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Recent Approaches for Wound Treatment

by Cinzia Pagano, César Antonio Viseras Iborra and Luana Perioli

Int. J. Mol. Sci. 2023, 24(6), 5959; https://doi.org/10.3390/ijms24065959 - 22 Mar 2023

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Abstract

Wounds are a serious global health problem [...] Full article

(This article belongs to the Special Issue Recent Approaches for Wound Treatment)

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16 pages, 6956 KiB

Open AccessArticle

Different Dimensional Copper-Based Metal–Organic Frameworks with Enzyme-Mimetic Activity for Antibacterial Therapy

by Chuyan Lin, Xiangjian Guo, Fayin Mo and Duanping Sun

Int. J. Mol. Sci. 2023, 24(4), 3173; https://doi.org/10.3390/ijms24043173 - 06 Feb 2023

Cited by 12 | Viewed by 2010

Abstract

Fighting against bacterial infection and accelerating wound healing remain important and challenging in infected wound care. Metal–organic frameworks (MOFs) have received much attention for their optimized and enhanced catalytic performance in different dimensions of these challenges. The size and morphology of nanomaterials are [...] Read more.

Fighting against bacterial infection and accelerating wound healing remain important and challenging in infected wound care. Metal–organic frameworks (MOFs) have received much attention for their optimized and enhanced catalytic performance in different dimensions of these challenges. The size and morphology of nanomaterials are important in their physiochemical properties and thereby their biological functions. Enzyme-mimicking catalysts, based on MOFs of different dimensions, display varying degrees of peroxidase (POD)-like activity toward hydrogen peroxide (H₂O₂) decomposition into toxic hydroxyl radicals (•OH) for bacterial inhibition and accelerating wound healing. In this study, we investigated the two most studied representatives of copper-based MOFs (Cu-MOFs), three-dimensional (3D) HKUST-1 and two-dimensional (2D) Cu-TCPP, for antibacterial therapy. HKUST-1, with a uniform and octahedral 3D structure, showed higher POD-like activity, resulting in H₂O₂ decomposition for •OH generation rather than Cu-TCPP. Because of the efficient generation of toxic •OH, both Gram-negative Escherichia coli and Gram-positive methicillin-resistant Staphylococcus aureus could be eliminated under a lower concentration of H₂O₂. Animal experiments indicated that the as-prepared HKUST-1 effectively accelerated wound healing with good biocompatibility. These results reveal the multivariate dimensions of Cu-MOFs with high POD-like activity, providing good potential for further stimulation of specific bacterial binding therapies in the future. Full article

(This article belongs to the Special Issue Recent Approaches for Wound Treatment)

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19 pages, 4354 KiB

Open AccessArticle

Electrospun Scaffolds Based on Poly(butyl cyanoacrylate) for Tendon Tissue Engineering

by Eleonora Bianchi, Barbara Vigani, Marco Ruggeri, Elena Del Favero, Caterina Ricci, Pietro Grisoli, Anita Ferraretto, Silvia Rossi, César Viseras and Giuseppina Sandri

Int. J. Mol. Sci. 2023, 24(4), 3172; https://doi.org/10.3390/ijms24043172 - 06 Feb 2023

Cited by 5 | Viewed by 1834

Abstract

Tendon disorders are common medical conditions that could lead to significant disability, pain, healthcare costs, and a loss of productivity. Traditional approaches require long periods of treatment, and they largely fail due to the tissues weakening and the postoperative alterations of the normal [...] Read more.

