmaceutics15010184 - 4 Jan 2023
Cited by 6 | Viewed by 1227
Abstract
Allogeneic dermal progenitor fibroblasts constitute cytotherapeutic contenders for modern cutaneous regenerative medicine. Based on advancements in the relevant scientific, technical, and regulatory fields, translational developments have slowly yet steadily led to the clinical application of such biologicals and derivatives. To set the appropriate [...] Read more.
Allogeneic dermal progenitor fibroblasts constitute cytotherapeutic contenders for modern cutaneous regenerative medicine. Based on advancements in the relevant scientific, technical, and regulatory fields, translational developments have slowly yet steadily led to the clinical application of such biologicals and derivatives. To set the appropriate general context, the first aim of this study was to provide a current global overview of approved cell and gene therapy products, with an emphasis on cytotherapies for cutaneous application. Notable advances were shown for North America, Europe, Iran, Japan, and Korea. Then, the second and main aim of this study was to perform a retrospective analysis on the various applications of dermal progenitor fibroblasts and derivatives, as clinically used under the Swiss progenitor cell transplantation program for the past three decades. Therein, the focus was set on the extent and versatility of use of the therapies under consideration, their safety parameters, as well as formulation options for topical application. Quantitative and illustrative data were summarized and reported for over 300 patients treated with various cell-based or cell-derived preparations (e.g., progenitor biological bandages or semi-solid emulsions) in Lausanne since 1992. Overall, this study shows the strong current interest in biological-based approaches to cutaneous regenerative medicine from a global developmental perspective, as well as the consolidated local clinical experience gathered with a specific and safe allogeneic cytotherapeutic approach. Taken together, these current and historical elements may serve as tangible working bases for the further optimization of local and modern translational pathways for the provision of topical cytotherapeutic care. Full article
(This article belongs to the Special Issue Emerging and Innovative Approaches for Wound Healing and Skin Regeneration: Current Status and Advances)
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14 pages, 1847 KiB  
Article
Glycyrrhizin-Based Hydrogels Accelerate Wound Healing of Normoglycemic and Diabetic Mouse Skin
by Maarten A. Mees, Fleur Boone, Thomas Bouwen, Frederik Vanaerschot, Charlotte Titeca, Hanna-Kaisa Vikkula, Leen Catrysse, Anja Vananroye, Erin Koos, Stelios Alexandris, Sabine Rosenfeldt, Samuel Eyley, Joachim Koetz, Geert van Loo, Wim Thielemans and Esther Hoste
Pharmaceutics 2023, 15(1), 27; https://doi.org/10.3390/pharmaceutics15010027 - 21 Dec 2022
Cited by 4 | Viewed by 2195
Abstract
Efficient wound repair is crucial for mammalian survival. Healing of skin wounds is severely hampered in diabetic patients, resulting in chronic non-healing wounds that are difficult to treat. High-mobility group box 1 (HMGB1) is an important signaling molecule that is released during wounding, [...] Read more.
Efficient wound repair is crucial for mammalian survival. Healing of skin wounds is severely hampered in diabetic patients, resulting in chronic non-healing wounds that are difficult to treat. High-mobility group box 1 (HMGB1) is an important signaling molecule that is released during wounding, thereby delaying regenerative responses in the skin. Here, we show that dissolving glycyrrhizin, a potent HMGB1 inhibitor, in water results in the formation of a hydrogel with remarkable rheological properties. We demonstrate that these glycyrrhizin-based hydrogels accelerate cutaneous wound closure in normoglycemic and diabetic mice by influencing keratinocyte migration. To facilitate topical application of glycyrrhizin hydrogels on cutaneous wounds, several concentrations of glycyrrhizinic acid in water were tested for their rheological, structural, and biological properties. By varying the concentration of glycyrrhizin, these hydrogel properties can be readily tuned, enabling customized wound care. Full article
(This article belongs to the Special Issue Emerging and Innovative Approaches for Wound Healing and Skin Regeneration: Current Status and Advances)
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23 pages, 5255 KiB  
Article
Wound Healing Efficacy of Rosuvastatin Transethosomal Gel, I Optimal Optimization, Histological and In Vivo Evaluation
by Randa Mohammed Zaki, Vidya Devanathadesikan Seshadri, Alanoud S. Mutayran, Lara A. Elsawaf, Abubaker M. Hamad, Alanood S. Almurshedi, Rehab Mohammad Yusif and Mayada Said
Pharmaceutics 2022, 14(11), 2521; https://doi.org/10.3390/pharmaceutics14112521 - 19 Nov 2022
Cited by 10 | Viewed by 2386
Abstract
This study aimed to make a formulation and statistical optimization of transethosomal formulations of rosuvastatin (ROS) to enhance its topical wound healing efficiency. Design-Expert® software was used to employ I optimal design. The formulation variables in the study were surfactant concentration (% [...] Read more.
