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Doxycycline Loaded Collagen-Chitosan Composite Scaffold for the Accelerated Healing of Diabetic Wounds

One major complication of diabetes mellitus is diabetic wounds (DW). The prolonged phase of inflammation in diabetes obstructs the further stages of an ...

JSS Academy of Higher Education & Research

Diabetic wounds are a common complication in patients with diabetes that often lead to amputation. Although the pathophysiology of diabetic wound is multifactorial, chronic inflammation and lack of tissue regeneration leads to impair wound healing in diabetes. Application of curcumin (CUR) which is a well-known anti-inflammatory and antioxidant agent could be better strategy in diabetic wound healing. However, low bioavailability and poor stability of CUR hinders its application. Hence, in present study a novel nanohybrid scaffold has been prepared by incorporating CUR in chitosan nanoparticles (CSNPs) to improve stability and solubility followed by impregnation of prepared CUR-CSNPs into collagen scaffold (nanohybrid scaffold) for better tissue regeneration application. The prepared CUR-CSNPs were evaluated for particle size, zeta potential, SEM, differential scanning calorimetry and X-ray powder diffraction studies and the novel nanohybrid is evaluated for morphology, biodegradability, biocompatibility, in vitro drug release and in vivo wound healing studies. The results of NPs evaluation suggest the better stability and solubility of CUR. The nanohybrid scaffold showed good in vitro characteristics in terms of better water uptake, biocompatibility and sustained drug availability. The results of in vivo wound closure analysis revealed that nanohybrid scaffold treated wounds contracted significantly (p<0.001) faster than the wounds from the control and placebo scaffold groups. Further, the obtained results suggest that complete epithelialization with thick granulation tissue formation occur in nanohybrid scaffold group, whereas lack of compact collagen deposition in placebo scaffold group and presence of inflammatory cells in control group was observed. Hence, the present study suggests that the synergistic combination of CUR (anti-inflammatory and anti-oxidant), chitosan (sustain drug carrier, wound healing) and collagen (established wound healer as scaffold) is a promising strategy to address various pathological manifestations of diabetic wounds and have better wound healing capability.

Curcumin loaded chitosan nanoparticles impregnated into collagen-alginate scaffolds for diabetic wound healing.

5-Aminosalicylic acid (5-ASA) is an aminosalicylate anti-inflammatory drug, which is also known as mesalazine or mesalamine. Currently employed in treating inflammatory bowel disease, ulcerative colitis, inflamed anus or rectum, and maintain remission in Crohn's disease. Evidence from the researchers highlighted its significant re-epithelization in allergic asthma, aphthous, and gastric ulcerative conditions. The objective of the study was to formulate the pluronic lecithin organogel (PLO) containing 5-ASA and evaluate its wound-healing ability in a full thickness excision wound rat model. The data obtained from in silico docking studies revealed 5-ASA is having an affinity towards the transforming growth factor-beta (TGF-β) specifically towards beta1. Among various formulations prepared (F1 to F8), F1, and F6 have shown a maximum in vitro drug release with optimum pH and viscosity. From MTT assay it was found that selected PLO formulations showed no toxicity and enhanced cell proliferation in HaCaT cell lines. In vivo wound-healing studies in albino Wistar rats has revealed that PLO accelerates wound closure and reepithelization to the statistically significant level on day 3 (p < .05) in comparison with untreated wounds. In conclusion, the overall results suggest that 5-ASA PLO gel is a potential therapeutic option for the treatments of wounds, however, further studies are highly warrened to determine the various mechanisms of 5-ASA in regulating the cell migration and reepithelization in wound healing to outspread its use in clinics.

Pluronic lecithin organogel of 5-aminosalicylic acid for wound healing.

