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New Advances in Complex Wound Management: Biofilms and Emerging Biotechnologies as Effective Therapies

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Biomedical Engineering and Materials".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 48084

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Special Issue Editors

Dr. Barbara De Angelis

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Guest Editor

Plastic and Reconstructive Surgery, University of Rome “Tor Vergata”, Rome, Italy
Interests: regenerative surgery; biomaterials; wound healing; biotechnology; wound infection; wound biofilm

Dr. Pietro Gentile

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Guest Editor

Associate Professor of Plastic and Reconstructive Surgery, Surgical Science Department, University of Rome “Tor Vergata”, Rome, Italy
Interests: regenerative plastic surgery; adipose-derived mesenchymal stem cells; fat grafting; platelet-rich plasma; growth factors; mesenchymal stem cells; biomaterials; hair loss; androgenetic alopecia
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Dr. Luigi Toma

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Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy
Interests: wound healing; wound biofilm; biomedicines

Dr. Rica Tanaka

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Guest Editor

School of Medicine, Department of Plastic and Reconstructive Surgery, Juntendo University, Tokyo, Japan
Interests: regenerative medicine; stem cell therapy; endothelial progenitor cells; wound healing; plastic surgery; angiogenesis; macrophages

Special Issue Information

Dear Colleagues,

Wound healing is still an evolving field of research. There are several approaches to achieving healing: multidisciplinarity, biotechnology, and strategies to counter biofilms. Infection and biofilm formation is one of the main causes of chronic wounds, and its removal is essential.

The union of the correct management of the wound and the use of new biotechnologies aimed at stimulating the healing of the same makes it possible to reach the goal in less time and with improvement of the patient’s quality of life. Several advanced dressings, biotechnologies, and biomaterials have been described with the aim of improving the wound healing; among these, hydrogel, platelet-rich plasma (PRP), and dermal substitutes are particularly promising.

In this Special Issue, we would like to highlight the wide variety of hydrogel, PRP, and dermal substitute applications in wound healing and regenerative surgery, analyzing also the biomolecular pathways through which they act. This Special Issue, which will serve as an updated reference for biomaterials and biotechnologies used in wound healing, will collect contributions (original research articles, reviews) dealing with innovative regenerative biomedical applications based on PRP, dermal substitutes, and advanced dressings. Both in vitro and in vivo studies are welcome, with the final goal of shedding light on the new frontiers of advanced dressing, and regenerative strategies in wound healing.

Dr. Barbara De Angelis
Dr. Pietro Gentile
Dr. Luigi Toma
Dr. Rica Tanaka
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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

regenerative surgery
biomaterials
wound healing
biotechnology
wound infection
wound biofilm
immune system
tissue regeneration
complex wounds
biomedicines

Published Papers (11 papers)

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Research

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12 pages, 2111 KiB

Open AccessArticle

Effect of MNCQQ Cells on Migration of Human Dermal Fibroblast in Diabetic Condition

by Sen Jiang, Rie Ito-Hirano, Tsubame Nishikai-Yan Shen, Satoshi Fujimura, Hiroshi Mizuno and Rica Tanaka

Biomedicines 2022, 10(10), 2544; https://doi.org/10.3390/biomedicines10102544 - 12 Oct 2022

Cited by 1 | Viewed by 1281

Abstract

A major symptom of diabetes mellitus (DM) is unfit hyperglycemia, which leads to impaired wound healing. It has been reported that the migration of fibroblasts can be suppressed under high glucose (HG) conditions. In our previous study, we introduced a serum-free culture method for mononuclear cells (MNCs) called quantity and quality control culture (QQc), which could improve the vasculogenic and tissue regeneration ability of MNCs. In this study, we described a culture model in which we applied a high glucose condition in human dermal fibroblasts to simulate the hyperglycemia condition in diabetic patients. MNC-QQ cells were cocultured with fibroblasts in this model to evaluate its role in improving fibroblasts dysfunction induced by HG and investigate its molecular mechanism. It was proven in this study that the impaired migration of fibroblasts induced by high glucose could be remarkably enhanced by coculture with MNC-QQ cells. PDGF B is known to play important roles in fibroblasts migration. Quantitative PCR revealed that MNC-QQ cells enhanced the gene expressions of PDGF B in fibroblasts under HG. Taken with these results, our data suggested a possibility that MNC-QQ cells accelerate wound healing via improving the fibroblasts migration and promote the gene expressions of PDGF B under diabetic conditions. Full article

