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Byrne M.,Dublin City University | Murphy R.,Dublin City University | Kapetanakis A.,Dublin City University | Ramsey J.,Royal College of Surgeons in Ireland | And 4 more authors.
Macromolecular Rapid Communications | Year: 2015

Significant advances in the synthesis of polypeptides by N-carboxyanhydride (NCA) polymerisation over the last decade have enabled the design of advanced polypeptide architectures such as star-shaped polypeptides. These materials combine the functionality offered by amino acids with the flexibility of creating stable nanoparticles with adjustable cargo space for therapeutic delivery. This review highlights recent advances in the synthesis of star polypeptides by NCA polymerisation followed by a critical review of the applications of this class of polymer in the delivery of therapeutic agents. This includes examples of traditional small-molecule drugs as well as the emerging class of biologics such as genetic therapeutics (gene delivery). The synthesis of well-defined star polypeptides by N-carboxyanhydride ring-opening polymerization is possible through advanced synthetic methodologies. Derived from natural building blocks (amino acids), these materials hold promises as biomaterials. This article reviews the synthetic pathways towards star-shaped polypeptides as well as reports of their use in drug- and gene-delivery applications. © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Fitzgerald K.A.,University College Cork | Malhotra M.,University College Cork | Curtin C.M.,Tissue Engineering Research Group | Curtin C.M.,Trinity College Dublin | And 5 more authors.
Journal of Controlled Release | Year: 2015

The development of safe, effective and patient-acceptable drug products is an expensive and lengthy process and the risk of failure at different stages of the development life-cycle is high. Improved biopharmaceutical tools which are robust, easy to use and accurately predict the in vivo response are urgently required to help address these issues. In this review the advantages and challenges of in vitro 3D versus 2D cell culture models will be discussed in terms of evaluating new drug products at the pre-clinical development stage. Examples of models with a 3D architecture including scaffolds, cell-derived matrices, multicellular spheroids and biochips will be described. The ability to simulate the microenvironment of tumours and vital organs including the liver, kidney, heart and intestine which have major impact on drug absorption, distribution, metabolism and toxicity will be evaluated. Examples of the application of 3D models including a role in formulation development, pharmacokinetic profiling and toxicity testing will be critically assessed. Although utilisation of 3D cell culture models in the field of drug delivery is still in its infancy, the area is attracting high levels of interest and is likely to become a significant in vitro tool to assist in drug product development thus reducing the requirement for unnecessary animal studies. © 2015 Elsevier B.V. All rights reserved. Source


Matsiko A.,Tissue Engineering Research Group | Matsiko A.,Trinity College Dublin | Matsiko A.,AMBER Inc | Gleeson J.P.,Tissue Engineering Research Group | And 5 more authors.
Tissue Engineering - Part A | Year: 2015

Recent investigations into micro-architecture of scaffolds has revealed that mean pore sizes are cell-type specific and influence cellular shape, differentiation, and extracellular matrix secretion. In this context, the overall goal of this study was to investigate whether scaffold mean pore sizes affect mesenchymal stem cell initial attachment, chondrogenic gene expression, and cartilage-like matrix deposition. Collagen-hyaluronic acid (CHyA) scaffolds, recently developed in our laboratory for in vitro chondrogenesis, were fabricated with three distinct mean pore sizes (94, 130, and 300μm) by altering the freeze-drying technique used. It was evident that scaffolds with the largest mean pore sizes (300μm) stimulated significantly higher cell proliferation, chondrogenic gene expression, cartilage-like matrix deposition, and resulting bulk compressive modulus after in vitro culture, relative to scaffolds with smaller mean pore sizes (94, 130μm). Taken together, these findings demonstrate the importance of scaffold micro-architecture in the development of advanced tissue engineering strategies for articular cartilage defect repair. © Mary Ann Liebert, Inc. 2015. Source


Brady R.T.,Tissue Engineering Research Group | Brady R.T.,Trinity College Dublin | Brady R.T.,University of Limerick | O'Brien F.J.,Tissue Engineering Research Group | And 3 more authors.
Biochemical and Biophysical Research Communications | Year: 2015

Bone formation requires the recruitment, proliferation and osteogenic differentiation of mesenchymal progenitors. A potent stimulus driving this process is mechanical loading, yet the signalling mechanisms underpinning this are incompletely understood. The objective of this study was to investigate the role of the mechanically-stimulated osteocyte and osteoblast secretome in coordinating progenitor contributions to bone formation. Initially osteocytes (MLO-Y4) and osteoblasts (MC3T3) were mechanically stimulated for 24hrs and secreted factors within the conditioned media were collected and used to evaluate mesenchymal stem cell (MSC) and osteoblast recruitment, proliferation and osteogenesis. Paracrine factors secreted by mechanically stimulated osteocytes significantly enhanced MSC migration, proliferation and osteogenesis and furthermore significantly increased osteoblast migration and proliferation when compared to factors secreted by statically cultured osteocytes. Secondly, paracrine factors secreted by mechanically stimulated osteoblasts significantly enhanced MSC migration but surprisingly, in contrast to the osteocyte secretome, inhibited MSC proliferation when compared to factors secreted by statically cultured osteoblasts. A similar trend was observed in osteoblasts. This study provides new information on mechanically driven signalling mechanisms in bone and highlights a contrasting secretome between cells at different stages in the bone lineage, furthering our understanding of loading-induced bone formation and indirect biophysical regulation of osteoprogenitors. © 2015 Elsevier Inc. All rights reserved. Source


Cunniffe G.M.,Trinity College Dublin | Vinardell T.,University College Dublin | Murphy J.M.,National University of Ireland | Thompson E.M.,Trinity College Dublin | And 7 more authors.
Acta Biomaterialia | Year: 2015

Clinical translation of tissue engineered therapeutics is hampered by the significant logistical and regulatory challenges associated with such products, prompting increased interest in the use of decellularized extracellular matrix (ECM) to enhance endogenous regeneration. Most bones develop and heal by endochondral ossification, the replacement of a hypertrophic cartilaginous intermediary with bone. The hypothesis of this study is that a porous scaffold derived from decellularized tissue engineered hypertrophic cartilage will retain the necessary signals to instruct host cells to accelerate endogenous bone regeneration. Cartilage tissue (CT) and hypertrophic cartilage tissue (HT) were engineered using human bone marrow derived mesenchymal stem cells, decellularized and the remaining ECM was freeze-dried to generate porous scaffolds. When implanted subcutaneously in nude mice, only the decellularized HT-derived scaffolds were found to induce vascularization and de novo mineral accumulation. Furthermore, when implanted into critically-sized femoral defects, full bridging was observed in half of the defects treated with HT scaffolds, while no evidence of such bridging was found in empty controls. Host cells which had migrated throughout the scaffold were capable of producing new bone tissue, in contrast to fibrous tissue formation within empty controls. These results demonstrate the capacity of decellularized engineered tissues as 'off-the-shelf' implants to promote tissue regeneration. © 2015 Acta Materialia Inc. Source

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