Drug delivery to the brain is challenging because of the low permeability of blood-brain barrier, and therefore, optimum concentration of chemotherapeutics in the target area specifically for glioblastoma, an aggressive brain tumor, opens a new path of research. To achieve the goal, the oral alkylating agent temozolomide was incorporated into niosomes, and the surface was modified with chlorotoxin, a small 36 amino acid peptide discovered from the venom of scorpion . Active targeting using nanosized particles facilitates an increase in the accumulation of drugs in the cerebri by 3.04-folds. Temozolomide-loaded niosomes were prepared using conventional thin-film hydration method and characterized. Niosomes coated with chlorotoxin were produced with the size of 220 ± 1.45 nm with an entrapment efficiency of 79.09 ± 1.56%. Quantitative tissue distribution studies indicate enhanced permeation of the drug into the brain because of surface modification with less deposition in the highly perfused organs.

Smart niosomes of temozolomide for enhancement of brain targeting.

The sample extraction process is considered as the essential step in the pesticide residue analysis, as it provides the base for the detection of the pesticides in trace level. Various factors need to be optimized during the extraction of pesticides due to the complexity of the matrix which is time-consuming and tedious. Therefore, the use of experimental design in the optimization process proves to be effective with minimum experiments and cost. This paper is aimed to overview the experimental designs that are frequently used for screening (full factorial, fractional factorial, Plackett-Burman Design) and optimizing (central composite design, Box-Behnken design, Taguchi design, Doehlert design, D-optimal design) the most influential factors to provide a sequential understanding of the linear and complex interactions in the pesticide extraction methods. Further, a systematic approach has been discussed about the use of experimental designs in pesticide extraction and also the softwares used for application-oriented readers.

Experimental design in pesticide extraction methods: A review.

An effective, simple and sensitive analytical method has been developed employing liquid chromatography coupled with tandem mass spectrometry and validated for estimation of five organophosphate pesticides at trace levels in six fruits and twelve vegetables. Plackett-Burman design and central composite design was used to screen and optimize the significant factors in modified QuEChERS (quick, easy, cheap, effective, rugged and safe) extraction method. The method evaluation was done by matrix-matched calibration with linearity ranging from 5 to 500 µg/L with a correlation coefficient more than 0.990. The detection and quantification limit ranged from 0.1 to 1.0 µg/kg and 0.5 to 5 µg/kg, respectively. The mean recoveries were in the range of 76.89-110.30 % with the relative standard deviation less than 13.26% for all pesticides. Further, the method developed was applied to analyze real samples cultivated in the hill areas of Nilgiris, South India.

Multivariate response surface methodology assisted modified QuEChERS extraction method for the evaluation of organophosphate pesticides in fruits and vegetables cultivated in Nilgiris, South India.

Diabetic wound is a major problem that often needs amputation of the concerned organ in patients suffering from diabetes. In diabetes, the prolonged phase of inflammation obstructs the further phases of healing which, in turn, lead to improper healing of the wounds in diabetes. Pioglitazone (Pio) hydrochloride is an antidiabetic drug with reported anti-inflammatory properties. The aim of this study was to develop a Pio-nanostructured lipid carrier (Pio-NLC)-loaded collagen/chitosan (COL-CS) scaffold and evaluate its healing ability in diabetic wounds. The results of characterization of composite scaffolds reveal that cross-linked scaffolds possess optimum porosity, low matrix degradation, and sustained drug release compared with noncross-linked scaffolds. The  studies reveal that the Pio-NLC-COL-CS scaffold was biocompatible and enhanced cell growth compared with control and NLC-COL-CS. Using the streptozotocin-induced diabetic wound model, significantly ( < 0.001) higher rates of wound contraction in Pio-NLC-COL-CS scaffold-treated group were observed in comparison with that in control and NLC-COL-CS-treated group. The enzyme-linked immunosorbent assay results indicate a significant ( < 0.001) decrease of matrix metalloproteinases-9 levels in the Pio-NLC-COL-CS-treated group compared with those in control group. Use of nanostructured lipid carrier (Pio-NLC-COL-CS) scaffold can prove to be a promising strategy for local treatment for diabetic wounds.

