pH-switchable nanozyme cascade catalysis: a strategy for spatial–temporal modulation of pathological wound microenvironment to rescue stalled healing in diabetic ulcer

The management of diabetic ulcer (DU) to rescue stalled wound healing remains a paramount clinical challenge due to the spatially and temporally coupled pathological wound microenvironment that features hyperglycemia, biofilm infection, hypoxia and excessive oxidative stress. Here we present a pH-switchable nanozyme cascade catalysis (PNCC) strategy for spatial–temporal modulation of pathological wound microenvironment to rescue stalled healing in DU. The PNCC is demonstrated by employing the nanozyme of clinically approved iron oxide nanoparticles coated with a shell of glucose oxidase (Fe3O4-GOx). The Fe3O4-GOx possesses intrinsic glucose oxidase (GOx), catalase (CAT) and peroxidase (POD)-like activities, and can catalyze pH-switchable glucose-initiated GOx/POD and GOx/CAT cascade reaction in acidic and neutral environment, respectively. Specifically, the GOx/POD cascade reaction generating consecutive fluxes of toxic hydroxyl radical spatially targets the acidic biofilm (pH ~ 5.5), and eradicates biofilm to shorten the inflammatory phase and initiate normal wound healing processes. Furthermore, the GOx/CAT cascade reaction producing consecutive fluxes of oxygen spatially targets the neutral wound tissue, and accelerates the proliferation and remodeling phases of wound healing by addressing the issues of hyperglycemia, hypoxia, and excessive oxidative stress. The shortened inflammatory phase temporally coupled with accelerated proliferation and remodeling phases significantly speed up the normal orchestrated wound-healing cascades. Remarkably, this Fe3O4-GOx-instructed spatial–temporal remodeling of DU microenvironment enables complete re-epithelialization of biofilm-infected wound in diabetic mice within 15 days while minimizing toxicity to normal tissues, exerting great transformation potential in clinical DU management. The proposed PNCC concept offers a new perspective for complex pathological microenvironment remodeling, and may provide a powerful modality for the treatment of microenvironment-associated diseases. Graphical Abstract

Oxygen-Releasing Composites: A Promising Approach in the Management of Diabetic Foot Ulcers

In diabetes, lower extremity amputation (LEA) is an irreversible diabetic-related complication that easily occurs in patients with diabetic foot ulcers (DFUs). Because DFUs are a clinical outcome of different causes including peripheral hypoxia and diabetic foot infection (DFI), conventional wound dressing materials are often insufficient for supporting the normal wound healing potential in the ulcers. Advanced wound dressing development has recently focused on natural or biocompatible scaffolds or incorporating bioactive molecules. This review directs attention to the potential of oxygenation of diabetic wounds and highlights current fabrication techniques for oxygen-releasing composites and their medical applications. Based on different oxygen-releasable compounds such as liquid peroxides and solid peroxides, for example, a variety of oxygen-releasing composites have been fabricated and evaluated for medical applications. This review provides the challenges and limitations of utilizing current oxygen releasable compounds and provides perspectives on advancing oxygen releasing composites for diabetic-related wounds associated with DFUs.

Characterisation of Rapid In Situ Forming Gelipin Hydrogel for Future Use in Irregular Deep Cutaneous Wound Healing

The irregular deep chronic wound is a grand challenge to be healed due to multiple factors including slow angiogenesis that causing regenerated tissue failure. The narrow gap of deep wounds could hinder and slow down normal wound healing. Thus, the current study aimed to develop a polymerised genipin-crosslinked gelatin (gelipin) hydrogel (GNP_GH) as a potential biodegradable filler for the abovementioned limitations. Briefly, GNP_GH bioscaffolds have been developed successfully within three-minute polymerisation at room temperature (22–24 °C). The physicochemical and biocompatibility of GNP_GH bioscaffolds were respectively evaluated. Amongst GNP_GH groups, the 0.1%GNP_GH10% displayed the highest injectability (97.3 ± 0.6%). Meanwhile, the 0.5%GNP_GH15% degraded within more than two weeks with optimum swelling capacity (108.83 ± 15.7%) and higher mechanical strength (22.6 ± 3.9 kPa) than non-crosslinked gelatin hydrogel 15% (NC_GH15%). Furthermore, 0.1%GNP_GH15% offered higher porosity (˃80%) and lower wettability (48.7 ± 0.3) than NC_GH15%. Surface and cross-section SEM photographs displayed an interconnected porous structure for all GNP_GH groups. The EDX spectra and maps represented no major changes after GNP modification. Moreover, no toxicity effect of GNP_GH against dermal fibroblasts was shown during the biocompatibility test. In conclusion, the abovementioned findings indicated that gelipin has excellent physicochemical properties and acceptable biocompatibility as an acellular rapid treatment for future use in irregular deep cutaneous wounds.

