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Novel Natural Compound for Wound and Tissue Repair and Regeneration 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 16602

Special Issue Editors

Dr. Elia Ranzato

E-Mail Website
Guest Editor
DiSIT-Dipartimento di Scienze e Innovazione Tecnologica, University of Piemonte Orientale, Viale Teresa Michel 11, 15121 Alessandria, Italy
Interests: wound healing; cell signalling; honeybee products; natural products; honey; confocal microscopy; Ca2+ signalling; oxidative stress
Special Issues, Collections and Topics in MDPI journals
Dr. Simona Martinotti

E-Mail Website
Guest Editor
DiSIT - Dipartimento di Scienze e Innovazione Tecnologica, University of Piemonte Orientale "Amedeo Avogadro", Viale Teresa Michel 11, 15121 Alessandria, Italy
Interests: cell biology; cancer; calcium signalling; confocal microscopy; wound repair; honey; honeybee products; natural compounds; malignant mesothelioma
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous successful Special Issue “Novel Natural Compound for Wound and Tissue Repair and Regeneration”.

Wound healing is of great importance for skin medicine, with particular interest focused on natural compounds.

Numerous studies have recognized the potential of natural products as wound-healing agents in terms of antibacterial, antioxidant, immunomodulatory, and pro-collagen synthesis properties.

The therapeutic virtues of natural compounds have been rediscovered by the medical profession and are gaining acceptance for treating wounds, ulcers, and other surface infections.

In spite of the extensive literature available on natural compounds’ clinical uses, the subjacent mechanisms are still largely unknown. With the growing interest in natural product utilization and the belief that they are safer than standard therapies, it is crucial to increase our knowledge of their efficacy and side effects.

Thus, original articles and reviews investigating the positive effects of natural compounds on wound healing along with the cellular and molecular mechanisms involved will be suitable for this Special Issue.

Dr. Elia Ranzato
Dr. Simona Martinotti
Guest Editors

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 repair
  • tissue regeneration
  • natural compounds
  • phytochemicals
  • molecular mechanisms

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Published Papers (15 papers)