Nanostructured Lipid Carriers of Pioglitazone Loaded Collagen/Chitosan Composite Scaffold for Diabetic Wound Healing.

Oral drug delivery is the most widely utilized route of administration among all the routes that have been explored for systemic delivery of drugs via pharmaceutical products of different dosage form and this oral route provides maximum active surface area among all drug delivery system for administration of various drugs. The attractiveness of these dosage forms is due to awareness of toxicity and ineffectiveness of drugs when administered by oral conventional method in the form of tablets and capsules. Usually, conventional dosage form produces wide range of fluctuation in drug concentration in the bloodstream and tissues with consequent undesirable toxicity and poor efficiency. The maintenance of concentration of drug in plasma within therapeutic index is very critical for effective treatment. These factors as well as factors such as repetitive dosing and unpredictable absorption lead to the concept of oral modified drug delivery systems like Sustained release, prolonged release, modified release, extended release. These formulations are used to identify drug delivery systems that are designed to achieve or extend therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose. This review describes the basic information regarding modified release dosage form like designed to release their medication in controlled manner, criteria for selecting modified release dosage form and factors influencing the dosage and release pattern.

Oral Modified Drug Release Solid Dosage Form with Special Reference to Design; An Overview.

Diabetes mellitus (DM) is an endocrine disorder that causes increased blood glucose than usual due to insulin impairment. In DM, several complications arise in which diabetic wound (DW) is the most devastating complication. About 25% of patients with DM expected to develop DWs in their lifetime and undergo limb amputations. Even though several treatments such as surgery, debridement, wound dressings, advanced therapies were available, the overall conclusion has been that with very few exceptions, patients still suffer from limitations like pain, frequent dress changing, high rates of failure, and cost involvement. Further, the treatments involving the delivery of therapeutic agents in treating DWs have limited success due to abnormal levels of proteases in the DW environment. In this backdrop, in situ gelling injectable hydrogels have gained special attention due to their easy encapsulation of therapeutic medications and prolonged release, filling the wound defect areas, ease of handling, and minimally invasive surgical procedures. Though the in situ gelling injectable hydrogels are developed a couple of decades ago, their use for treating DW has not yet been explored thoroughly. Thus, in this review, we have covered the sequential events of DW healing, pathophysiology, current treatments, and its limitations, along with a particular emphasis on the mechanism of action of these in situ gelling injectable hydrogels treating DWs.

Overview of in situ gelling injectable hydrogels for diabetic wounds.

Diabetes mellitus (DM) is a complex disease that affects almost all the body's vital organs. Around 415 million people have been diagnosed with DM worldwide, and most of them are due to type 2 DM. The incidence of DM is estimated to increase by 642 million individuals by 2040. DM is considered to have many complications among which diabetic wound (DW) is one of the most distressing complication. DW affects 15% of people with diabetes and is triggered by the loss of glycaemic control, peripheral neuropathy, vascular diseases, and immunosuppression. For timely treatment, early detection, debridement, offloading, and controlling infection are crucial. Even though several treatments are available, the understanding of overlying diabetes-related wound healing mechanisms as therapeutic options has increased dramatically over the past decades. Conventional dressings are cost-effective; however, they are not productive enough to promote the overall process of DW healing. Thanks to tissue engineering developments, one of the promising current trends in innovative wound dressings such as hydrocolloids, hydrogels, scaffolds, films, and nanofibers which merges traditional healing agents and modern products/practices. Nanofibers prepared by electrospinning with enormous porosity, excellent absorption of moisture, the better exchange rate of oxygen, and antibacterial activities have increased interest. The application of these nanofibers can be extended by starting with a careful selection of polymers, loading with active therapeutic moieties such as peptides, proteins, active pharmaceutical ingredients (API), and stem cells, etc. to make them as potential dosage forms in the management of DWs. This review explains the potential applications of electrospun nanofibers in DW healing. A schematic view of role of nanofibers in diabetic wounds.

