Ivan Wall

Bone formation controlled by biologically relevant inorganic ions: role and controlled delivery from phosphate-based glasses.

The role of metal ions in the body and particularly in the formation, regulation and maintenance of bone is only just starting to be unravelled. The role of some ions, such as zinc, is more clearly understood due to its central importance in proteins. However, a whole spectrum of other ions is known to affect bone formation but the exact mechanism is unclear as the effects can be complex, multifactorial and also subtle. Furthermore, a significant number of studies utilise single doses in cell culture medium, whereas the continual, sustained release of an ion may initiate and mediate a completely different response. We have reviewed the role of the most significant ions that are known to play a role in bone formation, namely calcium, zinc, strontium, magnesium, boron, titanium and also phosphate anions as well as copper and its role in angiogenesis, an important process interlinked with osteogenesis. This review will also examine how delivery systems may offer an alternative way of providing sustained release of these ions which may effect and potentiate a more appropriate and rapid tissue response.

Potential role of anaerobic cocci in impaired human wound healing

Although more than 80% of infected and 70% of noninfected leg ulcers have been shown to harbor anaerobic organisms, their role in mediating impaired wound healing in the skin is frequently overlooked. There is now increasing evidence that the gram‐positive anaerobic cocci play a role (both directly and indirectly) in mediating impaired wound healing in vivo. This article discusses the mechanisms by which these microorganisms may interfere with the inflammation, repair, and remodeling phases of the wound healing process. (WOUND REP REG 2002;10:–353)

Bioprocess Forces and Their Impact on Cell Behavior: Implications for Bone Regeneration Therapy

Bioprocess forces such as shear stress experienced during routine cell culture are considered to be harmful to cells. However, the impact of physical forces on cell behavior is an area of growing interest within the tissue engineering community, and it is widely acknowledged that mechanical stimulation including shear stress can enhance osteogenic differentiation. This paper considers the effects of bioprocess shear stress on cell responses such as survival and proliferation in several contexts, including suspension-adapted cells used for recombinant protein and monoclonal antibody manufacture, adherent cells for therapy in suspension, and adherent cells attached to their growth substrates. The enhanced osteogenic differentiation that fluid flow shear stress is widely found to induce is discussed, along with the tissue engineering of mineralized tissue using perfusion bioreactors. Recent evidence that bioprocess forces produced during capillary transfer or pipetting of cell suspensions can enhance osteogenic responses is also discussed.

Role of vitronectin and fibronectin receptors in oral mucosal and dermal myofibroblast differentiation

Background information. The activation of fibroblasts into myofibroblasts is a crucial event in healing that is linked to remodelling and scar formation, therefore we determined whether regulation of myofibroblast differentiation via integrins might affect wound healing responses in populations of patient‐matched HOFs (human oral fibroblasts) compared with HDFs (human dermal fibroblasts).

Administration of growth factors for bone regeneration

Growth factors (GFs) such as BMPs, FGFs, VEGFs and IGFs have significant impacts on osteoblast behavior, and thus have been widely utilized for bone tissue regeneration. Recently, securing biological stability for a sustainable and controllable release to the target tissue has been a challenge to practical applications. This challenge has been addressed to some degree with the development of appropriate carrier materials and delivery systems. This review highlights the importance and roles of those GFs, as well as their proper administration for targeting bone regeneration. Additionally, the in vitro and in vivo performance of those GFs with or without the use of carrier systems in the repair and regeneration of bone tissue is systematically addressed. Moreover, some recent advances in the utility of the GFs, such as using fusion technology, are also reviewed.

Titanium phosphate glass microspheres for bone tissue engineering

We have demonstrated the successful production of titanium phosphate glass microspheres in the size range of ∼10-200 μm using an inexpensive, efficient, easily scalable process and assessed their use in bone tissue engineering applications. Glasses of the following compositions were prepared by melt-quench techniques: 0.5P₂O₅-0.4CaO-(0.1-x)Na₂O-xTiO₂, where x=0.03, 0.05 and 0.07 mol fraction (denoted as Ti3, Ti5 and Ti7 respectively). Several characterization studies such as differential thermal analysis, degradation (performed using a novel time lapse imaging technique) and pH and ion release measurements revealed significant densification of the glass structure with increased incorporation of TiO₂ in the glass from 3 to 5 mol.%, although further TiO₂ incorporation up to 7 mol.% did not affect the glass structure to the same extent. Cell culture studies performed using MG63 cells over a 7-day period clearly showed the ability of the microspheres to provide a stable surface for cell attachment, growth and proliferation. Taken together, the results confirm that 5 mol.% TiO₂ glass microspheres, on account of their relative ease of preparation and favourable biocompatibility, are worthy candidates for use as substrate materials in bone tissue engineering applications.