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Research

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15 pages, 5712 KiB  
Article
Solanum lycopersicum (Tomato)-Derived Nanovesicles Accelerate Wound Healing by Eliciting the Migration of Keratinocytes and Fibroblasts
by Valeria Daniello, Vincenzo De Leo, Maria Lasalvia, Md Niamat Hossain, Annalucia Carbone, Lucia Catucci, Roberto Zefferino, Chiara Ingrosso, Massimo Conese and Sante Di Gioia
Int. J. Mol. Sci. 2024, 25(5), 2452; https://doi.org/10.3390/ijms25052452 - 20 Feb 2024
Viewed by 793
Abstract
Plant-derived nanovesicles have been considered interesting in medicine for their breakthrough biological effects, including those relevant to wound healing. However, tomato-derived nanovesicles (TDNVs) have not been studied for their effects on wound closure yet. TDNVs were isolated from Solanum lycopersicum (var. Piccadilly) ripe [...] Read more.
Plant-derived nanovesicles have been considered interesting in medicine for their breakthrough biological effects, including those relevant to wound healing. However, tomato-derived nanovesicles (TDNVs) have not been studied for their effects on wound closure yet. TDNVs were isolated from Solanum lycopersicum (var. Piccadilly) ripe tomatoes by ultracentrifugation. Extract (collected during the isolation procedure) and NVs (pellet) were characterized by transmission electron microscopy and laser Doppler electrophoresis. Wound healing in the presence of Extract or NVs was analyzed by a scratch assay with monocultures of human keratinocytes (HUKE) or NIH-3T3 mouse fibroblasts. Cell proliferation and migration were studied by MTT and agarose spot assay, respectively. The vesicles in the Extract and NV samples were nanosized with a similar mean diameter of 115 nm and 130 nm, respectively. Both Extract and NVs had already accelerated wound closure of injured HUKE and NIH-3T3 monocultures by 6 h post-injury. Although neither sample exerted a cytotoxic effect on HUKE and NIH-3T3 fibroblasts, they did not augment cell proliferation. NVs and the Extract increased cell migration of both cell types. NVs from tomatoes may accelerate wound healing by increasing keratinocyte and fibroblast migration. These results indicate the potential therapeutic usefulness of TDNVs in the treatment of chronic or hard-to-heal ulcers. Full article
(This article belongs to the Special Issue Novel Natural Compound for Wound and Tissue Repair and Regeneration 2.0)
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14 pages, 2953 KiB  
Article
Impact of a High-Fat Diet at a Young Age on Wound Healing in Mice
by Kevin Arnke, Pablo Pfister, Gregory Reid, Mauro Vasella, Tim Ruhl, Ann-Kathrin Seitz, Nicole Lindenblatt, Paolo Cinelli and Bong-Sung Kim
Int. J. Mol. Sci. 2023, 24(24), 17299; https://doi.org/10.3390/ijms242417299 - 09 Dec 2023
Viewed by 989
Abstract
As the prevalence of juvenile-onset obesity rises globally, the multitude of related health consequences gain significant importance. In this context, obesity is associated with impaired cutaneous wound healing. In experimental settings, mice are the most frequently used model for investigating the effect of [...] Read more.
As the prevalence of juvenile-onset obesity rises globally, the multitude of related health consequences gain significant importance. In this context, obesity is associated with impaired cutaneous wound healing. In experimental settings, mice are the most frequently used model for investigating the effect of high-fat diet (HFD) chow on wound healing in wild-type or genetically manipulated animals, e.g., diabetic ob/ob and db/db mice. However, these studies have mainly been performed on adult animals. Thus, in the present study, we introduced a mouse model for a juvenile onset of obesity. We exposed 4-week-old mice to an investigational feeding period of 9 weeks with an HFD compared to a regular diet (RD). At a mouse age of 13 weeks, we performed excisional and incisional wounding and measured the healing rate. Wound healing was examined by serial photographs with daily wound size measurements of the excisional wounds. Histology from incisional wounds was performed to quantify granulation tissue (thickness, quality) and angiogenesis (number of blood vessels per mm2). The expression of extracellular matrix proteins (collagen types I/III/IV, fibronectin 1, elastin), inflammatory cytokines (MIF, MIF-2, IL-6, TNF-α), myofibroblast differentiation (α-SMA) and macrophage polarization (CD11c, CD301b) in the incisional wounds were evaluated by RT-qPCR and by immunohistochemistry. There was a marked delay of wound closure in the HFD group with a decrease in granulation tissue quality and thickness. Additionally, inflammatory cytokines (MIF, IL-6, TNF-α) were significantly up-regulated in HFD- when compared to RD-fed mice measured at day 3. By contrast, MIF-2 and blood vessel expression were significantly reduced in the HFD animals, starting at day 1. No significant changes were observed in macrophage polarization, collagen expression, and levels of TGF-β1 and PDGF-A. Our findings support that an early exposition to HFD resulted in juvenile obesity in mice with impaired wound repair mechanisms, which may be used as a murine model for obesity-related studies in the future. Full article