Tendon disorders are common medical conditions that could lead to significant disability, pain, healthcare costs, and a loss of productivity. Traditional approaches require long periods of treatment, and they largely fail due to the tissues weakening and the postoperative alterations of the normal joint mechanics. To overcome these limitations, innovative strategies for the treatment of these injuries need to be explored. The aim of the present work was the design of nano-fibrous scaffolds based on poly(butyl cyanoacrylate) (PBCA), a well-known biodegradable and biocompatible synthetic polymer, doped with copper oxide nanoparticles and caseinphosphopeptides (CPP), able to mimic the hierarchical structure of the tendon and to improve the tissue healing potential. These were developed as implants to be sutured to reconstruct the tendons and the ligaments during surgery. PBCA was synthetized, and then electrospun to produce aligned nanofibers. The obtained scaffolds were characterized for their structure and physico-chemical and mechanical properties, highlighting that CuO and CPP loading, and the aligned conformation determined an increase in the scaffold mechanical performance. Furthermore, the scaffolds loaded with CuO showed antioxidant and anti-inflammatory properties. Moreover, human tenocytes adhesion and proliferation to the scaffolds were assessed in vitro. Finally, the antibacterial activity of the scaffolds was evaluated using Escherichia coli and Staphylococcus aureus as representative of Gram-negative and Gram-positive bacteria, respectively, demonstrating that the CuO-doped scaffolds possessed a significant antimicrobial effect against E. coli. In conclusion, scaffolds based on PBCA and doped with CuO and CPP deserve particular attention as enhancers of the tendon tissue regeneration and able to avoid bacterial adhesion. Further investigation on the scaffold efficacy in vivo will assess their capability for enhancing the tendon ECM restoration in view of accelerating their translation to the clinic. Full article

(This article belongs to the Special Issue Recent Approaches for Wound Treatment)

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18 pages, 2824 KiB

Open AccessArticle

The In Vitro Impact of Isoxazole Derivatives on Pathogenic Biofilm and Cytotoxicity of Fibroblast Cell Line

by Urszula Bąchor, Adam Junka, Malwina Brożyna and Marcin Mączyński

Int. J. Mol. Sci. 2023, 24(3), 2997; https://doi.org/10.3390/ijms24032997 - 03 Feb 2023

Cited by 6 | Viewed by 1626

Abstract

The microbial, biofilm-based infections of chronic wounds are one of the major challenges of contemporary medicine. The use of topically administered antiseptic agents is essential to treat wound-infecting microorganisms. Due to observed microbial tolerance/resistance against specific clinically-used antiseptics, the search for new, efficient [...] Read more.

The microbial, biofilm-based infections of chronic wounds are one of the major challenges of contemporary medicine. The use of topically administered antiseptic agents is essential to treat wound-infecting microorganisms. Due to observed microbial tolerance/resistance against specific clinically-used antiseptics, the search for new, efficient agents is of pivotal meaning. Therefore, in this work, 15 isoxazole derivatives were scrutinized against leading biofilm wound pathogens Staphylococcus aureus and Pseudomonas aeruginosa, and against Candida albicans fungus. For this purpose, the minimal inhibitory concentration, biofilm reduction in microtitrate plates, modified disk diffusion methods and antibiofilm dressing activity measurement methods were applied. Moreover, the cytotoxicity and cytocompatibility of derivatives was tested toward wound bed-forming cells, referred to as fibroblasts, using normative methods. Obtained results revealed that all isoxazole derivatives displayed antimicrobial activity and low cytotoxic effect, but antimicrobial activity of two derivatives, 2-(cyclohexylamino)-1-(5-nitrothiophen-2-yl)-2-oxoethyl 5-amino-3-methyl-1,2-oxazole-4-carboxylate (PUB9) and 2-(benzylamino)-1-(5-nitrothiophen-2-yl)-2-oxoethyl 5-amino-3-methyl-1,2-oxazole-4-carboxylate (PUB10), was noticeably higher compared to the other compounds analyzed, especially PUB9 with regard to Staphylococcus aureus, with a minimal inhibitory concentration more than x1000 lower compared to the remaining derivatives. The PUB9 and PUB10 derivatives were able to reduce more than 90% of biofilm-forming cells, regardless of the species, displaying at the same time none (PUB9) or moderate (PUB10) cytotoxicity against fibroblasts and high (PUB9) or moderate (PUB10) cytocompatibility against these wound cells. Therefore, taking into consideration the clinical demand for new antiseptic agents for non-healing wound treatment, PUB9 seems to be a promising candidate to be further tested in advanced animal models and later, if satisfactory results are obtained, in the clinical setting. Full article

(This article belongs to the Special Issue Recent Approaches for Wound Treatment)

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14 pages, 4651 KiB

Open AccessArticle

Biomaterial Inks from Peptide-Functionalized Silk Fibers for 3D Printing of Futuristic Wound-Healing and Sensing Materials

by Maria Rachele Ceccarini, Valentina Palazzi, Raffaele Salvati, Irene Chiesa, Carmelo De Maria, Stefania Bonafoni, Paolo Mezzanotte, Michela Codini, Lorenzo Pacini, Fosca Errante, Paolo Rovero, Antonino Morabito, Tommaso Beccari, Luca Roselli and Luca Valentini

Int. J. Mol. Sci. 2023, 24(2), 947; https://doi.org/10.3390/ijms24020947 - 04 Jan 2023

Cited by 7 | Viewed by 1980

Abstract

This study illustrates the sensing and wound healing properties of silk fibroin in combination with peptide patterns, with an emphasis on the printability of multilayered grids, and envisions possible applications of these next-generation silk-based materials. Functionalized silk fibers covalently linked to an arginine–glycine–aspartic [...] Read more.