This study aimed to make a formulation and statistical optimization of transethosomal formulations of rosuvastatin (ROS) to enhance its topical wound healing efficiency. Design-Expert® software was used to employ I optimal design. The formulation variables in the study were surfactant concentration (%w/v), ethanol concentration (%w/v) and surfactant type (span 60 or tween 80), while the dependent responses were entrapment efficiency percent (EE%), vesicle size (VS) and zeta potential (ZP). The numerical optimization process employed by the design expert software resulted in an optimum formula composed of 0.819439 (%w/v) span 60, 40 (%w/v) ethanol and 100 mg lecithin with a desirability of 0.745. It showed a predicted EE% value of 66.5517 vs. 277.703 nm and a ZP of −33. When it was prepared and validated, it showed less than a 5% deviation from the predicted values. The optimum formula was subjected to further characterizations, such as DSC, XRD, TEM, in vitro release, the effect of aging and wound healing efficiency. The DSC thermogram made a confirmation of the compatibility of ROS with the ingredients used in the formulation. XRD showed the encapsulation of ROS in the transethosomal vesicles. The TEM image pointed out the spherical nature of the nanovesicles with the absence of aggregation. Additionally, the optimum formula revealed an enhancement of drug release in comparison with the drug suspension. It also showed good stability for one month. Furthermore, it revealed good wound healing efficiency when compared with the standard silver sulphadiazine (1% w/w) ointment or the drug-loaded gel, which could be related to the enhanced penetration of the nanosized vesicles of TESMs into the skin, which enhances the wound healing process. So, it could be regarded as a promising carrier of ROS for the treatment of chronic wounds. Full article
(This article belongs to the Special Issue Emerging and Innovative Approaches for Wound Healing and Skin Regeneration: Current Status and Advances)
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19 pages, 4617 KiB  
Article
Topical Wound Treatment with a Nitric Oxide-Releasing PDE5 Inhibitor Formulation Enhances Blood Perfusion and Promotes Healing in Mice
by Maya Ben-Yehuda Greenwald, Yu-Hang Liu, Weiye Li, Paul Hiebert, Maria Zubair, Hermann Tenor, Tobias Braun, Reto Naef, Daniel Razansky and Sabine Werner
Pharmaceutics 2022, 14(11), 2358; https://doi.org/10.3390/pharmaceutics14112358 - 31 Oct 2022
Cited by 3 | Viewed by 1886
Abstract
Chronic, non-healing wounds constitute a major health problem, and the current therapeutic options are limited. Therefore, pharmaceuticals that can be locally applied to complicated wounds are urgently needed. Such treatments should directly target the underlying causes, which include diabetes mellitus, chronic local pressure [...] Read more.