(This article belongs to the Special Issue New Advances in Complex Wound Management: Biofilms and Emerging Biotechnologies as Effective Therapies)

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9 pages, 1395 KiB

Open AccessArticle

Paper-Based Interleukin-6 Test Strip for Early Detection of Wound Infection

by Shin-Chen Pan, Yu-Feng Wu, Yu-Chen Lin, Sheng-Wen Lin and Chao-Min Cheng

Biomedicines 2022, 10(7), 1585; https://doi.org/10.3390/biomedicines10071585 - 03 Jul 2022

Cited by 2 | Viewed by 1655

Abstract

The early stage of wound infection is always non-specific. Prompt intervention may help to prevent the wound from worsening. We developed a new protocol, based on previous research, that employs a paper-based IL-6 test strip used in combination with a spectrum-based optical reader to detect IL-6 in normal tissue (n = 19), acute wounds (n = 31), and chronic wounds (n = 32). Our data indicated the presence of significantly higher levels of IL-6 in acute wound tissues, but no significant difference in serum CRP. Receiver operating characteristics were used to determine clinical sensitivity and specificity of tissue IL-6 and systemic CRP. The area under the curve values were 0.87 and 0.63, respectively. The cut-off value of 30 pg/mL for IL-6 provided good sensitivity (75.0%) and superior specificity (88.9%). We found a high correlation between the IL-6 test strip and conventional ELISA results (R² = 0.85, p < 0.001), and good agreement was also observed according to Bland-Altman analysis. We showed a promising role of tissue IL-6 to help early diagnosis of wound infection when clinical symptoms were non-specific. The advantages of this wound detection protocol included minimal invasiveness, small sample requirements, speed, sample preparation ease, and user-friendliness. This methodology could help care providers quickly clarify wound infection status and implement timely, optimal management. Full article

(This article belongs to the Special Issue New Advances in Complex Wound Management: Biofilms and Emerging Biotechnologies as Effective Therapies)

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14 pages, 1699 KiB

Open AccessArticle

Point-of-Care Wound Blotting with Alcian Blue Grading versus Fluorescence Imaging for Biofilm Detection and Predicting 90-Day Healing Outcomes

by Yu-Feng Wu, Yu-Chen Lin, Hung-Wei Yang, Nai-Chen Cheng and Chao-Min Cheng

Biomedicines 2022, 10(5), 1200; https://doi.org/10.3390/biomedicines10051200 - 22 May 2022

Cited by 2 | Viewed by 2788

Abstract

Biofilm infection has been identified as a crucial factor of the pathogenesis of chronic wound, but wound biofilm diagnosis remains as an unmet clinical need. We previously proposed a modified wound blotting technique using Alcian blue staining for biofilm detection that was characterized as being non-invasive, time-saving, non-expansive, and informative for biofilm distribution. In this study, we adapted a novel Alcian blue grading method as the severity of biofilm infection for the wound blotting technique and compared its biofilm detection efficacy with MolecuLight i:X- a point-of-care florescence imaging device to detect bacteria and biofilm in wounds. Moreover, their predictive value of complete wound healing at 90 days was analyzed. When validated with wound culture results in the 53 enrolled subjects with chronic wounds, the modified wound blotting method showed a strong association with wound culture, while MolecuLight i:X only exhibited a weak association. In predicting 90-day wound outcomes, the modified wound blotting method showed a strong association (Kendall’s tau value = 0.563, p < 0.001), and the wound culture showed a moderate association (Spearman’s rho = 0.535, p < 0.001), but MolecuLight i:X exhibited no significant association (p = 0.184). In this study, modified wound blotting with the Alcian blue grading method showed superior value to MolecuLight i:X both in biofilm detection and predictive validity in 90-day wound-healing outcomes. Full article

