Publications by authors named "Garry P Duffy"

61 Publications

Enhancing delivery of small molecule and cell-based therapies for ovarian cancer using advanced delivery strategies.

Adv Ther (Weinh) 2020 Nov 16;3(11). Epub 2020 Aug 16.

Department of Biomedical Engineering, School of Engineering, College of Science and Engineering, National University of Ireland Galway, Ireland.

Ovarian cancer is the most lethal gynecological malignancy with a global five-year survival rate of 30-50%. First-line treatment involves cytoreductive surgery and administration of platinum-based small molecules and paclitaxel. These therapies were traditionally administered via intravenous infusion, although intraperitoneal delivery has also been investigated. Initial clinical trials of intraperitoneal administration for ovarian cancer indicated significant improvements in overall survival compared to intravenous delivery, but this result is not consistent across all studies performed. Recently cell-based immunotherapy has been of interest for ovarian cancer. Direct intraperitoneal delivery of cell-based immunotherapies might prompt local immunoregulatory mechanisms to act synergistically with the delivered immunotherapy. Based on this theory, pre-clinical studies have delivered these cell-based immunotherapies via the intraperitoneal route, with promising results. However, successful intraperitoneal delivery of cell-based immunotherapy and clinical adoption of this technique will depend on overcoming challenges of intraperitoneal delivery and finding the optimal combinations of dose, therapeutic and delivery route. We review the potential advantages and disadvantages of intraperitoneal delivery of cell-based immunotherapy for ovarian cancer and the pre-clinical and clinical work performed so far. Potential advanced delivery strategies, which might improve the efficacy and adoption of intraperitoneal delivery of therapy for ovarian cancer, are also outlined.
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http://dx.doi.org/10.1002/adtp.202000144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942751PMC
November 2020

Nidogen-1 Mitigates Ischemia and Promotes Tissue Survival and Regeneration.

Adv Sci (Weinh) 2021 Feb 21;8(4):2002500. Epub 2020 Dec 21.

Department of Bioengineering Eberhard Karls University Tübingen Tübingen 72076 Germany.

Ischemia impacts multiple organ systems and is the major cause of morbidity and mortality in the developed world. Ischemia disrupts tissue homeostasis, driving cell death, and damages tissue structure integrity. Strategies to heal organs, like the infarcted heart, or to replace cells, as done in pancreatic islet -cell transplantations, are often hindered by ischemic conditions. Here, it is discovered that the basement membrane glycoprotein nidogen-1 attenuates the apoptotic effect of hypoxia in cardiomyocytes and pancreatic -cells via the v3 integrin and beneficially modulates immune responses in vitro. It is shown that nidogen-1 significantly increases heart function and angiogenesis, while reducing fibrosis, in a mouse postmyocardial infarction model. These results demonstrate the protective and regenerative potential of nidogen-1 in ischemic conditions.
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http://dx.doi.org/10.1002/advs.202002500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887579PMC
February 2021

Towards the use of localised delivery strategies to counteract cancer therapy-induced cardiotoxicities.

Drug Deliv Transl Res 2021 Jan 15. Epub 2021 Jan 15.

Tissue Engineering Research Group (TERG), Department of Anatomy, RCSI University of Medicine and Health Sciences, 123, St. Stephens Green, Dublin 2, Dublin, D02 YN77, Ireland.

Cancer therapies have significantly improved cancer survival; however, these therapies can often result in undesired side effects to off target organs. Cardiac disease ranging from mild hypertension to heart failure can occur as a result of cancer therapies. This can warrant the discontinuation of cancer treatment in patients which can be detrimental, especially when the treatment is effective. There is an urgent need to mitigate cardiac disease that occurs as a result of cancer therapy. Delivery strategies such as the use of nanoparticles, hydrogels, and medical devices can be used to localise the treatment to the tumour and prevent off target side effects. This review summarises the advancements in localised delivery of anti-cancer therapies to tumours. It also examines the localised delivery of cardioprotectants to the heart for patients with systemic disease such as leukaemia where localised tumour delivery might not be an option.
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http://dx.doi.org/10.1007/s13346-020-00885-3DOI Listing
January 2021

Fluorescence lifetime metabolic mapping of hypoxia-induced damage in pancreatic pseudo-islets.

J Biophotonics 2020 12 15;13(12):e202000375. Epub 2020 Oct 15.

Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University Tübingen, Tübingen, Germany.

Pancreatic islet isolation from donor pancreases is an essential step for the transplantation of insulin-secreting β-cells as a therapy to treat type 1 diabetes mellitus. This process however damages islet basement membranes, which can lead to islet dysfunction or death. Posttransplantation, islets are further stressed by a hypoxic environment and immune reactions that cause poor engraftment and graft failure. The current standards to assess islet quality before transplantation are destructive procedures, performed on a small islet population that does not reflect the heterogeneity of large isolated islet batches. In this study, we incorporated fluorescence lifetime imaging microscopy (FLIM) into a pancreas-on-chip system to establish a protocol to noninvasively assess the viability and functionality of pancreatic β-cells in a three-dimensional in vitro model (= pseudo-islets). We demonstrate how (pre-) hypoxic β-cell-composed pseudo-islets can be discriminated from healthy functional pseudo-islets according to their FLIM-based metabolic profiles. The use of FLIM during the pretransplantation pancreatic islet selection process has the potential to improve the outcome of β-cell islet transplantation.
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http://dx.doi.org/10.1002/jbio.202000375DOI Listing
December 2020

Collagen and Endothelial Cell Coculture Improves β-Cell Functionality and Rescues Pancreatic Extracellular Matrix.

Tissue Eng Part A 2020 Nov 6. Epub 2020 Nov 6.

Department of Bioengineering, Eberhard Karls University Tübingen, Tübingen, Germany.

