Topical Iron Chelator Therapy: Current Status and Future Prospects.

Objectives: Wound healing and tissue regeneration have raised serious challenges for healthcare systems worldwide, affecting both aesthetic and health-related aspects of the community well-being. Wound healing is a complex sequence of physical, cellular, and molecular events involving cell recruitment, proliferation, as well as the synthesis and accumulation of the new extracellular matrix components. The present study aimed to histopathologically evaluate the application of zinc nanoparticles in conjunction with chitosan dressing for the wound healing of methicillin-resistant Staphylococcus aureus (MRSA) infected skin wounds in rats. Materials and Methods: In this experimental investigation, 28 healthy male rats were randomly divided into 4 groups, each of which including 7 rats. The wound healing process was evaluated based on histopathological studies and biochemical findings on days 7, 14, and 21. Results: According to the results from the two-way ANOVA analysis, the means of wound area in the study groups were statistically and significantly different on all evaluated days (P<0.001). The highest wound area was associated with group III (i.e., wound with zinc oxide) on days 6, 18, 15, 12, and 9, while the lowest wound area was observed in group IV (i.e., wound with chitosan-nanoparticles-zinc oxide). A statistically significant difference was also found among the study groups in terms of the mean values of hydroxyproline (P<0.001). According to the post hoc Tukey test for pairwise comparisons, a significant difference was observed among all groups regarding the hydroxyproline values (P<0.001). Additionally, the highest collagen density was detected in the chitosan-nanoparticles-zinc oxide group. Conclusions: The application of biodegradable chitosan-nanoparticles-zinc oxide dressing significantly improved the histopathological and biochemical indices of the full-thickness skin wound healing. This study highlighted the effectiveness of chitosan-nanoparticles-zinc oxide dressing in wound healing enhancement, indicating its potential application in wound healing.

Purpose: Chronic wounds that are difficult to heal pose a major challenge for clinicians and researchers. Currently, common treatment methods focus on isolating the wound from the outside world, relying on the tissue at the wound site to grow and heal unaided. Umbilical cord mesenchymal stem cell (MSC) exosomes can promote wound healing by enhancing new blood vessel growth at the wound site. Valproic acid (VPA) reduces the inflammatory response and acts on macrophages to accelerate wound closure. In this study, VPA was loaded into umbilical cord MSC exosomes to form a drug carrier exosome (VPA-EXO) with the aim of investigating the effect of VPA-EXO on wound healing. Methods: This study first isolated and obtained umbilical cord MSC exosomes, then added VPA to the exosomes and explored the ability of VPA-EXO to promote the proliferation and migration of human skin fibroblasts (HSFs) and human umbilical vein endothelial cells (HUVECs), as well as the ability to promote the angiogenesis of HUVECs, by using scratch, Transwell, and angiogenesis assays. An in vitro cell model was established and treated with VPA-EXO, and the expression levels of inflammation and pro-angiogenesis-related proteins and genes were examined using Western blot and qRT-PCR. The therapeutic effect of VPA-EXO on promoting wound healing in a whole skin wound model was investigated using image analysis of the wound site, H&E staining, and immunohistochemical staining experiments in a mouse wound model. Results: The in vitro model showed that VPA-EXO effectively promoted the proliferation and migration of human skin fibroblast cells and human umbilical vein endothelial cells; significantly inhibited the expression of MMP-9, IL-1β, IL-8, TNF-α, and PG-E2; and promoted the expression of vascular endothelial growth factors. In the mouse wound model, VPA-EXO reduced inflammation at the wound site, accelerated wound healing, and significantly increased the collagen content of tissue at the wound site. Conclusions: As a complex with dual efficacy in simultaneously promoting tissue regeneration and inhibiting inflammation, VPA-EXO has potential applications in tissue wound healing and vascular regeneration. In future studies, we will further investigate the mechanism of action and application scenarios of drug-loaded exosome complexes in different types of wound healing and vascular regeneration.

Gellan gum and collagen are two biomaterials that have been extensively studied for their potential use in wound healing and tissue engineering applications. Gellan gum is a biologically inert natural polymer that is increasingly favored as a biomaterial to form hydrogels. Collagen, on the other hand, is a major component of the extracellular matrix and is widely used in tissue engineering applications due to its biocompatibility and ability to promote cell adhesion and proliferation. In this review, the recent research will be discussed related to gellan gum and collagen, their properties, and their potential applications in wound healing and tissue engineering.