Chronic, non-healing wounds constitute a major health problem, and the current therapeutic options are limited. Therefore, pharmaceuticals that can be locally applied to complicated wounds are urgently needed. Such treatments should directly target the underlying causes, which include diabetes mellitus, chronic local pressure and/or vascular insufficiency. A common consequence of these disorders is impaired wound angiogenesis. Here, we investigated the effect of topical application of a nitric oxide-releasing phosphodiesterase 5 inhibitor (TOP-N53)-containing liquid hydrogel on wound repair in mice. The drug-loaded hydrogel promoted re-epithelialization and angiogenesis in wounds of healthy and healing-impaired diabetic mice. Using a non-invasive label-free optoacoustic microscopy approach combined with automated vessel analysis, we show that the topical application of TOP-N53 formulation increases the microvascular network density and promotes the functionality of the newly formed blood vessels, resulting in enhanced blood perfusion of the wounds. These results demonstrate a remarkable healing-stimulating activity of topically applied TOP-N53 formulation, supporting its further development as a wound therapeutic. Full article
(This article belongs to the Special Issue Emerging and Innovative Approaches for Wound Healing and Skin Regeneration: Current Status and Advances)
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15 pages, 4112 KiB  
Article
Continuous NPWT Regulates Fibrosis in Murine Diabetic Wound Healing
by Mengfan Wu, Dany Y. Matar, Zhen Yu, Ziyu Chen, Samuel Knoedler, Brian Ng, Oliver A. Darwish, Sadaf Sohrabi, Leigh Friedman, Valentin Haug, George F. Murphy, Yuval Rinkevich, Dennis P. Orgill and Adriana C. Panayi
Pharmaceutics 2022, 14(10), 2125; https://doi.org/10.3390/pharmaceutics14102125 - 6 Oct 2022
Cited by 7 | Viewed by 2850
Abstract
Scarring is associated with significant morbidity. The mechanical signaling factor yes-associated protein (YAP) has been linked to Engrailed-1 (En1)-lineage positive fibroblasts (EPFs), a pro-scarring fibroblast lineage, establishing a connection between mechanotransduction and fibrosis. In this study, we investigate the impact of micromechanical forces [...] Read more.
Scarring is associated with significant morbidity. The mechanical signaling factor yes-associated protein (YAP) has been linked to Engrailed-1 (En1)-lineage positive fibroblasts (EPFs), a pro-scarring fibroblast lineage, establishing a connection between mechanotransduction and fibrosis. In this study, we investigate the impact of micromechanical forces exerted through negative pressure wound therapy (NPWT) on the pathophysiology of fibrosis. Full-thickness excisional dorsal skin wounds were created on diabetic (db/db) mice which were treated with occlusive covering (control) or NPWT (continuous, −125 mmHg, 7 days; NPWT). Analysis was performed on tissue harvested 10 days after wounding. NPWT was associated with increased YAP (p = 0.04) but decreased En1 (p = 0.0001) and CD26 (p < 0.0001). The pro-fibrotic factors Vimentin (p = 0.04), α-SMA (p = 0.04) and HSP47 (p = 0.0008) were decreased with NPWT. Fibronectin was higher (p = 0.01) and collagen deposition lower in the NPWT group (p = 0.02). NPWT increased cellular proliferation (p = 0.002) and decreased apoptosis (p = 0.03). Western blotting demonstrated increased YAP (p = 0.02) and RhoA (p = 0.03) and decreased Caspase-3 (p = 0.03) with NPWT. NPWT uncouples YAP from EPF activation, through downregulation of Caspace-3, a pro-apoptotic factor linked to keloid formation. Mechanotransduction decreases multiple pro-fibrotic factors. Through this multifactorial process, NPWT significantly decreases fibrosis and offers promising potential as a mode to improve scar appearance. Full article
(This article belongs to the Special Issue Emerging and Innovative Approaches for Wound Healing and Skin Regeneration: Current Status and Advances)
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12 pages, 1570 KiB  
Communication
Initial Steps towards Spatiotemporal Signaling through Biomaterials Using Click-to-Release Chemistry
by Merel Gansevoort, Jona Merx, Elly M. M. Versteeg, Isidora Vuckovic, Thomas J. Boltje, Toin H. van Kuppevelt and Willeke F. Daamen
Pharmaceutics 2022, 14(10), 1991; https://doi.org/10.3390/pharmaceutics14101991 - 21 Sep 2022
Viewed by 1683
Abstract
The process of wound healing is a tightly controlled cascade of events, where severe skin wounds are resolved via scar tissue. This fibrotic response may be diminished by applying anti-fibrotic factors to the wound, thereby stimulating regeneration over scarring. The development of tunable [...] Read more.