(This article belongs to the Special Issue Novel Natural Compound for Wound and Tissue Repair and Regeneration 2.0)
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19 pages, 10482 KiB  
Article
Chitosan-Based Hydrogels for Controlled Delivery of Asiaticoside-Rich Centella asiatica Extracts with Wound Healing Potential
by Katarzyna Witkowska, Magdalena Paczkowska-Walendowska, Tomasz Plech, Daria Szymanowska, Bożena Michniak-Kohn and Judyta Cielecka-Piontek
Int. J. Mol. Sci. 2023, 24(24), 17229; https://doi.org/10.3390/ijms242417229 - 07 Dec 2023
Cited by 2 | Viewed by 1104
Abstract
Centella asiatica extract is a valued plant material with known anti-inflammatory and anti-microbiological properties. Using the Design of Experiment (DoE) approach, it was possible to obtain an optimized water/alcoholic extract from Centella asiatica, which allowed the preparation of the final material with [...] Read more.
Centella asiatica extract is a valued plant material with known anti-inflammatory and anti-microbiological properties. Using the Design of Experiment (DoE) approach, it was possible to obtain an optimized water/alcoholic extract from Centella asiatica, which allowed the preparation of the final material with biological activity in the wound healing process. Studies on the novel applications of Centella asiatica in conjunction with the multifunctional chitosan carrier have been motivated by the plant’s substantial pharmacological activity and the need to develop new and effective methods for the treatment of chronic wounds. The controlled release of asiaticoside was made possible by the use of chitosan as a carrier. Based on the findings of investigations using the PAMPA skin assay, which is a model imitating the permeability of actives through skin, this compound, characterized by sustained release from the chitosan delivery system, was identified as being well able to permeate biological membranes such as skin. Chitosan and the lyophilized extract of Centella asiatica worked synergistically to block hyaluronidase, exert efficient microbiological activity and take part in the wound healing process, as proven in an in vitro model. A formulation containing 3% extract with 3% medium-molecular-weight chitosan was indicated as a potentially new treatment with high compliance and effectiveness for patients. Optimization of the chitosan-based hydrogel preparation ensured the required rheological properties necessary for the release of the bioactive from the chitosan delivery system and demonstrated a satisfactory antimicrobial activity. Full article
(This article belongs to the Special Issue Novel Natural Compound for Wound and Tissue Repair and Regeneration 2.0)
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21 pages, 10591 KiB  
Article
Polyphenolic Compounds Nanostructurated with Gold Nanoparticles Enhance Wound Repair
by Adriana Martínez-Cuazitl, María del Consuelo Gómez-García, Salvador Pérez-Mora, Marlon Rojas-López, Raúl Jacobo Delgado-Macuil, Juan Ocampo-López, Gustavo Jesús Vázquez-Zapién, Mónica Maribel Mata-Miranda and David Guillermo Pérez-Ishiwara
Int. J. Mol. Sci. 2023, 24(24), 17138; https://doi.org/10.3390/ijms242417138 - 05 Dec 2023
Cited by 2 | Viewed by 958
Abstract
Gold nanoparticles (AuNPs) have been used in a wide range of applications, conferring to bio-molecules diverse properties such as delivery, stabilization, and reduction of the adverse effects of drugs or plant extracts. Polyphenolic compounds from Bacopa procumbens (B. procumbens) (BP) can modulate [...] Read more.
Gold nanoparticles (AuNPs) have been used in a wide range of applications, conferring to bio-molecules diverse properties such as delivery, stabilization, and reduction of the adverse effects of drugs or plant extracts. Polyphenolic compounds from Bacopa procumbens (B. procumbens) (BP) can modulate proliferation, adhesion, migration, and cell differentiation, reducing the artificial scratch area in fibroblast cultures and promoting wound healing in an in vivo model. Here, chemically synthesized AuNPs conjugated with BP (AuNP-BP) were characterized using UV-Vis, ATR-FTIR, DLS, zeta-potential, and TEM analysis. The results showed an overlap of the FTIR spectra of the polyphenolic compounds from B. procumbens adhered to the surface