January 18, 2021

IBAL Formulation Topical Application Wound Healing References

Biomaterials and Nanotherapeutics for Enhancing Skin Wound Healing


Biomaterials have been successfully used in manufacturing clinically approved products for aiding wound healing. However, there are no biomaterials currently approved that release bioactive components (like growth factors, cytokines, chemokines, plasmids, recombinant proteins, small molecules, cellular therapy, etc.) that directly influence the wound healing cascade. Nanoparticles have become significant in the regenerative medicine field in the last two decades. Many biological processes happen at through mechanisms that fundamentally act at the nanometer scale. Thus, materials such as NPs can be used as unique tools for drug delivery, imaging, sensing, and probing biological processes. In the context of wound healing, the special properties of NPs like electric conductivity, antimicrobial activity, high surface to volume ratio, swelling, and contraction make NPs versatile resources. Emerging treatments using biomaterials or NPs to target multiple aspects have great promise for enhancing wound care and will add to the clinical armamentarium to address poorly healing wounds.


Factors Affecting Wound Healing


Several micronutrients have been shown to be important for optimal repair. Magnesium functions as a cofactor for many enzymes involved in protein and collagen synthesis, while copper is a required cofactor for cytochrome oxidase, for cytosolic antioxidant superoxide dismutase, and for the optimal cross-linking of collagen. Zinc is a co-factor for both RNA and DNA polymerase, and a zinc deficiency causes a significant impairment in wound healing. Iron is required for the hydroxylation of proline and lysine, and, as a result, severe iron deficiency can result in impaired collagen production. Wound healing is a complex biological process that consists of hemostasis, inflammation, proliferation, and remodeling. Single or multiple factors may play a role in any one or more individual phases, contributing to the overall outcome of the healing process.


Metal ions in macrophage antimicrobial pathways: emerging roles for zinc and copper


The interplay between zinc and macrophages is complex. Zinc appears to enhance the microbicidal activity of macrophages, while at the same time limiting excessive inflammatory responses that may be deleterious to the host. The redistribution of the intracellular zinc pool to phagosomes and other vesicular compartments may enable macrophages to harness the activity of this metal ion for microbial destruction. Conversely, this sequestration away from the cytoplasm, as well as inducible export of cytoplasmic zinc from macrophages, may also enable these cells to starve certain pathogens of zinc to limit growth. Macrophages may utilize copper in host defence strategies through several mechanisms including acute and delayed generation of ROS, as well as iron export as a means of limiting bacterial growth. Many of the copper transport genes have also been implicated in macrophage-mediated host defence (e.g. CTR1, CTR2, ATP7A, CP).


Zinc and skin health: overview of physiology and pharmacology


Zinc is known to have a critical role in overall human physiology, which likely explains many of its therapeutic uses for the last several thousand years. The specific roles zinc plays in skin health and function are less widely known yet are likely just as critical based on the manifestations of dietary zinc deprivation, which include moderate to severe dermatitis. OBJECTIVE: To provide a critical review of the scientific literature as to the physiologic importance of zinc to skin, the biochemical basis for these effects, and pharmacologic aspects of zinc therapeutics. RESULTS AND CONCLUSIONS: Skin is in a continual state of renewal, placing a high demand on zinc-based enzymes and proteins that direct this process. The importance of zinc physiologically is especially evident in studies of wound healing and inflammation reduction. During these processes, the high needs for zinc can be supplemented externally, generally increasing the rates of the natural processes. Topical zinc delivery involves the pharmacologic optimization of zinc delivery, often mediated by the solubility of the zinc material and interactions within the product matrix.


Nanotechnology-Driven Therapeutic Interventions in Wound Healing: Potential Uses and Applications


The intrinsic antibacterial properties of zinc oxide nanoparticles (nZnO) prompt the use of these nanomaterials in several hydrogel-based wound dressing. 


