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Chronic wounds have harmful effects on both patients and healthcare systems. Wound chronicity is attributed to an impaired healing process due to several host and local factors that affect healing pathways. The resulting ulcers contain a wide variety of microorganisms that are mostly resistant to antimicrobials and possess the ability to form mono/poly-microbial biofilms. The search for new, effective and safe compounds to handle chronic wounds has come a long way throughout the history of medicine, which has included several studies and trials of conventional treatments. Treatments focus on fighting the microbial colonization that develops in the wound by multidrug resistant pathogens. The development of molecular medicine, especially in antibacterial agents, needs an in vitro model similar to the in vivo chronic wound environment to evaluate the efficacy of antimicrobial agents. The Lubbock chronic wound biofilm (LCWB) model is an in vitro model developed to mimic the pathogen colonization and the biofilm formation of a real chronic wound, and it is suitable to screen the antibacterial activity of innovative compounds. In this review, we focused on the characteristics of chronic wound biofilms and the contribution of the LCWB model both to the study of wound poly-microbial biofilms and as a model for novel treatment strategies.

Wound repair and skin regeneration is a very complex orchestrated process that is generally composed of four phases: hemostasis, inflammation, proliferation, and remodeling. Each phase involves the activation of different cells and the production of various cytokines, chemokines, and other inflammatory mediators affecting the immune response. The microbial skin composition plays an important role in wound healing. Indeed, skin commensals are essential in the maintenance of the epidermal barrier function, regulation of the host immune response, and protection from invading pathogenic microorganisms. Chronic wounds are common and are considered a major public health problem due to their difficult-to-treat features and their frequent association with challenging chronic infections. These infections can be very tough to manage due to the ability of some bacteria to produce multicellular structures encapsulated into a matrix called biofilms. The bacterial species contained in the biofilm are often different, as is their capability to influence the healing of chronic wounds. Biofilms are, in fact, often tolerant and resistant to antibiotics and antiseptics, leading to the failure of treatment. For these reasons, biofilms impede appropriate treatment and, consequently, prolong the wound healing period. Hence, there is an urgent necessity to deepen the knowledge of the pathophysiology of delayed wound healing and to develop more effective therapeutic approaches able to restore tissue damage. This work covers the wound-healing process and the pathogenesis of chronic wounds infected by biofilm-forming pathogens. An overview of the strategies to counteract biofilm formation or to destroy existing biofilms is also provided.

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.

Bacterial invasion, protracted inflammation, and angiogenesis inhibition are hallmarks of chronic diabetic wounds, bringing about patient morbidity and rising healthcare costs. For such wounds, there are currently few efficient therapies available. We reported the development of carboxymethyl chitosan (CMCS)-based self-healing hydrogel loaded with ultra-small copper nanoparticles (Cunps) for local treatment of diabetic wound healing. The structure of Cunps was identified by XRD, TEM, XPS and other methods, and the characterization of the synthesized Cunps-loaded self-healing carboxymethyl chitosan (CMCS)-protocatechualdehyde (PCA) hydrogel (Cunps@CMCS-PCA hydrogel) was further investigated. The therapeutic effect of Cunps@CMCS-PCA hydrogel in diabetic wound healing was explored in vitro and in vivo. The findings showed that a kind of ultra-small size copper nanoparticles with excellent biocompatibility was prepared. CMCS was chemically conjugated to PCA to form self-healing hydrogels via the formation of an amide bond followed by the loading of ultra-small copper nanoparticles. The obtained Cunps@CMCS-PCA hydrogel showed a typical three-dimensional interlinked network structure with self-healing ability and porosity. It exhibited good biocompatibility in diabetic wounds. Furthermore, Cunps@CMCS-PCA hydrogel group significantly prevented bacterial growth in the skin wound of diabetic rats as compared to model group and CMCS-PCA hydrogel-treated group. After 3 days, no visible bacterial proliferation was observed. It also increased angiogenesis through Cunps mediated activation of ATP7A to prevent induction of autophagy. Furthermore, Cunps@CMCS-PCA hydrogel mainly depended on PCA-induced inhibition on inflammation of macrophage via JAK2/STAT3 signaling pathway. As a result, compared with delayed wound healing process with lower wound healing rate valued at 68.6% within 7 days in the model group, Cunps@CMCS-PCA significantly accelerated wound healing recovery and increased wound healing rate to 86.5%, suggesting that Cunps@CMCS-PCA hydrogel effectively accelerated wound healing. Cunps@CMCS-PCA hydrogel offered a new therapeutic approach for quickening diabetic wound healing.