The use of biomaterials and biomaterial functionalization is a promising approach to support pancreatic islet viability posttransplantation in an effort to reduce insulin dependence for patients afflicted with diabetes mellitus type 1. Extracellular matrix (ECM) proteins are known to impact numerous reparative functions in the body. Assessing how endogenously expressed pancreatic ECM proteins are affected by posttransplant-like hypoxic conditions may provide significant insights toward the development of tissue-engineered therapeutic strategies to positively influence β-cell survival, proliferation, and functionality. Here, we investigated the expression of three relevant groups of pancreatic ECM proteins in human native tissue, including basement membrane (BM) proteins (collagen type 4 [COL4], laminins [LAM]), proteoglycans (decorin [DCN], nidogen-1 [NID1]), and fibril-forming proteins (fibronectin [FN], collagen type 1 [COL1]). In an hypoxia model, we identified that ECM proteins were differently affected by hypoxic conditions, contributing to an overall loss of β-cell functionality. The use of a COL1 hydrogel as carrier material demonstrated a protective effect on β-cells mitigating the effect of hypoxia on proteoglycans as well as fibril-forming protein expression, supporting β-cell functionality in hypoxia. We further showed that providing endothelial cells (ECs) into the COL1 hydrogel improves β-cell response as well as the expression of relevant BM proteins. Our data show that β-cells benefit from a microenvironment composed of structure-providing COL1 with the incorporation of ECs to withstand the harsh conditions of hypoxia. Such hydrogels support β-cell survival and can serve as an initial source of ECM proteins to allow cell engraftment while preserving cell functionality posttransplantation. Impact statement Expression analysis identifies hypoxia-induced pathological changes in extracellular matrix (ECM) homeostasis as potential targets to support β-cell transplants by encapsulation in biomaterials for the treatment of diabetes mellitus. A collagen-1 hydrogel is shown to attenuate the effect of hypoxia on β-cells and their ECM expression. The functionalization of the hydrogel with endothelial cells increases the β-cell response to glucose and rescues essential basement membrane proteins.
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http://dx.doi.org/10.1089/ten.TEA.2020.0250DOI Listing
November 2020

Development of a Sustained Release Nano-In-Gel Delivery System for the Chemotactic and Angiogenic Growth Factor Stromal-Derived Factor 1α.

Pharmaceutics 2020 Jun 4;12(6). Epub 2020 Jun 4.

Drug Delivery & Advanced Materials Team, School of Pharmacy & Biomolecular Sciences, Royal College of Surgeons in Ireland (RCSI), Dublin 2, Ireland.

Stromal-Derived Factor 1α (SDF) is an angiogenic, chemotactic protein with significant potential for applications in a range of clinical areas, including wound healing, myocardial infarction and orthopaedic regenerative approaches. The 26-min in vivo half-life of SDF, however, has limited its clinical translation to date. In this study, we investigate the use of star-shaped or linear poly(glutamic acid) (PGA) polypeptides to produce PGA-SDF nanoparticles, which can be incorporated into a tyramine-modified hyaluronic acid hydrogel (HA-TA) to facilitate sustained localised delivery of SDF. The physicochemical properties and biocompatibility of the PGA-SDF nanoparticle formulations were extensively characterised prior to incorporation into a HA-TA hydrogel. The biological activity of the SDF released from the nano-in-gel system was determined on Matrigel, scratch and Transwell migration assays. Both star-shaped and linear PGA facilitated SDF nanoparticle formation with particle sizes from 255-305 nm and almost complete SDF complexation. Star-PGA-SDF demonstrated superior biocompatibility and was incorporated into a HA-TA gel, which facilitated sustained SDF release for up to 35 days in vitro. Released SDF significantly improved gap closure on a scratch assay, produced a 2.8-fold increase in HUVEC Transwell migration and a 1.5-fold increase in total tubule length on a Matrigel assay at 12 h compared to untreated cells. Overall, we present a novel platform system for the sustained delivery of bioactive SDF from a nano-in-gel system which could be adapted for a range of biomedical applications.
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http://dx.doi.org/10.3390/pharmaceutics12060513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355599PMC
June 2020

Implantable Therapeutic Reservoir Systems for Diverse Clinical Applications in Large Animal Models.

Adv Healthc Mater 2020 06 27;9(11):e2000305. Epub 2020 Apr 27.

Anatomy & Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine Nursing and Health Sciences, National University of Ireland, Galway, H91 W5P7, Ireland.

Regenerative medicine approaches, specifically stem cell technologies, have demonstrated significant potential to treat a diverse array of pathologies. However, such approaches have resulted in a modest clinical benefit, which may be attributed to poor cell retention/survival at the disease site. A delivery system that facilitates regional and repeated delivery to target tissues can provide enhanced clinical efficacy of cell therapies when localized delivery of high doses of cells is required. In this study, a new regenerative reservoir platform (Regenervoir) is described for use in large animal models, with relevance to cardiac, abdominal, and soft tissue pathologies. Regenervoir incorporates multiple novel design features essential for clinical translation, with a focus on scalability, mechanism of delivery, fixation to target tissue, and filling/refilling with a therapeutic cargo, and is demonstrated in an array of clinical applications that are easily translated to human studies. Regenervoir consists of a porous reservoir fabricated from a single material, a flexible thermoplastic polymer, capable of delivering cargo via fill lines to target tissues. A radiopaque shear thinning hydrogel can be delivered to the therapy reservoir and multiple fixation methods (laparoscopic tacks and cyanoacrylate bioadhesive) can be used to secure Regenervoir to target tissues through a minimally invasive approach.
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http://dx.doi.org/10.1002/adhm.202000305DOI Listing
June 2020

Rapid bone repair with the recruitment of CD206M2-like macrophages using non-viral scaffold-mediated miR-133a inhibition of host cells.

Acta Biomater 2020 06 3;109:267-279. Epub 2020 Apr 3.

