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Article: Hydrogels: 3D Drug Delivery Systems for Nanoparticles and Extracellular Vesicles.

Chabria, Yashna / Duffy, Garry P / Lowery, Aoife J / Dwyer, Róisín M

2021 Volume 9, Issue 11

Abstract: Synthetic and naturally occurring nano-sized particles present versatile vehicles for the delivery of therapy in a range of clinical settings. Their small size and modifiable physicochemical properties support refinement of targeting capabilities, immune ...

Abstract	Synthetic and naturally occurring nano-sized particles present versatile vehicles for the delivery of therapy in a range of clinical settings. Their small size and modifiable physicochemical properties support refinement of targeting capabilities, immune response, and therapeutic cargo, but rapid clearance from the body and limited efficacy remain a major challenge. This highlights the need for a local sustained delivery system for nanoparticles (NPs) and extracellular vesicles (EVs) at the target site that will ensure prolonged exposure, maximum efficacy and dose, and minimal toxicity. Biocompatible hydrogels loaded with therapeutic NPs/EVs hold immense promise as cell-free sustained and targeted delivery systems in a range of disease settings. These bioscaffolds ensure retention of the nano-sized particles at the target site and can also act as controlled release systems for therapeutics over a prolonged period of time. The encapsulation of stimuli sensitive components into hydrogels supports the release of the content on-demand. In this review, we highlight the prospect of the sustained and prolonged delivery of these nano-sized therapeutic entities from hydrogels for broad applications spanning tissue regeneration and cancer treatment. Further understanding of the parameters controlling the release rate of these particles and efficient transfer of cargo to target cells will be fundamental to success.
Language	English
Publishing date	2021-11-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines9111694
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Article ; Online: Resveratrol significantly improves cell survival in comparison to dexrazoxane and carvedilol in a h9c2 model of doxorubicin induced cardiotoxicity.

Monahan, David S / Flaherty, Eimhear / Hameed, Aamir / Duffy, Garry P

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2021 Volume 140, Page(s) 111702

Abstract: Cancer is one of the leading causes of deaths worldwide with 18.1 million deaths per year. Although there have been significant advances in anti-cancer therapies, they can often result in side effects with cardiovascular complications being the most ... ...

Abstract	Cancer is one of the leading causes of deaths worldwide with 18.1 million deaths per year. Although there have been significant advances in anti-cancer therapies, they can often result in side effects with cardiovascular complications being the most severe. Dexrazoxane is the only currently approved treatment for prevention of anthracycline induced cardiotoxicity but there are concerns about its use due to the development of secondary malignancies and myelodysplastic syndrome. Additionally, it is only recommended in patients who are due to receive a total cumulative dose of 300 mg/m
MeSH term(s)	Animals ; Antibiotics, Antineoplastic ; Cardiotonic Agents/pharmacology ; Cardiotoxicity/drug therapy ; Carvedilol/pharmacology ; Cell Line ; Cell Survival/drug effects ; Dexrazoxane/pharmacology ; Doxorubicin ; Rats ; Reactive Oxygen Species/metabolism ; Resveratrol/pharmacology
Chemical Substances	Antibiotics, Antineoplastic ; Cardiotonic Agents ; Reactive Oxygen Species ; Dexrazoxane (048L81261F) ; Carvedilol (0K47UL67F2) ; Doxorubicin (80168379AG) ; Resveratrol (Q369O8926L)
Language	English
Publishing date	2021-05-17
Publishing country	France
Document type	Comparative Study ; Journal Article
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2021.111702
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Article ; Online: Intermittent actuation attenuates fibrotic behaviour of myofibroblasts.

Ward, Niamh A / Hanley, Shirley / Tarpey, Ruth / Schreiber, Lucien H J / O'Dwyer, Joanne / Roche, Ellen T / Duffy, Garry P / Dolan, Eimear B

Acta biomaterialia

2023 Volume 173, Page(s) 80–92

Abstract: The foreign body response (FBR) to implanted materials culminates in the deposition of a hypo-permeable, collagen rich fibrotic capsule by myofibroblast cells at the implant site. The fibrotic capsule can be deleterious to the function of some medical ... ...