The prevalence of chronic wounds is predicted to increase within the aging populations in industrialized countries. Patients experience significant distress due to pain, wound secretions, and the resulting immobilization. As the number of wounds continues to rise, their adequate care becomes increasingly costly in terms of health care resources worldwide. eHealth support systems are being increasingly integrated into patient care. However, to date, no systematic analysis of such apps for chronic wounds has been published. The aims of this study were to systematically identify and subjectively assess publicly available German- or English-language mobile apps for patients with chronic wounds, with quality assessments performed by both patients and physicians. Two reviewers independently conducted a systematic search and assessment of German- or English-language mobile apps for patients with chronic wounds that were available in the Google Play Store and Apple App Store from April 2022 to May 2022. In total, 3 apps met the inclusion and exclusion criteria and were reviewed independently by 10 physicians using the German Mobile App Rating Scale (MARS) and the System Usability Scale (SUS). The app with the highest mean MARS score was subsequently reviewed by 11 patients with chronic wounds using the German user version of the MARS (uMARS) and the SUS. Additionally, Affinity for Technology Interaction (ATI) scale scores were collected from both patients and physicians. This study assessed mobile apps for patients with chronic wounds that were selected from a pool of 118 identified apps. Of the 73 apps available in both app stores, 10 were patient oriented. After excluding apps with advertisements or costs, 3 apps were evaluated by 10 physicians. Mean MARS scores ranged from 2.64 (SD 0.65) to 3.88 (SD 0.65) out of 5, and mean SUS scores ranged from 50.75 (SD 27) to 80.5 (SD 17.7) out of 100. WUND APP received the highest mean MARS score (mean 3.88, SD 0.65 out of 5) among physicians. Hence, it was subsequently assessed by 11 patients and achieved a similar rating (uMARS score: mean 3.89, SD 0.4 out of 5). Technical affinity, as measured with the ATI scale, was slightly lower in patients (score: mean 3.62, SD 1.35 out of 6) compared to physicians (score: mean 3.88, SD 1.03 out 6). The quality ratings from physicians and patients were comparable and indicated mediocre app quality. Technical affinity, as assessed by using the ATI scale, was slightly lower for patients. Adequate apps for patients with chronic wounds remain limited, emphasizing the need for improved app development to meet patient needs. The ATI scale proved valuable for assessing technical affinity among different user groups.

Chronic wounds often host pathogens like Staphylococcus aureus , prompting interest in developing new antimicrobial and wound healing strategies, including the utilisation of extracellular vesicles (EVs). Whilst there has been a recent emphasis within the EV community to ensure standardization of characterization and isolation techniques, there has been less focus placed on the upstream tissue culture methodologies used for collection of vesicle-containing conditioned medium (CM). Hence, this study investigated the antimicrobial properties of the CM used for EV enrichment. CM exhibited bacteriostatic effects against penicillin-sensitive S. aureus NCTC 6571, but not penicillin-resistant S. aureus 1061 A. Further analysis revealed that the antimicrobial activity was due to residual antibiotics rather than cell-secreted factors, specifically the retention and release of penicillin to tissue culture plastic surfaces. Pre-washing cells and minimizing antibiotic concentrations in basal medium reduced this carry-over effect. These findings emphasize the importance of controlling antibiotic use in tissue culture to avoid misleading conclusions about the antimicrobial potential of CM or EVs. Researchers should carefully consider medium selection and supplementation during method development as accurately determining the antimicrobial mechanisms of any CM is essential for validating future cell-based therapeutic applications.

Bromelain is a set of proteolytic enzymes usually obtained from pineapple (Ananas comosus). Although bromelain has distinguished therapeutic properties, little is known about its proteolytic potential against opportunistic pathogens related to wound healing complications, such as Staphylococcus aureus. This study aimed to investigate the antibiofilm and antibacterial activity of bromelain in 43 clinical strains of S. aureus isolated from chronic wounds and blood cultures. Bromelain’s activity against S. aureus biofilm in vitro was assessed by analyzing biofilm formation in cultures grown in the presence of 1% bromelain and biofilm destruction after the addition of 1% bromelain to mature biofilms. Proteinase K and sodium metaperiodate were also added to mature biofilms in parallel to compare their activity with that of bromelain and, together with exopolysaccharide and protein production rate assays, to determine the chemical composition of the biofilm extracellular matrix of selected strains of S. aureus. Bromelain was also evaluated for its DNase activity and impact on cellular hydrophobicity and auto-aggregation. Mueller-Hinton agar dilution was used to determine bromelain minimal inhibitory concentration (MIC). Biofilm assays showed that 1% bromelain significantly inhibits S. aureus biofilm formation (p = 0.0157) by up to 4-fold and destroys its mature biofilms (p < 0.0001) by up to 6.4-fold, both compared to the control grown without bromelain. Biofilms of methicillin-resistant S. aureus strains isolated from chronic wounds were the most affected by bromelain treatment. No antibacterial activity was detected with bromelain MIC assays and the proteolytic activity of bromelain was identified as the main antibiofilm mechanism of the enzyme, though its DNase activity may also contribute. The epithelial therapeutic properties of bromelain combined with its antibiofilm activity against S. aureus make it a promising alternative to compose the therapeutic arsenal for the control of S. aureus biofilms in the context of wound care.