Oxidative stress action in cellular aging


The increase of ROS levels can lead to necrosis by causing the transition of mitochondrial permeability, disabling the power and recovery of cellular ATP. The ischemia may affect the antioxidant defense mechanisms of the cells accumulating free radicals by producing superoxide anions due to indirect and incomplete reduction of oxygen by amended mitochondria, or by the action of leukocytes oxidase and parenchymal cells. Another type of cell death is by apoptosis (silent cell death), designed to remove the unwanted cells from the host by activation of internally programmed events, those made by a group of gene products. The induction of apoptotic process may occur by hydrophobic bile acids, which probably held the release of cytochrome C, originated from the oxidative stress, increasing the activity of specific caspase and leading to fragmentation of DNA, which triggers the characteristic biochemical apoptosis. In relation to amyotrophic lateral sclerosis, report studies that associated oxidative stress with the pathogenesis of the disease, due to the verification of increased concentration of aldehyde 4-hydroxy-2-trans nonenal of 8-OHdG and nitrotyrosine in patients with the disease. The presence of enzymes that degrade the nucleotides, ATP, ADP and AMP in non-transferable chronic diseases of neurological order indicate the involvement of oxidative stress in the genesis of the disease, since the brain consumes high amounts of oxygen and is susceptible to the oxidative stress because the metabolism of neurotransmitters such as glutamate and dopamine, which generates ROS, consume the antioxidant defenses, causing lipid peroxidation of neuronal membranes as well as changes in cellular homeostasis. The tests performed with non-enzymatic antioxidants (vitamins A, E, C, flavonoids, carotenoids and minerals) and calorie restriction and physical exercises had been proved as beneficial alternatives to reduce, protect, and prevent the expansion of biomolecules oxidative damages and cell aging.


Nature and Properties of Metal Cations in Aqueous Solutions


The total content of calcium and magnesium in seawater, according to its elaborated models, is determined by means of equations of the type below and considering formation of the three basic associated molecules: ( ) 2+ 2+ 0 + 0 4 3 3 tot M = M + MSO + MHCO + MCO                 where 2+ M stands for the 2+ Ca or 2+ Mg ions. It gets out of accessible data that ca. 91% of 2+ Ca ions present in seawater occur in a form of free ions and participation of consecutive ion pairs adequately amount to 8.0, 1.0 and 0.2%. In the case of 2+ Mg ions the participation of free ions is lower and amounts to 87% and participation of ion pairs adequate amounts to 11.0, 1.0 and 0.3%. Ions belonging to the above-mentioned group of elements determine the basic physicochemical properties of seawater. Cations of trace elements occur in much lower concentrations, i.e. in micro and sub microgram quantities per 1 kilogram of seawater. These are such ions as 3+ Fe , 2+ Zn , 2+ Mn , 2+ Ni , 2+ Co and 2+ Cu . They are of principal importance in the case of the whole biological processes series occurring in the sea environment.


Current wound healing procedures and potential care


Wound healing including acute and chronic wounds, is one of the major clinical challenges in the world. Other wound healing methods such as skin dressing and growth factor delivery also need significant improvement in order to heal wounds in suitable manner without delaying. New wound healing strategies are emerging including SiRNA delivery, and targeting mRNA molecules and receptors in the wound microenvironment. Stem cells isolated from different tissues such as bone marrow, adipose, and umbilical cord Wharton's jelly also have high potential to use in acute and chronic wound healing. 


Transition from inflammation to proliferation: a critical step during wound healing


Abnormal wound healing such as hard-to-heal ulcers and excessive scarring is associated with inefficient or failed transition between these two phases, indicating that targeting the inflammatory–proliferative phase transition could provide a new avenue for therapeutic development. It has been suggested that suppression of inflammation may be beneficial for promoting healing of chronic wounds and reducing scarring.


Redefining the Chronic-Wound Microbiome: Fungal Communities Are Prevalent, Dynamic, and Associated with Delayed Healing


Fungal communities (the mycobiome) in chronic wounds are predictive of healing time, associated with poor outcomes, and form mixed fungal-bacterial biofilms. We longitudinally profiled 100, nonhealing diabetic-foot ulcers with high-throughput sequencing of the pan-fungal internal transcribed spacer 1 (ITS1) locus, estimating that up to 80% of wounds contain fungi, whereas cultures performed in parallel captured only 5% of colonized wounds. The “mycobiome” was highly heterogeneous over time and between subjects. Fungal diversity increased with antibiotic administration and onset of a clinical complication. The proportions of the phylum Ascomycotawere significantly greater (P = 0.015) at the beginning of the study in wounds that took >8 weeks to heal. Wound necrosis was distinctly associated with pathogenic fungal species, while taxa identified as allergenic filamentous fungi were associated with low levels of systemic inflammation. Directed culturing of wounds stably colonized by pathogens revealed that interkingdom biofilms formed between yeasts and co-isolated bacteria.