Abstract	The foreign body response (FBR) to implanted materials culminates in the deposition of a hypo-permeable, collagen rich fibrotic capsule by myofibroblast cells at the implant site. The fibrotic capsule can be deleterious to the function of some medical implants as it can isolate the implant from the host environment. Modulation of fibrotic capsule formation has been achieved using intermittent actuation of drug delivery implants, however the mechanisms underlying this response are not well understood. Here, we use analytical, computational, and in vitro models to understand the response of human myofibroblasts (WPMY-1 stromal cell line) to intermittent actuation using soft robotics and investigate how actuation can alter the secretion of collagen and pro/anti-inflammatory cytokines by these cells. Our findings suggest that there is a mechanical loading threshold that can modulate the fibrotic behaviour of myofibroblasts, by reducing the secretion of soluble collagen, transforming growth factor beta-1 and interleukin 1-beta, and upregulating the anti-inflammatory interleukin-10. By improving our understanding of how cells involved in the FBR respond to mechanical actuation, we can harness this technology to improve functional outcomes for a wide range of implanted medical device applications including drug delivery and cell encapsulation platforms. STATEMENT OF SIGNIFICANCE: A major barrier to the successful clinical translation of many implantable medical devices is the foreign body response (FBR) and resultant deposition of a hypo-permeable fibrotic capsule (FC) around the implant. Perturbation of the implant site using intermittent actuation (IA) of soft-robotic implants has previously been shown to modulate the FBR and reduce FC thickness. However, the mechanisms of action underlying this response were largely unknown. Here, we investigate how IA can alter the activity of myofibroblast cells, and ultimately suggest that there is a mechanical loading threshold within which their fibrotic behaviour can be modulated. These findings can be harnessed to improve functional outcomes for a wide range of medical implants, particularly drug delivery and cell encapsulation devices.
MeSH term(s)	Humans ; Foreign-Body Reaction/pathology ; Myofibroblasts/metabolism ; Foreign Bodies/pathology ; Anti-Inflammatory Agents ; Collagen/pharmacology ; Collagen/metabolism ; Fibrosis
Chemical Substances	Anti-Inflammatory Agents ; Collagen (9007-34-5)
Language	English
Publishing date	2023-11-14
Publishing country	England
Document type	Journal Article
ZDB-ID	2173841-5
ISSN	1878-7568 ; 1742-7061
ISSN (online)	1878-7568
ISSN	1742-7061
DOI	10.1016/j.actbio.2023.11.017
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Article: Soft robotic platform for controlled, progressive and reversible aortic constriction in a small animal model.

Rosalia, Luca / Wang, Sophie X / Ozturk, Caglar / Huang, Wei / Bonnemain, Jean / Beatty, Rachel / Duffy, Garry P / Nguyen, Christopher T / Roche, Ellen T

Research square

2023

Abstract: Our understanding of cardiac remodeling processes due to left ventricular pressure overload derives largely from animal models of aortic banding. However, these studies fail to simultaneously enable control over disease progression and reversal, ... ...

Abstract	Our understanding of cardiac remodeling processes due to left ventricular pressure overload derives largely from animal models of aortic banding. However, these studies fail to simultaneously enable control over disease progression and reversal, hindering their clinical relevance. Here, we describe a method for controlled, progressive, and reversible aortic banding based on an implantable expandable actuator that can be finely controlled to modulate aortic banding and debanding in a rat model. Through catheterization, imaging, and histologic studies, we demonstrate that our model can recapitulate the hemodynamic and structural changes associated with pressure overload in a controllable manner. We leverage the ability of our model to enable non-invasive aortic debanding to show that these changes can be partly reversed due to cessation of the biomechanical stimulus. By recapitulating longitudinal disease progression and reversibility, this model could elucidate fundamental mechanisms of cardiac remodeling and optimize timing of intervention for pressure overload.
Language	English
Publishing date	2023-07-19
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3100659/v1
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Article ; Online: Dual scaffold delivery of miR-210 mimic and miR-16 inhibitor enhances angiogenesis and osteogenesis to accelerate bone healing.

Castaño, Irene Mencía / Raftery, Rosanne M / Chen, Gang / Cavanagh, Brenton / Quinn, Brian / Duffy, Garry P / Curtin, Caroline M / O'Brien, Fergal J

Acta biomaterialia

2023 Volume 172, Page(s) 480–493

Abstract: Angiogenesis is critical for successful bone repair, and interestingly, miR-210 and miR-16 possess counter-active targets involved in both angiogenesis and osteogenesis: miR-210 acts as an activator by silencing EFNA3 & AcvR1b, while miR-16 inhibits both ...