Chronic wounds have become an epidemic in millions of patients and result in amputations. In order to overcome this, immediate treatment is a realistic strategy to minimize the risk of complications and aid in the healing rate of the cutaneous wound. Functionalized engineered biomaterials are proven to be a potential approach to embarking on skin wound management. Thus, this study aimed to evaluate the efficacy of a quercetin-embedded gelatin–elastin (Gelastin) injectable hydrogel to act as a provisional biotemplate with excellent physicochemical properties, to be utilized for future cutaneous application. Briefly, the hydrogel was homogenously pre-mixed with genipin (GNP), followed by the incorporation of quercetin (QC). The physicochemical properties comprised the contact angle, swelling ratio, crosslinking degree, enzymatic biodegradation, and water vapor transmission rate (WVTR), as well as chemical characterization. Energy-dispersive X-ray (EDX), XRD, and Fourier transform infra-red (FTIR) analyses were conducted. Briefly, the findings demonstrated that the crosslinked hybrid biomatrix demonstrated better resilience at >100%, a contact angle of >20°, a swelling ratio average of 500 ± 10%, a degradation rate of <0.05 mg/hour, and a successful crosslinking degree (<70%free amine group), compared to the non-crosslinked hybrid biomatrix. In addition, the WVTR was >1500 g/m2 h, an optimal moisture content designed to attain regular cell function and proliferation. The outcomes convey that Gelastin-QC hydrogels deliver the optimum features to be used as a provisional biotemplate for skin tissue engineering purposes.

A chronic wound is a wound that fails to progress through the normal stages of healing within a typical time frame, often remaining open and unhealed for more than 4 to 6 weeks. The delayed healing is often associated with comorbidities, and its clinical consequences have posed great concern to patients, caregivers, and researchers. The use of electrostimulation to enhance healing in chronic wounds has received attention in the last 20 years. Innovative wearable electroceutical devices are engineered to enhance the healing of chronic wounds while prioritizing patient convenience. These devices employ controlled micro-electrostimulation to reactivate endogenous bioelectric activities needed for cellular signaling. However, these devices and their mechanisms of electrostimulation have not been fully explored. In this systematic review, three databases with articles published between 2000 and 2023 were searched and screened using strict inclusion criteria while adhering to the PRISMA checklist. We identified direct, pulsed, and alternating electric currents as the primary modalities by electroceutical devices to deliver electrical stimulation in chronic wounds. Typical chronic wounds identified include diabetic foot ulcers, pressure ulcers, and diabetic venous ulcers. Additionally, a few materials crucial for chronic wound healing were reviewed, and recent devices in research were considered in this study. Various devices, including triboelectric and piezo-nanogenerators, were identified for their potential functionalities in generating electrical stimulation relevant to chronic wound applications. The literature lacked closed-loop electroceutical platforms for treatment and concurrent monitoring of wound healing. The analysis taken from this systematic review provides opportunities at the intersection of epidermal soft bioelectronics, wound care, and remote sensing.

Chronic wounds experiencing infections with multidrug-resistant bacteria can be fatal, and in severe cases can lead to sepsis. Antimicrobial peptides are widely used in the field of wound care for their broad-spectrum antibacterial properties and good anti-drug resistance. We prepared bacterial cell membrane chromatography (BCMC) by extracting cell membranes of bacteria using SiO 2 microspheres as stationary phase. A library of antimicrobial peptides was synthesized in solid phase and screened by BCMC to identify the antimicrobial peptide LKAHR (later named LS5), which is characterized by biosafety, broad-spectrum antibacterial activity, and drug resistance, and a gelatin-based antimicrobial hydrogel (LS5-gel) was prepared to be better applied to wounds. LS5-gel was found to have good in vivo bactericidal properties as well as the ability to promote wound healing in a wound healing model. In the sepsis model, LS5 was found to have a significant inhibitory effect on sepsis infection. It is important for the selection of next-generation antimicrobial drugs and the treatment of chronic wound healing.