The process of wound healing is a tightly controlled cascade of events, where severe skin wounds are resolved via scar tissue. This fibrotic response may be diminished by applying anti-fibrotic factors to the wound, thereby stimulating regeneration over scarring. The development of tunable biomaterials that enable spatiotemporal control over the release of anti-fibrotics would greatly benefit wound healing. Herein, harnessing the power of click-to-release chemistry for regenerative medicine, we demonstrate the feasibility of such an approach. For this purpose, one side of a bis-N-hydroxysuccinimide-trans-cyclooctene (TCO) linker was functionalized with human epidermal growth factor (hEGF), an important regulator during wound healing, whereas on the other side a carrier protein was conjugated—either type I collagen scaffolds or bovine serum albumin (BSA). Mass spectrometry demonstrated the coupling of hEGF–TCO and indicated a release following exposure to dimethyl-tetrazine. Type I collagen scaffolds could be functionalized with the hEGF–TCO complex as demonstrated by immunofluorescence staining and Western blotting. The hEGF–TCO complex was also successfully ligated to BSA and the partial release of hEGF upon dimethyl-tetrazine exposure was observed through Western blotting. This work establishes the potential of click-to-release chemistry for the development of pro-regenerative biomaterials. Full article
(This article belongs to the Special Issue Emerging and Innovative Approaches for Wound Healing and Skin Regeneration: Current Status and Advances)
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15 pages, 3122 KiB  
Article
In Vivo Skin Regeneration and Wound Healing Using Cell Micro-Transplantation
by Lucia Nanić, Andrea Cedilak, Nikolina Škrobot Vidaček, Florian Gruber, Miljenko Huzak, Michael Bader and Ivica Rubelj
Pharmaceutics 2022, 14(9), 1955; https://doi.org/10.3390/pharmaceutics14091955 - 15 Sep 2022
Cited by 1 | Viewed by 1866
Abstract
Background: The accumulation of senescent cells in tissues alters tissue homeostasis and affects wound healing. It is also considered to be the main contributing factor to aging. In addition to losing their ability to divide, senescent cells exert detrimental effects on surrounding tissues [...] Read more.
Background: The accumulation of senescent cells in tissues alters tissue homeostasis and affects wound healing. It is also considered to be the main contributing factor to aging. In addition to losing their ability to divide, senescent cells exert detrimental effects on surrounding tissues through their senescence-associated secretory phenotype (SASP). They also affect stem cells and their niche, reducing their capacity to divide which increasingly reduces tissue regenerative capacity over time. The aim of our study was to restore aged skin by increasing the fraction of young cells in vivo using a young cell micro-transplantation technique on Fischer 344 rats. Employing the same technique, we also used wild-type skin fibroblasts and stem cells in order to heal Dominant Dystrophic Epidermolysis Bulosa (DDEB) wounds and skin blistering. Results: We demonstrate that implantation of young fibroblasts restores cell density, revitalizes cell proliferation in the dermis and epidermis, rejuvenates collagen I and III matrices, and boosts epidermal stem cell proliferation in rats with advancing age. We were also able to reduce blistering in DDEB rats by transplantation of skin stem cells but not skin fibroblasts. Conclusions: Our intervention proves that a local increase of young cells in the dermis changes tissue homeostasis well enough to revitalize the stem cell niche, ensuring overall skin restoration and rejuvenation as well as healing DDEB skin. Our method has great potential for clinical applications in skin aging, as well as for the treatment of various skin diseases. Full article
(This article belongs to the Special Issue Emerging and Innovative Approaches for Wound Healing and Skin Regeneration: Current Status and Advances)
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18 pages, 6514 KiB  
Article
Topological Distribution of Wound Stiffness Modulates Wound-Induced Hair Follicle Neogenesis
by Hans I-Chen Harn, Po-Yuan Chiu, Chein-Hong Lin, Hung-Yang Chen, Yung-Chih Lai, Fu-Shiuan Yang, Chia-Ching Wu, Ming-Jer Tang, Cheng-Ming Chuong and Michael W. Hughes
Pharmaceutics 2022, 14(9), 1926; https://doi.org/10.3390/pharmaceutics14091926 - 12 Sep 2022
Cited by 4 | Viewed by 2189
Abstract
In the large full-thickness mouse skin regeneration model, wound-induced hair neogenesis (WIHN) occurs in the wound center. This implies a spatial regulation of hair regeneration. The role of mechanotransduction during tissue regeneration is poorly understood. Here, we created wounds with equal area but [...] Read more.