Abstract	Angiogenesis is critical for successful bone repair, and interestingly, miR-210 and miR-16 possess counter-active targets involved in both angiogenesis and osteogenesis: miR-210 acts as an activator by silencing EFNA3 & AcvR1b, while miR-16 inhibits both pathways by silencing VEGF & Smad5. It was thus hypothesized that dual delivery of both a miR-210 mimic and a miR-16 inhibitor from a collagen-nanohydroxyapatite scaffold system may hold significant potential for bone repair. Therefore, this systems potential to rapidly accelerate bone repair by directing enhanced angiogenic-osteogenic coupling in host cells in a rat calvarial defect model at a very early 4 week timepoint was assessed. In vitro, the treatment significantly enhanced angiogenic-osteogenic coupling of human mesenchymal stem cells, with enhanced calcium deposition after just 10 days in 2D and 14 days on scaffolds. In vivo, these dual-miRNA loaded scaffolds showed more than double bone volume and vessel recruitment increased 2.3 fold over the miRNA-free scaffolds. Overall, this study demonstrates the successful development of a dual-miRNA mimic/inhibitor scaffold for enhanced in vivo bone repair for the first time, and the possibility of extending this 'off-the-shelf' platform system to applications beyond bone offers immense potential to impact a myriad of other tissue engineering areas. STATEMENT OF SIGNIFICANCE: miRNAs have potential as a new class of bone healing therapeutics as they can enhance the regenerative capacity of bone-forming cells. However, angiogenic-osteogenic coupling is critical for successful bone repair. Therefore, this study harnesses the delivery of miR-210, known to be an activator of both angiogenesis and osteogenesis, and miR-16 inhibitor, as miR-16 is known to inhibit both pathways, from a collagen-nanohydroxyapatite scaffold system to rapidly enhance osteogenesis in vitro and bone repair in vivo in a rat calvarial defect model. Overall, it describes the successful development of the first dual-miRNA mimic/inhibitor scaffold for enhanced in vivo bone repair. This 'off-the-shelf' platform system offers immense potential to extend beyond bone applications and impact a myriad of other tissue engineering areas.
MeSH term(s)	Humans ; Rats ; Animals ; Osteogenesis/genetics ; Tissue Scaffolds ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Bone and Bones/metabolism ; Tissue Engineering ; Collagen ; Bone Regeneration ; Cell Differentiation
Chemical Substances	MicroRNAs ; Collagen (9007-34-5) ; MIRN16 microRNA, human ; MIRN210 microRNA, human ; MIRN16 microRNA, rat ; MIRN210 microRNA, rat
Language	English
Publishing date	2023-10-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2173841-5
ISSN	1878-7568 ; 1742-7061
ISSN (online)	1878-7568
ISSN	1742-7061
DOI	10.1016/j.actbio.2023.09.049
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Article ; Online: Exploring therapy transport from implantable medical devices using experimentally informed computational methods.

Trask, Lesley / Ward, Niamh A / Tarpey, Ruth / Beatty, Rachel / Wallace, Eimear / O'Dwyer, Joanne / Ronan, William / Duffy, Garry P / Dolan, Eimear B

Biomaterials science

2024

Abstract: Implantable medical devices that can facilitate therapy transport to localized sites are being developed for a number of diverse applications, including the treatment of diseases such as diabetes and cancer, and tissue regeneration after myocardial ... ...

Abstract	Implantable medical devices that can facilitate therapy transport to localized sites are being developed for a number of diverse applications, including the treatment of diseases such as diabetes and cancer, and tissue regeneration after myocardial infraction. These implants can take the form of an encapsulation device which encases therapy in the form of drugs, proteins, cells, and bioactive agents, in semi-permeable membranes. Such implants have shown some success but the nature of these devices pose a barrier to the diffusion of vital factors, which is further exacerbated upon implantation due to the foreign body response (FBR). The FBR results in the formation of a dense hypo-permeable fibrous capsule around devices and is a leading cause of failure in many implantable technologies. One potential method for overcoming this diffusion barrier and enhancing therapy transport from the device is to incorporate local fluid flow. In this work, we used experimentally informed inputs to characterize the change in the fibrous capsule over time and quantified how this impacts therapy release from a device using computational methods. Insulin was used as a representative therapy as encapsulation devices for Type 1 diabetes are among the most-well characterised. We then explored how local fluid flow may be used to counteract these diffusion barriers, as well as how a more practical pulsatile flow regimen could be implemented to achieve similar results to continuous fluid flow. The generated model is a versatile tool toward informing future device design through its ability to capture the expected decrease in insulin release over time resulting from the FBR and investigate potential methods to overcome these effects.
Language	English
Publishing date	2024-04-29
Publishing country	England
Document type	Journal Article
ZDB-ID	2693928-9
ISSN	2047-4849 ; 2047-4830
ISSN (online)	2047-4849
ISSN	2047-4830
DOI	10.1039/d4bm00107a
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Article ; Online: Towards the use of localised delivery strategies to counteract cancer therapy-induced cardiotoxicities.