(This article belongs to the Special Issue New Advances in Complex Wound Management: Biofilms and Emerging Biotechnologies as Effective Therapies)

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15 pages, 4389 KiB

Open AccessArticle

Wound Healing Modulation through the Local Application of Powder Collagen-Derived Treatments in an Excisional Cutaneous Murine Model

by Selma Benito-Martínez, Bárbara Pérez-Köhler, Marta Rodríguez, Jesús María Izco, José Ignacio Recalde and Gemma Pascual

Biomedicines 2022, 10(5), 960; https://doi.org/10.3390/biomedicines10050960 - 21 Apr 2022

Cited by 7 | Viewed by 3301

Abstract

Wound healing includes dynamic processes grouped into three overlapping phases: inflammatory, proliferative, and maturation/remodeling. Collagen is a critical component of a healing wound and, due to its properties, is of great interest in regenerative medicine. This preclinical study was designed to compare the effects of a new collagen-based hydrolysate powder on wound repair to a commercial non-hydrolysate product, in a murine model of cutaneous healing. Circular excisional defects were created on the dorsal skin of Wistar rats (n = 36). Three study groups were established according to the treatment administered. Animals were euthanized after 7 and 18 days. Morphometric and morphological studies were performed to evaluate the healing process. The new collagen treatment led to the smallest open wound area throughout most of the study. After seven days, wound morphometry, contraction, and epithelialization were similar in all groups. Treated animals showed reduced granulation tissue formation and fewer inflammatory cells, and induction of vasculature with respect to untreated animals. After 18 days, animals treated with the new collagen treatment showed accelerated wound closure, significantly increased epithelialization, and more organized repair tissue. Our findings suggest that the new collagen treatment, compared to the untreated control group, produces significantly faster wound closure and, at the same time, promotes a slight progression of the reparative process compared with the rest of the groups. Full article

(This article belongs to the Special Issue New Advances in Complex Wound Management: Biofilms and Emerging Biotechnologies as Effective Therapies)

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11 pages, 6079 KiB

Open AccessArticle

Far-Infrared Therapy Accelerates Diabetic Wound Healing via Recruitment of Tissue Angiogenesis in a Full-Thickness Wound Healing Model in Rats

by Rong-Fu Chen, Keng-Fan Liu, Su-Shin Lee, Shu-Hung Huang, Yi-Chia Wu, Yun-Nan Lin, Chun-Ting Wang and Yur-Ren Kuo

Biomedicines 2021, 9(12), 1922; https://doi.org/10.3390/biomedicines9121922 - 15 Dec 2021

Cited by 3 | Viewed by 3642

Abstract

Far-infrared ray (FIR) therapy has been applied in the tissue regeneration field. Studies have revealed that FIR could enhance wound healing. However, the biological effects of FIR on diabetic wounds remain unclear. Our study aims to investigate whether FIR could accelerate diabetic wound healing and analyze the biomechanisms. A dorsal skin defect (area, 6 × 5 cm²) in a streptozotocin (STZ)-induced diabetes rodent model was designed. Thirty-two male Wistar rats were divided into 4 groups (n = 8 each subgroup). Group 1 consisted of sham, non-diabetic control; group 2, diabetic control without treatment; group 3, diabetic rats received 20 min FIR (FIR-20, 20 min per session, triplicate/weekly for 4 weeks) and group 4, diabetic rats received 40 min FIR (FIR-40, 40 min per session, triplicate in one week for 4 weeks). The wound healing was assessed clinically. Skin blood flow was measured by laser Doppler. The vascular endothelial growth factor (VEGF), 8-hydroxy-2-deoxyguanosine (8-OHdG), eNOS, and Ki-67, were analyzed with immunohistochemical (IHC) staining. Laser Doppler flowmetry analysis of the blood flow of wounding area revealed the blood flow was higher in diabetic rats who received 40 min FIR (FIR-40) as compared to that in FIR-20 group. The wounding area was significantly reduced in the FIR-40 group than in the diabetic control groups. Histological findings of peri-wounding tissue revealed a significant increase in the neo-vessels in the FIR-treated groups as compared to the controls. IHC staining of periwounding biopsy tissue showed significant increases in angiogenesis expressions (VEGF, eNOS, and EGF), cell proliferation (Ki-67), and suppressed inflammatory response and oxygen radicles (CD45, 8-OHdG) expressions in the FIR-treated groups as compared to that in controls. Treatment with the optimal dosage of FIR significantly facilitated diabetic wound healing and associated with suppressed pro-inflammatory response and increased neovascularization and tissue regeneration. Full article