This study illustrates the sensing and wound healing properties of silk fibroin in combination with peptide patterns, with an emphasis on the printability of multilayered grids, and envisions possible applications of these next-generation silk-based materials. Functionalized silk fibers covalently linked to an arginine–glycine–aspartic acid (RGD) peptide create a platform for preparing a biomaterial ink for 3D printing of grid-like piezoresistors with wound-healing and sensing properties. The culture medium obtained from 3D-printed silk fibroin enriched with RGD peptide improves cell adhesion, accelerating skin repair. Specifically, RGD peptide-modified silk fibroin demonstrated biocompatibility, enhanced cell adhesion, and higher wound closure rates at lower concentration than the neat peptide. It was also shown that the printing of peptide-modified silk fibroin produces a piezoresistive transducer that is the active component of a sensor based on a Schottky diode harmonic transponder encoding information about pressure. We discovered that such biomaterial ink printed in a multilayered grid can be used as a humidity sensor. Furthermore, humidity activates a transition between low and high conductivity states in this medium that is retained unless a negative voltage is applied, paving the way for utilization in non-volatile organic memory devices. Globally, these results pave the way for promising applications, such as monitoring parameters such as human wound care and being integrated in bio-implantable processors. Full article

(This article belongs to the Special Issue Recent Approaches for Wound Treatment)

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11 pages, 879 KiB

Open AccessArticle

Effectiveness of Semi-Supervised Active Learning in Automated Wound Image Segmentation

by Nico Curti, Yuri Merli, Corrado Zengarini, Enrico Giampieri, Alessandra Merlotti, Daniele Dall’Olio, Emanuela Marcelli, Tommaso Bianchi and Gastone Castellani

Int. J. Mol. Sci. 2023, 24(1), 706; https://doi.org/10.3390/ijms24010706 - 31 Dec 2022

Cited by 6 | Viewed by 2043

Abstract

Appropriate wound management shortens the healing times and reduces the management costs, benefiting the patient in physical terms and potentially reducing the healthcare system’s economic burden. Among the instrumental measurement methods, the image analysis of a wound area is becoming one of the [...] Read more.

Appropriate wound management shortens the healing times and reduces the management costs, benefiting the patient in physical terms and potentially reducing the healthcare system’s economic burden. Among the instrumental measurement methods, the image analysis of a wound area is becoming one of the cornerstones of chronic ulcer management. Our study aim is to develop a solid AI method based on a convolutional neural network to segment the wounds efficiently to make the work of the physician more efficient, and subsequently, to lay the foundations for the further development of more in-depth analyses of ulcer characteristics. In this work, we introduce a fully automated model for identifying and segmenting wound areas which can completely automatize the clinical wound severity assessment starting from images acquired from smartphones. This method is based on an active semi-supervised learning training of a convolutional neural network model. In our work, we tested the robustness of our method against a wide range of natural images acquired in different light conditions and image expositions. We collected the images using an ad hoc developed app and saved them in a database which we then used for AI training. We then tested different CNN architectures to develop a balanced model, which we finally validated with a public dataset. We used a dataset of images acquired during clinical practice and built an annotated wound image dataset consisting of 1564 ulcer images from 474 patients. Only a small part of this large amount of data was manually annotated by experts (ground truth). A multi-step, active, semi-supervised training procedure was applied to improve the segmentation performances of the model. The developed training strategy mimics a continuous learning approach and provides a viable alternative for further medical applications. We tested the efficiency of our model against other public datasets, proving its robustness. The efficiency of the transfer learning showed that after less than 50 epochs, the model achieved a stable DSC that was greater than 0.95. The proposed active semi-supervised learning strategy could allow us to obtain an efficient segmentation method, thereby facilitating the work of the clinician by reducing their working times to achieve the measurements. Finally, the robustness of our pipeline confirms its possible usage in clinical practice as a reliable decision support system for clinicians. Full article

