Eoin Cunningham

Review of Patents on Microneedle Applicators

Transdermal drug delivery offers certain advantages over conventional oral or parenteral administration. However, transdermal delivery is not available to many promising therapeutic agents, especially high molecular weight hydrophilic compounds. This is due to the excellent barrier property of the superficial skin layer, the stratum corneum (SC). Only drugs with very specific physicochemical properties (molecular weight < 500 Da, adequate lipophilicity, and low melting point) can be successfully administered transdermally. Of the several active approaches used to enhance the transport of drugs through the SC, the use of microneedles (MNs) has recently been shown to be very promising and has attracted considerable attention by researchers from both industry and academia. MNs, when used to puncture skin, will by-pass the SC and create transient aqueous transport pathways of micron dimensions and enhance the transdermal permeability. However, for effective performance of these MNs in drug delivery applications, irrespective of the type, material, height and density, it is imperative that they penetrate into the skin with the greatest possible accuracy and reproducibility. Due to the inherent elasticity and irregular surface topography of the skin, it remains a major challenge to the reproducibility of MN penetration. Therefore, in order to achieve uniform and reproducible MN penetration into skin, an external source of assistance could be very useful. Accordingly, this review deals with various innovative applicator designs developed by industry and research centres in the context of effective application of MN arrays for transdermal drug delivery, as disclosed in the recent patent literature.

High-solid-content hydroxyapatite slurry for the production of bone substitute scaffolds.

Abstract Key to various bone substitute scaffold production techniques is the development of free-flowing ceramic slurry with optimum rheological properties. The aim is to achieve a colloidal suspension with as high a solid content as possible while maintaining a low viscosity which easily penetrates the pores of relevant sacrificial templates. The following investigation describes the optimization of a hydroxyapatite slip and demonstrates its potential application in scaffold production. Using predominantly spherical particles of hydroxyapatite of between 0.82 μm and 16.2 μm, coupled with a 2 wt % addition of the anionic polyelectrolyte, ammonium polyacrylate, an 80 wt % (55.9 vol %) hydroxyapatite solid loaded slip with a viscosity of approximately 126 mPa s has been developed. Its ability to infiltrate and replicate porous preforms has been shown using polyurethane foam. The enhanced particle packing achieved has allowed for the production of scaffolds with highly dense and uniform grain structures. The results represent a significant improvement in current slurry production techniques and can be utilized to develop high-density ceramic bone substitute scaffolds.

Comparative Characterisation of 3-D Hydroxyapatite Scaffolds Developed Via Replication of Synthetic Polymer Foams and Natural Marine Sponges

The production of complex inorganic forms, based on naturally occurring scaffolds offers an exciting avenue for the construction of a new generation of ceramic-based bone substitute scaffolds. The following study reports an investigation into the architecture (porosity, pore size distribution, pore interconnectivity and permeability), mechanical properties and cytotoxic response of hydroxyapatite bone substitutes produced using synthetic polymer foam and natural marine sponge performs. Infiltration of polyurethane foam (60 pores/in2) using a high solid content (80wt %), low viscosity (0.126Pas) hydroxyapatite slurry yielded 84-91% porous replica scaffolds with pore sizes ranging from 50?m - 1000?m (average pore size 577?m), 99.99% pore interconnectivity and a permeability value of 46.4 x10-10m2. Infiltration of the natural marine sponge, Spongia agaricina , yielded scaffolds with 56- 61% porosity, with 40% of pores between 0-50?m, 60% of pores between 50-500?m (average pore size 349 ?m), 99.9% pore interconnectivity and a permeability value of 16.8 x10-10m2. The average compressive strengths and compressive moduli of the natural polymer foam and marine sponge replicas were 2.46±1.43MPa/0.099±0.014GPa and 8.4±0.83MPa /0.16±0.016GPa respectively. Cytotoxic response proved encouraging for the HA Spongia agaricina scaffolds; after 7 days in culture medium the scaffolds exhibited endothelial cells (HUVEC and HDMEC) and osteoblast (MG63) attachment, proliferation on the scaffold surface and penetration into the pores. It is proposed that the use of Spongia agaricina as a precursor material allows for the reliable and repeatable production of ceramic-based 3-D tissue engineered scaffolds exhibiting the desired architectural and mechanical characteristics for use as a bone 3 scaffold material. Moreover, the Spongia agaricina scaffolds produced exhibit no adverse cytotoxic response.

Effects of Poly (ε-caprolactone) Coating on the Properties of Three-Dimensional Printed Porous Structures

Powder-based inkjet three-dimensional printing (3DP) to fabricate pre-designed 3D structures has drawn increasing attention. However there are intrinsic limitations associated with 3DP technology due to the weak bonding within the printed structure, which significantly compromises its mechanical integrity. In this study, calcium sulphate ceramic structures demonstrating a porous architecture were manufactured using 3DP technology and subsequently post-processed with a poly (ε-caprolactone) (PCL) coating. PCL concentration, immersion time, and number of coating layers were the principal parameters investigated and improvement in compressive properties was the measure of success. Interparticle spacing within the 3DP structures were successfully filled with PCL material. Consequently the compressive properties, wettability, morphology, and in vitro resorption behaviour of 3DP components were significantly augmented. The average compressive strength, Young׳s modulus, and toughness increased 217%, 250%, and 315%, following PCL coating. Addition of a PCL surface coating provided long-term structural support to the host ceramic material, extending the resorption period from less than 7 days to a minimum of 56 days. This study has demonstrated that application of a PCL coating onto a ceramic 3DP structure was a highly effective approach to addressing some of the limitations of 3DP manufacturing and allows this advanced technology to be potentially used in a wider range of applications.

