Thashree Marimuthu

A Review of Injectable Polymeric Hydrogel Systems for Application in Bone Tissue Engineering

Biodegradable, stimuli-responsive polymers are essential platforms in the field of drug delivery and injectable biomaterials for application of bone tissue engineering. Various thermo-responsive hydrogels display water-based homogenous properties to encapsulate, manipulate and transfer its contents to the surrounding tissue, in the least invasive manner. The success of bioengineered injectable tissue modified delivery systems depends significantly on their chemical, physical and biological properties. Irrespective of shape and defect geometry, injectable therapy has an unparalleled advantage in which intricate therapy sites can be effortlessly targeted with minimally invasive procedures. Using material testing, it was found that properties of stimuli-responsive hydrogel systems enhance cellular responses and cell distribution at any site prior to the transitional phase leading to gelation. The substantially hydrated nature allows significant simulation of the extracellular matrix (ECM), due to its similar structural properties. Significant current research strategies have been identified and reported to date by various institutions, with particular attention to thermo-responsive hydrogel delivery systems, and their pertinent focus for bone tissue engineering. Research on future perspective studies which have been proposed for evaluation, have also been reported in this review, directing considerable attention to the modification of delivering natural and synthetic polymers, to improve their biocompatibility and mechanical properties.

Ca3(PO4)2 precipitated layering of an in situ hybridized PVA/Ca2O4Si nanofibrous antibacterial wound dressing.

The aim of this study was to develop an in situ hybridized poly(vinyl alcohol)/calcium silicate (PVA/Ca2OSi) nanofibrous antibacterial wound dressing with calcium phosphate [Ca3(PO4)2] surface precipitation for enhanced bioactivity. This was achieved by hybridizing the antibacterial ions Zn(2+) and/or Ag(+) in a Ca2O4Si composite. The hybridization effect on the thermal behavior, physicochemical, morphological, and physicomechanical properties of the nanofibers was studied using Differential Scanning calorimetric (DSC), X-ray Diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM) and Textural Analysis, respectively. In vitro bioactivity, biodegradation and pH variations of the nanofiber composite were evaluated in Simulated Body Fluid (SBF). The antibacterial activity was assessed against Staphylococcus aureus and Pseudomonas aeruginosa. Hybridization of Zn(2+) and/or Ag(+) into the PVA/Ca2O4Si nanofiber composite was confirmed by DSC, XRD and FTIR. The thickness of the nanofibers was dependent on the presence of Zn(2+) and Ag(+) as confirmed by SEM. The nanofibers displayed enhanced tensile strength (19-115.73MPa) compared to native PVA. Zn(2+) and/or Ag(+) hybridized nanofibers showed relatively enhanced in vitro bioactivity, biodegradation (90%) and antibacterial activity compared with the native PVA/Ca2O4Si nanofiber composite. Results of this study has shown that the PVA/Ca2O4Si composite hybridized with both Zn(2+) and Ag(+) may be promising as an antibacterial wound dressing with a nanofibrous archetype with enhanced bioactivity.

A dual pH/Redox responsive copper-ligand nanoliposome bioactive complex for the treatment of chronic inflammation.

A novel dual pH/redox-responsive polymeric nanoliposome system (NLs) loaded with a copper-liganded bioactive complex was prepared and designed as a controlled delivery system for the management of inflammation. The NLs were synthesised after preparation of the copper-glyglycine-prednisolone succinate] ([(Cu(glygly)(PS)]) complex, and the dual pH/redox responsive biopolymer respectively. The methodology undertaken for the development of the drug delivery system involved coordination of the bioactive to Copper (II), preparation of dual pH/redox responsive biopolymer, and the synthesis of dual pH/redox nanoliposomes. Characterisations of the prepared copper-liganded bioactive [Copper-glyglycine-prednisolone succinate] ([(Cu(glygly)(PS)]) complex, dual pH/redox responsive biopolymer (Eudragit E100-cystamine) and [(Cu(glygly)(PS)]-loaded NLs were carried out using spectroscopic and physicochemical techniques. Results indicated a high inflammatory/oxidant inhibitory activity of [Cu(glygly)(PS)] in comparison to the free PS drug. The [Cu(glygly)(PS)] complex exhibited a significant free radical-scavenging activity (60.1±1.2%) and lipoxygenase (LOX-5) inhibitory activity (36.6±1.3%) in comparison to PS which resulted in activity of 4.4±1.4% and inhibition of 6.1±2.6% respectively. The [Cu(glygly)(PS)] loaded NLs demonstrated low release profiles of 22.9±5.4% in 6h at pH 7.4, in comparison to a significant accelerated release at pH 5 in a reducing environment of 75.9±3.7% over 6h duration. Results suggest that the novel copper-liganded bioactive delivery system with controlled drug release mechanism could serve as a potential drug delivery system candidate in the management of inflammation.