Generating iPSCs: translating cell reprogramming science into scalable and robust biomanufacturing strategies.

Induced pluripotent stem cells (iPSCs) have the potential to transform drug discovery and healthcare in the 21(st) century. However, successful commercialization will require standardized manufacturing platforms. Here we highlight the need to define standardized practices for iPSC generation and processing and discuss current challenges to the robust manufacture of iPSC products.

Novel therapeutic core–shell hydrogel scaffolds with sequential delivery of cobalt and bone morphogenetic protein-2 for synergistic bone regeneration

UNLABELLED Enabling early angiogenesis is a crucial issue in the success of bone tissue engineering. Designing scaffolds with therapeutic potential to stimulate angiogenesis as well as osteogenesis is thus considered a promising strategy. Here, we propose a novel scaffold designed to deliver angiogenic and osteogenic factors in a sequential manner to synergize the bone regeneration event. Hydrogel fibrous scaffolds comprised of a collagen-based core and an alginate-based shell were constructed. Bone morphogenetic protein 2 (BMP2) was loaded in the core, while the shell incorporated Co ions, enabled by the alginate crosslinking in CoCl2/CaCl2 solution. The incorporation of Co ions was tunable by altering the concentration of Co ions in the crosslinking solution. The incorporated Co ions, that are known to play a role in angiogenesis, were released rapidly within a week, while the BMP2, acting as an osteogenic factor, was released in a highly sustainable manner over several weeks to months. The release of Co ions significantly up-regulated the in vitro angiogenic properties of cells, including the expression of angiogenic genes (CD31, VEGF, and HIF-1α), secretion of VEGF, and the formation of tubule-like networks. However, BMP2 did not activate the angiogenic processes. Osteogenesis was also significantly enhanced by the release of Co ions as well as BMP2, characterized by higher expression of osteogenic genes (OPN, ALP, BSP, and OCN), and OCN protein secretion. An in vivo study on the designed scaffolds implanted in rat calvarium defect demonstrated significantly enhanced bone formation, evidenced by new bone volume and bone density, due to the release of BMP2 and Co ions. This is the first study using Co ions as an angiogenic element together with the osteogenic factor BMP2 within scaffolds, and the results demonstrated the possible synergistic role of Co ions with BMP2 in the bone regeneration process, suggesting a novel potential therapeutic scaffold system. STATEMENT OF SIGNIFICANCE This is the first report that utilizes Co ion as a pro-angiogenic factor in concert with osteogenic factor BMP-2 in the fine-tuned core-shell hydrogel fiber scaffolds, and ultimately achieves osteo/angiogenesis of MSCs and bone regeneration through the sequential delivery of both biofactors. This novel approach facilitates a new class of therapeutic scaffolds, aiming at successful bone regeneration with the help of angiogenesis.

Silk fibroin–polyurethane blends: Physical properties and effect of silk fibroin content on viscoelasticity, biocompatibility and myoblast differentiation

As a way to modify both the physical and biological properties of a highly elastic and degradable polyurethane (PU), silk fibroin (SF) was blended with the PU at differing ratios. With increasing SF content, the tensile strength decreased as did the strain at break; the stiffness increased to around 35 MPa for the highest silk content. C2C12 (a mouse myoblast cell line) cells were used for in vitro experiments and showed significantly improved cell responses with increasing SF content. With increasing SF content the number of non-adherent cells was reduced at both 4 and 8h compared to the sample with the lowest SF content. In addition, muscle marker genes were upregulated compared to the sample containing no SF, and in particular sarcomeric actin and α-actin.

Synthesis of elastic biodegradable polyesters of ethylene glycol and butylene glycol from sebacic acid

High molecular weight biodegradable polyesters were prepared from sebacic acid, ethylene glycol and butylene glycol through a simple non-solvent polycondensation with a low toxicity catalyst. The successful synthesis of the polyesters was confirmed by gel permeation chromatography, (1)H-nuclear magnetic resonance and Fourier transform-infrared spectroscopies and differential scanning calorimetry. The degradation tests were performed at 37 °C in phosphate buffer solution (pH 7.4) and showed a mass loss of ~5% over 12 weeks compared with only 2% for polycaprolactone (PCL). Reverse transcription polymerase chain reaction results following culture of osteoblasts on the polymer surface showed that poly(ethylene sebacate) and poly(butylene sebacate) films were optimal for osteoblast formation in terms of Runx 2 and osteocalcin gene expression.