In the large full-thickness mouse skin regeneration model, wound-induced hair neogenesis (WIHN) occurs in the wound center. This implies a spatial regulation of hair regeneration. The role of mechanotransduction during tissue regeneration is poorly understood. Here, we created wounds with equal area but different shapes to understand if perturbing mechanical forces change the area and quantity of de novo hair regeneration. Atomic force microscopy of wound stiffness demonstrated a stiffness gradient across the wound with the wound center softer than the margin. Reducing mechanotransduction signals using FAK or myosin II inhibitors significantly increased WIHN and, conversely, enhancing these signals with an actin stabilizer reduced WIHN. Here, α-SMA was downregulated in FAK inhibitor-treated wounds and lowered wound stiffness. Wound center epithelial cells exhibited a spherical morphology relative to wound margin cells. Differential gene expression analysis of FAK inhibitor-treated wound RNAseq data showed that cytoskeleton-, integrin-, and matrix-associated genes were downregulated, while hair follicular neogenesis, cell proliferation, and cell signaling genes were upregulated. Immunohistochemistry staining showed that FAK inhibition increased pSTAT3 nuclear staining in the regenerative wound center, implying enhanced signaling for hair follicular neogenesis. These findings suggest that controlling wound stiffness modulates tissue regeneration encompassing epithelial competence, tissue patterning, and regeneration during wound healing. Full article
(This article belongs to the Special Issue Emerging and Innovative Approaches for Wound Healing and Skin Regeneration: Current Status and Advances)
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12 pages, 1534 KiB  
Article
Non-Invasive Physical Plasma for Preventing Radiation Dermatitis in Breast Cancer: A First-In-Human Feasibility Study
by Cas Stefaan Dejonckheere, Adriana Torres-Crigna, Julian Philipp Layer, Katharina Layer, Shari Wiegreffe, Gustavo Renato Sarria, Davide Scafa, David Koch, Christina Leitzen, Mümtaz Ali Köksal, Thomas Müdder, Alina Abramian, Christina Kaiser, Andree Faridi, Matthias Bernhard Stope, Alexander Mustea, Frank Anton Giordano and Leonard Christopher Schmeel
Pharmaceutics 2022, 14(9), 1767; https://doi.org/10.3390/pharmaceutics14091767 - 24 Aug 2022
Cited by 7 | Viewed by 2176
Abstract
Radiation dermatitis (RD) is the most common acute side effect of breast irradiation. More than a century following the therapeutic utilisation of X-rays, potent preventative and therapeutic options are still lacking. Non-invasive physical plasma (NIPP) is an emerging approach towards treatment of various [...] Read more.