(This article belongs to the Special Issue Recent Approaches for Wound Treatment)

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16 pages, 4180 KiB

Open AccessArticle

Optimization of an Ex-Vivo Human Skin/Vein Model for Long-Term Wound Healing Studies: Ground Preparatory Activities for the ‘Suture in Space’ Experiment Onboard the International Space Station

by Francesca Cialdai, Stefano Bacci, Virginia Zizi, Aleandro Norfini, Michele Balsamo, Valerio Ciccone, Lucia Morbidelli, Laura Calosi, Chiara Risaliti, Lore Vanhelden, Desirée Pantalone, Daniele Bani and Monica Monici

Int. J. Mol. Sci. 2022, 23(22), 14123; https://doi.org/10.3390/ijms232214123 - 16 Nov 2022

Cited by 2 | Viewed by 2107

Abstract

This study is preliminary to an experiment to be performed onboard the International Space Station (ISS) and on Earth to investigate how low gravity influences the healing of sutured human skin and vein wounds. Its objective was to ascertain whether these tissue explants [...] Read more.

This study is preliminary to an experiment to be performed onboard the International Space Station (ISS) and on Earth to investigate how low gravity influences the healing of sutured human skin and vein wounds. Its objective was to ascertain whether these tissue explants could be maintained to be viable ex vivo for long periods of time, mimicking the experimental conditions onboard the ISS. We developed an automated tissue culture chamber, reproducing and monitoring the physiological tensile forces over time, and a culture medium enriched with serelaxin (60 ng/mL) and (Zn(PipNONO)Cl) (28 ng/mL), known to extend viability of explanted organs for transplantation. The results show that the human skin and vein specimens remained viable for more than 4 weeks, with no substantial signs of damage in their tissues and cells. As a further clue about cell viability, some typical events associated with wound repair were observed in the tissue areas close to the wound, namely remodeling of collagen fibers in the papillary dermis and of elastic fibers in the vein wall, proliferation of keratinocyte stem cells, and expression of the endothelial functional markers eNOS and FGF-2. These findings validate the suitability of this new ex vivo organ culture system for wound healing studies, not only for the scheduled space experiment but also for applications on Earth, such as drug discovery purposes. Full article

(This article belongs to the Special Issue Recent Approaches for Wound Treatment)

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15 pages, 2858 KiB

Open AccessArticle

Influence of Acidic pH on Wound Healing In Vivo: A Novel Perspective for Wound Treatment

by Pivian Sim, Xanthe L. Strudwick, YunMei Song, Allison J. Cowin and Sanjay Garg

Int. J. Mol. Sci. 2022, 23(21), 13655; https://doi.org/10.3390/ijms232113655 - 07 Nov 2022

Cited by 35 | Viewed by 4776

Abstract

There has been little understanding of acidification functionality in wound healing, highlighting the need to study the efficacy of wound acidification on wound closure and cellular activity in non-infected wounds. This study is focused on establishing the healing potential of wound acidification in [...] Read more.

There has been little understanding of acidification functionality in wound healing, highlighting the need to study the efficacy of wound acidification on wound closure and cellular activity in non-infected wounds. This study is focused on establishing the healing potential of wound acidification in non-infected wounds. Acidic buffers, constituting either phosphoric or citric acid, were employed to modify the physiological pH of non-infected full-thickness excisional murine wounds. Acidification of the wound by acidic buffers was found to be an effective strategy to improve wound healing. A significant improvement in wound healing parameters was observed as early as 2 days post-treatment with acidic buffers compared to controls, with faster rate of epithelialization, wound closure and higher levels of collagen at day 7. pH is shown to play a role in mediating the rate of wound healing, with acidic buffers formulated at pH 4 observed to stimulate faster recovery of wounded tissues than pH 6 buffers. Our study shows the importance of maintaining an acidic wound microenvironment at pH 4, which could be a potential therapeutic strategy for wound management. Full article

(This article belongs to the Special Issue Recent Approaches for Wound Treatment)

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22 pages, 11633 KiB

Open AccessArticle

Investigation of the Properties of Linen Fibers and Dressings

by Tomasz Gębarowski, Izabela Jęśkowiak and Benita Wiatrak

Int. J. Mol. Sci. 2022, 23(18), 10480; https://doi.org/10.3390/ijms231810480 - 09 Sep 2022

Cited by 4 | Viewed by 2262

Abstract

In antiquity, flax was used as a dressing for healing wounds. Currently, work is underway on the genetic modification of flax fibers to improve their properties. Genetic modifications have resulted in an increased content of antioxidants and more favorable mechanical properties. The works [...] Read more.