SURVEY OF ETHNO MEDICINAL PLANT SHOWING WOUND HEALING ACTIVITY

In most recent couple of a few years, there has been a unprecedented advancement in understanding the biochemical and cell occasions of typical injury recuperating or wound healing. Healing is survival mechanism and represents a trial to take care of normal complex body part and performance.Wound healing could be a process by which tissue regeneration occurs. Healing of wounds, either accidental or surgical interventions, involves complex activities of blood cells, tissues, soluble mediators, cytokines and several other growth factors. This increased cellular activity of damaged tissue enhances metabolic demands and active drug therapy. The main objective of treating a wound is to either shorten the time required for healing process or to reduce the undue effects. Plants because of presence of assorted valuable active phytoconstituents have immense potential for management and treatment of wounds over the years. All the Traditional systems of medicine, Ayurveda, Siddha and Unani describe applications of medication of plant, mineral and animal origin to treat and heal wounds. Herbal drugs induce healing and regeneration of lost tissue by number of mechanisms. Due to their traditional applicability, affordability and safety plants gained a reputed position within the world of wound management and repair.The present review is a trial to focus on various Indian ethno-medicinal plants which are to be scientifically proved for the treatment of wounds. Beside this review also emphasis on normal wound healing process, pharmacological activities and role of plants in wound management and parameters accustomed assess wound healing.

The Role of Antioxidants on Wound Healing: A Review of the Current Evidence

(1) Background: Reactive oxygen species (ROS) play a crucial role in the preparation of the normal wound healing response. Therefore, a correct balance between low or high levels of ROS is essential. Antioxidant dressings that regulate this balance are a target for new therapies. The purpose of this review is to identify the compounds with antioxidant properties that have been tested for wound healing and to summarize the available evidence on their effects. (2) Methods: A literature search was conducted and included any study that evaluated the effects or mechanisms of antioxidants in the healing process (in vitro, animal models or human studies). (3) Results: Seven compounds with antioxidant activity were identified (Curcumin, N-acetyl cysteine, Chitosan, Gallic Acid, Edaravone, Crocin, Safranal and Quercetin) and 46 studies reporting the effects on the healing process of these antioxidants compounds were included. (4) Conclusions: this review offers a map of the research on some of the antioxidant compounds with potential for use as wound therapies and basic research on redox balance and oxidative stress in the healing process. Curcumin, NAC, quercetin and chitosan are the antioxidant compounds that shown some initial evidence of efficacy, but more research in human is needed.

Antibiotic Susceptibility and Biofilm Formation of Clinical Isolates of Pseudomonas Species from Wounds Specimens

Purpose: The aim of the study is to investigate biofilm forming capacity and the antibiotic susceptibility profile of Pseudomonas aeruginosa strains isolated from clinical wound specimen. Method: A total number of 60 wound specimens were submitted to the bacteriology laboratory of Abubakar Tafawa Balewa University Teaching Hospital for investigation, and screened for Pseudomonas aeruginosa. The strains were identified on the basis of cultural characteristics, Gram staining, biochemical tests such as citrate, urease, indole, fermentation of sugar using triple sugar agar. The biofilm forming capacity of the strains are tested using the test tube method after standardizing the strains to approximately standard inoculated into a cooked meat broth. The growth rate of Pseudomonas aeruginosa clinical strains after 48 hours incubation are measured by taking the absorbance using Densi-Check. The strain growth rate is also checked. Biofilm formation at the liquid interface (pellicle) is qualitatively scored from the first to the last strain. The clinical significance of the Pseudomonas aeruginosa biofilm forming capacity and resistance to antibiotics which could result to none healing, delayed healing, foul smell of wound infection are checked for the experiment. Results: The analysis of the study shows that the strains are more susceptible to Ciprofloxacin and Streptomycin while the strains are less susceptible to Orfloxacin and Gentamycin. Conclusion: the data derived from human clinical studies make clear that biofilm have an important adverse effect on wound healing. Despite this, more fundamental scientific studies are required to understand what biofilm do to normal wound healing processes from cellular and immunological perspective.