Static and dynamic degradation of sintered calcium phosphate ceramics

The chemical compositions of calcium phosphate materials are similar to that of bone making them very attractive for use in the repair of critical size bone defects. The bioresorption of calcium phosphate occurs principally by dissolution. To determine the impact of composition and flow conditions on dissolution rates, calcium phosphate tablets were prepared by slip casting of ceramic slips with different ratios of hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP). Dissolution was evaluated at pH4 using both a static and dynamic flow regime. Both the composition of the HA:β-TCP tablet and flow regime noticeably influenced the rate of dissolution; the 50:50 HA:β-TCP composition demonstrating the greatest level of dissolution, and, exposure of the ceramic specimens to dynamic conditions producing the highest rate of dissolution. Understanding the impact of phase composition and flow condition with respect to the dissolution of calcium phosphate will aid in the development and improvement of materials for bone substitution.

Development of three-dimensional printing polymer-ceramic scaffolds with enhanced compressive properties and tuneable resorption

In this study, bone tissue engineered scaffolds fabricated via powder-based 3D printing from hydroxyapatite (HA) and calcium sulphate (CaSO4) powders were investigated. The combination of using a fast resorbing CaSO4 based powder and the relatively slower HA powder represents a promising prospect for tuning the bioresorption of 3D printed (3DP) scaffolds. These properties could then be tailored to coincide with tissue growth rate for different surgical procedures. The manufactured scaffolds were infiltrated with poly(ε‑caprolactone) (PCL). The PCL infiltrated the inter-particle spacing within the 3DP structures due to the nature of a loosely-packed powder bed and also covered the surface of ceramic-based scaffolds. Consequently, the average compressive strength, compressive modulus and toughness increased by 314%, 465% and 867%, respectively. The resorption behaviour of the 3DP scaffolds was characterised in vitro using a high-throughput system that mimicked the physiological environment and dynamic flow conditions relevant to the human body. A rapid release of CaSO4 between Day 0 and 28 was commensurate with a reduction in scaffold mass and compressive properties, as well as an increase in medium absorption. In spite of this, HA particles, connected by PCL fibrils, remained within the microstructure after 56 days resorption under dynamic conditions. Consequently, a high level of structural integrity was maintained within the 3DP scaffold. This study presented a porous PCL-HA-CaSO4 3DP structure with the potential to encourage new tissue growth during the initial stages of implantation and also offering sufficient structural and mechanical support during the bone healing phase.

Correction to: Process-induced degradation of bioresorbable PDLGA in bone tissue scaffold production

The original version of this article unfortunately contained a mistake. E. Themistou was missing from the author group and so is now included with this erratum.

Process-Induced Degradation of Bioresorbable PDLGA in Bone Tissue Scaffold Production

Process-induced degradation of clinically relevant resorbable polymers was investigated for two thermal techniques, filament extrusion followed by fused deposition modelling (FDM). The aim was to develop a clear understanding of the relationship between temperature, processing time and resultant process-induced degradation. This acts to address the current knowledge gap in studies involving thermal processing of resorbable polymers. Poly(DL-lactide-co-glycolide) (PDLGA) was chosen for its clinically relevant resorption properties. Furthermore, a comparative study of controlled thermal exposure was conducted through compression moulding PDLGA at a selected range of temperatures (150–225 °C) and times (0.5–20 min). Differential scanning calorimetry (DSC) and gel permeation chromatography (GPC) were used to characterise thermally induced degradation behaviour. DSC proved insensitive to degradation effects, whereas GPC demonstrated distinct reductions in molecular weight allowing for the quantification of degradation. A near-exponential pattern of degradation was identified. Through the application of statistical chain scission equations, a predictive plot of theoretical degradation was created. Thermal degradation was found to have a significant effect on the molecular weight with a reduction of up to 96% experienced in the controlled processing study. The proposed empirical model may assist prediction of changes in molecular weight, however, accuracy limitations are highlighted for twin-screw extrusion, accredited to high-shear mixing. The results from this study highlight the process sensitivity of PDLGA and proposes a methodology for quantification and prediction, which contributes to efforts in understanding the influence of manufacture on performance of degradable medical implants.

Bio-inspired calcium phosphate materials for hard tissue repair

Abstract With the ongoing realization of the limitations of traditional bone repair, tissue engineers have a responsibility to develop alternatives that will enhance the functional capabilities of bone substitutes and eliminate the need for auto-, allo- or xeno-grafts. Recognizing that nature’s capabilities are significantly ahead of modern-day technologies, engineers continue to mimic, with varying degrees of success, the highly effective and energy-efficient biological mechanisms found in organisms around the world. The solutions arrived at by millennia of evolution are a source of inspiration and an excellent starting point in the search for answers to modern-day problems. With regard to the development of bone substitutes, the past few decades have seen a plethora of biomimetic approaches as the prevailing theory is that the probability of successful in vivo integration is strengthened if the structure and composition mimics that of the healthy naturally interconnected bone it aims to replace. In attempting to achieve a compositional match, calcium phosphates have gained widespread clinical acceptance due to crystallographic similarities with the mineral component of human bone. Successful integration into the body, however, depends heavily on balancing interlinked and often opposing structural and biological requirements. This chapter aims to provide a brief insight into the evolution of biomimetic approaches and affirm the concept that complex inorganic forms, inspired by naturally occurring architectures, offers an exciting avenue for the construction of a new generation of calcium phosphate-based bone substitute scaffolds.