Radiation dermatitis (RD) is the most common acute side effect of breast irradiation. More than a century following the therapeutic utilisation of X-rays, potent preventative and therapeutic options are still lacking. Non-invasive physical plasma (NIPP) is an emerging approach towards treatment of various dermatological disorders. In this study, we sought to determine the safety and feasibility of a NIPP device on RD. Thirty patients undergoing hypofractionated whole-breast irradiation were included. Parallel to radiation treatment, the irradiated breast was treated with NIPP with different application regimens. RD was assessed during and after NIPP/radiation, using clinician- and patient-reported outcomes. Additionally, safety and feasibility features were recorded. None of the patients was prescribed topical corticosteroids and none considered the treatment to be unpleasant. RD was less frequent and milder in comparison with standard skin care. Neither NIPP-related adverse events nor side effects were reported. This proven safety and feasibility profile of a topical NIPP device in the prevention and treatment of RD will be used as the framework for a larger intrapatient-randomised double-blind placebo-controlled trial, using objective and patient-reported outcome measures as an endpoint. Full article
(This article belongs to the Special Issue Emerging and Innovative Approaches for Wound Healing and Skin Regeneration: Current Status and Advances)
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16 pages, 1624 KiB  
Article
Localized Controlled Release of Kynurenic Acid Encapsulated in Synthetic Polymer Reduces Implant—Induced Dermal Fibrosis
by Layla Nabai, Aziz Ghahary and John Jackson
Pharmaceutics 2022, 14(8), 1546; https://doi.org/10.3390/pharmaceutics14081546 - 25 Jul 2022
Cited by 4 | Viewed by 1542
Abstract
Excessive fibrosis following surgical procedures is a challenging condition with serious consequences and no effective preventive or therapeutic option. Our group has previously shown the anti-fibrotic effect of kynurenic acid (KynA) in vitro and as topical cream formulations or nanofiber dressings in open [...] Read more.
Excessive fibrosis following surgical procedures is a challenging condition with serious consequences and no effective preventive or therapeutic option. Our group has previously shown the anti-fibrotic effect of kynurenic acid (KynA) in vitro and as topical cream formulations or nanofiber dressings in open wounds. Here, we hypothesized that the implantation of a controlled release drug delivery system loaded with KynA in a wound bed can prevent fibrosis in a closed wound. Poly (lactic-co-glycolic acid) (PLGA), and a diblock copolymer, methoxy polyethylene glycol-block-poly (D, L-lactide) (MePEG-b-PDLLA), were used for the fabrication of microspheres which were evaluated for their characteristics, encapsulation efficiency, in vitro release profile, and in vivo efficacy for reduction of fibrosis. The optimized formulation exhibited high encapsulation efficiency (>80%), low initial burst release (~10%), and a delayed, gradual release of KynA. In vivo evaluation of the fabricated microspheres in the PVA model of wound healing revealed that KynA microspheres effectively reduced collagen deposition inside and around PVA sponges and α-smooth muscle actin expression after 66 days. Our results showed that KynA can be efficiently encapsulated in PLGA microspheres and its controlled release in vivo reduces fibrotic tissue formation, suggesting a novel therapeutic option for the prevention or treatment of post-surgical fibrosis. Full article
(This article belongs to the Special Issue Emerging and Innovative Approaches for Wound Healing and Skin Regeneration: Current Status and Advances)
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0 pages, 9612 KiB  
Article
RETRACTED: Fluoxetine Ecofriendly Nanoemulsion Enhances Wound Healing in Diabetic Rats: In Vivo Efficacy Assessment
by Nabil A. Alhakamy, Giuseppe Caruso, Anna Privitera, Osama A. A. Ahmed, Usama A. Fahmy, Shadab Md, Gamal A. Mohamed, Sabrin R. M. Ibrahim, Basma G. Eid, Ashraf B. Abdel-Naim and Filippo Caraci
Pharmaceutics 2022, 14(6), 1133; https://doi.org/10.3390/pharmaceutics14061133 - 26 May 2022
Cited by 12 | Viewed by 2278 | Retraction
Abstract
Impaired diabetic wound healing is a major concern for health care professionals worldwide, imposing an intense financial burden and reducing the quality of life of patients. A dysregulation of this process can be responsible for the development of intractable ulcers and the formation [...] Read more.
