title: A stimuli responsive liposome loaded hydrogel provides flexible on-demand release of therapeutic agents.
abstract: Lysolipid-based thermosensitive liposomes (LTSL) embedded in a chitosan-based thermoresponsive hydrogel matrix (denoted Lipogel) represents a novel approach for the spatiotemporal release of therapeutic agents. The entrapment of drug-loaded liposomes in an injectable hydrogel permits local liposome retention, thus providing a prolonged release in target tissues. Moreover, release can be controlled through the use of a minimally invasive external hyperthermic stimulus. Temporal control of release is particularly important for complex multi-step physiological processes, such as angiogenesis, in which different signals are required at different times in order to produce a robust vasculature. In the present work, we demonstrate the ability of Lipogel to provide a flexible, easily modifiable release platform. It is possible to tune the release kinetics of different drugs providing a passive release of one therapeutic agent loaded within the gel and activating the release of a second LTSL encapsulated agent via a hyperthermic stimulus. In addition, it was possible to modify the drug dosage within Lipogel by varying the duration of hyperthermia. This can allow for adaption of drug dosing in real time. As an in vitro proof of concept with this system, we investigated Lipogels ability to recruit stem cells and then elevate their production of vascular endothelial growth factor (VEGF) by controlling the release of a pro-angiogenic drug, desferroxamine (DFO) with an external hyperthermic stimulus. Initial cell recruitment was accomplished by the passive release of hepatocyte growth factor (HGF) from the hydrogel, inducing a migratory response in cells, followed by the delayed release of DFO from thermosensitive liposomes, resulting in a significant increase in VEGF expression. This delayed release could be controlled up to 14days. Moreover, by changing the duration of the hyperthermic pulse, a fine control over the amount of DFO released was achieved. The ability to trigger the release of therapeutic agents at a specific timepoint and control dosing level through changes in duration of hyperthermia enables sequential multi-dose profiles.
  
  
  
  This paper details the development of a heat responsive liposome loaded hydrogel for the controlled release of pro-angiogenic therapeutics. Lysolipid-based thermosensitive liposomes (LTSLs) embedded in a chitosan-based thermoresponsive hydrogel matrix represents a novel approach for the spatiotemporal release of therapeutic agents. This hydrogel platform demonstrates remarkable flexibility in terms of drug scheduling and sequencing, enabling the release of multiple agents and the ability to control drug dosing in a minimally invasive fashion. The possibility to tune the release kinetics of different drugs independently represents an innovative platform to utilise for a variety of treatments. This approach allows a significant degree of flexibility in achieving a desired release profile via a minimally invasive stimulus, enabling treatments to be tuned in response to changing symptoms and complications.
authors: Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland; Trinity Centre for Bioengineering, Trinity College Dublin (TCD), Dublin, Ireland; Advanced Materials and Bioengineering Research (AMBER) Centre, RCSI & TCD, Dublin, Ireland; School of Pharmacy, RCSI, Dublin, Ireland.
authors: Hugh S
authors: HS
authors: O'Neill
authors: Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland; Trinity Centre for Bioengineering, Trinity College Dublin (TCD), Dublin, Ireland; Advanced Materials and Bioengineering Research (AMBER) Centre, RCSI & TCD, Dublin, Ireland.
authors: Caroline C
authors: CC
authors: Herron
authors: Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland; Trinity Centre for Bioengineering, Trinity College Dublin (TCD), Dublin, Ireland; Advanced Materials and Bioengineering Research (AMBER) Centre, RCSI & TCD, Dublin, Ireland.
authors: Conn L
authors: CL
authors: Hastings
authors: University Medical Centre, Image Science Institute, Utrecht, The Netherlands; Dept. of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors: Roel
authors: R
authors: Deckers
authors: Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland; Trinity Centre for Bioengineering, Trinity College Dublin (TCD), Dublin, Ireland; Advanced Materials and Bioengineering Research (AMBER) Centre, RCSI & TCD, Dublin, Ireland; School of Pharmacy, RCSI, Dublin, Ireland.
authors: Adolfo
authors: A
authors: Lopez Noriega
authors: Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland; School of Pharmacy, RCSI, Dublin, Ireland.
authors: Helena M
authors: HM
authors: Kelly
authors: Dept. of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors: Wim E
authors: WE
authors: Hennink
authors: Dept. of Vascular Surgery, Mater Misericordiae University Hospital, Dublin, Ireland.
authors: Ciarán O
authors: CO
authors: McDonnell
authors: Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland; Trinity Centre for Bioengineering, Trinity College Dublin (TCD), Dublin, Ireland; Advanced Materials and Bioengineering Research (AMBER) Centre, RCSI & TCD, Dublin, Ireland.
authors: Fergal J
authors: FJ
authors: O'Brien
authors: Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland; Trinity Centre for Bioengineering, Trinity College Dublin (TCD), Dublin, Ireland; Advanced Materials and Bioengineering Research (AMBER) Centre, RCSI & TCD, Dublin, Ireland; School of Pharmacy, RCSI, Dublin, Ireland. Electronic address: eduardorhernandez@rcsi.ie.
authors: Eduardo
authors: E
authors: Ruiz-Hernández
authors: Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland; Trinity Centre for Bioengineering, Trinity College Dublin (TCD), Dublin, Ireland; Advanced Materials and Bioengineering Research (AMBER) Centre, RCSI & TCD, Dublin, Ireland. Electronic address: garryduffy@rcsi.ie.
authors: Garry P
authors: GP
authors: Duffy
mesh_terms: D001672:Biocompatible Materials / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D048271:Chitosan / Q000737:chemistry; D003676:Deferoxamine / Q000494:pharmacology*; D065546:Drug Liberation; D005994:Glycerophosphates / Q000737:chemistry; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry*; D006979:Hyperthermia, Induced; D008081:Liposomes; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D001672:Biocompatible Materials; D005994:Glycerophosphates; D008081:Liposomes; D042461:Vascular Endothelial Growth Factor A; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D017228:Hepatocyte Growth Factor; D048271:Chitosan; D003676:Deferoxamine; C031463:beta-glycerophosphoric acid
keywords: Angiogenesis; Controlled release; Dual release; Growth factor delivery; Thermoresponsive hydrogel; Thermosensitive liposomes