In antiquity, flax was used as a dressing for healing wounds. Currently, work is underway on the genetic modification of flax fibers to improve their properties. Genetic modifications have resulted in an increased content of antioxidants and more favorable mechanical properties. The works published so far have presented independent tests of fibers and dressings after appropriate technological treatments in cell cultures. This study aimed to compare the properties of the fibers and the dressing produced in cell cultures—hamster fibroblasts—V79. The research material was traditional NIKE fibers; genetically modified M, B, and MB fibers; and linen dressings obtained from these fibers. The extract from 48-h incubation of 40 mg of fiber in the culture medium, which was desolved into 10, 20, and 30 mg, was administered to the cell culture. On the other hand, a linen dressing was placed on cells with an area of 0.5 cm², 1 cm², 1.5 cm², and 2 cm². Cells with fiber or dressing were incubated for 48 h, and then, biological tests were performed, including cell viability (in propidium iodide staining), cell proliferation (in the SRB assay), evaluation of the intracellular free radical level (in the DCF-DA assay), genotoxicity (in the comet assay), assessment of the apoptotic and necrotic cells (in staining anexin-V and iodide propidium), the course of the cell cycle, and the scratch test. The correlation between apoptosis and genotoxicity and the levels of free radicals and genotoxicity were determined for the tested linen fibers and fabrics. The tests presented that the fibers are characterized by the ability to eliminate damaged cells in the elimination phase. However, the obtained fabrics gain different properties during the technological processing of the fibers into linen dressings. Linen fabrics have better regenerative properties for cells than fibers. The linseed dressing made of MB fiber has the most favorable regenerative properties. Full article

(This article belongs to the Special Issue Recent Approaches for Wound Treatment)

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18 pages, 2733 KiB

Open AccessArticle

Human Umbilical Cord Lining-Derived Epithelial Cells: A Potential Source of Non-Native Epithelial Cells That Accelerate Healing in a Porcine Cutaneous Wound Model

by Jonah Ee Hsiang Kua, Chun Wei Siow, Wee Keng Lim, Jeyakumar Masilamani, Monica Suryana Tjin, Joe Yeong, Tony Kiat Hon Lim, Toan Thang Phan and Alvin Wen Choong Chua

Int. J. Mol. Sci. 2022, 23(16), 8918; https://doi.org/10.3390/ijms23168918 - 10 Aug 2022

Cited by 2 | Viewed by 1784

Abstract

Human umbilical cord lining epithelial cells [CLECs) are naïve in nature and can be ethically recovered from cords that are routinely discarded. The success of using oral mucosal epithelial cells for cornea defects hints at the feasibility of treating cutaneous wounds using non-native [...] Read more.

Human umbilical cord lining epithelial cells [CLECs) are naïve in nature and can be ethically recovered from cords that are routinely discarded. The success of using oral mucosal epithelial cells for cornea defects hints at the feasibility of treating cutaneous wounds using non-native CLECs. Herein, we characterized CLECs using flow cytometry (FC) and skin organotypic cultures in direct comparison with skin keratinocytes (KCs). This was followed by wound healing study to compare the effects of CLEC application and the traditional use of human skin allografts (HSGs) in a porcine wound model. While CLECs were found to express all the epidermal cell markers probed, the major difference between CLECs and KCs lies in the level of expression (in FC analysis) as well as in the location of expression (of the epithelium in organotypic cultures) of some of the basal cell markers probed. On the pig wounds, CLEC application promoted accelerated healing with no adverse reaction compared to HSG use. Though CLECs, like HSGs, elicited high levels of local and systemic immune responses in the animals during the first week, these effects were tapered off more quickly in the CLEC-treated group. Overall, the in vivo porcine data point to the potential of CLECs as a non-native and safe source of cells to treat cutaneous wounds. Full article