of the AuNPs. UV-vis analysis indicated that the average size of the AuNP-BP was 28 nm, while DLS analysis showed a size of 44.58 nm and, by TEM, a size of 16.5 nm with an icosahedral morphology was observed. These measurements suggest an increase in the size of the nanoparticles after conjugation with BP, compared to the sizes of 9 nm, 44.51 nm, and 14.17 nm for the unconjugated AuNPs, respectively. Furthermore, the zeta potential of the AuNPs, which was originally −36.3 ± 12.3 mV shifted to −18.2 ± 7.02 mV after conjugation with BP, indicating improved stability of the nanoparticles. Enhancement of the wound healing effect was evaluated by morphometric, histochemical, and FTIR changes in a rat wound excision model. Results showed that the nanoconjugation process reduced the BP concentrations by 100-fold to have the same wound healing effect as BP alone. Besides, histological and FTIR spectroscopy analyses demonstrated that AuNP-BP treatment exhibited better macroscopical performance, showing a reduction in inflammatory cells and an increased synthesis and improved organization of collagen fibers. Full article
(This article belongs to the Special Issue Novel Natural Compound for Wound and Tissue Repair and Regeneration 2.0)
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20 pages, 4126 KiB  
Article
Macrocystis pyrifera Lipids Reduce Cytokine-Induced Pro-Inflammatory Signalling and Barrier Dysfunction in Human Keratinocyte Models
by Jamie M. L. Kok, Georgina C. Dowd, Jaydee D. Cabral and Lyn M. Wise
Int. J. Mol. Sci. 2023, 24(22), 16383; https://doi.org/10.3390/ijms242216383 - 16 Nov 2023
Viewed by 953
Abstract
Atopic dermatitis is a chronic condition where epidermal barrier dysfunction and cytokine production by infiltrating immune cells exacerbate skin inflammation and damage. A total lipid extract from Macrocystis pyrifera, a brown seaweed, was previously reported to suppress inflammatory responses in monocytes. Here, [...] Read more.
Atopic dermatitis is a chronic condition where epidermal barrier dysfunction and cytokine production by infiltrating immune cells exacerbate skin inflammation and damage. A total lipid extract from Macrocystis pyrifera, a brown seaweed, was previously reported to suppress inflammatory responses in monocytes. Here, treatment of human HaCaT keratinocytes with M. pyrifera lipids inhibited tumour necrosis factor (TNF)-α induced TNF receptor-associated factor 2 and monocyte chemoattractant protein (MCP)-1 protein production. HaCaT cells stimulated with TNF-α, interleukin (IL)-4, and IL-13 showed loss of claudin-1 tight junctions, but little improvement was observed following lipid pre-treatment. Three-dimensional cultures of HaCaT cells differentiated at the air–liquid interface showed increased MCP-1 production, loss of claudin-1 tight junctions, and trans-epidermal leakage with TNF-α, IL-4, and IL-13 stimulation, with all parameters reduced by lipid pre-treatment. These findings suggest that M. pyrifera lipids have anti-inflammatory and barrier-protective effects on keratinocytes, which may be beneficial for the treatment of atopic dermatitis or other skin conditions. Full article
(This article belongs to the Special Issue Novel Natural Compound for Wound and Tissue Repair and Regeneration 2.0)
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14 pages, 8772 KiB  
Article
A Chitosan-Based Biomaterial Combined with Mesenchymal Stem Cell-Conditioned Medium for Wound Healing and Skin Regeneration
by Filip Humenik, Ján Danko, Lenka Krešáková, Katarína Vdoviaková, Vladimír Vrabec, Emília Vasilová, Mária Giretová, Štefan Tóth, Zuzana Fagová, Ján Babík and Ľubomír Medvecký
Int. J. Mol. Sci. 2023, 24(22), 16080; https://doi.org/10.3390/ijms242216080 - 08 Nov 2023
Viewed by 1358
Abstract
The aim of this study was to provide a beneficial treatment effect of novel chitosan bio-polymeric material enriched with mesenchymal stem cell products derived from the canine adipose tissue (AT-MSC) on the artificial skin defect in a rabbit model. For the objectivity of [...] Read more.
The aim of this study was to provide a beneficial treatment effect of novel chitosan bio-polymeric material enriched with mesenchymal stem cell products derived from the canine adipose tissue (AT-MSC) on the artificial skin defect in a rabbit model. For the objectivity of the regeneration evaluation, we used histological analysis and a scoring system created by us, taking into account all the attributes of regeneration, such as inflammatory reaction, necrosis, granulation, formation of individual skin layers and hair follicles. We observed an acceleration and improvement in the healing of an artificially created skin defect after eight and ten weeks in comparison with negative control (spontaneous healing without biomaterial). Moreover, we were able to described hair follicles and epidermis layer in histological skin samples treated with a chitosan-based biomaterial on the eighth week after grafting. Full article
