Royal Free Hampstead NHS Trust Hospital

London, United Kingdom

Royal Free Hampstead NHS Trust Hospital

London, United Kingdom

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De Mel A.,Center for Nanotechnology and Regenerative Medicine | Murad F.,University College London | Seifalian A.M.,George Washington University | Seifalian A.M.,Royal Free Hampstead NHS Trust Hospital
Chemical Reviews | Year: 2011

The impact of NO on the attenuation of thrombotic events and a possible role in ischemia reperfusion injury (IRI) in studies associated with cardiovascular grafts are examined. NO acts primarily through its interactions with soluble guanylyl/guanylate cyclase (sGC), a heterodimeric heme protein leading to cyclic guanosine-3',5'-monophosphate (cGMP), which acts as a second messenger and modulates the cardiovascular protective roles. Hemodynamics has a major role in determining the bioavailability of NO from implanted vascular grafts. Uncoupling of NOS affects the bioavailability of NO as a result of altered production of nitric oxide synthase (NOS) and rapid degradation due to the reactions with free radicals. Nitrites are reduced to NO, and myoglobin has been shown to function as an endogenous nitrite reductase at low oxygen levels. NO concentrations of a functionalized graft can vary when exposed to physiological flow conditions according to the mechanical properties of the vascular graft of concern.

Yildirimer L.,University College London | Thanh N.T.K.,University College London | Thanh N.T.K.,Royal Institution of Great Britain | Loizidou M.,University College London | And 2 more authors.
Nano Today | Year: 2011

In recent years, nanoparticles (NPs) have increasingly found practical applications in technology, research and medicine. The small particle size coupled to their unique chemical and physical properties is thought to underlie their exploitable biomedical activities. Here, we review current toxicity studies of NPs with clinical potential. Mechanisms of cytotoxicity are discussed and the problem of extrapolating knowledge gained from cell-based studies into a human scenario is highlighted. The so-called 'proof-of-principle' approach, whereby ultra-high NP concentrations are used to ensure cytotoxicity, is evaluated on the basis of two considerations; firstly, from a scientific perspective, the concentrations used are in no way related to the actual doses required which, in many instances, discourages further vital investigations. Secondly, these inaccurate results cast doubt on the science of nanomedicine and thus, quite dangerously, encourage unnecessary alarm in the public. In this context, the discrepancies between in vitro and in vivo results are described along with the need for a unifying protocol for reliable and realistic toxicity reports. © 2011 Elsevier Ltd.

Yildirimer L.,University College London | Seifalian A.M.,University College London | Seifalian A.M.,Royal Free Hampstead NHS Trust Hospital
Biotechnology Advances | Year: 2014

The apparent difficulty to precisely control fine-tuning of biomaterial degradation has initiated the recent paradigm shift from conventional top-down fabrication methods to more nature-inspired bottom-up assemblies. Sophistication of material fabrication techniques allows today's scientists to reach beyond conventional natural materials in order to synthesise tomorrow's 'designer material'. Material degradation into smaller components and subsequent release of encapsulated cells or cell-signalling agents have opened medically exploitable avenues, transforming the area of regenerative medicine into a dynamic and self-propagating branch of modern medicine. The aim to synthesise ever more refined scaffolding structures in order to create micro- and nanoenvironments resembling those found in natural tissues now represents an ever growing niche in the materials sciences. Recently, we have developed and conducted the world's first in-human tracheal transplantation using a non-degradable completely synthetic biomaterial. Fuelled by such clinical potential, we are currently developing a biodegradable version suitable for skin tissue engineering and paediatric applications. However, despite enormous efforts, current, as yet insurmountable challenges include precise biomaterial degradation within pre-determined spatial and temporal confines in an effort to release bio-signalling agents in such orchestrated fashion as to fully regenerate functioning tissues. In this review, the authors, almost anti-climactically, ask the readers to step out of the artificially over-constructed spiral of ever more convoluted scaffold fabrication techniques and consider the benefits of controllable bottom-up scaffold fabrication methods. It will further be investigated how scaffold designs and fabrication methods may influence degradation and subsequent release of incorporated elements. A focus will be placed on the delivery of growth factors, stem cells and therapeutic agents alone or in parallel. The difficulties of designing a delivery vehicle capable of delivering multiple factors whilst maintaining distinct release kinetics will be highlighted. Finally, this review will be rounded off with an insight into current literature addressing the recurring issues of degradation product toxicities and suggests means of overcoming those. © 2014 Elsevier Inc.