Impaired diabetic wound healing is a major concern for health care professionals worldwide, imposing an intense financial burden and reducing the quality of life of patients. A dysregulation of this process can be responsible for the development of intractable ulcers and the formation of excessive scars. Therefore, the identification of novel pharmacological strategies able to promote wound healing and restore the mechanical integrity of injured tissue becomes essential. In the present study, fluoxetine ecofriendly nanoemulsion (FLX-EFNE) was prepared and its potential efficacy in enhancing wound healing was tested in diabetic rats. The Box–Behnken response surface design was used to select the optimized formulation that was prepared by the high-shear homogenization-based technique. A Zetasizer was used for the characterization of the optimized formulation, providing a FLX-EFNE with a globule size of 199 nm. For the in vivo study, a wound was induced by surgical methods, and diabetic rats (streptozotocin-induced) were divided into five groups: untreated control, vehicle-treated, FLX, FLX-EFNE, and positive control receiving a commercially available formula. The treatment continued from the day of wound induction to day 21. Then, the animals were sacrificed and skin tissues were collected at the site of wounding and used for biochemical, histopathological, immunohistochemical, and mRNA expression assessments. In the FLX-EFNE treated group, the rate of wound contraction and signs of healing were significantly higher compared to all other groups. In addition, angiogenesis, proliferation, and collagen deposition were enhanced, while oxidative stress and inflammation decreased. The present data highlight the enhanced wound healing activity of the optimized FLX-EFNE formulation. Full article
(This article belongs to the Special Issue Emerging and Innovative Approaches for Wound Healing and Skin Regeneration: Current Status and Advances)
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Review

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21 pages, 4042 KiB  
Review
Phosphatidylglycerol to Treat Chronic Skin Wounds in Diabetes
by Yonghong Luo, Edymarie Vivaldi Marrero, Vivek Choudhary and Wendy B. Bollag
Pharmaceutics 2023, 15(5), 1497; https://doi.org/10.3390/pharmaceutics15051497 - 14 May 2023
Cited by 1 | Viewed by 1990
Abstract
This review proposes the use of dioleoylphosphatidylglycerol (DOPG) to enhance diabetic wound healing. Initially, the characteristics of diabetic wounds are examined, focusing on the epidermis. Hyperglycemia accompanying diabetes results in enhanced inflammation and oxidative stress in part through the generation of advanced glycation [...] Read more.
This review proposes the use of dioleoylphosphatidylglycerol (DOPG) to enhance diabetic wound healing. Initially, the characteristics of diabetic wounds are examined, focusing on the epidermis. Hyperglycemia accompanying diabetes results in enhanced inflammation and oxidative stress in part through the generation of advanced glycation end-products (AGEs), in which glucose is conjugated to macromolecules. These AGEs activate inflammatory pathways; oxidative stress results from increased reactive oxygen species generation by mitochondria rendered dysfunctional by hyperglycemia. These factors work together to reduce the ability of keratinocytes to restore epidermal integrity, contributing to chronic diabetic wounds. DOPG has a pro-proliferative action on keratinocytes (through an unclear mechanism) and exerts an anti-inflammatory effect on keratinocytes and the innate immune system by inhibiting the activation of Toll-like receptors. DOPG has also been found to enhance macrophage mitochondrial function. Since these DOPG effects would be expected to counteract the increased oxidative stress (attributable in part to mitochondrial dysfunction), decreased keratinocyte proliferation, and enhanced inflammation that characterize chronic diabetic wounds, DOPG may be useful in stimulating wound healing. To date, efficacious therapies to promote the healing of chronic diabetic wounds are largely lacking; thus, DOPG may be added to the armamentarium of drugs to enhance diabetic wound healing. Full article
(This article belongs to the Special Issue Emerging and Innovative Approaches for Wound Healing and Skin Regeneration: Current Status and Advances)
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15 pages, 332 KiB  
Review
New Horizons of Macrophage Immunomodulation in the Healing of Diabetic Foot Ulcers
by Ching-Wen Lin, Chien-Min Hung, Wan-Jiun Chen, Jui-Ching Chen, Wen-Yen Huang, Chia-Sing Lu, Ming-Liang Kuo and Shyi-Gen Chen
Pharmaceutics 2022, 14(10), 2065; https://doi.org/10.3390/pharmaceutics14102065 - 27 Sep 2022
Cited by 26 | Viewed by 22109
Abstract
Diabetic foot ulcers (DFUs) are one of the most costly and troublesome complications of diabetes mellitus. The wound chronicity of DFUs remains the main challenge in the current and future treatment of this condition. Persistent inflammation results in chronic wounds characterized by dysregulation [...] Read more.