Tissue Engineering Research Group, Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland (RCSI), 123 Saint Stephen's Green, Dublin 2, Dublin, Ireland; Trinity Centre for Bioengineering, Trinity College Dublin, Dublin, Ireland; Advanced Materials and Bioengineering Research Centre (AMBER), RCSI and TCD, Dublin, Ireland. Electronic address:

microRNAs offer vast therapeutic potential for multiple disciplines. From a bone perspective, inhibition of miR-133a may offer potential to enhance Runx2 activity and increase bone repair. This study aims to assess the therapeutic capability of antagomiR-133a delivery from collagen-nanohydroxyapatite (coll-nHA) scaffolds following cell-free implantation in rat calvarial defects (7 mm diameter). This is, to the best of our knowledge, the first report of successful in vivo antagomiR uptake in host cells of fully immunocompetent animals without distribution to other off-target tissues. Our results demonstrate the localized release of antagomiR-133a to the implant site at 1 week post-implantation with increased calcium deposits already evident in the antagomiR-133a loaded scaffolds at this early timepoint. This was followed by an approximate 2-fold increase in bone volume versus antagomiR-free scaffolds and a significant 10-fold increase over the empty defect controls, after just 4 weeks. An increase in host CD206 cells suggests an accelerated pro-remodeling response by M2-like macrophages accompanying bone repair with this treatment. Overall, this non-viral scaffold-mediated antagomiR-133a delivery platform demonstrates capability to accelerate bone repair in vivo - without the addition of exogenous cells - and underlines the role of M2 macrophage-like cells in directing accelerated bone repair. Expanding the repertoire of this platform to deliver alternative miRNAs offers exciting possibilities for a variety of therapeutic indications. STATEMENT OF SIGNIFICANCE: microRNAs, small non-coding RNA molecules involved in gene regulation, may have potential as a new class of bone healing therapeutics as they can enhance the regenerative capacity of bone-forming cells. We developed a collagen-nanohydroxyapatite-microRNA scaffold system to investigate whether miR133a inhibition can enhance osteogenesis in rat MSCs and ultimately accelerate endogenous bone repair by host cells in vivo without pre-seeding cells prior to implantation. Overall, this off-the-shelf, non-viral scaffold-mediated antagomiR-133a delivery platform demonstrates capability to accelerate bone repair in vivo - without the requirement of exogenous cells - and highlights the role of CD206M2 macrophage-like cells in guiding accelerated bone repair. Translating the repertoire of this platform to deliver alternative miRNAs offers exciting possibilities for a vast myriad of therapeutic indications.
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http://dx.doi.org/10.1016/j.actbio.2020.03.042DOI Listing
June 2020

Pre-culture of mesenchymal stem cells within RGD-modified hyaluronic acid hydrogel improves their resilience to ischaemic conditions.

Acta Biomater 2020 04 4;107:78-90. Epub 2020 Mar 4.

Tissue Engineering Research Group, Department of Anatomy, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, Dublin 2, Dublin, Ireland; Trinity Centre for Bioengineering (TCBE), Trinity College Dublin (TCD), Dublin 2, Dublin, Ireland; Advanced Materials and Bioengineering Research Centre (AMBER), NUIG, RCSI and TCD, Dublin, Ireland; Anatomy & Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland. Electronic address:

The incorporation of the RGD peptide (arginine-glycine-aspartate) into biomaterials has been proposed to promote cell adhesion to the matrix, which can influence and control cell behaviour and function. While many studies have utilised RGD modified biomaterials for cell delivery, few have examined its effect under the condition of reduced oxygen and nutrients, as found at ischaemic injury sites. Here, we systematically examine the effect of RGD on hMSCs in hyaluronic acid (HA) hydrogel under standard and ischaemic culture conditions, to elucidate under what conditions RGD has beneficial effects over unmodified HA and its effectiveness in improving cell viability. Results demonstrate that under standard culture conditions, RGD significantly increased hMSC spreading and the release of vascular endothelial factor-1 (VEGF) and monocyte chemoattractant factor-1 (MCP-1), compared to unmodified HA hydrogel. As adhesion is known to influence cell survival, we hypothesised that cells in RGD hydrogels would exhibit increased cell viability under ischaemic culture conditions. However, results demonstrate that cell viability and protein release was comparable in both RGD modified and unmodified HA hydrogels. Confocal imaging revealed cellular morphology indicative of weak cell adhesion. Subsequent investigations found that RGD was could exert positive effects on encapsulated cells under ischaemic conditions but only if hMSCs were pre-cultured under standard conditions to allow strong adhesion to RGD before exposure. Together, these results provide novel insight into the value of RGD introduction and suggest that the adhesion of hMSCs to RGD prior to delivery could improve survival and function at ischaemic injury sites. STATEMENT OF SIGNIFICANCE: The development of a biomaterial scaffold capable of maintaining cell viability while promoting cell function is a major research goal in the field of cardiac tissue engineering. This study confirms the suitability of a modified HA hydrogel whereby stem cells in the modified hydrogel showed significantly greater cell spreading and protein secretion compared to cells in the unmodified HA hydrogel. A pre-culture period allowing strong adhesion of the cells to the modified hydrogel was shown to improve cell survival under conditions that mimic the myocardium post-MI. This finding may have a significant impact on the use and timelines of modifications to improve stem cell survival in harsh environments like the injured heart.
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http://dx.doi.org/10.1016/j.actbio.2020.02.043DOI Listing
April 2020

Enhancing medial layer recellularization of tissue-engineered blood vessels using radial microchannels.

Regen Med 2019 11 20;14(11):1013-1028. Epub 2019 Nov 20.

Trinity Centre for Biomedical Engineering (TCBE), Trinity Biomedical Sciences Institute, TCD, Dublin, Ireland.

Cell repopulation of tissue-engineered vascular grafts (TEVGs) from decellularized arterial scaffolds is limited by dense concentric tunica media layers which impede cells migrating radially between the layers. We aimed to develop and validate a new microneedle device to modify decellularized carotid arteries with radial microchannels to enhance medial layer repopulation. Modified decellularized porcine arteries were seeded with rat mesenchymal stem cells using either standard longitudinal injection, or a dual vacuum-perfusion bioreactor. Mechanical tests were used to assess the arterial integrity following modification. The method herein achieved radial recellularization of arteries without significant loss of mechanical integrity, Thus, we report a novel method for successful radial repopulation of decellularized carotid artery-based tissue-engineered vascular grafts.
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http://dx.doi.org/10.2217/rme-2019-0011DOI Listing
November 2019

Development of a nanomedicine-loaded hydrogel for sustained delivery of an angiogenic growth factor to the ischaemic myocardium.