Chapter 3 - Nitric Oxide-Donating Devices for Topical Applications

Dear Sir Malaria with estimated annual global mortality from 700,000 to 2.7 million, caused by Plasmodium falciparum, the most deadly Plasmodium species prevails mainly in Africa (1,2). The pleomorphic clinical outcomes display a remarkable range of disease from acute primary stages to complicated clinical presentations, depending on the transmission intensity, age, immunity and genetic background of the affected individuals (3). Cerebral malaria (CM) is one of the manifestations of sever malaria with enormous morbidity and mortality worldwide. It affects approximately more than 500 million people annually, primarily in sub-Saharan Africa (WHO 2011). CM with the high case fatality rate remains one of the major causes of acquired disability throughout much of the tropical and subtropical world plagued by malaria (4,5). It imposes a substantial economic and palliative care and cost burden to households, which impedes economic development in countries with low national gross products. CM is characterised by a generalised systemic process with high overall level of cytokines related to predominant Th1 response. The shift of immune balance towards Th1 arm is simultaneous with under presentation of the Th2/T (reg) immune regulatory (5). Overproduction of Th1-related proinflammatory cytokines, mainly as interferon-γ, tumour necrosis factor-α (TNF-α), interleukin-1b (IL-1b) and IL-6 combined with underproduction of Th2-related anti-inflammatory cytokines, mainly as IL-10, IL-4 and transforming growth factor-β (TGF-β) is seen in CM (6,7). Raised levels of proinflammatory cytokines have been consistently observed in the cases affected with CM followed by schizont rupture (8). Th1-related proinflammatory cytokines modulate production of eicosanoides (prostaglandines and leukotrienes), thromboxane B2, 5-LOX, phospholipase A2, COX1 and COX2 in peripheral circulation (9). The balance between induced immune suppressive versus immune stimulating state by prostaglandins and leukotrines, respectively, is critical for development of CM (9). Finally, these excreted inflammatory mediators lead to the upregulation of intercellular adhesion molecule-1 (ICAM-1), nitric oxide (NO) production and immune proliferation within spleen (10,11). The pathological scenario evolved from these molecular events is enhanced vessel leakage following pronounced cytoadherence of parasitised erythrocytes and activated mononuclear cells to vascular endothelial cells (6). Preliminary animal and human investigations showed that prior infection with parasites such as Schistosoma hematonium, Ascaris lumbricoides and hookworms has been associated with reduced malaria severity in an age and dose-dependent manner (6,12). Pre-existing helmintic infection has been shown to exert 64% protection against murine CM (6). The suppression of both cellular and humoral immune responses essential for establishment and maintenance of coinfected parasites has been speculated as the main mechanism (13). This competitive parasitic milieu is owned by the influential effects of excessive production of IL-4 and IL-10 by stimulated Th2 lymphocytes and decreased Th1 responses (6). Decreased TNF-α production and IL-6 secretion could simply reflect amplified Th2 responses through non specific B lymphocyte presentation (13). This pattern of cytokine expression is also observed consistently in non CM (6). The induced CD23/NO pathway, increased immunoglobulin E concentrations, decreased ICAM-1 expression and cytoadherence of parasitised red blood cells exert additive effects in this context (12). Therefore, it is translated clinically that factors which alter the polarisation of naÏve T helper cells towards the Th2 phenotype can potentially improve disease profile. Several factors rather than pathogens can influence the host immune network particularly those causing chronic inflammation. Chronic non healing wounds, associated with arose chronic inflammatory state, alter the sum of Th1 versus Th2/T (reg) cytokines with promoted differentiation of precursor Th cells into the Th1 subset (14). Mutually, wounds might get chronic non healing state by standing in deteriorating Th1-dominant immune milieu. Complex inflammatory cascade in chronic non healing wounds is extensively characterised by suppression of IL-10, a prowound healing cytokine (14). Thus coexistence of persistent wounds might play a role in changing the clinical course of CM through elicited pathogenic Th1-type immune response. Lack of IL-10 predominance in chronic non healing wounds is such event seen in episodes of CM (6). The observed microcirculatory dysfunction and angiogenic failure in chronic non healing wounds is a favoured milieu for induction of CM's pathogenesis (15,16). Hence, non healing wounds would synergistically enhance load on immune system in CM. The possible influence of chronic wounds on the acquisition of immunity against CM would likely result in a higher rate of CM. This combination might confer lethality and exacerbation of symptoms. It needs to be determined at the population level whether patients with underlying chronic non healing wounds require a higher sequestered parasite biomass to develop CM or not. Each stage of wound carriage might play an important role in shaping the immunity against malaria and CM and this shared exposure should not be neglected simply. Both of these multifactorial diseases are largely seen in association with poor nutrition and socioeconomic status. The possible influence of chronic wounds on the immune response to malaria, parasite development and cytoadherence phenomena needs to be determined. Chronic non healing wounds continue to be a pandemic health problem (17). Animal studies would be of paramount value in this regard. Chronic wounds are major public-health problem in developing countries prone to CM: coendemic. The possibility that chronic non healing wounds could markedly affect the CM disease burden in malaria endemic area and their relevance to clinical disease deserves further investigations. Comparison between rate of CM resistance or tolerance between population widely devastated by chronic wounds and wound-free areas will illuminate the possible wound–CM interaction. Comparison of wound distribution among sites with peak occurrence of CM and variable malaria transmission intensities also seems helpful. This implies that treating one burden (wounds) could potentially relieve the other (CM), but it is not yet clinically proved. This would offer affordable means to roll back CM and its consequent complications and costs. If deleterious effects of concomitant non healing wounds on CM are confirmed, vigorous therapeutic measures for chronic wounds might become a priority in malaria endemic area before the progress towards CM. Perhaps, little paid attentions to the pre-existing non healing wounds merely before the onset of rainy seasons with the peak malaria transmissions would be of paramount impact on CM elimination. This seasonal attention to wounds or even every factor able to aggravate much of the hyperimmune responsiveness associated with CM expected to be economically more cost effective. The data regarding favoured season could be derived from district statistics and informed to resident clinicians. Considering the high prevalence of chronic non healing wounds in malaria endemic area as sub-Saharan Africa and the fatality rate of CM in this area, the fundamental practical implication of dewounding on the outcome of CM will be perceived easier. It is also convincible to address this hypothesis that wounds will get non healing fate in the cases experienced fatal CM. Mohaddeseh Behjati 1 The author declares no conflicts of interest.

