Nowsheen Goonoo

Polydioxanone-based bio-materials for tissue engineering and drug/gene delivery applications

Since the commercialization of polydioxanone (PDX) as a biodegradable monofilament suture by Ethicon in 1981, the polymer has received only limited interest until recently. The limitations of polylactide-co-glycolide (PLGA) coupled with the growing need for materials with enhanced features and the advent of new fabrication techniques such as electrospinning have revived interest for PDX in medical devices, tissue engineering and drug delivery applications. Electrospun PDX mats show comparable mechanical properties as the major structural components of native vascular extracellular matrix (ECM) i.e. collagen and elastin. In addition, PDXs unique shape memory property provides rebound and kink resistance when fabricated into vascular conduits. The synthesis of methyl dioxanone (MeDX) monomer and copolymers of dioxanone (DX) and MeDX have opened up new perspectives for poly(ester-ether)s, enabling the design of the next generation of tissue engineering scaffolds for application in regenerating such tissues as arteries, peripheral nerve and bone. Tailoring of polymer properties and their formulation as nanoparticles, nanomicelles or nanofibers have brought along important developments in the area of controlled drug or gene delivery. This paper reviews the synthesis of PDX and its copolymers and provides for the first time an exhaustive account of its applications in the (bio)medical field with focus on tissue engineering and drug/gene delivery.

Third generation poly(hydroxyacid) composite scaffolds for tissue engineering

Bone tissue engineering based on scaffolds is quite a complex process as a whole gamut of criteria needs to be satisfied to promote cellular attachment, proliferation and differentiation: biocompatibility, right surface properties, adequate mechanical performance, controlled bioresorbability, osteoconductivity, angiogenic cues, and vascularization. Third generation scaffolds are more of composite types to maximize biological-mechanical-chemical properties. In the present review, our focus is on the performance of micro-organism-derived polyhydroxyalkanoates (PHAs)-polyhydroxybutyrate (PHB) and polyhydroxybutyrate-co-valerate (PHBV)-composite scaffolds with ceramics and natural polymers for tissue engineering applications with emphasis on bone tissue. We particularly emphasize on how material properties of the composites affect scaffold performance. PHA-based composites have demonstrated their biocompatibility with a range of tissues and their capacity to induce osteogenesis due to their piezoelectric properties. Electrospun PHB/PHBV fiber mesh in combination with human adipose tissue-derived stem cells (hASCs) were shown to improve vascularization in engineered bone tissues. For nerve and skin tissue engineering applications, natural polymers such as collagen and chitosan remain the gold standard but there is scope for development of scaffolds combining PHAs with other natural polymers which can address some of the limitations such as brittleness, lack of bioactivity and slow degradation rate presented by the latter.

Naltrexone: a review of existing sustained drug delivery systems and emerging nano-based systems.

Narcotic antagonists such as naltrexone (NTX) have shown some efficiency in the treatment of both opiate addiction and alcohol dependence. A few review articles have focused on clinical findings and pharmacogenetics of NTX, advantages and limitations of sustained release systems as well as pharmacological studies of NTX depot formulations for the treatment of alcohol and opioid dependency. To date, three NTX implant systems have been developed and tested in humans. In this review, we summarize the latest clinical data on commercially available injectable and implantable NTX-sustained release systems and discuss their safety and tolerability aspects. Emphasis is also laid on recent developments in the area of nanodrug delivery such as NTX-loaded micelles and nanogels as well as related research avenues. Due to their ability to increase the therapeutic index and to improve the selectivity of drugs (targeted delivery), nanodrug delivery systems are considered as promising sustainable drug carriers for NTX in addressing opiate and alcohol dependence.

