Pullulan-Based Hydrogels in Wound Healing and Skin Tissue Engineering Applications: A Review.

Wound healing is a complex process of overlapping phases with the primary aim of the creation of new tissues and restoring their anatomical functions. Wound dressings are fabricated to protect the wound and accelerate the healing process. Biomaterials used to design dressing of wounds could be natural or synthetic as well as the combination of both materials. Polysaccharide polymers have been used to fabricate wound dressings. The applications of biopolymers, such as chitin, gelatin, pullulan, and chitosan, have greatly expanded in the biomedical field due to their non-toxic, antibacterial, biocompatible, hemostatic, and nonimmunogenic properties. Most of these polymers have been used in the form of foams, films, sponges, and fibers in drug carrier devices, skin tissue scaffolds, and wound dressings. Currently, special focus has been directed towards the fabrication of wound dressings based on synthesized hydrogels using natural polymers. The high-water retention capacity of hydrogels makes them potent candidates for wound dressings as they provide a moist environment in the wound and remove excess wound fluid, thereby accelerating wound healing. The incorporation of pullulan with different, naturally occurring polymers, such as chitosan, in wound dressings is currently attracting much attention due to the antimicrobial, antioxidant and nonimmunogenic properties. Despite the valuable properties of pullulan, it also has some limitations, such as poor mechanical properties and high cost. However, these properties are improved by blending it with different polymers. Additionally, more investigations are required to obtain pullulan derivatives with suitable properties in high quality wound dressings and tissue engineering applications. This review summarizes the properties and wound dressing applications of naturally occurring pullulan, then examines it in combination with other biocompatible polymers, such chitosan and gelatin, and discusses the facile approaches for oxidative modification of pullulan.

A Review on Chitosan and Cellulose Hydrogels for Wound Dressings.

Wound management remains a challenging issue around the world, although a lot of wound dressing materials have been produced for the treatment of chronic and acute wounds. Wound healing is a highly dynamic and complex regulatory process that involves four principal integrated phases, including hemostasis, inflammation, proliferation, and remodeling. Chronic non-healing wounds are wounds that heal significantly more slowly, fail to progress to all the phases of the normal wound healing process, and are usually stalled at the inflammatory phase. These wounds cause a lot of challenges to patients, such as severe emotional and physical stress and generate a considerable financial burden on patients and the general public healthcare system. It has been reported that about 1-2% of the global population suffers from chronic non-healing wounds during their lifetime in developed nations. Traditional wound dressings are dry, and therefore cannot provide moist environment for wound healing and do not possess antibacterial properties. Wound dressings that are currently used consist of bandages, films, foams, patches and hydrogels. Currently, hydrogels are gaining much attention as a result of their water-holding capacity, providing a moist wound-healing milieu. Chitosan is a biopolymer that has gained a lot of attention recently in the pharmaceutical industry due to its unique chemical and antibacterial nature. However, with its poor mechanical properties, chitosan is incorporated with other biopolymers, such as the cellulose of desirable biocompatibility, at the same time having the improved mechanical and physical properties of the hydrogels. This review focuses on the study of biopolymers, such as cellulose and chitosan hydrogels, for wound treatment.

Study of the Nanofibers Fabrication Conditions from the Mixture of Poly(vinyl alcohol) and Chitosan by Electrospinning Method.

Nanofiber fabrication is attracting great attention from scientists and technologists due to its applications in many fields of life. In order to design a nanosized polymer-based drug delivery system, we studied the conditions for the fabrication of electrospun nanofibers from poly (vinyl alcohol) (PVA) and chitosan (CS), which are well-known as biocompatible, biodegradable and non-toxic polymers that are widely used in the medical field. Aiming to develop nanofibers that can directly target diseased cells for treatment, such as cancerous cells, the ideal choice would be a system that contains the highest CS content as well as high quality fibers. In the present manuscript, it is expected to become the basis for improving the low bioavailability of medicinal drugs limited by poor solubility and low permeability. PVA-CS nanofibers were obtained by electrospinning at a PVA:CS ratio of 5:5 in a 60% (w/w) acetic acid solution under the following parameters: voltage 30 kV, feed rate 0.2 mL/h, needle-collector distance 14 cm. The obtained fibers were relatively uniform, with a diameter range of 77-292 nm and average diameter of 153 nm. The nanofiber system holds promise as a potential material for the integration of therapeutic drugs.