Drug Deliv Transl Res 2020 04;10(2):440-454

Drug Delivery & Advanced Materials Team, School of Pharmacy & Biomolecular Sciences, Royal College of Surgeons in Ireland (RCSI), Dublin 2, Ireland.

The 5-year mortality rate for heart failure borders on 50%. The main cause is an ischaemic cardiac event where blood supply to the tissue is lost and cell death occurs. Over time, this damage spreads and the heart is no longer able to pump efficiently. Increasing vascularisation of the affected area has been shown to reduce patient symptoms. The growth factors required to do this have short half-lives making development of an efficacious therapy difficult. Herein, the angiogenic growth factor Vascular Endothelial Growth Factor (VEGF) is complexed electrostatically with star-shaped or linear polyglutamic acid (PGA) polypeptides. Optimised PGA-VEGF nanomedicines provide VEGF encapsulation of > 99% and facilitate sustained release of VEGF for up to 28 days in vitro. The star-PGA-VEGF nanomedicines are loaded into a percutaneous delivery compliant hyaluronic acid hydrogel. Sustained release of VEGF from the composite nano-in-gel system is evident for up to 35 days and the released VEGF has comparable bioactivity to free, fresh VEGF when tested on both Matrigel and scratch assays. The final star-PGA-VEGF nanomedicine-loaded hydrogel is biocompatible and provides sustained release of bioactive VEGF. Therefore, we report the development of novel, self-assembling PGA-VEGF nanomedicines and their incorporation into a hyaluronic acid hydrogel that is compatible with medical devices to enable minimally invasive delivery to the heart. The final star-PGA-VEGF nanomedicine-loaded hydrogel is biocompatible and provides sustained release of bioactive VEGF. This formulation provides the basis for optimal spatiotemporal delivery of an angiogenic growth factor to the ischaemic myocardium.
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http://dx.doi.org/10.1007/s13346-019-00684-5DOI Listing
April 2020

Vascular Endothelial Growth Factor-Releasing Microspheres Based on Poly(ε-Caprolactone-PEG-ε-Caprolactone)-b-Poly(L-Lactide) Multiblock Copolymers Incorporated in a Three-Dimensional Printed Poly(Dimethylsiloxane) Cell Macroencapsulation Device.

J Pharm Sci 2020 01 22;109(1):863-870. Epub 2019 Oct 22.

Department of Pharmaceutics, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands. Electronic address:

Pancreatic islet transplantation is a promising advanced therapy that has been used to treat patients suffering from diabetes type 1. Traditionally, pancreatic islets are infused via the portal vein, which is subsequently intended to engraft in the liver. Severe immunosuppressive treatments are necessary, however, to prevent rejection of the transplanted islets. Novel approaches therefore have focused on encapsulation of the islets in biomaterial implants which can protect the islets and offer an organ-like environment. Vascularization of the device's surface is a prerequisite for the survival and proper functioning of transplanted pancreatic islets. We are pursuing a prevascularization strategy by incorporation of vascular endothelial growth factor (VEGF)-loaded microspheres in 3-dimensional printed poly(dimethylsiloxane)-based devices prior to their prospective loading with transplanted cells. Microspheres (~50 μm) were based on poly(ε-caprolactone-PEG-ε-caprolactone)-b-poly(L-lactide) multiblock copolymers and were loaded with 10 μg VEGF/mg microspheres, and subsequently dispersed in a hyaluronic acid carrier liquid. In vitro release studies at 37°C demonstrated continuous release of fully bioactive VEGF for 4 weeks. In conclusion, our results demonstrate that incorporation of VEGF-releasing microspheres ensures adequate release of VEGF for a time window of 4 weeks, which is attractive in view of the vascularization of artificial pancreas implants.
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http://dx.doi.org/10.1016/j.xphs.2019.10.028DOI Listing
January 2020

Sustained Release of Vascular Endothelial Growth Factor from Poly(ε-caprolactone-PEG-ε-caprolactone)--Poly(l-lactide) Multiblock Copolymer Microspheres.

ACS Omega 2019 Jul 1;4(7):11481-11492. Epub 2019 Jul 1.

Department of Pharmaceutics, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.

Vascular endothelial growth factor (VEGF) is the major regulating factor for the formation of new blood vessels, also known as angiogenesis. VEGF is often incorporated in synthetic scaffolds to promote vascularization and to enhance the survival of cells that have been seeded in these devices. Such applications require sustained local delivery of VEGF of around 4 weeks for stable blood vessel formation. Most delivery systems for VEGF only provide short-term release for a couple of days, followed by a release phase with very low VEGF release. We now have developed VEGF-loaded polymeric microspheres that provide sustained release of bioactive VEGF for 4 weeks. Blends of two swellable poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone)--poly(l-lactide) ([PCL-PEG-PCL]--[PLLA])-based multiblock copolymers with different PEG content and PEG molecular weight were used to prepare the microspheres. Loading of the microspheres was established by a solvent evaporation-based membrane emulsification method. The resulting VEGF-loaded microspheres had average sizes of 40-50 μm and a narrow size distribution. Optimized formulations of a 50:50 blend of the two multiblock copolymers had an average VEGF loading of 0.79 ± 0.09%, representing a high average VEGF loading efficiency of 78 ± 16%. These microspheres released VEGF continuously over 4 weeks in phosphate-buffered saline pH 7.4 at 37 °C. This release profile was preserved after repeated and long-term storage at -20 °C for up to 9 months, thereby demonstrating excellent storage stability. VEGF release was governed by diffusion through the water-filled polymer matrix, depending on PEG molecular weight and PEG content of the polymers. The bioactivity of the released VEGF was retained within the experimental error in the 4-week release window, as demonstrated using a human umbilical vein endothelial cells proliferation assay. Thus, the microspheres prepared in this study are suitable for embedment in polymeric scaffolds with the aim of promoting their functional vascularization.
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http://dx.doi.org/10.1021/acsomega.9b01272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681988PMC
July 2019

A bioresorbable biomaterial carrier and passive stabilization device to improve heart function post-myocardial infarction.