Poly(ester-ether)s: II. Properties of electrospun nanofibres from polydioxanone and poly(methyl dioxanone) blends and human fibroblast cellular proliferation†

This article deals with an in-depth study of the thermal, mechanical and degradation behaviours of nanofibres from polydioxanone (PDX) and polydl-3-methyl-1,4-dioxan-2-one (PMeDX) and a comparison with their blend films. Varying ratios of both polymers were blended and electrospun from solution. Electrospun fibres exhibited a melting transition at 109 °C independently of the PMeDX content, which corresponds to the melting of PDX nanofibres. As a result of the drawing process, PMeDX had a reduced plasticizing effect on PDX. In general, it was observed that overall crystallinity of the fibres decreased from 53% to 36% with increasing PMeDX content and this impacted on their mechanical properties. The Youngs moduli decreased as the PMeDX content of the fibres increased. However, an increase in strain at break and peak stress was noted as a result of a decrease in the fibre diameter. AFM images of the electrospun fibres showed an increasing degree of morphological heterogeneity with increasing PMeDX content. Thermal degradation studies showed that electrospun mats were thermally more stable than blend films, as confirmed by a two-fold increase in activation energy. The hydrolytic degradation of the electrospun mats conducted in phosphate buffer solution at 37 °C showed that the degradation followed a surface erosion mechanism as opposed to bulk degradation observed for blend films. Degradation of fibres was found to be mainly dependent on their diameter. On the other hand, the degradation of blend films depended on the overall crystallinity of the blends. Electrospun PDX/PMeDX nanofibrous scaffolds were also subjected to cell viability studies with human dermal fibroblasts, in which they did not show illicit response and demonstrated excellent cell attachment and proliferation.

In vitro and in vivo cytocompatibility of electrospun nanofiber scaffolds for tissue engineering applications

The use of polymeric-based nanofibers has gained more and more attention during the past decade in the biomedical and pharmaceutical fields and as a result, nanotoxicology research is inevitable to satisfy the requirements of regulating agencies such as FDA as well as biosafety needs. Recent advances have witnessed the emergence of an increasing number of nanosized materials. While the number of potential applications related to the use of electrospun nanofibers continues to increase, studies to characterize their effects after exposure and to address their potential cytocompatibility are few in comparison. A comprehensive understanding of nano-bio and physico-chemical interactions is necessary from the early stage of nanomaterial conception to prevent pitfalls of materials failure at preclinical and clinical stages. This review presents a summary of both in vitro and in vivo cytocompatibility data currently available on synthetic and natural polymer-based electrospun nanofibers under investigation for tissue engineering applications. Cellular response dependence on cell type and nature of scaffold is also addressed.

Poly(ester-ether)s: III. assessment of cell behaviour on nanofibrous scaffolds of PCL, PLLA and PDX blended with amorphous PMeDX

The aim of this paper is to investigate the physico-chemical properties, degradation behaviour and cellular response of electrospun fibre-scaffolds of semi-crystalline PCL, PLLA and PDX blended with amorphous poly(methyl dioxanone) (PMeDX). Electrospun PCL/PMeDX and PLLA/PMeDX blend mats in varying weight ratios of the two components were fabricated and their overall performance was compared with similar composition PDX/PMeDX scaffolds. DSC analysis showed almost no change in crystallization temperature of PCL with increasing PMeDX content and TGA showed a different degradation profile as PMeDX content increased. The appearance of two crystallization peaks for PLLA/PMeDX blends suggested stereocomplex formation. As noted from AFM images, addition of PMeDX caused a change in the width of the lamellae from 14.8 ± 2.9 nm in 100/0 mat to 32.0 ± 11.5 nm in 85/15 mat. Moreover, PCL/PMeDX blend mats show a significant drop in Youngs modulus for 93/7, 90/10 and 85/15 compositions compared to 100/0 and 98/2. On the other hand, no clear trend in mechanical properties was observed for espun PLLA/PMeDX mats with increasing PMeDX content. Based on these analyses, it was concluded that PCL and PMeDX were immiscible while miscible blends were obtained with PLLA and PMeDX. Initial degradation of electrospun mats over a period of 5 weeks appears to occur via a surface erosion mechanism. In vitro cell culture studies using HDFs showed that the scaffolds were bioactive and a greater density of viable cells was noted on electrospun PCL/PMeDX and PLLA/PMeDX scaffolds compared to PCL and PLLA mats respectively. HDFs infiltrated through the entire thickness of espun 85/15 PLLA/PMeDX scaffold due to a combination of factors including morphology, porosity, surface characteristics and mechanical properties.