Mangiferin as New Potential Anti-Cancer Agent and Mangiferin-Integrated Polymer Systems-A Novel Research Direction.

For a long time, the pharmaceutical industry focused on natural biologically active molecules due to their unique properties, availability and significantly less side-effects. Mangiferin is a naturally occurring C-glucosylxantone that has substantial potential for the treatment of various diseases thanks to its numerous biological activities. Many research studies have proven that mangiferin possesses antioxidant, anti-infection, anti-cancer, anti-diabetic, cardiovascular, neuroprotective properties and it also increases immunity. It is especially important that it has no toxicity. However, mangiferin is not being currently applied to clinical use because its oral bioavailability as well as its absorption in the body are too low. To improve the solubility, enhance the biological action and bioavailability, mangiferin integrated polymer systems have been developed. In this paper, we review molecular mechanisms of anti-cancer action as well as a number of designed polymer-mangiferin systems. Taking together, mangiferin is a very promising anti-cancer molecule with excellent properties and the absence of toxicity.

Synthesis of Tamoxifen-Artemisinin and Estrogen-Artemisinin Hybrids Highly Potent Against Breast and Prostate Cancer.

In the search for new and effective treatments of breast and prostate cancer, a series of hybrid compounds based on tamoxifen, estrogens, and artemisinin were successfully synthesized and analyzed for their in vitro activities against human prostate (PC-3) and breast cancer (MCF-7) cell lines. Most of the hybrid compounds exhibit a strong anticancer activity against both cancer cell lines - for example, EC50 (PC-3) down to 1.07 µM, and EC50 (MCF-7) down to 2.08 µM - thus showing higher activities than their parent compounds 4-hydroxytamoxifen (afimoxifene, 7; EC50 =75.1 (PC-3) and 19.3 µM (MCF-7)), dihydroartemisinin (2; EC50 =263.6 (PC-3) and 49.3 µM (MCF-7)), and artesunic acid (3; EC50 =195.1 (PC-3) and 32.0 µM (MCF-7)). The most potent compounds were the estrogen-artemisinin hybrids 27 and 28 (EC50 =1.18 and 1.07 µM, respectively) against prostate cancer, and hybrid 23 (EC50 =2.08 µM) against breast cancer. These findings demonstrate the high potential of hybridization of artemisinin and estrogens to further improve their anticancer activities and to produce synergistic effects between linked pharmacophores.

Novel structural features increase the antioxidant effect of estrogen analogues on low density lipoprotein.

Many known estrogens, both natural and synthetic, may act as antioxidants. We designed and synthesized 22 novel estrogen analogues with different ring junctions or substitutions, such as fluorine. We studied the antioxidant capacity in vitro of 35 synthetic estrogen analogues in aqueous lipoprotein solution by monitoring the formation of conjugated dienes. In addition to a free C-3 hydroxyl group, the two most active antioxidants had either a methyl group at C-4 and a six-carbon D-ring, or a fluorine atom at C-2 and an unsaturated B-ring. Extension of the D-ring increased the antioxidant capacity of 6-oxa estrogens. Compounds with a fluorine atom at C-2 were similar or more potent antioxidants compared with the principal endogenous estrogen, 17ß-estradiol. In compounds with a substituted C-3 hydroxyl group, the antioxidant capacity could be significantly increased by additional double bonds in the C- or D-rings. In conclusion, we show that the antioxidant capacity of estrogen analogues could be increased by structural changes.

Synthesis and investigation of biological properties of modified 6-oxa-estra-1,3,5(10),8(9)-tetraenes.

To investigate the relationship between structure and biological activity of analogues of steroid estrogens we have developed the synthesis of 7α-methyl-6-oxa-estra-1,3,5(10),8(9)-tetraenes with cis- and trans-junction of C and D rings. We found that such compounds have stronger osteoprotective, cholesterol-lowering and antioxidant properties in comparison with uterotrophic activity; that is the advantage in comparison with clinically used 17α-ethynylestradiol.