Biomedical applications of electrospun nanofibers in the management of diabetic wounds.

Ganoderma lucidium extract powder (GLEP) contains various polysaccharides which are well known for their antioxidant and anti-inflammatory actions. Probiotics (PB) are well-established for providing a plethora of health benefits. Hence, use of mushroom polysaccharides and probiotics as carriers to solidify liquisolid formulation is anticipated to function as functional excipients i.e. as adsorbent that may provide therapeutic benefits. Quercetin (QUR) has been used as model lipophilic drug in this study. QUR loaded liquisolid compacts (LSCs) were formulated using Tween 80 as solvent. These were further solidified using a combination of PB and GLEP as carriers. Aerosil-200 (A-200) was used as coating agent. The formulation exhibited very good flow characteristics. Dissolution rate of raw QUR was found to be less than 10% in 60 min while in case of QUR loaded LSCs, more than 90% drug release was observed within 5 min. Absence of crystalline peaks of QUR in the DSC and PXRD reports of LSCs and their porous appearance in SEM micrographs indicate that QUR was successfully incorporated in the LSCs. The developed formulation was found to be stable on storage under accelerated stability conditions.

Exploring role of polysaccharides present in Ganoderma lucidium extract powder and probiotics as solid carriers in development of liquisolid formulation loaded with quercetin: A novel study.

Diabetic wound (DW) is one of the leading complications of patients having a long history of uncontrolled diabetes. Moreover, it also imposes an economic burden on people suffering from wounds to manage the treatment. The major impending factors in the treatment of DW are infection, prolonged inflammation and decreased oxygen levels. Since these non-healing wounds are associated with an extended recovery period, the existing therapies provide treatment for a limited period only. The areas covered in this review are general sequential events of wound healing along with DW's pathophysiology, the origin of DW and success, as well as limitations of existing therapies. This systematic review's significant aspect is to highlight the fabrication, characterization and applications of various acellular scaffolds used to heal DW. In addition to that, cellular scaffolds are also described to a limited extent.

Acellular Scaffolds as Innovative Biomaterial Platforms for the Management of Diabetic Wounds.

The treatment of diabetic wounds (DWs) is always challenging for the medical community because of its multifaceted pathophysiology. Due to practical and ethical considerations, direct studies of therapeutic interventions on human subjects are limited. Thus, it is ideal for performing studies on animals having less genetic and biological variability. An ideal DW model should progress toward reproducibility, quantifiable interpretation, therapeutic significance, and effective translation into clinical use. In the last couple of decades, various animal models were developed to examine the complex cellular and biochemical process of skin restoration in DW healing. Also, these models were used to assess the potency of developed active pharmaceutical ingredients and formulations. However, many animal models lack studying mechanisms that can appropriately restate human DW, stay a huge translational challenge. This review discusses the available animal models with their significance in DW experiments and their limitations, focusing on levels of proof of effectiveness in selecting appropriate models to restate the human DW to improve clinical outcomes. Although numerous newer entities and combinatory formulations are very well appreciated preclinically for DW management, they fail in clinical trials, which may be due to improper selection of the appropriate model. The major future challenge could be developing a model that resembles the human DW environment, can potentiate translational research in DW care.

Veera Venkata Satyanarayana Reddy Karri

Department of Pharmaceutics,
JSS College of Pharmacy,
Department of Pharmaceutics, JSS College of Pharmacy

JSS Academy of Higher Education & Research

Doxycycline Loaded Collagen-Chitosan Composite Scaffold for the Accelerated Healing of Diabetic Wounds

Veera Venkata Satyanarayana Reddy Karri

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JSS Academy of Higher Education & Research

Doxycycline Loaded Collagen-Chitosan Composite Scaffold for the Accelerated Healing of Diabetic Wounds

Department of Pharmaceutics,
JSS College of Pharmacy,
Department of Pharmaceutics, JSS College of Pharmacy