Chaloupka K.,University College London | Chaloupka K.,University of Zürich | Malam Y.,University College London | Seifalian A.M.,University College London | Seifalian A.M.,Royal Free Hampstead NHS Trust Hospital
Trends in Biotechnology | Year: 2010

Nanosilver (NS), comprising silver nanoparticles, is attracting interest for a range of biomedical applications owing to its potent antibacterial activity. It has recently been demonstrated that NS has useful anti-inflammatory effects and improves wound healing, which could be exploited in developing better dressings for wounds and burns. The key to its broad-acting and potent antibacterial activity is the multifaceted mechanism by which NS acts on microbes. This is utilized in antibacterial coatings on medical devices to reduce nosocomial infection rates. Many new synthesis methods have emerged and are being evaluated for NS production for medical applications. NS toxicity is also critically discussed to reflect on potential concerns before widespread application in the medical field. © 2010 Elsevier Ltd.

Tan A.,University College London | de la Pena H.,University of Cambridge | Seifalian A.M.,University College London | Seifalian A.M.,Royal Free Hampstead NHS Trust Hospital
International Journal of Nanomedicine | Year: 2010

Cancer is a leading cause of death globally, and it is predicted and projected to continue rising as life expectancy increases. Although patient survival rates for some forms of cancers are high due to clinical advances in treatment protocols, the search for effective cancer vaccines remains the ultimate Rosetta Stone in oncology. Cervarix®, Gardasil®, and hepatitis B vaccines are currently employed in preventing certain forms of viral cancers. However, they are, strictly speaking, not 'true' cancer vaccines as they are prophylactic rather than therapeutic, are only effective against the oncogenic viruses, and do not kill the actual cancer cells. On April 2010, a new prostate cancer vaccine Provenge® (sipuleucel-T) was approved by the US FDA, and it is the first approved therapeutic vaccine that utilizes antigenpresenting cell technology involving dendritic cells in cancer immunotherapy. Recent evidence suggests that the use of nanoscale particles like exosomes in immunotherapy could form a viable basis for the development of novel cancer vaccines, via antigen-presenting cell technology, to prime the immune system to recognize and kill cancer cells. Coupled with nanotechnology, engineered exosomes are emerging as new and novel avenues for cancer vaccine development. Here, we review the current knowledge pertaining to exosome technology in immunotherapy and also seek to address the challenges and future directions associated with it, in hopes of bringing this exciting application a step closer toward an effective clinical reality. © 2010 Tan et al, publisher and licensee Dove Medical Press Ltd.

Desai M.,Royal Free Hampstead NHS Trust Hospital
Cochrane database of systematic reviews (Online) | Year: 2011

Despite advances in perioperative care, elective major vascular surgical procedures carry a significant risk of morbidity and mortality. Remote ischaemic preconditioning is initiated by brief, non-lethal periods of ischaemia in a vascular bed different from the one which will be subjected to ischaemic insult during surgery. It has the potential to provide local tissue protection from further prolonged periods of ischaemia. The aim of this review was to compare the outcomes from vascular and endovascular surgical procedures with and without the use of remote ischaemic preconditioning. The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (June 2011) and CENTRAL (2011, Issue 2). The authors searched MEDLINE via PubMed (July 2011), EMBASE (June 2011), and Science Citation Index Expanded (July 2011). We considered for inclusion all randomised controlled trials that evaluated the role of remote ischaemic preconditioning in reducing mortality and systemic injury in patients undergoing open vascular or endovascular surgery. We collected the data on characteristics of the trial, methodological quality, the remote ischaemic preconditioning stimulus used, mortality, morbidity, operating time and hospital stay from each trial. We analysed the data with both the fixed-effect and the random-effects models using RevMan analysis. For each outcome we calculated the risk ratio (RR) or mean difference with 95% confidence interval (CI) based on an intention-to-treat analysis. We included four studies with a total of 115 patients randomised to undergo a vascular procedure with remote ischaemic preconditioning and 117 patients randomised to have the procedure without remote ischaemic preconditioning. None of the trials were of low risk of bias. There was no significant difference in mortality between the two groups (RR 1.70, 95% CI 0.51 to 5.72). Similarly, there was no statistically significant difference between the two groups for all other outcomes except reduced risk of myocardial infarction in the remote ischaemic preconditioning group, which was significant by the fixed-effect model (RR 0.31, 95% CI 0.10 to 0.90) but not by the random-effects model (RR 0.34, 95% CI 0.11 to 1.08). This positive effect was from the results of only one trial and was not consistently observed. Furthermore, it was noted that there was an observed trend of high incidence of unplanned critical care admission in the remote ischaemic preconditioning group, although this was not statistically significant (RR 2.15, 95% CI 0.87 to 5.33). Based on current evidence from small pilot trials, there are too few data to be able to say whether remote ischaemic preconditioning has any beneficial or harmful effects. The safety of this technique needs to be confirmed in adequately powered trials. Therefore, further randomised trials on this technique are required.