Introduction Chronic wounds represent a major problem in medicine today as their incidence is continuously increasing due to an ageing population and a rise in the incidence of underlying diseases. Cutaneous wound healing is a complex biological process. Chronic wounds are characterised by a prolonged inflammation, persistent infections, formation of drugresistant microbial biofilms and the inability of dermal and/or epidermal cells to respond to regenerative stimuli. As conventional treatment strategies often fail, innovative therapies have been investigated over the last decade, including stem cell-based therapies. After the initial use of embryonic stem cells, the focus has been set on autologous mesenchymal stem cells over the past years. They can be isolated in large amounts from various tissues and hold no ethical concerns. A promising and cost-effective source of autologous mesenchymal stem cells is subcutaneous adipose tissue. Recent in vitro and in vivo studies have shown that adiposederived stem cells have a positive impact on wound healing, as they are attracted to the wound site and influence regeneration processes via paracrine mechanisms. They are pluripotent and secrete a variety of growth factors. The aim of this critical review was to discuss adiposederived stem cells in wound healing. Conclusion Mesenchymal stem cells-derived from adipose tissue are a promising alternative to embryonic or bone marrow-derived stem cells in the therapy of chronic wounds. Because the use of adipose-derived stem cells in wound healing applications is still limited by a lack of clinical data, further studies have to pave the way for their routine clinical application. Introduction Due to demographic changes the number of patients with multimorbidity is continuously increasing in western countries. One of the associated disorders is the chronic wound. This includes a rise in the incidence of impaired wound healing, causing a reduced patients’ quality of life and rising health care costs. Conventional therapies of chronic wounds are increasingly reaching their limits, motivating the search for alternative treatment options, including stem cell-based therapies1. This paper discusses the recent in vitro and in vivo results of adipose-derived stem cells (ASCs) in wound healing. Physiological wound healing Wound healing is a complex biological process consisting of the four different but partially overlying steps coagulation, inflammation, formation of granulation tissue (proliferative phase) and remodelling or scar formation. After injury, initiation of a bloodclotting cascade prevents excessive bleeding and provides temporary protection of the wound area. During this process platelet-derived growth factor and transforming growth factors A1 and 2 (TGF-A1 and TGF-2) are released, causing attraction of inflammatory cells such as leukocytes and macrophages. Within a few days after injury, apoptosis of inflammatory cells occurs. Anti-inflammatory cytokines such as TGF-A1 and Interleukin (IL) 1 as well as bioactive lipids are assumed to be involved in this process (Figure 1). In the following proliferative phase, production of growth factors and activation of dermal and epidermal cells lead to new tissue formation. Endothelial progenitor cells, which are essential for physiological wound healing, are mobilised by nitric oxide, vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP9). Formation of extra-cellular matrix (ECM)rich tissue occurs in response to stromal cell-derived factor (SDF)-1 and insulin-like growth factor (IGF). In the last step of wound healing, matrix remodelling and/or scar formation through cellular migration, proliferation and angiogenic induction is initiated by TGF-A, MMPs and tumour necrosis factor (TNF)2. Impaired wound healing A chronic wound is defined as a wound that does not heal in a certain period of time in spite of appropriate therapy. However, the exact-time point is in discussion. Most authors refer to a chronic wound as a wound that exists for more than three months3. Impaired wound healing is associated with senescence, ischaemia and bacterial colonisation. Wound chronification is caused by local factors such as infection, venous insufficiency, mechanical trauma, * Corresponding author Email: Carolin.Fromm-Dornieden@uni-wh.de 1 Institute for Research in Operative Medicine, University of Witten/Herdecke, Ostmerheimer Str. 200, D-51109 Cologne, Germany 2 Department of Trauma and Orthopaedic Surgery, Cologne-Merheim Medical Center, University of Witten/Herdecke, Cologne, Germany