(This article belongs to the Special Issue New Advances in Complex Wound Management: Biofilms and Emerging Biotechnologies as Effective Therapies)

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12 pages, 1735 KiB

Open AccessArticle

Topical Administration of Heat-Killed Enterococcus faecalis Strain KH2 Promotes Re-Epithelialization and Granulation Tissue Formation during Skin Wound-Healing

by Hiromasa Tanno, Emi Kanno, Shiho Kurosaka, Yukari Oikawa, Takumi Watanabe, Ko Sato, Jun Kasamatsu, Tomomitsu Miyasaka, Shinyo Ishi, Miki Shoji, Naoyuki Takagi, Yoshimichi Imai, Keiko Ishii, Masahiro Tachi and Kazuyoshi Kawakami

Biomedicines 2021, 9(11), 1520; https://doi.org/10.3390/biomedicines9111520 - 22 Oct 2021

Cited by 5 | Viewed by 3041

Abstract

Lactic acid bacteria (LAB) are known to have beneficial effects on immune responses when they are orally administered as bacterial products. Although the beneficial effects of LAB have been reported for the genera Lactobacillus and Lactococcus, little has been uncovered on the effects of the genus Enterococcus on skin wound-healing. In this study, we aimed to clarify the effect of heat-killed Enterococcus faecalis KH2 (heat-killed KH2) strain on the wound-healing process and to evaluate the therapeutic potential in chronic skin wounds. We analyzed percent wound closure, re-epithelialization, and granulation area, and cytokine and growth factor production. We found that heat-killed KH2 contributed to the acceleration of re-epithelialization and the formation of granulation tissue by inducing tumor necrosis factor-α, interleukin-6, basic fibroblast growth factor, transforming growth factor (TGF)-β1, and vascular endothelial growth factor production. In addition, heat-killed KH2 also improved wound closure, which was accompanied by the increased production of TGF-β1 in diabetic mice. Topical administration of heat-killed KH2 might have therapeutic potential for the treatment of chronic skin wounds in diabetes mellitus. In the present study, we concluded that heat-killed KH2 promoted skin wound-healing through the formation of granulation tissues and the production of inflammatory cytokines and growth factors. Full article

(This article belongs to the Special Issue New Advances in Complex Wound Management: Biofilms and Emerging Biotechnologies as Effective Therapies)

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15 pages, 3690 KiB

Open AccessArticle

Complementary Effect of Non-Persistent Silver Nano-Architectures and Chlorhexidine on Infected Wound Healing

by Mykola Pernakov, Maria Laura Ermini, Oksana Sulaieva, Domenico Cassano, Marco Santucci, Yevhenia Husak, Viktoriia Korniienko, Giulia Giannone, Aziza Yusupova, Iryna Liubchak, Maria Teodora Hristova, Anton Savchenko, Viktoriia Holubnycha, Valerio Voliani and Maksym Pogorielov

Biomedicines 2021, 9(9), 1215; https://doi.org/10.3390/biomedicines9091215 - 14 Sep 2021