Compendium of Conventional and Targeted Drug Delivery Formulation Used for the Treatment and Management of the Wound Healing

: Wound healing is a complex and dynamic phenomenon that involves the restoration of normal physiology and functioning of injured tissue. The process of wound healing is primarily regulated by various cytokines, inflammatory mediators, and growth factors at the molecular level. Any intervention in the normal wound healing process leads to further tissue damage, which in turn leads to delayed wound healing. Several natural, synthetic drugs and their combinations were used to restored and accelerate the wound healing process. However, the conventional delivery carriers were not much effective, and thus, nowadays, nanocarriers are gaining much popularity since they are playing a pivotal role in drug delivery. Since nanocarriers have their own applicability and benefits (enhance the bioavailability, site-specific targeting) so, they can accelerate wound healing more efficiently. This review briefly discussed about the various events that take place during the wound healing process with emphasis on various natural, synthetic, and combination drug therapy used for accelerating wound healing and the role of nanotechnology-based approaches in chronic wound healing.

Implant Fibrosis and the Underappreciated Role of Myofibroblasts in the Foreign Body Reaction

Body implants and implantable medical devices have dramatically improved and prolonged the life of countless patients. However, our body repair mechanisms have evolved to isolate, reject, or destroy any object that is recognized as foreign to the organism and inevitably mounts a foreign body reaction (FBR). Depending on its severity and chronicity, the FBR can impair implant performance or create severe clinical complications that will require surgical removal and/or replacement of the faulty device. The number of review articles discussing the FBR seems to be proportional to the number of different implant materials and clinical applications and one wonders, what else is there to tell? We will here take the position of a fibrosis researcher (which, coincidentally, we are) to elaborate similarities and differences between the FBR, normal wound healing, and chronic healing conditions that result in the development of peri-implant fibrosis. After giving credit to macrophages in the inflammatory phase of the FBR, we will mainly focus on the activation of fibroblastic cells into matrix-producing and highly contractile myofibroblasts. While fibrosis has been discussed to be a consequence of the disturbed and chronic inflammatory milieu in the FBR, direct activation of myofibroblasts at the implant surface is less commonly considered. Thus, we will provide a perspective how physical properties of the implant surface control myofibroblast actions and accumulation of stiff scar tissue. Because formation of scar tissue at the surface and around implant materials is a major reason for device failure and extraction surgeries, providing implant surfaces with myofibroblast-suppressing features is a first step to enhance implant acceptance and functional lifetime. Alternative therapeutic targets are elements of the myofibroblast mechanotransduction and contractile machinery and we will end with a brief overview on such targets that are considered for the treatment of other organ fibroses.

Method development and characterisation of the low-molecular-weight peptidome of human wound fluids

The normal wound healing process is characterised by proteolytic events, whereas infection results in dysfunctional activations by endogenous and bacterial proteases. Peptides, downstream reporters of these proteolytic actions, could therefore serve as a promising tool for diagnosis of wounds. Using mass-spectrometry analyses, we here for the first time characterise the peptidome of human wound fluids. Sterile post-surgical wound fluids were found to contain a high degree of peptides in comparison to human plasma. Analyses of the peptidome from uninfected healing wounds and Staphylococcus aureus -infected wounds identify unique peptide patterns of various proteins, including coagulation and complement factors, proteases, and antiproteinases. Together, the work defines a workflow for analysis of peptides derived from wound fluids and demonstrates a proof-of-concept that such fluids can be used for analysis of qualitative differences of peptide patterns from larger patient cohorts, providing potential biomarkers for wound healing and infection.