Chronic wounds including pressure, venous, arterial and diabetic neuropathic ulcers, represent a significant burden to the healthcare system. These different chronic wound types do not share origin or cause, however they have common features as bacterial infection and continuing influx of polymorphonuclear neutrophils that release high concentrations of matrix metalloproteases (MMPs), myeloperoxidase (MPO) and reactive oxidative species causing excessive degradation of the extracellular matrix (ECM) and the growth factors. Because of the multifactorial nature of virtually all chronic wounds, the therapeutic wound healing approach should emphasize the necessity to investigate wound dressings that possess the ability to directly and indirectly modulate the biochemical environment based on the pathology of chronic to encourage the healing process. The overall aim of the present work was to develop biopolymer wound dressings capable to improve the management of chronic wounds. The specific research objective was defined in three main targets: i) to balance the proteolytic activity of MMPs, ii) to balance the MPO activity and the oxidative environment, and iii) antimicrobial protection. The first part of the thesis aimed to provide suitable materials to perform bioactive biopolymer-based wound dressings. The first step was to provide a versatile functionalization of chitosan platform to improve the sequestering ability over metal dependent enzymes (MMPs) in chronic wounds. In order to impart to chitosan the ability to inhibit MMP, chitosan was functionalized with deferent thiol moieties, which can chelate the zinc cation in the active site of the enzyme, modifying MMP activity. In addition the combination of -NH2 and -SH chemistry allowed grafting of other active agents on the chitosan platform. The second step was the identification and evaluation of natural active agents as chronic wound healing promoters. Polyphenols from bark, twigs and leaf extracts from the medicinal plant Hamamelis virginiana (Witch hazel) were studied for this porpoise and it was found to have both a strong antioxidant activity and an inhibitory effect on MPO and collagenase. The second part of the thesis was focused in the performance and evaluation of new materials for wound healing applications. To this aim, chitosan and/or thiolated chitosan were modified with H. virginiana extracts following different approaches. The first approach was focused to develop a new method for covalent functionalization of thiolated chitosan with polyphenols from H. virginiana extracts. The novelty of this approach consists in the use of thiolysis - a common analytical method for proanthocyanidins characterization - to covalently functionalize natural macromolecules such as chitosan with bioactive phenolic moieties. The phenolics-functionalized chitosan showed improved therapeutic properties in vitro. The second approach focused on the use of laccase-assisted cross-linking between phenolic moieties of H. virginiana with chitosan and gelatin as a functionalization method to obtain stable and bioactive hydrogel wound dressings. H. virginiana extract was oxidized by laccase in a one-step process under mild reaction conditions to covalently crosslink chitosan and gelatin. The physical and mechanical properties of these hydrogels were investigated using different analytical techniques and their potential for chronic wound treatment was evaluated in vitro in terms of antibacterial and inhibitory effect on MPO and collagenase. The results indicated that the polyphenols exerted a dual role in the hydrogel: i) "passive" being a structural element, and ii) "active" modifying the chronic wound environment by attenuating the deleterious MMPs, MPO and ROS activities, and reducing the bacterial load.

