Development of a 3D-printed bioabsorbable composite scaffold with mechanical properties suitable for treating large, load-bearingarticular cartilage defects.

Extracellular matrix (ECM) biomaterials have shown promise for treating small artucular-joint defetcs. However, ECM-based biomaterials generally lack appropriate mechanical properties to support physiological loads and are prone to delamination in larger cartilage defects. To overcome these common mechanical limitations, a collagen hyaluronic-acid (CHyA) matrix, with proven regenerative potential, was reinforced with a bioabsorbable 3D-printed framework to support physiological loads. Polycaprolactone (PCL) was 3D-printed in two configurations, rectilinear and gyroid designs, that were extensively mechanically characterised. Both scaffold designs increased the compressive modulus of the CHyA matrices by three orders of magnitude, mimicking the physiological range (0.5-2.0 MPa) of healthy cartilage. The gyroid scaffold proved to be more flexible compared to the rectilinear scaffold, thus better contouring to the curvature of a femoral condyle. Additionally, PCL reinforcement of the CHyA matrix increased the tensile modulus and allowed for suture fixation of the scaffold to the subchondral bone, thus addressing the major challenge of biomaterial fixation to articular joint surfaces in shallow defects. In vitro evaluation confirmed successful infiltration of human mesenchymal stromal cells (MSCs) within the PCL-CHyA scaffolds, which resulted in increased production of sulphated glycosaminoglycans (sGAG/DNA; p = 0.0308) compared to non-reinforced CHyA matrices. Histological staining using alcian blue confirmed these results, while also indicating greater spatial distribution of sGAG throughout the PCL-CHyA scaffold. These findings have a great clinical importance as they provide evidence that reinforced PCL-CHyA scaffolds, with their increased chondroinductive potential and compatibility with joint fixation techniques, could be used to repair large-area chondral defects that currently lack effective treatment options.

Spatiotemporal dispersion and wave envelopes with relativistic and pseudorelativistic characteristics.

A generic nonparaxial model for pulse envelopes is presented. Classic Schrödinger-type descriptions of wave propagation have their origins in slowly-varying envelopes combined with a Galilean boost to the local time frame. By abandoning these two simplifications, a picture of pulse evolution emerges in which frame-of-reference considerations and space-time transformations take center stage. A wide range of effects, analogous to those in special relativity, then follows for both linear and nonlinear systems. Explicit demonstration is presented through exact bright and dark soliton pulse solutions.

Site-specific gene expression profiling as a novel strategy for unravelling keloid disease pathobiology.

Keloid disease (KD) is a fibroproliferative cutaneous tumour characterised by heterogeneity, excess collagen deposition and aggressive local invasion. Lack of a validated animal model and resistance to a multitude of current therapies has resulted in unsatisfactory clinical outcomes of KD management. In order to address KD from a new perspective, we applied for the first time a site-specific in situ microdissection and gene expression profiling approach, through combined laser capture microdissection and transcriptomic array. The aim here was to analyse the utility of this approach compared with established methods of investigation, including whole tissue biopsy and monolayer cell culture techniques. This study was designed to approach KD from a hypothesis-free and compartment-specific angle, using state-of-the-art microdissection and gene expression profiling technology. We sought to characterise expression differences between specific keloid lesional sites and elucidate potential contributions of significantly dysregulated genes to mechanisms underlying keloid pathobiology, thus informing future explorative research into KD. Here, we highlight the advantages of our in situ microdissection strategy in generating expression data with improved sensitivity and accuracy over traditional methods. This methodological approach supports an active role for the epidermis in the pathogenesis of KD through identification of genes and upstream regulators implicated in epithelial-mesenchymal transition, inflammation and immune modulation. We describe dermal expression patterns crucial to collagen deposition that are associated with TGFß-mediated signalling, which have not previously been examined in KD. Additionally, this study supports the previously proposed presence of a cancer-like stem cell population in KD and explores the possible contribution of gene dysregulation to the resistance of KD to conventional therapy. Through this innovative in situ microdissection gene profiling approach, we provide better-defined gene signatures of distinct KD regions, thereby addressing KD heterogeneity, facilitating differential diagnosis with other cutaneous fibroses via transcriptional fingerprinting, and highlighting key areas for future KD research.

Dermal substitute-assisted healing: enhancing stem cell therapy with novel biomaterial design.

The use of dermal substitutes is increasingly widespread but the outcomes of substitute-assisted healing remain functionally deficient. Presently, the most successful scaffolds are acellular polymer matrices, prepared through lyophilization and phase separation techniques, designed to mimic the dermal extracellular matrix. The application of scaffolds containing viable cells has proven to be problematic due to short shelf-life, high cost and death of transplanted cells as a result of immune rejection and apoptosis. Recent advances in biomaterial science have made new techniques available capable of increasing scaffold complexity, allowing the creation of 3D microenvironments that actively control cell behaviour. Importantly, it may be possible through these sophisticated novel techniques, including bio-printing and electrospinning, to accurately direct stem cell behaviour. This complex proposal involves the incorporation of cell-matrix, cell-cell, mechanical cues and soluble factors delivered in a spatially and temporally pertinent manner. This requires accurate modelling of three-dimensional stem cell interactions within niche environments to identify key signalling molecules and mechanisms. The application of stem cells within substitutes containing such environments may result in greatly improved transplanted cell viability. Ultimately this may increase cellular organization and complexity of skin substitutes. This review discusses progress made in improving the efficacy of cellular dermal substitutes for the treatment of cutaneous defects and the potential of evolving new technology to improve current results.

Chemical synthesis and cytotoxicity of some azinomycin analogues devoid of the 1-azabicyclo[3.1.0]hexane subunit.

A series of compounds related to the left-hand domain of the azinomycins have been made and evaluated for cytotoxic activity against a small panel of human tumour cell lines. The epoxide ring is shown to be essential for biological activity. Cytotoxicity is also shown to be sensitive to changes in the substitution pattern on the aromatic ring and the amide group.