Design of a Versatile pH-Responsive Hydrogel for Potential Oral Delivery of Gastric-Sensitive Bioactives

A pH-responsive hydrogel system was prepared by free radical polymerization of acrylamide and methyl acrylic acid in the presence of N-N′-methylene bisacrylamide. Sodium bicarbonate was further applied as a blowing agent, which afforded a porous hydrogel structure. The hydrogel system achieved a constant super swelling rate within simulated intestinal buffer (~4%/min) and remained relatively static within simulated gastric buffer (~0.8%/min). The hydrogel system was able to achieve matrix resilience greater than 30% under a relatively high strain of 40%. In addition, the hydrogel system demonstrated significant swelling properties in response to simulated intestinal environmental over 24 h, with contrasting characteristics in simulated gastric buffer. The hydrogel demonstrated type IV isotherm porosity characteristics, with remarkable MRI and SEM variations in gastric and intestinal simulated fluids. Drug loading was observed to be greater than 98% using theophylline as a prototype drug, evaluating its controlled release kinetics over 24 h. The hydrogel exhibited substantial pH-responsive activity, which could be used as a versatile platform for targeted release of gastric-sensitive therapeutics to the small intestine.

Development of an injectable pseudo-bone thermo-gel for application in small bone fractures

A pseudo-bone thermo-gel was synthesized and evaluated for its physicochemical, mechanical and rheological properties, with its application to treat small bone fractures. The pseudo-bone thermo-gel was proven to have thermo-responsive properties, behaving as a solution in temperatures below 25°C, and forming a gelling technology when maintained at physiological conditions. Poly propylene fumerate (PPF), Pluronic F127 and PEG-PCL-PEG were strategically blended, obtaining a thermo-responsive delivery system, to mimic the mechanical properties of bone with sufficient matrix hardness and resilience. A Biopharmaceutics Classification System (BCS) class II drug, simvastatin, was loaded in the pseudo-bone thermo-gel, selected for its bone healing properties. In vitro release analysis was undertaken on a series of experimental formulations, with the ideal formulations obtaining its maximum controlled drug release profile up to 14days. Ex vivo studies were undertaken on an induced 4mm diameter butterfly-fractured osteoporotic human clavicle bone samples. X-ray, ultrasound as well as textural analysis, undertaken on the fractured bones before and after treatment displayed significant bone filling, matrix hardening and matrix resilience properties. These characteristics of the pseudo-bone thermo-gel thus proved significant potential for application in small bone fractures.

Nanocomposites for therapeutic application in multiple sclerosis

Abstract Multiple sclerosis (MS) is a debilitating inflammatory autoimmune disease with characteristic neuron demyelination and irreversible damage of neuronal axons and oligodendrocytes. This chapter discusses research lessons learnt from nanotherapeutic interventions for neurodegenerative disorders, as a potential approach forward for application in MS. Advanced drug delivery systems have shown encouraging success to negate these barriers, specifically as nanocomposites derived through various formulation techniques, resulting in nanoliposomes, stimuli-responsive polymeric systems, and inorganic/organic nanoparticles (NPs), which have been researched as promising carrier systems in MS treatment. These new approaches of NPs application are employed in two techniques; antiinflammatory and neuro-protection. Nanocomposite systems have demonstrated superior therapeutic efficacy, evaluated in either experimental autoimmune encephalomyelitis (EAE) or MS-induced animal models. This chapter therefore highlights most recent nanocomposite-driven drug delivery systems for therapeutic application in MS, and their significance compared to traditional nanostrategies, with a positive future outlook employing nanocomposite designs.

Dexamethasone-Loaded, PEGylated, Vertically Aligned, Multiwalled Carbon Nanotubes for Potential Ischemic Stroke Intervention

The complete synthesis, optimization, purification, functionalization and evaluation of vertically aligned multiwalled carbon nanotubes (VA-MWCNTs) was reported for potential application in dexamethasone delivery to the ischemic brain tissue. The conditions for high yield were optimized and carbon nanotubes functionalized and PEGylated prior to dexamethasone loading. Morphological changes were confirmed by SEM and TEM. Addition of functional groups to MWCNTs was demonstrated by FTIR. Thermal stability reduced following MWCNTs functionalization as demonstrated in TGA. The presence of carbon at 2θ of 25° and iron at 2θ of 45° in MWCNTs was illustrated by XRD. Polydispersive index and zeta potential were found to be 0.261 and −15.0 mV, respectively. Dexamethasone release increased by 55%, 65% and 95% in pH of 7.4, 6.5 and 5.5 respectively as evaluated by UV-VIS. The functionalized VA-MWCNTs were demonstrated to be less toxic in PC-12 cells in the concentration range from 20 to 20,000 µg/mL. These findings have demonstrated the potential of VA-MWCNTs in the enhancement of fast and prolonged release of dexamethasone which could lead to the effective treatment of ischemic stroke. More work is under way for targeting ischemic sites using atrial natriuretic peptide antibody in stroke rats.