For effective application of electrospinning and electrospun fibrous meshes in wound dressing, we have in situ electrospun poly(vinyl pyrrolidone)/iodine (PVP/I), PVP/poly(vinyl pyrrolidone)-iodine (PVPI) complex, and poly(vinyl butyral) (PVB)/PVPI solutions into fibrous membranes by a handheld electrospinning apparatus. The morphologies of the electrospun fibers were examined by SEM, and the hydrophobicity, gas permeability, and antibacterial properties of the as-spun meshes were also investigated. The flexibility and feasibility of in situ electrospinning PVP/I, PVP/PVPI, and PVB/PVPI membranes, as well as the excellent gas permeabilities and antibacterial properties of the as-spun meshes, promised their potential applications in wound healing.

Biosynthesis and Characterization of Ixora coccinea-Based Iron Oxide Nanoparticles: Potential Applications in Wound Healing and Therapeutics

The preparation of hydrogels based on biopolymers like collagen and gum arabic gives a chance to provide novel options that can be used in biomedical field. Through a polymeric semi-interpenetration technique, collagen-based polymeric matrices can be associated with gum arabic while controlling its physicochemical and biological properties. To create novel hydrogels with their potential use in the treatment of wounds, the semi-interpenetration process, altering the concentration (0-40% by wt) of gum arabic in a collagen matrix is explored. The ability of gum arabic to create intermolecular hydrogen bonds in the collagen matrix enables the development of semi-interpenetrating polymeric networks (semi-IPN)-based hydrogels with a faster gelation time and higher crosslinking. Amorphous granular surfaces with linked porosity are present in matrices with 30% (by wt) of gum arabic, enhancing the storage modulus and thermal degradation resistance. The hydrogels swell to very high extent in hydrolytic and proteolytic environments, good hemocompatibility, and suppression of growth of pathogens like E. coli, and all it is enhanced by gum arabic included them, in addition to enabling the controlled release of ketorolac. The chemical composition of theses semi-IPN matrices have no deleterious effects on monocytes or fibroblasts, promoting their proliferation, and lowering alpha tumor necrosis factor (α-TNF) secretion in human monocytes.

Antibacterial dual-drug delivery fiber system via a multi-layered porous Poly(caprolactone)/poly lactic acid/ZIF-8 composites.

Regenerative peptides are gaining attention in regenerative medicine and plastic surgery for their potential to enhance surgical recovery and tissue regeneration. This review synthesizes evidence on four key peptides-focusing on their potential applications in wound healing, scar optimization, and aesthetic plastic surgery. Preclinical studies show promise, safety profiles appear favorable, but rigorous clinical trials are lacking. The paucity of human studies highlights an urgent need for high-quality research. Plastic surgeons are well-positioned to lead investigations, integrating regenerative peptides into perioperative care and evaluating their ability to optimize outcomes in aesthetic procedures.

In the original publication [...].

In this study, hybrid nanofiber scaffolds composed of polyvinyl alcohol (PVA), polyethylene oxide (PEO), and titanium dioxide (TiO2) nanoparticles were fabricated via electrospinning and evaluated for their physicochemical, antibacterial, and anticancer properties. The incorporation of TiO2 into the PVA/PEO matrix aimed to enhance the functional bioactivity of the scaffold for potential biomedical applications. Morphological analysis using scanning electron microscopy (SEM) confirmed the formation of uniform, bead-free nanofibers with TiO2 uniformly distributed within the fiber matrix. Structural and thermal characteristics were assessed through Fourier-transform infrared spectroscopy (FTIR) and (TGA), respectively. The antibacterial efficacy was tested against both Gram-positive (S. aureus), and Gram-negative (E. coli MDR, P. aeruginosa, K. pneumoniae) bacteria besides the fungi Candida tropicalis, demonstrating significant inhibition zones and microbial reduction with increasing TiO2 content. Additionally, in vitro cytotoxicity assay against human cancer cell lines (HepG2, Liver cancer cells) revealed notable anticancer activity, attributed to the photocatalytic and oxidative stress-inducing effects of TiO2 nanoparticles. These findings suggest that the developed PVA/PEO/TiO2 nanofiber scaffolds possess promising dual functionality as both antibacterial and anticancer agents, supporting their potential application in wound healing, cancer therapy, and tissue engineering.

Wound healing assay on a gravity-driven unidirectional perfusion microfluidic device