Mater Sci Eng C Mater Biol Appl 2019 Oct 15;103:109751. Epub 2019 May 15.

Tissue Engineering Research Group, Department of Anatomy, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland; Anatomy, School of Medicine, College of Medicine Nursing and Health Sciences, National University of Ireland Galway, Ireland; Advanced Materials and BioEngineering Research Centre (AMBER), Trinity College Dublin, Royal College of Surgeons Ireland, & National University of Ireland Galway, Ireland. Electronic address:

The limited regenerative capacity of the heart after a myocardial infarct results in remodeling processes that can progress to congestive heart failure (CHF). Several strategies including mechanical stabilization of the weakened myocardium and regenerative approaches (specifically stem cell technologies) have evolved which aim to prevent CHF. However, their final performance remains limited motivating the need for an advanced strategy with enhanced efficacy and reduced deleterious effects. An epicardial carrier device enabling a targeted application of a biomaterial-based therapy to the infarcted ventricle wall could potentially overcome the therapy and application related issues. Such a device could play a synergistic role in heart regeneration, including the provision of mechanical support to the remodeling heart wall, as well as providing a suitable environment for in situ stem cell delivery potentially promoting heart regeneration. In this study, we have developed a novel, single-stage concept to support the weakened myocardial region post-MI by applying an elastic, biodegradable patch (SPREADS) via a minimal-invasive, closed chest intervention to the epicardial heart surface. We show a significant increase in %LVEF 14 days post-treatment when GS (clinical gold standard treatment) was compared to GS + SPREADS + Gel with and without cells (p ≤ 0.001). Furthermore, we did not find a significant difference in infarct quality or blood vessel density between any of the groups which suggests that neither infarct quality nor vascularization is the mechanism of action of SPREADS. The SPREADS device could potentially be used to deliver a range of new or previously developed biomaterial hydrogels, a remarkable potential to overcome the translational hurdles associated with hydrogel delivery to the heart.
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http://dx.doi.org/10.1016/j.msec.2019.109751DOI Listing
October 2019

Insulin-like growth factor-1 (IGF-1) poly (lactic-co-glycolic acid) (PLGA) microparticles - development, characterisation, and assessment of bioactivity for cardiac applications.

J Microencapsul 2019 May 14;36(3):267-277. Epub 2019 Jun 14.

a Tissue Engineering Research Group (TERG), Department of Anatomy , Royal College of Surgeons in Ireland (RSCI) , Dublin , Ireland.

The aim of this study was to evaluate the formulation of a synthetic IGF-1 (pIGF-1) in PLGA microparticles (MP). Poly (lactic-co-glycolic acid) (PLGA) MPs loaded with pIGF-1 were prepared, characterised and evaluated using double emulsion solvent evaporation method. Spherical MPs showed an average particle size of 2 µm, encapsulation efficiency (EE) of 67% and 50% degradation over 15 days. With a view to enhancing retention in the myocardium, the MP formulation was encapsulated in a cross-linked hyaluronic acid hydrogel. pIGF-1 released from MPs and from MPs suspended in hyaluronic acid hydrogel remained bioactive, determined by a significant increase in cellular proliferation of c-kit cells. This formulation has potential for loco-regional delivery to damaged myocardium to promote the survival of cardiomyocytes.
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http://dx.doi.org/10.1080/02652048.2019.1622605DOI Listing
May 2019

Sustained release of targeted cardiac therapy with a replenishable implanted epicardial reservoir.

Nat Biomed Eng 2018 06 11;2(6):416-428. Epub 2018 Jun 11.

John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA.

The clinical translation of regenerative therapy for the diseased heart, whether in the form of cells, macromolecules or small molecules, is hampered by several factors: the poor retention and short biological half-life of the therapeutic agent, the adverse side effects from systemic delivery, and difficulties with the administration of multiple doses. Here, we report the development and application of a therapeutic epicardial device that enables sustained and repeated administration of small molecules, macromolecules and cells directly to the epicardium via a polymer-based reservoir connected to a subcutaneous port. In a myocardial infarct rodent model, we show that repeated administration of cells over a four-week period using the epicardial reservoir provided functional benefits in ejection fraction, fractional shortening and stroke work, compared to a single injection of cells and to no treatment. The pre-clinical use of the therapeutic epicardial reservoir as a research model may enable insights into regenerative cardiac therapy, and assist the development of experimental therapies towards clinical use.
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http://dx.doi.org/10.1038/s41551-018-0247-5DOI Listing
June 2018

RGD-decorated cholesterol stabilized polyplexes for targeted siRNA delivery to glioblastoma cells.

Drug Deliv Transl Res 2019 06;9(3):679-693

Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG, Utrecht, The Netherlands.

The development of an effective and safe treatment for glioblastoma (GBM) represents a significant challenge in oncology today. Downregulation of key mediators of cell signal transduction by RNA interference is considered a promising treatment strategy but requires efficient, intracellular delivery of siRNA into GBM tumor cells. Here, we describe novel polymeric siRNA nanocarriers functionalized with cRGD peptide that mediates targeted and efficient reporter gene silencing in U87R invasive human GBM cells. The polymer was synthesized via RAFT copolymerization of N-(2-hydroxypropyl)-methacrylamide (HPMA) and N-acryloxysuccinimide (NAS), followed by post-polymerization modification with cholesterol for stabilization, cationic amines for siRNA complexation, and azides for copper-free click chemistry. The novel resultant cationic polymer harboring a terminal cholesterol group, self-assembled with siRNA to yield nanosized polyplexes (~ 40 nm) with good colloidal stability at physiological ionic strength. Post-modification of the preformed polyplexes with PEG-cRGD end-functionalized with bicyclo[6.1.0]nonyne (BCN) group resulted in enhanced cell uptake and increased luciferase gene silencing in U87R cells, compared to polyplexes lacking cRGD-targeting groups.
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http://dx.doi.org/10.1007/s13346-019-00637-yDOI Listing
June 2019

An injectable alginate/extra cellular matrix (ECM) hydrogel towards acellular treatment of heart failure.

Drug Deliv Transl Res 2019 02;9(1):1-13

Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.