(This article belongs to the Special Issue Novel Natural Compound for Wound and Tissue Repair and Regeneration 2.0)
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19 pages, 4373 KiB  
Article
Tetracalcium Phosphate Biocement Hardened with a Mixture of Phytic Acid–Phytase in the Healing Process of Osteochondral Defects in Sheep
by Maros Varga, Lenka Kresakova, Jan Danko, Katarina Vdoviakova, Filip Humenik, Pavol Rusnak, Maria Giretova, Tatiana Spakovska, Zuzana Andrejcakova, Marian Kadasi, Marko Vrzgula, Zuzana Criepokova, Sonja Ivaskova, Filip Korim and Lubomir Medvecky
Int. J. Mol. Sci. 2023, 24(21), 15690; https://doi.org/10.3390/ijms242115690 - 28 Oct 2023
Viewed by 704
Abstract
Hyaline articular cartilage has unique physiological, biological, and biomechanical properties with very limited self-healing ability, which makes the process of cartilage regeneration extremely difficult. Therefore, research is currently focused on finding new and potentially better treatment options. The main objective of this in [...] Read more.
Hyaline articular cartilage has unique physiological, biological, and biomechanical properties with very limited self-healing ability, which makes the process of cartilage regeneration extremely difficult. Therefore, research is currently focused on finding new and potentially better treatment options. The main objective of this in vivo study was to evaluate a novel biocement CX consisting of tetracalcium phosphate–monetit biocement hardened with a phytic acid–phytase mixture for the regeneration of osteochondral defects in sheep. The results were compared with tetracalcium phosphate–monetit biocement with classic fast-setting cement systems and untreated defects. After 6 months, the animals were sacrificed, and the samples were evaluated using macroscopic and histologic methods as well as X-ray, CT, and MR-imaging techniques. In contrast to the formation of fibrous or fibrocartilaginous tissue on the untreated side, treatment with biocements resulted in the formation of tissue with a dominant hyaline cartilage structure, although fine fibres were present (p < 0.001). There were no signs of pathomorphological changes or inflammation. Continuous formation of subchondral bone and hyaline cartilage layers was present even though residual biocement was observed in the trabecular bone. We consider biocement CX to be highly biocompatible and suitable for the treatment of osteochondral defects. Full article
(This article belongs to the Special Issue Novel Natural Compound for Wound and Tissue Repair and Regeneration 2.0)
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22 pages, 5258 KiB  
Article
Synthesis and Characterization of a Biopolymer Pectin/Ethanolic Extract from Olive Mill Wastewater: In Vitro Safety and Efficacy Tests on Skin Wound Healing
by Francesca Aiello, Rocco Malivindi, Marisa Francesca Motta, Pasquale Crupi, Rosa Nicoletti, Cinzia Benincasa, Maria Lisa Clodoveo, Vittoria Rago, Umile Gianfranco Spizzirri and Donatella Restuccia
Int. J. Mol. Sci. 2023, 24(20), 15075; https://doi.org/10.3390/ijms242015075 - 11 Oct 2023
Viewed by 965
Abstract
Wound-healing delay is one of the major problems of type 2 diabetes, representing also a clinical emergency in non-healing chronic wounds. Natural antioxidants show interesting wound-healing properties, including those extracted from waste derived from olive oil production. Olive mill wastewater is one of [...] Read more.
Wound-healing delay is one of the major problems of type 2 diabetes, representing also a clinical emergency in non-healing chronic wounds. Natural antioxidants show interesting wound-healing properties, including those extracted from waste derived from olive oil production. Olive mill wastewater is one of the main by-products of the olive oil-making process, and it is rich in high-value secondary metabolites, mainly hydroxytyrosol. We proposed an eco-friendly extraction method, employing both ultrasound-assisted and Soxhlet techniques and ethanol as a solvent, to recover valuable molecules from Roggianella cv (Olea europea L.) olive mill wastewater, which was further entrapped in a pectin polymer via an enzymatic reaction using porcine pancreatic lipase. Pectin, in combination with other substances, promoted and accelerated wound healing and demonstrated good potential to produce a biomedical conjugate for wound treatment. The antioxidant activity of the extracts and conjugate were evaluated against lipophilic (IC50 equal to 0.152 mg mL−1) and hydrophilic (IC50 equal to 0.0371 mg mL−1) radical species as well as the in vitro cytotoxicity via NRU, h-CLAT, and a wound-healing scratch assay and assessment. The pectin conjugate did not exert hemolytic effects on the peripheral blood, demonstrating interesting wound-healing properties due to its ability to stimulate cell proliferation in a dose-dependent manner. Full article