Diabetic foot ulcers (DFUs) are one of the most costly and troublesome complications of diabetes mellitus. The wound chronicity of DFUs remains the main challenge in the current and future treatment of this condition. Persistent inflammation results in chronic wounds characterized by dysregulation of immune cells, such as M1 macrophages, and impairs the polarization of M2 macrophages and the subsequent healing process of DFUs. The interactive regulation of M1 and M2 macrophages during DFU healing is critical and seems manageable. This review details how cytokines and signalling pathways are co-ordinately regulated to control the functions of M1 and M2 macrophages in normal wound repair. DFUs are defective in the M1-to-M2 transition, which halts the whole wound-healing machinery. Many pre-clinical and clinical innovative approaches, including the application of topical insulin, CCL chemokines, micro RNAs, stem cells, stem-cell-derived exosomes, skin substitutes, antioxidants, and the most recent Phase III-approved ON101 topical cream, have been shown to modulate the activity of M1 and M2 macrophages in DFUs. ON101, the newest clinically approved product in this setting, is designed specifically to down-regulate M1 macrophages and further modulate the wound microenvironment to favour M2 emergence and expansion. Finally, the recent evolution of macrophage modulation therapies and techniques will improve the effectiveness of the treatment of diverse DFUs. Full article
(This article belongs to the Special Issue Emerging and Innovative Approaches for Wound Healing and Skin Regeneration: Current Status and Advances)

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27 pages, 1386 KiB  
Systematic Review
Herbal Products and Their Active Constituents for Diabetic Wound Healing—Preclinical and Clinical Studies: A Systematic Review
by Anna Herman and Andrzej Przemysław Herman
Pharmaceutics 2023, 15(1), 281; https://doi.org/10.3390/pharmaceutics15010281 - 14 Jan 2023
Cited by 10 | Viewed by 3585
Abstract
The purpose of this review is to provide verified data on the current knowledge acquired in preclinical and clinical studies regarding topically used herbal products and their active constituents (formulations and dressings) with diabetic wound healing activity. Moreover, herbal products and their active [...] Read more.
The purpose of this review is to provide verified data on the current knowledge acquired in preclinical and clinical studies regarding topically used herbal products and their active constituents (formulations and dressings) with diabetic wound healing activity. Moreover, herbal products and their active constituents used for diabetic wound infections, and various cellular and molecular mechanisms of their actions will also be described. The electronic databases were searched for articles published from 2012 to 2022. Publications with oral or systemic administration of herbal products in diabetic wound healing, published before 2012, available only as an abstract, or in languages other than English were excluded from the study. The 59 articles comparing topically used herbal products in diabetic wound healing treatment versus control treatments (placebo or active therapy) were selected. Herbal products through different mechanisms of action, including antimicrobial, anti-inflammatory, antioxidant activity, stimulation of angiogenesis, production of cytokines and growth factors, keratinocytes, and fibroblast migration and proliferation may be considered as an important support during conventional therapy or even as a substitute for synthetic drugs used for diabetic wound treatment. Full article
(This article belongs to the Special Issue Emerging and Innovative Approaches for Wound Healing and Skin Regeneration: Current Status and Advances)
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