As treatments for myocardial infarction (MI) continue to improve, the population of people suffering from heart failure (HF) is rising significantly. Novel treatment strategies aimed at achieving long-term functional stabilisation and improvement in heart function post MI include the delivery of biomaterial hydrogels and myocardial matrix-based therapies to the left ventricle wall. Individually alginate hydrogels and myocardial matrix-based therapies are at the most advanced stages of commercial/clinical development for this potential treatment option. However, despite these individual successes, the potential synergistic effect gained by combining the two therapies remains unexplored. This study serves as a translational step in evaluating the minimally invasive delivery of dual acting alginate-based hydrogels to the heart. We have successfully developed new production methods for hybrid alginate/extracellular matrix (ECM) hydrogels. We have identified that the high G block alginate/ECM hybrid hydrogel has appropriate rheological and mechanical properties (1.6 KPa storage modulus, 29 KPa compressive modulus and 14 KPa dynamic modulus at day 1) and can be delivered using a minimally invasive delivery device. Furthermore, we have determined that these novel hydrogels are not cytotoxic and are capable of enhancing the metabolic activity of dermal fibroblasts in vitro (p < 0.01). Overall these results suggest that an effective minimally invasive HF treatment option could be achieved by combining alginate and ECM particles.
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http://dx.doi.org/10.1007/s13346-018-00601-2DOI Listing
February 2019

Advanced Material Catheter (AMCath), a minimally invasive endocardial catheter for the delivery of fast-gelling covalently cross-linked hyaluronic acid hydrogels.

J Biomater Appl 2018 11 25;33(5):681-692. Epub 2018 Oct 25.

1 Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.

Injectable hydrogels that aim to mechanically stabilise the weakened left ventricle wall to restore cardiac function or to deliver stem cells in cardiac regenerative therapy have shown promising data. However, the clinical translation of hydrogel-based therapies has been limited due to difficulties injecting them through catheters. We have engineered a novel catheter, Advanced Materials Catheter (AMCath), that overcomes translational hurdles associated with delivering fast-gelling covalently cross-linked hyaluronic acid hydrogels to the myocardium. We developed an experimental technique to measure the force required to inject such hydrogels and determined the mechanical/viscoelastic properties of the resulting hydrogels. The preliminary in vivo feasibility of delivering fast-gelling hydrogels through AMCath was demonstrated by accessing the porcine left ventricle and showing that the hydrogel was retained in the myocardium post-injection (three 200 μL injections delivered, 192, 204 and 183 μL measured). However, the mechanical properties of the hydrogels were reduced by passage through AMCath (≤20.62% reduction). We have also shown AMCath can be used to deliver cardiopoietic adipose-derived stem cell-loaded hydrogels without compromising the viability (80% viability) of the cells in vitro. Therefore, we show that hydrogel/catheter compatibility issues can be overcome as we have demonstrated the minimally invasive delivery of a fast-gelling covalently cross-linked hydrogel to the beating myocardium.
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http://dx.doi.org/10.1177/0885328218805878DOI Listing
November 2018

Hydrogels in adipose tissue engineering-Potential application in post-mastectomy breast regeneration.

J Tissue Eng Regen Med 2018 12 8;12(12):2234-2247. Epub 2018 Nov 8.

Discipline of Anatomy, School of Medicine, College of Medicine Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland.

Current methods of breast reconstruction are associated with significant shortcomings, including capsular contracture, infection, rupture, the need for reoperation in implant-based reconstruction, and donor site morbidity in autologous reconstruction. These limitations result in severe physical and psychological issues for breast cancer patients. Recently, research has moved into the field of adipose tissue engineering to overcome these limitations. A wide range of regenerative strategies has been devised utilising various scaffold designs and biomaterials. A scaffold capable of providing appropriate biochemical and biomechanical cues for adipogenesis is required. Hydrogels have been widely studied for their suitability for adipose tissue regeneration and are advantageous secondary to their ability to accurately imitate the native extracellular matrix. The aim of this review was to analyse the use of hydrogel scaffolds in the field of adipose tissue engineering.
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http://dx.doi.org/10.1002/term.2753DOI Listing
December 2018

Towards Alternative Approaches for Coupling of a Soft Robotic Sleeve to the Heart.

Ann Biomed Eng 2018 Oct 15;46(10):1534-1547. Epub 2018 May 15.

Harvard-MIT Program in Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.

Efficient coupling of soft robotic cardiac assist devices to the external surface of the heart is crucial to augment cardiac function and represents a hurdle to translation of this technology. In this work, we compare various fixation strategies for local and global coupling of a direct cardiac compression sleeve to the heart. For basal fixation, we find that a sutured Velcro band adheres the strongest to the epicardium. Next, we demonstrate that a mesh-based sleeve coupled to the myocardium improves function in an acute porcine heart failure model. Then, we analyze the biological integration of global interface material candidates (medical mesh and silicone) in a healthy and infarcted murine model and show that a mesh interface yields superior mechanical coupling via pull-off force, histology, and microcomputed tomography. These results can inform the design of a therapeutic approach where a mesh-based soft robotic DCC is implanted, allowed to biologically integrate with the epicardium, and actuated for active assistance at a later timepoint. This strategy may result in more efficient coupling of extracardiac sleeves to heart tissue, and lead to increased augmentation of heart function in end-stage heart failure patients.
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http://dx.doi.org/10.1007/s10439-018-2046-2DOI Listing
October 2018

Harnessing an Inhibitory Role of miR-16 in Osteogenesis by Human Mesenchymal Stem Cells for Advanced Scaffold-Based Bone Tissue Engineering.

Tissue Eng Part A 2019 01 10;25(1-2):24-33. Epub 2018 Apr 10.