(This article belongs to the Special Issue Novel Natural Compound for Wound and Tissue Repair and Regeneration 2.0)
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23 pages, 12496 KiB  
Article
Oleanolic Acid Complexation with Cyclodextrins Improves Its Cell Bio-Availability and Biological Activities for Cell Migration
by Javier Stelling-Férez, Santiago López-Miranda, José Antonio Gabaldón and Francisco José Nicolás
Int. J. Mol. Sci. 2023, 24(19), 14860; https://doi.org/10.3390/ijms241914860 - 03 Oct 2023
Cited by 1 | Viewed by 1077
Abstract
Wound healing is a complex process to restore skin. Plant-derived bioactive compounds might be a source of substances for the treatment of wounds stalled in a non-resolving stage of wound healing. Oleanolic acid (OA), a pentacyclic triterpene, has shown favorable wound healing properties [...] Read more.
Wound healing is a complex process to restore skin. Plant-derived bioactive compounds might be a source of substances for the treatment of wounds stalled in a non-resolving stage of wound healing. Oleanolic acid (OA), a pentacyclic triterpene, has shown favorable wound healing properties both in vitro and in vivo. Unfortunately, OA cannot be solubilized in aqueous media, and it needs to be helped by the use of dimethyl sulfoxide (DMSO). In this paper, we have shown that cyclodextrins (CDs) are a good alternative to DMSO as agents to deliver OA to cells, providing better features than DMSO. Cyclodextrins are natural macromolecules that show a unique tridimensional structure that can encapsulate a wide variety of hydrophobic compounds. We have studied the cyclodextrin-encapsulated form of OA with OA/DMSO, comparing their stability, biological properties for cell migration, and cell viability. In addition, detailed parameters related to cell migration and cytoskeletal reorganization have been measured and compared. Our results show that OA-encapsulateds compound exhibit several advantages when compared to non-encapsulated OA in terms of chemical stability, migration enhancement, and preservation of cell viability. Full article
(This article belongs to the Special Issue Novel Natural Compound for Wound and Tissue Repair and Regeneration 2.0)
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18 pages, 3715 KiB  
Article
Methacrylated Gelatin as a Scaffold for Mechanically Isolated Stromal Vascular Fraction for Cutaneous Wound Repair
by Mauro Vasella, Kevin Arnke, Dalia Dranseikiene, Elia Guzzi, Francesca Melega, Gregory Reid, Holger Jan Klein, Riccardo Schweizer, Mark W. Tibbitt and Bong-Sung Kim
Int. J. Mol. Sci. 2023, 24(18), 13944; https://doi.org/10.3390/ijms241813944 - 11 Sep 2023
Viewed by 1106
Abstract
Mechanically processed stromal vascular fraction (mSVF) is a highly interesting cell source for regenerative purposes, including wound healing, and a practical alternative to enzymatically isolated SVF. In the clinical context, SVF benefits from scaffolds that facilitate viability and other cellular properties. In the [...] Read more.
Mechanically processed stromal vascular fraction (mSVF) is a highly interesting cell source for regenerative purposes, including wound healing, and a practical alternative to enzymatically isolated SVF. In the clinical context, SVF benefits from scaffolds that facilitate viability and other cellular properties. In the present work, the feasibility of methacrylated gelatin (GelMA), a stiffness-tunable, light-inducible hydrogel with high biocompatibility is investigated as a scaffold for SVF in an in vitro setting. Lipoaspirates from elective surgical procedures were collected and processed to mSVF and mixed with GelMA precursor solutions. Non-encapsulated mSVF served as a control. Viability was measured over 21 days. Secreted basic fibroblast growth factor (bFGF) levels were measured on days 1, 7 and 21 by ELISA. IHC was performed to detect VEGF-A, perilipin-2, and CD73 expression on days 7 and 21. The impact of GelMA-mSVF on human dermal fibroblasts was measured in a co-culture assay by the same viability assay. The viability of cultured GelMA-mSVF was significantly higher after 21 days (p < 0.01) when compared to mSVF alone. Also, GelMA-mSVF secreted stable levels of bFGF over 21 days. While VEGF-A was primarily expressed on day 21, perilipin-2 and CD73-positive cells were observed on days 7 and 21. Finally, GelMA-mSVF significantly improved fibroblast viability as compared with GelMA alone (p < 0.01). GelMA may be a promising scaffold for mSVF as it maintains cell viability and proliferation with the release of growth factors while facilitating adipogenic differentiation, stromal cell marker expression and fibroblast proliferation. Full article