(This article belongs to the Special Issue Recent Approaches for Wound Treatment)

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15 pages, 2513 KiB

Open AccessArticle

In Vitro Wound Healing Properties of Novel Acidic Treatment Regimen in Enhancing Metabolic Activity and Migration of Skin Cells

by Pivian Sim, Yunmei Song, Gink N. Yang, Allison J. Cowin and Sanjay Garg

Int. J. Mol. Sci. 2022, 23(13), 7188; https://doi.org/10.3390/ijms23137188 - 28 Jun 2022

Cited by 6 | Viewed by 1703

Abstract

Strategies that alter the pH of wounds to improve healing outcomes are an emerging area of interest. Currently, there is limited understanding of the effect of hydrogen (H⁺) on the functionality of skin cells during proliferation and migration, highlighting the need [...] Read more.

Strategies that alter the pH of wounds to improve healing outcomes are an emerging area of interest. Currently, there is limited understanding of the effect of hydrogen (H⁺) on the functionality of skin cells during proliferation and migration, highlighting the need for research to determine the effect of pH during wound healing. This study aimed to determine the effect of acidification on the metabolic activity and migration of human immortalized keratinocytes (HaCaT) and human foreskin fibroblasts (HFF). In vitro models were used with phosphoric and citric acid buffers at a pH range between 3 and 7. Our results showed that cells were more viable in buffers with low rather than high ionic strength. A time-dependent effect of the acidification treatment was also observed with cell metabolic activity varying with treatment duration and frequency. Our results showed that a 24 h treatment and subsequent resting phase significantly improved cell proliferation and migration. This in vitro study is the first to establish a correlation between the role of acidic pH, molarity and treatment regimen in cellular activity. Our data demonstrated a positive effect of acidic pH on cell metabolic activity and migration rate, suggesting a clinical potential in indications such as wound healing. Full article

(This article belongs to the Special Issue Recent Approaches for Wound Treatment)

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13 pages, 15350 KiB

Open AccessArticle

Antimicrobial Combined Action of Graphene Oxide and Light Emitting Diodes for Chronic Wound Management

by Silvia Di Lodovico, Firas Diban, Paola Di Fermo, Morena Petrini, Antonella Fontana, Mara Di Giulio, Adriano Piattelli, Simonetta D’Ercole and Luigina Cellini

Int. J. Mol. Sci. 2022, 23(13), 6942; https://doi.org/10.3390/ijms23136942 - 22 Jun 2022

Cited by 10 | Viewed by 1973

Abstract

Innovative non-antibiotic compounds such as graphene oxide (GO) and light-emitting diodes (LEDs) may represent a valid strategy for managing chronic wound infections related to resistant pathogens. This study aimed to evaluate 630 nm LED and 880 nm LED ability to enhance the GO [...] Read more.

Innovative non-antibiotic compounds such as graphene oxide (GO) and light-emitting diodes (LEDs) may represent a valid strategy for managing chronic wound infections related to resistant pathogens. This study aimed to evaluate 630 nm LED and 880 nm LED ability to enhance the GO antimicrobial activity against Staphylococcus aureus- and Pseudomonas aeruginosa-resistant strains in a dual-species biofilm in the Lubbock chronic wound biofilm (LCWB) model. The effect of a 630 nm LED, alone or plus 5-aminolevulinic acid (ALAD)-mediated photodynamic therapy (PDT) (ALAD-PDT), or an 880 nm LED on the GO (50 mg/l) action was evaluated by determining the CFU/mg reductions, live/dead analysis, scanning electron microscope observation, and reactive oxygen species assay. Among the LCWBs, the best effect was obtained with GO irradiated with ALAD-PDT, with percentages of CFU/mg reduction up to 78.96% ± 0.21 and 95.17% ± 2.56 for S. aureus and P. aeruginosa, respectively. The microscope images showed a reduction in the cell number and viability when treated with GO + ALAD-PDT. In addition, increased ROS production was detected. No differences were recorded when GO was irradiated with an 880 nm LED versus GO alone. The obtained results suggest that treatment with GO irradiated with ALAD-PDT represents a valid, sustainable strategy to counteract the polymicrobial colonization of chronic wounds. Full article

(This article belongs to the Special Issue Recent Approaches for Wound Treatment)

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