Role of superoxide dismutase 3 in skin inflammation


In 1982, a third SOD enzyme was discovered by Marklund and co-workers and named SOD3 on extracellular superoxide dismutase (EC-SOD), as it was shown to be the predominant form in extracellular fluids such as lymph, synovial fluid, and plasma. Many studies have focused on the anti-oxidative effect of SOD3 in the lung and vascular wall where it is highly expressed. Thus, the roles of SOD3 as an anti-oxidative enzyme in ROS-mediated lung inflammation and vascular disease such as ischemia and atherosclerosis, and its mechanism have been extensively studied. However, our studies revealed that the role of SOD3 in inflammation is not simply due to radical scavenging; it affects immune responses and signal initiation. Further, we found that SOD3 is expressed throughout the epidermis and dermis, and its levels were altered upon the progression of inflammation. Considering that skin is the primarily contact with the exogenous environment, including UV, pathogens, and chemicals, it is necessary to understand the role of SOD3 in the prevention or suppression of skin inflammation. Here, we address the emerging role of SOD3 in the suppression of skin inflammation and immune response.


The Roles of Oxidative Stress and Antioxidant Treatment in Experimental Diabetic Neuropathy


Oxidative stress is present in the diabetic state. Oxidative stress appears to be primarily due to the processes of nerve ischemia and hyperglycemia auto-oxidation.


Clinical study of superoxide dismutase in recurrent aphthous ulceration


Activity of superoxide dismutase (SOD) was determined in erythrocytes obtained from 74 patients with recurrent aphthous ulcerations (RAU) and 100 healthy individuals. The results showed that activity level of SOD in RAU was significantly lower as compared with that in the controls (P less than 0.01). The activity of SOD in 30 cases of RAU at interval period was elevated on reexamination, but it was still lower than that in the controls (P less than 0.01). There is evidence that damage of superoxide radicals (O.2) and decrease of activity of SOD may play important roles in the pathogenesis of RAU. A random double-blind, placebo-controlled, crossover trial on membrane SOD was carried out in 40 patients with RAU. The results demonstrated that the effective rate of SOD was 90%, being markedly higher than that of placebo. It is suggested that membrane SOD, as a topical medicine, could increase the concentration of SOD on the ulcerous surfaces, prevent O.2-induced injury, decrease capillary permeability, relieve inflammation and improve cure of ulcer.


A copper sulfate and hydroxylysine treatment regimen for enhancing collagen


Results found copper sulfate to significantly increase pyridinoline (PYR) cross-links in all copper sulfate-containing groups over controls. When copper sulfate and hydroxylysine were combined, the result was synergistic, with a 10-fold increase in PYR content over controls. This increase in PYR cross-links manifested in a 3.3-fold significant increase in the tensile properties of the copper sulfate + hydroxylysine group. In addition, a 123% increase over control values was detected in the copper sulfate group in terms of the aggregate modulus. These data elucidate the role of copper sulfate and hydroxylysine toward improving the biomechanical properties of neo tissues through collagen cross-linking enhancement.


Skin penetration by metal compounds with special reference to copper


Transformation of data from that study, based on certain assumptions, lead to estimated Kp values of 10(-6) to 10(-5) cm/h for the copper salts tested, values that lie at the lower end of skin diffusivity rates measured for transition metal salts. Permeability coefficients for aqueous copper sulfate and acetate through human epidermis in vitro measured in our laboratory are of the order of 10(-6) cm/h. For copper compounds formulated in combination with zinc compounds for therapeutic purposes, applied on dermatomed human skin in vitro in various vehicles, the apparent penetration coefficients Kp were in the range of 3.2 x 10(-6) and 1.6 x 10(-5) cm/h.


Copper-induced vascular endothelial growth factor expression and wound healing


Angiogenesis plays a central role in wound healing. Among many known growth factors, vascular endothelial growth factor (VEGF) is believed to be the most prevalent, efficacious, and long-term signal that is known to stimulate angiogenesis in wounds. Whereas a direct role of copper to facilitate angiogenesis has been evident two decades ago, the specific targets of copper action remained unclear.Copper-based therapeutics represents a feasible approach to promote dermal wound healing.