(This article belongs to the Special Issue Novel Natural Compound for Wound and Tissue Repair and Regeneration 2.0)
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16 pages, 7693 KiB  
Article
Comparative Study of the Efficacy of EHO-85, a Hydrogel Containing Olive Tree (Olea europaea) Leaf Extract, in Skin Wound Healing
by Bárbara Torrecillas-Baena, Marta Camacho-Cardenosa, María Dolores Carmona-Luque, Gabriel Dorado, Miriam Berenguer-Pérez, José Manuel Quesada-Gómez, María Ángeles Gálvez-Moreno and Antonio Casado-Díaz
Int. J. Mol. Sci. 2023, 24(17), 13328; https://doi.org/10.3390/ijms241713328 - 28 Aug 2023
Cited by 2 | Viewed by 1067
Abstract
Olive tree (Olea europaea) leaf extract (OELE) has important antioxidant and anti-inflammatory properties, supporting its use in human clinical practice. We recently designed an amorphous hydrogel called EHO-85 (EHO indicates olive leaf extract in Spanish) containing OELE for skin ulcer treatments. [...] Read more.
Olive tree (Olea europaea) leaf extract (OELE) has important antioxidant and anti-inflammatory properties, supporting its use in human clinical practice. We recently designed an amorphous hydrogel called EHO-85 (EHO indicates olive leaf extract in Spanish) containing OELE for skin ulcer treatments. Yet, its effectiveness has not been previously compared with other products used in routine clinical practice. This is necessary to evaluate its potential translation to the human clinic. Thus, in this study, the effect of EHO-85 on healing was evaluated in comparison with treatments containing Indian/Asiatic pennywort (Centella asiatica), hyaluronic acid, or dexpanthenol in a rat model. The speed of wound closure and histological parameters after seven and 14 days were analyzed. All treatments accelerated wound closure, but there were differences between them. Dexpanthenol after seven days produced the highest epithelialization and the lowest inflammation and vascularization. EHO-85 also promoted epithelialization and reduced vascularization. After 14 days, wounds treated with EHO-85 showed less inflammation and higher levels of collagen in the extracellular matrix. This indicates a higher degree of maturity in the regenerated tissue. In conclusion, the effect of EHO-85 on healing was equal to or superior to that of other treatments routinely used in human clinical practice. Therefore, these results, together with previous data on the effects of this hydrogel on ulcer healing in humans, indicate that EHO-85 is a suitable, low-cost, and efficient therapeutic option for wound healing. Full article
(This article belongs to the Special Issue Novel Natural Compound for Wound and Tissue Repair and Regeneration 2.0)
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16 pages, 15469 KiB  
Article
Double Network Physical Crosslinked Hydrogel for Healing Skin Wounds: New Formulation Based on Polysaccharides and Zn2+
by Shenghao Cui, Faming Yang, Dingyi Yu, Chao Shi, Di Zhao, Liqi Chen and Jingdi Chen
Int. J. Mol. Sci. 2023, 24(17), 13042; https://doi.org/10.3390/ijms241713042 - 22 Aug 2023
Cited by 2 | Viewed by 1144
Abstract
Developing convenient, efficient, and natural wound dressings remain the foremost strategy for treating skin wounds. Thus, we innovatively combined the semi-dissolved acidified sol-gel conversion method with the internal gelation method to fabricate SA (sodium alginate)/CS (chitosan)/Zn2+ physically cross-linked double network hydrogel and [...] Read more.
Developing convenient, efficient, and natural wound dressings remain the foremost strategy for treating skin wounds. Thus, we innovatively combined the semi-dissolved acidified sol-gel conversion method with the internal gelation method to fabricate SA (sodium alginate)/CS (chitosan)/Zn2+ physically cross-linked double network hydrogel and named it SA/CS/Zn2+ PDH. The characterization results demonstrated that increased Zn2+ content led to hydrogels with improved physical and chemical properties, such as rheology, water retention, and swelling capacity. Moreover, the hydrogels exhibited favorable antibacterial properties and biocompatibility. Notably, the establishment of an in vitro pro-healing wound model further confirmed that the hydrogel had a superior ability to repair wounds and promote skin regeneration. In future, as a natural biomaterial with antimicrobial properties, it has the potential to promote wound healing. Full article
(This article belongs to the Special Issue Novel Natural Compound for Wound and Tissue Repair and Regeneration 2.0)
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Review