Yildirimer L.,University College London | Thanh N.T.K.,University College London | Thanh N.T.K.,Royal Institution of Great Britain | Seifalian A.M.,University College London | Seifalian A.M.,Royal Free Hampstead NHS Trust Hospital
Trends in Biotechnology | Year: 2012

Skin wounds are a major social and financial burden. However, current treatments are suboptimal. The gradual comprehension of the finely orchestrated nature of intercellular communication has stimulated scientists to investigate growth factor (GF) or stem cell (SC) incorporation into suitable scaffolds for local delivery into wound beds in an attempt to accelerate healing. This review provides a critical evaluation of the status quo of current research into GF and SC therapy and subsequent future prospects, including benefits and possible long-term dangers associated with their use. Additionally, we stress the importance of a bottom-up approach in scaffold fabrication to enable controlled factor incorporation as well as production of complex scaffold micro- and nanostructures resembling that of natural extracellular matrix. © 2012 Elsevier Ltd.

Ahmed M.,University College London | Ghanbari H.,University College London | Cousins B.G.,University College London | Hamilton G.,Royal Free Hampstead NHS Trust Hospital | Seifalian A.M.,University College London
Acta Biomaterialia | Year: 2011

There is a significant worldwide demand for a small calibre vascular graft for use as a bypass or replacement conduit. An important feature in determining the success of a graft is the wall structure, which includes porosity, pore size and pore interconnectivity, as these play a crucial role in determining the long-term patency of a bypass graft. In this study we fabricate a small diameter (<5 mm) vascular graft from polyhedral oligomeric silsesquioxane- poly(carbonate urea)urethane (POSS-PCU) via an extrusion, phase inversion method using an automated, custom built machine. Through the dispersion of a porogen, sodium bicarbonate (NaHCO 3), in controlled concentrations (0-55%) we were able to produce grafts with well-defined pore morphologies. The impact of NaHCO 3 concentration on the structure of the graft wall and its influence on the mechanical and haemocompatibility properties are evaluated here. Scanning electron microscopy and mercury porosimetry were used to characterise graft structure. Atomic force microscopy elucidated any changes in surface morphology. The addition of NaHCO 3 improved the pore interconnectivity and increasing the concentration of NaHCO 3 led to grafts with rougher surfaces and larger pore sizes. The ultimate tensile strength and suture retention decreased with increasing concentrations of NaHCO 3, while graft compliance increased. To evaluate haemocompatibility platelets and peripheral blood mononuclear cells (PBMC) were incubated on a range of different graft samples. Platelet adhesion, PBMC surface receptor expression (CD14, CD86, CD69 and HLA-DR) and cytokine release (PF4, IL-1β, IL-6, IL-10, TNFα) were all measured. Increasing numbers of platelets adhered to grafts produced with no NaHCO 3, which exhibited a smooth surface morphology, and PBMC adherent on these grafts expressed higher levels of CD14 and CD86. Whilst the different graft samples induced varying levels of cytokine secretion in vitro, no distinct pattern suggesting a non-trivial relationship was observed. © 2011 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Wilson A.,University College London | Butler P.E.,University College London | Butler P.E.,Royal Free Hampstead NHS Trust Hospital | Seifalian A.M.,University College London
Cell Proliferation | Year: 2011

The use of stem cells derived from adipose tissue as an autologous and self-replenishing source for a variety of differentiated cell phenotypes, provides a great deal of promise for reconstructive surgery. In this article, we review available literature encompassing methods of extraction of pluripotent adipose stem cells (ASCs) from lipoaspirate locations, their storage, options for culture, growth and differentiation, cryopreservation and its effect on stem cell survival and proliferation, and new technologies involving biomaterials and scaffolds. We will conclude by assessing potential avenues for developing this incredibly promising field. © 2010 Blackwell Publishing Ltd.

Malam Y.,University College London | Lim E.J.,University College London | Seifalian A.M.,University College London | Seifalian A.M.,Royal Free Hampstead NHS Trust Hospital
Current Medicinal Chemistry | Year: 2011

The discovery of new biologically active compounds that can be exploited therapeutically to treat disease has stalled, with fewer new drugs entering the market every year. The spotlight has now turned onto nanoparticles (NPs) as a versatile and multifaceted platform for the delivery of drugs. NPs offer better pharmacokinetic properties, controlled and sustained release, and targeting of specific cells, tissues or organs. All these features can improve the efficacy of existing drugs. The use of NPs can dramatically impact the treatment of many diseases. Many potential therapeutics that exist for alleviating brain diseases such as epilepsy, Alzheimer's disease and tumours are not feasible due to a lack of means to deliver drugs across the blood brain barrier. NPs offer an alternative solution, since they can be modified to cross the blood brain barrier. Additionally, NPs can also play a part in alternative methods of non-parental administration of drugs e.g. pulmonary and transdermally. Through active targeting and the enhanced permeation and retention effect, NPs reduce the systemic toxicity of chemotherapeutic drugs by ensuring delivery only to the site of the tumour, thus enhancing cancer treatment. We critically review the literature to provide a summary of current synthesis methodologies and applications of NPs in drug delivery. © 2011 Bentham Science Publishers Ltd.

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