1 Tissue Engineering Research Group, Department of Anatomy, Royal College of Surgeons in Ireland, Dublin, Ireland.

MicroRNA (miRNA) therapeutics is increasingly being developed to either target bone-related diseases such as osteoporosis and osteoarthritis or as the basis for novel bone tissue engineering strategies. A number of miRNAs have been reported as potential osteo-therapeutics but no consensus has yet been established on the optimal target. miR-16 has been studied extensively in nonosteogenic functions and used as functionality reporter target in the development of nonviral miRNA delivery platforms. This study hypothesized that miR-16 may also play an inhibitory role in osteogenesis due to its ability to directly target Smad5 and AcvR2a. This study thus aimed to assess the potential of miR-16 inhibition to increase osteogenesis in human mesenchymal stem cells (hMSCs) using a previously established miRNA delivery platform composed of nanohydroxyapatite (nHA) particles as nonviral vectors in combination with collagen-nHA scaffolds designed specifically for bone repair. Initial results showed that antagomiR-16 delivery efficiently increased the relative levels of both putative targets and Runx2, the key transcription factor for osteogenesis, while also increasing osteocalcin levels. Furthermore, significant increases in mineral calcium deposition by hMSCs were found in both monolayer and most importantly in scaffold-based osteodifferentiation studies, ultimately demonstrating that miR-16 inhibition further enhances the therapeutic potential of a scaffold with known potential for bone repair applications and thus holds significant therapeutic potential as a novel bone tissue engineering strategy. Furthermore, we suggest that harnessing the additional functions known to miR-16 by incorporating either its enhancers or inhibitors to tissue-specific tailored scaffolds provides exciting opportunities for a diverse range of therapeutic indications.
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http://dx.doi.org/10.1089/ten.TEA.2017.0460DOI Listing
January 2019

Direct UV-Triggered Thiol-ene Cross-Linking of Electrospun Polyester Fibers from Unsaturated Poly(macrolactone)s and Their Drug Loading by Solvent Swelling.

Biomacromolecules 2017 Dec 14;18(12):4292-4298. Epub 2017 Nov 14.

Department of Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons in Ireland , 123 St. Stephens Green, Dublin 2, Ireland.

Electrospinning is considered a relatively simple and versatile technique to form high porosity porous scaffolds with micron to nanoscale fibers for biomedical applications. Here, electrospinning of unsaturated aliphatic polyglobalide (PGl) into well-defined fibers with an average diameter of 9 μm is demonstrated. Addition of a dithiol cross-linker and a photoinitiator to the polymer solution enabled the UV-triggered intracross-linking of the fibers during the spinning process. The in situ cross-linking of the fibers resulted in amorphous material able to swell up to 14% in tetrahydrofurane (THF) without losing the fiber morphology. Seeding mesenchymal stem cells (MSCs) onto both cross-linked and non-cross-linked PGl fibers proved their compatibility with MSCs and suitability as scaffolds for cell growth and proliferation of MSCs. Moreover, the ability to directly load cross-linked PGl with hydrophobic molecules by soaking the fiber mesh in solution is shown with Rhodamine B and Indomethacin, a hydrophobic anti-inflammatory drug. This marks an advantage over conventional aliphatic polyesters and opens opportunities for the design of drug loaded polyester scaffolds for biomedical applications or tissue engineering.
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http://dx.doi.org/10.1021/acs.biomac.7b01335DOI Listing
December 2017

Olfactory Derived Stem Cells Delivered in a Biphasic Conduit Promote Peripheral Nerve Repair In Vivo.

Stem Cells Transl Med 2017 10;6(10):1894-1904

Tissue Engineering Research Group, Department of Anatomy, Royal College of Surgeons in Ireland, Dublin, Ireland.

Peripheral nerve injury presents significant therapeutic challenges for recovery of motor and sensory function in patients. Different clinical approaches exist but to date there has been no consensus on the most effective method of treatment. Here, we investigate a novel approach to peripheral nerve repair using olfactory derived stem (ONS) cells delivered in a biphasic collagen and laminin functionalized hyaluronic acid based nerve guidance conduit (NGC). Nerve regeneration was studied across a 10-mm sciatic nerve gap in Sprague Dawley rats. The effect of ONS cell loading of NGCs with or without nerve growth factor (NGF) supplementation on nerve repair was compared to a cell-free NGC across a variety of clinical, functional, electrophysiological, and morphologic parameters. Animals implanted with ONS cell loaded NGCs demonstrated improved clinical and electrophysiological outcomes compared to cell free NGC controls. The nerves regenerated across ONS cell loaded NGCs contained significantly more axons than cell-free NGCs. A return of the nocioceptive withdrawal reflex in ONS cell treated animals indicated an advanced repair stage at a relatively early time point of 8 weeks post implantation. The addition of NGF further improved the outcomes of the repair indicating the potential beneficial effect of a combined stem cell/growth factor treatment strategy delivered on NGCs. Stem Cells Translational Medicine 2017;6:1894-1904.
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http://dx.doi.org/10.1002/sctm.16-0420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430049PMC
October 2017

Advances in polymeric islet cell encapsulation technologies to limit the foreign body response and provide immunoisolation.

Curr Opin Pharmacol 2017 10 31;36:66-71. Epub 2017 Aug 31.

Tissue Engineering Research Group, Department of Anatomy, Royal College of Surgeons in Ireland, 123 St Stephens Green, Dublin 2, Ireland; Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; Advanced Materials and Bioengineering Research (AMBER) Centre, Royal College of Surgeons in Ireland and Trinity College Dublin, Dublin, Ireland. Electronic address:

Islet transplantation for the treatment of type 1 diabetes (T1D) is hampered by the shortage of donor tissue and the need for life-long immunosuppression. The engineering of materials to limit host immune rejection opens the possibilities of utilising allogeneic and even xenogeneic cells without the need for systemic immunosuppression. Here we discuss the most recent developments in immunoisolation of transplanted cells using advanced polymeric biomaterials, utilising macroscale to nanoscale approaches, to limit aberrant immune responses.
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http://dx.doi.org/10.1016/j.coph.2017.07.013DOI Listing
October 2017

A collagen cardiac patch incorporating alginate microparticles permits the controlled release of hepatocyte growth factor and insulin-like growth factor-1 to enhance cardiac stem cell migration and proliferation.

J Tissue Eng Regen Med 2018 01 19;12(1):e384-e394. Epub 2017 Jun 19.

Tissue Engineering Research Group, Department of Anatomy, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.