Cited by 4 | Viewed by 2719

Abstract

Surgical site infection (SSI) substantially contributes each year to patients’ morbidity and mortality, accounting for about 15% of all nosocomial infections. SSI drastically increases the rehab stint and expenses while jeopardizing health outcomes. Besides prevention, the treatment regime relies on an adequate antibiotic therapy. On the other hand, resistant bacterial strains have currently reached up to 34.3% of the total infections, and this percentage grows annually, reducing the efficacy of the common treatment schemes. Thus, new antibacterial strategies are urgently demanded. Here, we demonstrated in rats the effectiveness of non-persistent silver nano-architectures (AgNAs) in infected wound healing together with their synergistic action in combination with chlorhexidine. Besides the in vivo efficacy evaluation, we performed analysis of the bacteriological profile of purulent wound, histological evaluations, and macrophages polarization quantifications to further validate our findings and elucidate the possible mechanisms of AgNAs action on wound healing. These findings open the way for the composition of robust multifunctional nanoplatforms for the translation of safe and efficient topical treatments of SSI. Full article

(This article belongs to the Special Issue New Advances in Complex Wound Management: Biofilms and Emerging Biotechnologies as Effective Therapies)

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20 pages, 9295 KiB

Open AccessEditor’s ChoiceArticle

Eradication of Mature Bacterial Biofilms with Concurrent Improvement in Chronic Wound Healing Using Silver Nanoparticle Hydrogel Treatment

by Hanif Haidari, Richard Bright, Sanjay Garg, Krasimir Vasilev, Allison J. Cowin and Zlatko Kopecki

Biomedicines 2021, 9(9), 1182; https://doi.org/10.3390/biomedicines9091182 - 08 Sep 2021

Cited by 36 | Viewed by 6650

Abstract

Biofilm-associated infections are a major cause of impaired wound healing. Despite the broad spectrum of anti-bacterial benefits provided by silver nanoparticles (AgNPs), these materials still cause controversy due to cytotoxicity and a lack of efficacy against mature biofilms. Herein, highly potent ultrasmall AgNPs were combined with a biocompatible hydrogel with integrated synergistic functionalities to facilitate elimination of clinically relevant mature biofilms in-vivo combined with improved wound healing capacity. The delivery platform showed a superior release mechanism, reflected by high biocompatibility, hemocompatibility, and extended antibacterial efficacy. In vivo studies using the S. aureus wound biofilm model showed that the AgNP hydrogel (200 µg/g) was highly effective in eliminating biofilm infection and promoting wound repair compared to the controls, including silver sulfadiazine (Ag SD). Treatment of infected wounds with the AgNP hydrogel resulted in faster wound closure (46% closure compared to 20% for Ag SD) and accelerated wound re-epithelization (60% for AgNP), as well as improved early collagen deposition. The AgNP hydrogel did not show any toxicity to tissue and/or organs. These findings suggest that the developed AgNP hydrogel has the potential to be a safe wound treatment capable of eliminating infection and providing a safe yet effective strategy for the treatment of infected wounds. Full article

(This article belongs to the Special Issue New Advances in Complex Wound Management: Biofilms and Emerging Biotechnologies as Effective Therapies)

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24 pages, 9132 KiB

Open AccessArticle

Plasma-Based Bioinks for Extrusion Bioprinting of Advanced Dressings

by Cristina Del Amo, Arantza Perez-Valle, Miguel Perez-Garrastachu, Ines Jauregui, Noelia Andollo, Jon Arluzea, Pedro Guerrero, Koro de la Caba and Isabel Andia

Biomedicines 2021, 9(8), 1023; https://doi.org/10.3390/biomedicines9081023 - 16 Aug 2021

