الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Polymeric nanoparticles are interesting delivery systems characterized by their versatility and tunable properties owing to the wide range of polymers available today. <Among the promising polymeric systems are alginate chitosan nanoparticles.
Chitosan and alginate are natural biodegradable, biocompatible, non-toxic, widely available and relatively cheap polymers. In addition, both polymers exhibit numerous biological activities. For instance, topically, chitosan has been found to possess anti-inflammatory, anti-microbial, hemostatic and wound healing properties.
< In the same context, alginate has also been found to promote wound healing. Both polymers are already present in the market as bandages or granules promoting wound
healing.
The available products consist of either chitosan or alginate, but a combination of both
polymers has not yet been marketed.
Combining the two polymers as chitosan alginate nanoparticles seems to be a promising approach for wound healing, especially for chronic wounds as diabetic bedsores, which up until now, have no standard effective treatment.
One< promising approach is the use of a delivery system with intrinsic wound healing properties.
<In addition, loading of a hydrophobic or hydrophilic drug with wound healing activity would offer
an additional mechanism of wound healing, thus maximizing the therapeutic outcome.
<The main objective of this thesis was to prepare and characterize blank chitosan alginate nanoparticles and evaluate their wound healing effect on diabetic and non-diabetic bedsores.
The possibility of loading a hydrophobic drug such as phenytoin, and a hydrophilic drug as deferoxamine was studied, along with evaluating the effectiveness of the drug-loaded systems in the healing of diabetic bedsores.
The work in this thesis was divided into three chapters:
Chapter One:
Development of placebo chitosan alginate biodegradable polymeric nanoparticles as a promising treatment for diabetic bedsores
Chitosan alginate nanoparticles were prepared by ionotropic gelation method.
<Different alginate (ALG) to chitosan (CS) weight ratios were used by varying CS concentration.
< The main criteria
for selecting optimum placebo NPs were particle size (PS), polydispersity index (PDI) and zeta potential (ZP).
<Increasing chitosan concentrations resulted in an increase in PS and ZP. Chitosanalginate NPs prepared with ALG: CS weight ratios of 1:0.67 and 1:1.5 showed acceptable PS,
PDI, negative and positive ZP, respectively.
< These negatively charged and positively charged chitosan alginate NPs were further used for coating with chitosan and alginate, respectively.
<TEM images confirmed the formation of spherical NPs with sizes in the nano-range. DSC and FT-IR confirmed the interaction between the amino groups of chitosan and carboxyl groups of alginate.
<In vivo studies were carried out to assess the potential healing effect of positively charged and negatively charged uncoated CA NPs.
In –vivo wound healing study on diabetic and non-diabetic rats was performed using a pressure ulcer model.
< NPs suspension was applied daily for 14 days and compared to control untreated wounds.
<Wound closure rate was calculated for all groups throughout the study.
A significantly higher healing rate was observed in the non-diabetic group compared to diabetic and control groups.
<In the non-diabetic group, positively charged CA NPs showed higher wound closure rates compared to the other groups.
In the diabetic group, both positively charged and negatively charged CA
NPs showed higher healing rates compared to control group.
<Histological examination of skin
samples at the end of the experiment showed better skin quality and less inflammation in the
treated non diabetic groups compared to the treated diabetic groups, with excess chitosan giving
better healing properties.
Also, histomorphometric analysis showed a relatively higher collagen deposition with groups treated with excess chitosan.
<Results of this chapter confirmed the feasibility of preparing CA NPs with varying polymers ratios and polymer coatings, thus producing a range of NPs with varying properties.
<Both positively charged and negatively charged CA NPs improved wound healing and quality of skin
formed after induction of pressure ulcers in diabetic and non-diabetic rats, compared to control
untreated groups.
<Chapter two: Chitosan alginate nanoparticles as a promising carrier for hydrophobic drug phenytoin: Preparation, characterization and in-vivo assessment for the treatment of bedsores in diabetic rats
In this chapter, the use of CA NPs as a carrier for a hydrophobic drug as phenytoin (PHT) was investigated. The effect of varying ALG : CS weight ratios and the effect of coating on PS, PDI,
ZP and % entrapment efficiency (%EE) were studied.
Increasing chitosan concentration resulted in an increase in PS, ZP and a decrease in %EE.
Coating also resulted in a decrease in % EE.
<DSC and FT-IR studies confirmed the encapsulation of PHT in CA NPs.
<In-vitro drug release in phosphate buffer with 1% SLS, pH 7.4 revealed relatively faster release rate and higher %
released in coated formulations compared to uncoated ones, and in formulations containing excess ALG compared to the ones with excess CS.
<In vivo studies were carried out to assess the potential healing effect of positively charged and negatively charged uncoated PHT-loaded CA NPs.
< <In-vivo wound healing study on diabetic rats was performed using a pressure ulcer model.
< <NPs suspension and PHT suspension in 1% HPMC equivalent to 1 mg PHT was applied daily for 14 days and compared to control untreated wounds.
<Wound closure rate was calculated for all groups throughout the study.
<Ulcers treated with PHTloaded positively charged CA NPs showed the fastest healing rate compared with the other groups.
Histological examination of skin samples at the end of the experiment showed better skin
quality and less inflammation in PHT-loaded CA NPs with high CS concentration compared to
other groups.
< <PHT-loaded CA NPs with excess ALG showed better skin quality compared to
PHT suspension and control groups. Histomorphometric analysis showed significantly higher
collagen density in the group treated with PHT-loaded positively charged CA NPs, with granulation tissue organization similar to that of normal skin.
<Results of this chapter confirmed the feasibility of PHT-loaded coated and uncoated CA NPs,
although uncoated showed better %EE and controlled release profiles.
<PHT-loaded CA NPs
successfully improved wound healing rates and skin quality when compared to blank CA NPs or drug suspension.
Chapter three: Chitosan alginate nanoparticles loaded with hydrophilic drug
deferoxamine: Preparation, characterization and in-vivo assessment for the treatment of bedsores in diabetic rats
In this chapter, loading a hydrophilic drug as deferoxamine (DFO) in CA NPs was carried out using reverse emulsion method. CA NPs were prepared in the aqueous phase of a w/o emulsion,
dispersed in a mixture of liquid paraffin and span 80. Different aqueous: oil and surfactant: oil ratios were used to determine the optimum ratios for stable emulsions.
A number of organic solvents were used in the washing step.
The main criteria for selecting the best solvent were removal of the excess oily phase without removing the encapsulated drug.
Aqueous: oil volume ratio 1:6, surfactant: oil percent ratio 5:95 and washing with petroleum ether and n-hexane successively were chosen for preparation and separation of DFO-loaded CA NPs.
In-vitro drug release was performed in water.
<Both positively charged and negatively charged CA NPs had similar release patterns, although positively charged CA NPs showed a relatively slower release rate.
<In vivo studies were carried out to assess the potential healing effect of positively charged DFOloaded CA NPs.
In-vivo wound healing study on diabetic rats was performed using a pressure ulcer model. NPs suspension and DFO solution in 1% HPMC equivalent to 0.5 mg DFO was applied daily for 14 days and compared to blank CA NPs and control untreated wounds.
DFOloaded CA NPs showed faster healing rate compared to other groups.
Histological examination
revealed better skin quality in DFO-treated group compared to other groups.
Results of this chapter confirmed the formation of CA NPs loaded with hydrophilic DFO.
DFOloaded CA NPs successfully enhanced healing of diabetic bedsores.