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31 pages, 2864 KiB  
Review
Natural Compounds and Biomimetic Engineering to Influence Fibroblast Behavior in Wound Healing
by Charlotte E. Berry, Camille Brenac, Caroline E. Gonzalez, Carter B. Kendig, Thalia Le, Nicholas An and Michelle F. Griffin
Int. J. Mol. Sci. 2024, 25(6), 3274; https://doi.org/10.3390/ijms25063274 - 14 Mar 2024
Viewed by 734
Abstract
Throughout history, natural products have played a significant role in wound healing. Fibroblasts, acting as primary cellular mediators in skin wound healing, exhibit behavioral responses to natural compounds that can enhance the wound healing process. Identifying bioactive natural compounds and understanding their impact [...] Read more.
Throughout history, natural products have played a significant role in wound healing. Fibroblasts, acting as primary cellular mediators in skin wound healing, exhibit behavioral responses to natural compounds that can enhance the wound healing process. Identifying bioactive natural compounds and understanding their impact on fibroblast behavior offers crucial translational opportunities in the realm of wound healing. Modern scientific techniques have enabled a detailed understanding of how naturally derived compounds modulate wound healing by influencing fibroblast behavior. Specific compounds known for their wound healing properties have been identified. Engineered biomimetic compounds replicating the natural wound microenvironment are designed to facilitate normal healing. Advanced delivery methods operating at micro- and nano-scales have been developed to effectively deliver these novel compounds through the stratum corneum. This review provides a comprehensive summary of the efficacy of natural compounds in influencing fibroblast behavior for promoting wound regeneration and repair. Additionally, it explores biomimetic engineering, where researchers draw inspiration from nature to create materials and devices mimicking physiological cues crucial for effective wound healing. The review concludes by describing novel delivery mechanisms aimed at enhancing the bioavailability of natural compounds. Innovative future strategies involve exploring fibroblast-influencing pathways, responsive biomaterials, smart dressings with real-time monitoring, and applications of stem cells. However, translating these findings to clinical settings faces challenges such as the limited validation of biomaterials in large animal models and logistical obstacles in industrial production. The integration of ancient remedies with modern approaches holds promise for achieving effective and scar-free wound healing. Full article
(This article belongs to the Special Issue Novel Natural Compound for Wound and Tissue Repair and Regeneration 2.0)
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15 pages, 1149 KiB  
Review
Scarring Skin: Mechanisms and Therapies
by Xinye Lin and Yuping Lai
Int. J. Mol. Sci. 2024, 25(3), 1458; https://doi.org/10.3390/ijms25031458 - 25 Jan 2024
Viewed by 939
Abstract
Skin injury always results in fibrotic, non-functional scars in adults. Although multiple factors are well-known contributors to scar formation, the precise underlying mechanisms remain elusive. This review aims to elucidate the intricacies of the wound healing process, summarize the known factors driving skin [...] Read more.
Skin injury always results in fibrotic, non-functional scars in adults. Although multiple factors are well-known contributors to scar formation, the precise underlying mechanisms remain elusive. This review aims to elucidate the intricacies of the wound healing process, summarize the known factors driving skin cells in wounds toward a scarring fate, and particularly to discuss the impact of fibroblast heterogeneity on scar formation. To the end, we explore potential therapeutic interventions used in the treatment of scarring wounds. Full article
(This article belongs to the Special Issue Novel Natural Compound for Wound and Tissue Repair and Regeneration 2.0)
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11 pages, 7981 KiB  
Review
Why Are There So Few FDA-Approved Therapeutics for Wound Healing?
by Mei Chen, Cheng Chang, Brandon Levian, David T. Woodley and Wei Li
Int. J. Mol. Sci. 2023, 24(20), 15109; https://doi.org/10.3390/ijms242015109 - 12 Oct 2023
Cited by 1 | Viewed by 1739
Abstract
Since the only and the milestone FDA approval of becaplermin gel (RegranexTM, 0.01% human recombinant PDGF-BB) as a (diabetic) wound healing therapeutic more than 25 years ago, no new therapeutic (excluding physical therapies, devices, dressings, anti-microbial agents, or other preventive treatments) [...] Read more.
Since the only and the milestone FDA approval of becaplermin gel (RegranexTM, 0.01% human recombinant PDGF-BB) as a (diabetic) wound healing therapeutic more than 25 years ago, no new therapeutic (excluding physical therapies, devices, dressings, anti-microbial agents, or other preventive treatments) for any type of wound healing has advanced to clinical applications. During the same period of time, the FDA has approved additional 250 new drugs for various human tumors, which were famously described as “wounds that do not heal”. Two similar pathological conditions have experienced such a dramatic difference in therapeutics. More surprisingly, few in the wound healing community seem to be alarmed by this mysterious deficit. As it is often said, “damaging is far easier than re-building”. In contrast to the primary duty of a cancer drug to damage a single molecule of the signaling network, a wound healing drug must be able to re-build the multi-level damages in the wound. No known single molecule alone is capable of repairing multi-cell-type and multi-pathway damages all at once. We argue that the previous single molecule-based strategy for developing wound healing therapeutics is profoundly flawed in theory. The future success of effective wound healing therapeutics requires a fundamental change in the paradigm. Full article
(This article belongs to the Special Issue Novel Natural Compound for Wound and Tissue Repair and Regeneration 2.0)
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