Cardiac stem cells (CSCs) represent a logical cell type to exploit as a regenerative treatment option for tissue damage accrued as a result of a myocardial infarction. However, the isolation and expansion of CSCs prior to cell transplantation is time consuming, costly and invasive, and the reliability of cell expansion may also prove to be a major obstacle in the clinical application of CSC-based transplantation therapy after a myocardial infarction. In order to overcome this, we propose the incorporation of growth factor-eluting alginate microparticles into collagen-based scaffolds as an implantable biomaterial to promote the recruitment and expansion of CSCs in the myocardium. In order to obtain scaffolds able to enhance the motogenic and proliferative potential of CSCs, the aim of this work was to achieve a sustained delivery of both hepatocyte growth factor and insulin-like growth factor-1. Both proteins were initially encapsulated in alginate microparticles by spray drying and subsequently incorporated into a collagen scaffold. Microparticles were seen to homogeneously distribute through the interconnected scaffold pore structure. The resulting scaffolds were capable of extending the release of both proteins up to 15 days, a three-fold increase over non-encapsulated proteins embedded in the scaffolds. In vitro assays with isolated CSCs demonstrated that the sustained release of both bioactive proteins resulted in an increased motogenic and proliferative effect. As presently practiced, the isolation and expansion of CSCs for autologous cell transplantation is slow, expensive and difficult to attain. Thus, there is a need for strategies to specifically activate in situ the intrinsic cardiac regenerative potential represented by the CSCs using combinations of growth factors obviating the need for cell transplantation. By favouring the natural regenerative capability of CSCs, it is hypothesized that the cardiac patch presented here will result in positive therapeutic outcomes in MI and heart failure patients in the future. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/term.2392DOI Listing
January 2018

Tissue Engineered Solutions for Intracardiac Septal Defects: A Large Step Forward in an Unmet Clinical Need.

Ann Surg 2017 Feb;265(2):e11-e12

*Department of Anatomy, Tissue Engineering Research Group, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, Dublin 2, Ireland †Trinity Centre for Bioengineering, Trinity College Dublin (TCD), College Green, Dublin 2, Ireland ‡Advanced Materials and Bioengineering Research (AMBER) Centre, RCSI & TCD, Dublin 2, Ireland §Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan ¶Department of Surgery, Section of Cardiothoracic Surgery, Aga Khan University, Karachi, Pakistan.

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http://dx.doi.org/10.1097/SLA.0000000000002060DOI Listing
February 2017

Nanomedicines for advanced cancer treatments: Transitioning towards responsive systems.

Int J Pharm 2016 Dec 7;515(1-2):132-164. Epub 2016 Oct 7.

Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland (RCSI), Dublin 2, Ireland; Trinity Centre for Bioengineering, Trinity College Dublin (TCD), Dublin 2, Ireland; Advanced Materials Bio-engineering Research (AMBER) centre, RCSI, Dublin 2, Ireland; School of Pharmacy, RCSI, Dublin 2, Ireland. Electronic address:

The development of nanomedicines for the treatment of cancer focuses on the local targeted delivery of chemotherapeutic drugs to enhance drug efficacy and reduce adverse effects. The nanomedicines which are currently approved for clinical use are mainly successful in terms of improved bioavailability and tolerability but do not necessarily increase drug performance. Therefore, there is a need for improved drug carrier systems which are able to deliver high doses of anti-cancer drugs to the tumor. Stimuli responsive carriers are promising candidates since drug release can be triggered locally in the tumor via internal (i.e. pH, redox potential, metabolite or enzyme concentration) or external (i.e. heat, ultrasound, light, magnetic field) stimuli. This review summarizes the recent progress in the transition towards stimuli responsive nanomedicines (i.e. liposomes, polymeric micelles, nanogels and mesoporous silica nanoparticles) and other therapy modalities that are currently developed in the fight against cancer like the application of ultrasound, tumor normalization and phototherapy. Furthermore, the potential role of image guided drug delivery in the development of new nanomedicines and its clinical application is discussed.
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http://dx.doi.org/10.1016/j.ijpharm.2016.10.013DOI Listing
December 2016

A stimuli responsive liposome loaded hydrogel provides flexible on-demand release of therapeutic agents.

Acta Biomater 2017 01 20;48:110-119. Epub 2016 Oct 20.

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:

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.

Statement Of Significance: 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.
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http://dx.doi.org/10.1016/j.actbio.2016.10.001DOI Listing
January 2017

An in vitro investigation to assess procedure parameters for injecting therapeutic hydrogels into the myocardium.

J Biomed Mater Res B Appl Biomater 2017 Nov 20;105(8):2618-2629. Epub 2016 Oct 20.

Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.

Localized delivery of stem cells is potentially a promising therapeutic strategy for regenerating damaged myocardium. Many studies focus on limiting the biologic component of cell loss, but few address the contribution of mechanical factors. This study investigates optimal parameters for retaining the largest volume of cell loaded hydrogels post intramyocardial injection, without compromising cell viability. In vitro, hydrogel was injected into porcine hearts using various needle designs. Hydrogel retention and distribution pattern was then determined. The two most promising needles were then investigated to understand the effect of needle geometry on stem cell viability. The needle to best impact cell viability was then used to investigate the effect of differing hydrogels on retention and distribution. Three-dimensional experimental modeling revealed needles with smaller diameter's to have greater poloxamer 407 hydrogel retention. No difference in retention existed among various needle designs of similar gauge, despite differences in bolus geometries. When hMSC's, embedded in fibrin hydrogel, were injected through helical and 26G bevel needles no difference in the percent of live cells was seen at 48 h. However, the helical group had almost half the metabolic activity of the 26G bevel group at both time points, and had a significant decline in the percent of live cells from 24 to 48 h. Varying gel type resulted in significantly more alginate being retained in the tissue in comparison to fibrin or poloxamer hydrogels. In conclusion, mechanical properties of injected hydrogels, and the diameter of the needle used, highly influences the volume of hydrogel retained. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2618-2629, 2017.
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http://dx.doi.org/10.1002/jbm.b.33802DOI Listing
November 2017