Customized Peptide Biomaterial Synthesis via an Environment-Reliant Auto-Programmer Stigmergic Approach

Stigmergy, a form of self-organization, was employed here to engineer a self-organizing peptide capable of forming a nano- or micro-structure and that can potentially be used in various drug delivery and biomedical applications. These self-assembling peptides exhibit several desirable qualities for drug delivery, tissue engineering, cosmetics, antibiotics, food science, and biomedical surface engineering. In this study, peptide biomaterial synthesis was carried out using an environment-reliant auto-programmer stigmergic approach. A model protein, α-gliadin (31, 36, and 38 kD), was forced to attain a primary structure with free –SH groups and broken down enzymatically into smaller fragments using chymotrypsin. This breakdown was carried out at different environment conditions (37 and 50 °C), and the fragments were allowed to self-organize at these temperatures. The new peptides so formed diverged according to the environmental conditions. Interestingly, two peptides (with molecular weights of 13.8 and 11.8 kD) were isolated when the reaction temperature was maintained at 50 °C, while four peptides with molecular weights of 54, 51, 13.8, and 12.8 kD were obtained when the reaction was conducted at 37 °C. Thus, at a higher temperature (50 °C), the peptides formed, compared to the original protein, had lower molecular weights, whereas, at a lower temperature (37 °C), two peptides had higher molecular weights and two had lower molecular weights.

A 3D bioprinted in situ conjugated-co-fabricated scaffold for potential bone tissue engineering applications: A 3D BIOPRINTED IN SITU CONJUGATED-CO-FABRICATED SCAFFOLD

There is a demand for progressive approaches in bone tissue engineering to repair and regenerate bone defects resulting from trauma or disease. This investigation sought to engineer a single-step in situ conjugated polymeric scaffold employing 3D printing technology as an innovative fabricating tool. A polymeric scaffold was engineered in situ employing sodium alginate as a bio-ink which interacted with a poly(ethyleneimine) solution on bioprinting to form a polyelectrolyte complex through ionic bond formation. Silica gel was included in the bio-ink as temporal inorganic support component and for ultimate enhancement of osteoinduction. Characterization of the biorelevant properties of the scaffold was undertaken via Fourier Transform Infrared Spectroscopy, Differential Scanning Calorimetry and Thermogravimentric Analysis, X-Ray diffraction, Scanning Electron Microscopy, and biomechanical testing. The scaffold maintained its 3D architecture for the duration of the 28-day degradation investigation, while potentially permitting the infiltration of nutrients, growth factor, and cells evident by the increased solvent penetration into the scaffold observed via Magnetic Resonance Imaging studies. The scaffold porosity and pore size were found to be 60% and 360 µm, respectively. Biomechanical evaluation revealed a Youngs modulus of 18.37 MPa highlighting that the scaffold in its current form possesses the mechanical capabilities for certain bone tissue engineering applications. This investigation provided highlighted the applicability of alginate-poly(ethyeneimine)/silica for 3D bioprinting as a scaffold which could possess potential as a bone tissue engineering scaffold.

Outlook on the Application of Metal-Liganded Bioactives for Stimuli-Responsive Release

Direct metal-liganded bioactive coordination complexes are known to be sensitive to stimuli such as pH, light, ion activation, or redox cues. This results in the controlled release of the bioactive(s). Compared to other drug delivery strategies based on metal complexation, this type of coordination negates a multi-step drug loading methodology and offers customized physiochemical properties through judicious choice of modulating ancillary ligands. Bioactive release depends on simple dissociative kinetics. Nonetheless, there are challenges encountered when translating the pure coordination chemistry into the biological and physiological landscape. The stability of the metal–bioactive complex in the biological milieu may be compromised, disrupting the stimuli-responsive release mechanism, with premature release of the bioactive. Research has therefore progressed to the incorporation of metal-liganded bioactives with established drug delivery strategies to overcome these limitations. This review will highlight and critically assess current research interventions in order to predict the direction that pharmaceutical scientists could pursue to arrive at tailored and effective metal-liganded bioactive carriers for stimuli-responsive drug release.