κ-Carrageenan Enhances the Biomineralization and Osteogenic Differentiation of Electrospun Polyhydroxybutyrate and Polyhydroxybutyrate Valerate Fibers

Novel electrospun materials for bone tissue engineering were obtained by blending biodegradable polyhydroxybutyrate (PHB) or polyhydroxybutyrate valerate (PHBV) with the anionic sulfated polysaccharide κ-carrageenan (κ-CG) in varying ratios. In both systems, the two components phase separated as shown by FTIR, DSC and TGA. According to the contact angle data, κ-CG was localized preferentially at the fiber surface in PHBV/κ-CG blends in contrast to PHB/κ-CG, where the biopolymer was mostly found within the fiber. In contrast to the neat polyester fibers, the blends led to the formation of much smaller apatite crystals (800 nm vs 7 μm). According to the MTT assay, NIH3T3 cells grew in higher density on the blend mats in comparison to neat polyester mats. The osteogenic differentiation potential of the fibers was determined by SaOS-2 cell culture for 2 weeks. Alizarin red-S staining suggested an improved mineralization on the blend fibers. Thus, PHBV/κ-CG fibers resulted in more pronounced bioactive and osteogenic properties, including fast apatite-forming ability and deposition of nanosized apatite crystals.

Biomineralization potential and cellular response of PHB and PHBV blends with natural anionic polysaccharides

In this paper, the biomineralization potential and cellular response of novel blend films of the anionic sulfated polysaccharides kappa-carrageenan (KCG) and fucoidan (FUC) derived from seaweeds with semi-crystalline polyhydroxybutyrate (PHB) and polyhydroxybutyrate-co-valerate (PHBV), respectively, were analyzed. The incorporation of KCG and FUC into PHB and PHBV, which has been studied here for the first time, led to an overall decrease in crystallinity, enhanced surface hydrophilicity, reduced brittleness and faster degradation of the polymer blend films. All PHB/KCG, PHBV/KCG and PHBV/FUC films exhibited a two-stage mass loss profiles with pH stabilization. PHBV/KCG film showed the highest biomineralization activity due the presence of sulfate groups on the surface of the films. NIH3T3 cells attached and proliferated well on all blend films on account of enhanced surface hydrophilicity and improved flexibility. PHBV/KCG led to a promoted cellular activity compared to PHBV/FUC, presumably due to phase separation and higher amount of biopolymer on the film surface that was a consequence of the immiscibility of the polymers in the blend films.

Poly(ester-ether)s: I. Investigation of the Properties of Blend Films of Polydioxanone and Poly(methyl dioxanone)

This study aimed at examining the properties of blends of semi-crystalline polydioxanone (PDX) and amorphous poly(methyl dioxanone) (PMeDX). The authors show that low amounts of PMeDX, within 15 wt% acts as plasticizer to high molar mass PDX as confirmed by an increase in Youngs modulus of films. The plasticizing effect on blends increased with decreasing reduced viscosity of PMeDX. Mechanical tests showed overall reduced tensile properties of the blends. Viscosity analysis coupled with SEM and AFM indicated immiscibility of the blends over the whole range of compositions. Blend samples with higher PMeDX contents degraded at faster rates with profiles differing from PDX.

Modulating Immunological Responses of Electrospun Fibers for Tissue Engineering

The promise of tissue engineering is to improve or restore functions of impaired tissues or organs. However, one of the biggest challenges to its translation to clinical applications is the lack of tissue integration and functionality. The plethora of cellular and molecular events occurring following scaffold implantation is a major bottleneck. Recent studies confirmed that inflammation is a crucial component influencing tissue regeneration. Immuno‐modulation or immune‐engineering has been proposed as a potential solution to overcome this key challenge in regenerative medicine. In this review, strategies to modify scaffold physicochemical properties through the use of the electrospinning technique to modulate host response and improve scaffold integration will be discussed. Electrospinning, being highly versatile allows the fabrication of ECM‐mimicking scaffolds and also offers the possibility to control scaffold properties for instance, tailoring of fiber properties, chemical conjugation or physical adsorption of non‐immunogenic materials on the scaffold surface, encapsulating cells or anti‐inflammatory molecules within the scaffold. Such electrospun scaffold‐based immune‐engineering strategies can significantly improve the resulting outcomes of tissue engineering scaffolds.