Vascular endothelial growth factor and oxidative stress effects by copper in dermal fibroblasts


This research investigated the mechanism for the anti-skin aging effect copper ions, from cuprous oxide powders. Dermal fibroblasts were exposed to copper and examined for expression (protein and/or promoter levels) of types I, III, V collagen, heat shock protein-47 (HSP-47), elastin, fibrillin-1, and fibrillin-2, TGF-β1, vascular endothelial growth factor (VEGF), and in addition for membrane damage and lipid peroxidation. The direct antioxidant activity of copper was also determined. The research indicates that copper’s anti-skin aging and skin regeneration potential is through its stimulation of ECM proteins, TGF-β1, VEGF, and inhibition of oxidative stress effects at physiological concentrations; and supports its use in cosmetics.


Studies on Zinc and Copper Ion in Relation to Wound Healing in Male and Female West African Dwarf Goats.


Wound healing remains a challenging clinical problem for which precise and efficient management is essential in order to curtail morbidity and mortality. Wound healing has been shown to depend upon the availability of appropriate trace elements like copper and zinc which serve as enzyme cofactors and structural components in tissue repair. This study aims at evaluating the distribution of zinc and copper found in the hair as well as skin during epidermal wound healing. The wound healed faster in female goat compared with the males. The ratio of copper to zinc is clinically more important than the concentration of either of these trace metals. 


Zinc sulphate administered by transdermal iontophoresis improves breaking strength of surgical wounds in skin of alloxan-induced diabetic rats


To investigate the effect of zinc sulphate administered by transdermal iontophoresis (TDI) on mechanical resistance of surgical wounds performed in the skin of diabetic rats. Zinc sulphate administered by transdermal iontophoresis had beneficial effect on the mechanical resistance of scars produced in the skin of diabetic rats. This therapeutic may have potential to reduce the complications observed in surgical wounds of the skin in diabetic subjects, mainly in most vulnerable stages of incisions to dehiscences, leakages and infections.


Cu-doped zinc oxide and its polythiophene composites: preparation and antibacterial properties


Cu-doped zinc oxide and its polythiophene nanocomposites were prepared by the Sol–Gel and in situ polymerization methods, respectively. The structures, morphologies and compositions of the samples were characterized. The antibacterial properties of the samples on three kinds of strains were determined by using powder inhibition zones, minimum inhibitory concentrations and minimal bactericidal concentrations. The study confirmed that the antibacterial activities of the composites were better than those of their each component. The antibacterial mechanisms of the samples were discussed further.


Systemic magnesium to improve quality of post-surgical recovery in outpatient segmental mastectomy: a randomized, double-blind, placebo-controlled trial.


This study showed systemic magnesium improves postoperative quality of recovery in patients undergoing outpatient segmental mastectomy. Systemic magnesium is a safe, inexpensive, efficacious strategy to improve quality of recovery after ambulatory surgery. It remains to be determined if perioperative systemic magnesium can improve postoperative quality of recovery of patients undergoing ambulatory procedures.


Antioxidant Micronutrients in Major Trauma and Burns: Evidence and Practice


There is sufficient evidence of the clinical benefits of trace element and vitamin supplements to justify both its introduction in clinical practice and to encourage further well-designed controlled trials of different proportions of micronutrients.


Copper and Zinc, Biological Role and Significance of Copper/Zinc Imbalance 



More than the concentration of Zn or Cu in blood serum, it is important the balance between them. If the balance is changed several organic systems can be affected. Different diseases can be prevented when supplements are taken, and different drugs affect Cu and Zn concentrations what can cause the onset of different diseases.


Antibacterial Properties of Magnesium In Vitro and in an In Vivo Model of Implant-Associated Methicillin-Resistant Staphylococcus aureus Infection


Implantation of an Mg intramedullary nail into the bone cavity of a rat protected the implant from bacterial contamination and improved new peri-implant bone formation. We suggest that biodegradable Mg-based biomaterials have a great potential for antibacterial orthopedic implant applications, to prevent and/or treat implant-associated infection, and thus to improve therapeutic efficacy and safety.


Bioactive wound dressing - Wound dressings – a review of 2015


The last type of modern wound dressing is bioactive dressings and is produced from biomaterials which play an important role in healing process. These dressings are known for their biocompatibility, biodegradability and non-toxic nature and are derived generally from natural tissues or artificial sources such as collagen, hyaluronic acid, chitosan, alginate and elastin. Polymers of these materials are used alone or in combination depending on the nature and type of wound. Biological dressings are sometimes incorporated with growth factors and antimicrobials to enhance wound healing process.

Related Publications