Cited by 3 | Viewed by 2826

Abstract

Extrusion bioprinting based on the development of novel bioinks offers the possibility of manufacturing clinically useful tools for wound management. In this study, we show the rheological properties and printability outcomes of two advanced dressings based on platelet-rich plasma (PRP) and platelet-poor plasma (PPP) blended with alginate and loaded with dermal fibroblasts. Measurements taken at 1 h, 4 days, and 18 days showed that both the PRP- and PPP-based dressings retain plasma and platelet proteins, which led to the upregulation of angiogenic and immunomodulatory proteins by embedded fibroblasts (e.g., an up to 69-fold increase in vascular endothelial growth factor (VEGF), an up to 188-fold increase in monocyte chemotactic protein 1 (MCP-1), and an up to 456-fold increase in hepatocyte growth factor (HGF) 18 days after printing). Conditioned media harvested from both PRP and PPP constructs stimulated the proliferation of human umbilical vein endothelial cells (HUVECs), whereas only those from PRP dressings stimulated HUVEC migration, which correlated with the VEGF/MCP-1 and VEGF/HGF ratios. Similarly, the advanced dressings increased the level of interleukin-8 and led to a four-fold change in the level of extracellular matrix protein 1. These findings suggest that careful selection of plasma formulations to fabricate wound dressings can enable regulation of the molecular composition of the microenvironment, as well as paracrine interactions, thereby improving the clinical potential of dressings and providing the possibility to tailor each composition to specific wound types and healing stages. Full article

(This article belongs to the Special Issue New Advances in Complex Wound Management: Biofilms and Emerging Biotechnologies as Effective Therapies)

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Review

Jump to: Research

11 pages, 1585 KiB

Open AccessReview

Porcine Small Intestinal Submucosa Alters the Biochemical Properties of Wound Healing: A Narrative Review

by Miki Fujii and Rica Tanaka

Biomedicines 2022, 10(9), 2213; https://doi.org/10.3390/biomedicines10092213 - 07 Sep 2022

Cited by 6 | Viewed by 2072

Abstract

Among the many biological scaffold materials currently available for clinical use, the small intestinal submucosa (SIS) is an effective material for wound healing. SIS contains numerous active forms of extracellular matrix that support angiogenesis, cell migration, and proliferation, providing growth factors involved in signaling for tissue formation and assisting wound healing. SIS not only serves as a bioscaffold for cell migration and differentiation, but also restores the impaired dynamic reciprocity between cells and the extracellular matrix, ultimately driving wound healing. Here, we review the evidence on how SIS can shift the biochemical balance in a wound from chronic to an acute state. Full article

(This article belongs to the Special Issue New Advances in Complex Wound Management: Biofilms and Emerging Biotechnologies as Effective Therapies)

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15 pages, 54718 KiB

Open AccessReview

Modern Wound Dressings: Hydrogel Dressings

by Valentin Brumberg, Tatiana Astrelina, Tatiana Malivanova and Alexander Samoilov

Biomedicines 2021, 9(9), 1235; https://doi.org/10.3390/biomedicines9091235 - 16 Sep 2021

Cited by 129 | Viewed by 16472

Abstract

Chronic wounds do not progress through the wound healing process in a timely manner and are considered a burden for healthcare system; they are also the most common reason for decrease in patient quality of life. Traditional wound dressings e.g., bandages and gauzes, although highly absorbent and effective for dry to mild, exudating wounds, require regular application, which therefore can cause pain upon dressing change. In addition, they have poor adhesional properties and cannot provide enough drainage for the wound. In this regard, the normalization of the healing process in chronic wounds is an extremely urgent task of public health and requires the creation and implementation of affordable dressings for patients with chronic wounds. Modern wound dressings (WDs) are aimed to solve these issues. At the same time, hydrogels, unlike other types of modern WDs (foam, films, hydrocolloids), have positive degradation properties that makes them the perfect choice in applications where a targeted delivery of bioactive substances to the wound is required. This mini review is focused on different types of traditional and modern WDs with an emphasis on hydrogels. Advantages and disadvantages of traditional and modern WDs as well as their applicability to different chronic wounds are elucidated. Furthermore, an effectiveness comparison between hydrogel WDs and the some of the frequently used biotechnologies in the field of regenerative medicine (adipose-derived mesenchymal stem cells (ADMSCs), mesenchymal stem cells, conditioned media, platelet-rich plasma (PRP)) is provided. Full article

(This article belongs to the Special Issue New Advances in Complex Wound Management: Biofilms and Emerging Biotechnologies as Effective Therapies)

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