Browsing by Author "Shakesheff, K.M."

Now showing 1 - 4 of 4
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    Fibroblast Growth Factor 7 Releasing Particles Enhance Islet Engraftment and Improve Metabolic Control Following Islet Transplantation in Mice with Diabetes
    (Wiley, 2021-01-11) Qutachi, Omar; Salamah, M.A.; Starkey Lewis, P.J.; Bond, A.; Noble, J.; Burgoyne, P.; Morton, N.; Carter, R.; Mann, J.; Ferreira-Gonzales, S.; Alvarez-Paino, M.; Forbes, S.J.; Shakesheff, K.M.; Forbes, S.
    Transplantation of islets in Type 1 diabetes is limited by poor islet engraftment into the liver, with 2-3 donor pancreases required per recipient. We aimed to condition the liver to enhance islet engraftment to improve long-term graft function. Diabetic mice received a non-curative islet transplant (n=400 islets) via the hepatic portal vein (HPV) with Fibroblast Growth Factor 7 loaded galactoslyated poly(DL-lactide-co-glycolic acid) (FGF7-GAL-PLGA) particles; 26μm diameter particles specifically targeted the liver, promoting hepatocyte proliferation in short-term experiments: in mice receiving 0.1mg FGF7-GAL-PLGA particles (60ng FGF7) versus vehicle, cell proliferation was induced specifically in the liver with greater efficacy and specificity than subcutaneous FGF7 (1.25mg/kg ×2 doses; ~75μg FGF7). Numbers of engrafted islets and vascularisation were greater in liver sections of mice receiving islets and FGF7-GAL-PLGA particles versus mice receiving islets alone, 72 hours post-transplant. More mice (6 out of 8) that received islets and FGF7-GAL-PLGA particles normalised blood glucose concentrations by 30- days post-transplantation, versus 0 of 8 mice receiving islets alone with no evidence of increased proliferation of cells within the liver at this stage and normal liver function tests. This work shows liver targeted FGF7-GAL-PLGA particles achieve selective FGF7 delivery to the liver promoting islet engraftment to help normalise blood glucose levels with a good safety profile.
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    Microparticles for sustained growth factor delivery in the regeneration of critically-sized segmental tibial bone defects
    (Multidisciplinary Digital Publishing Institute, 2016-03-31) Kirby, G.T.S.; White, L.J.; Steck, R.; Berner, A.; Bogoevski, K.; Qutachi, Omar; Jones, B.; Saifzadeh, S.; Hutmacher, D.W.; Shakesheff, K.M.; Woodruff, M.A.
    This study trialled the controlled delivery of growth factors within a biodegradable scaffold in a large segmental bone defect model. We hypothesised that co-delivery of vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) followed by bone morphogenetic protein-2 (BMP-2) could be more effective in stimulating bone repair than the delivery of BMP-2 alone. Poly(lactic-co-glycolic acid) (PLGA ) based microparticles were used as a delivery system to achieve a controlled release of growth factors within a medical-grade Polycaprolactone (PCL) scaffold. The scaffolds were assessed in a well-established preclinical ovine tibial segmental defect measuring 3 cm. After six months, mechanical properties and bone tissue regeneration were assessed. Mineralised bone bridging of the defect was enhanced in growth factor treated groups. The inclusion of VEGF and PDGF (with BMP-2) had no significant effect on the amount of bone regeneration at the six-month time point in comparison to BMP-2 alone. However, regions treated with VEGF and PDGF showed increased vascularity. This study demonstrates an effective method for the controlled delivery of therapeutic growth factors in vivo, using microparticles.
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    Surface modification of PdlLGA microspheres with gelatine methacrylate: evaluation of adsorption, entrapment, and oxygen plasma treatment approaches
    (Elsevier, 2017-04-15) Baki, A.; Rahman, C.V.; White, L.J.; Scurr, D.J.; Qutachi, Omar; Shakesheff, K.M.
    Injectable poly (dl-lactic-co-glycolic acid) (PdlLGA) microspheres are promising candidates as biodegradable controlled release carriers for drug and cell delivery applications; however, they have limited functional groups on the surface to enable dense grafting of tissue specific biocompatible molecules. In this study we have evaluated surface adsorption, entrapment and oxygen plasma treatment as three approaches to modify the surfaces of PdlLGA microspheres with gelatine methacrylate (gel-MA) as a biocompatible and photo cross-linkable macromolecule. Time of flight secondary ion mass spectroscopy (TOF SIMS) and X-ray photoelectron spectroscopy (XPS) were used to detect and quantify gel-MA on the surfaces. Fluorescent and scanning electron microscopies (SEM) were used to image the topographical changes. Human mesenchymal stem cells (hMSCs) of immortalised cell line were cultured on the surface of gel-MA modified PdlLGA microspheres and Presto-Blue assay was used to study the effect of different surface modifications on cell proliferation. Data analysis showed that the oxygen plasma treatment approach resulted in the highest density of gel-MA deposition. This study supports oxygen plasma treatment as a facile approach to modify the surface of injectable PdlLGA microspheres with macromolecules such as gel-MA to enhance proliferation rate of injected cells and potentially enable further grafting of tissue specific molecules.
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    Targeted protein delivery: carbodiimide crosslinking influences protein release from microparticles incorporated within collagen scaffolds
    (Oxford University Press, 2019-03-11) Qutachi, Omar; Tanase, Constantin, Edi; White, L.J.; Shakesheff, K.M.; McCaskie, Andrew, W; Best, S.; Cameron, Ruth, E
    Tissue engineering response may be tailored via controlled, sustained release of active agents from protein-loaded degradable microparticles incorporated directly within three-dimensional (3D) ice-templated collagen scaffolds. However, the effects of covalent crosslinking during scaffold preparation on the availability and release of protein from the incorporated microparticles have not been explored. Here, we load 3D ice-templated collagen scaffolds with controlled additions of poly-(DL-lactide-co-glycolide) microparticles. We probe the effects of subsequent N-(3-dimethylaminopropyl)- N0-ethylcarbodiimide hydrochloride crosslinking on protein release, using microparticles with different internal protein distributions. Fluorescein isothiocyanate labelled bovine serum albumin is used as a model protein drug. The scaffolds display a homogeneous microparticle distribution, and a reduction in pore size and percolation diameter with increased microparticle addition, although these values did not fall below those reported as necessary for cell invasion. The protein distribution within the microparticles, near the surface or more deeply located within the microparticles, was important in determining the release profile and effect of crosslinking, as the surface was affected by the carbodiimide crosslinking reaction applied to the scaffold. Crosslinking of microparticles with a high proportion of protein at the surface caused both a reduction and delay in protein release. Protein located within the bulk of the microparticles, was protected from the crosslinking reaction and no delay in the overall release profile was seen.