Monahan, David S / Almas, Talal / Wyile, Robert / Cheema, Faisal H / Duffy, Garry P / Hameed, Aamir

Drug delivery and translational research

2021 Volume 11, Issue 5, Page(s) 1924–1942

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Cardiotoxicity/drug therapy ; Cardiotoxicity/etiology ; Cardiotoxicity/prevention & control ; Heart Failure ; Humans ; Immunotherapy/adverse effects ; Neoplasms/drug therapy
Language	English
Publishing date	2021-01-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2590155-2
ISSN	2190-3948 ; 2190-393X
ISSN (online)	2190-3948
ISSN	2190-393X
DOI	10.1007/s13346-020-00885-3
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Article ; Online: Tethering zwitterionic polymer coatings to mediated glucose biosensor enzyme electrodes can decrease sensor foreign body response yet retain sensor sensitivity to glucose.

Jayakumar, Kavita / Lielpetere, Anna / Domingo-Lopez, Daniel A / Levey, Ruth E / Duffy, Garry P / Schuhmann, Wolfgang / Leech, Dónal

Biosensors & bioelectronics

2022 Volume 219, Page(s) 114815

Abstract: Foreign body response (FBR) is a major challenge that affects implantable biosensors and medical devices, including glucose biosensors, leading to a deterioration in device response over time. Polymer shields are often used to mitigate this issue. ... ...

Abstract	Foreign body response (FBR) is a major challenge that affects implantable biosensors and medical devices, including glucose biosensors, leading to a deterioration in device response over time. Polymer shields are often used to mitigate this issue. Zwitterionic polymers (ZPs) are a promising class of materials that reduce biofouling of implanted devices. A series of ZPs each containing tetherable epoxide functional groups was synthesised for application as a polymer shield for eventual application as implantable glucose biosensors. The polymer shields were initially tested for the ability to resist fibrinogen adsorption and fibroblast adhesion. All synthesised ZPs showed comparable behaviour to a commercial Lipidure ZP in resisting fibrinogen adsorption. Nafion, a common anionic shield used against electrochemical interferents, showed higher protein adsorption and comparable cell adhesion resistance as uncoated control surfaces. However, a poly(2-methacryloyloxyethyl phosphorylcholine-co-glycidyl methacrylate) (MPC)-type ZP showed similar behaviour to Lipidure, with approximately 50% reduced fibrinogen adsorption and 80% decrease in fibroblast adhesion compared to uncoated controls. An MPC-coated amperometric glucose biosensor showed comparable current density and a 1.5-fold increase in sensitivity over an uncoated control biosensor, whereas all other polymer shields tested, including Lipidure, Nafion and a poly(ethyleneglycol) polymer, resulted in lower sensitivity and current density. Collectively, these characteristics make MPC-polymer shield coatings an appealing possibility for use in implantable glucose sensors and other implanted devices with the aim of reducing FBR while maintaining sensor performance.
Language	English
Publishing date	2022-10-18
Publishing country	England
Document type	Journal Article
ZDB-ID	1011023-9
ISSN	1873-4235 ; 0956-5663
ISSN (online)	1873-4235
ISSN	0956-5663
DOI	10.1016/j.bios.2022.114815
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Article ; Online: A method of characterising the complex anatomy of vascular occlusions and 3D printing biomimetic analogues.

O'Reilly, Muireann / Beatty, Rachel / McBride, Shauna / Brennan, Benjamin / Dockery, Peter / Duffy, Garry P

Journal of anatomy

2022 Volume 242, Issue 1, Page(s) 64–75

Abstract: Chronic total occlusions (CTOs) occur in approximately 40% of individuals with symptomatic peripheral arterial disease and are indicative of critical limb ischaemia. Currently, few medical devices can effectively treat CTOs long-term, with amputation ... ...

Abstract	Chronic total occlusions (CTOs) occur in approximately 40% of individuals with symptomatic peripheral arterial disease and are indicative of critical limb ischaemia. Currently, few medical devices can effectively treat CTOs long-term, with amputation often required. This is due to a lack of knowledge of CTO anatomy, making device design and testing difficult. This study is a proof-of-concept study, which aimed to develop a workflow for further characterising the complex multi-material anatomy of CTOs and creating 3D models of CTO components, which may be useful in producing a vascular CTO biomimetic for device testing. Here, we establish such a workflow using samples of atheromatous plaques. We focus on a high-resolution, non-destructive microcomputed tomography (μCT) technique which enables visualisation of occlusion anatomy at a greater resolution than computed tomography angiography (CTA), which is the typical modality used for CTO clinical visualisation. Four arteries (n = 2 superficial femoral; n = 2 popliteal) with evidence of atheromatous plaques were cut into 8 cm segments, which were then stained with iodine and scanned at low resolution, with calcified regions rescanned at high resolution. Resulting files were manually segmented to generate 3D models, which were then 3D printed in resin using a stereolithography printer to produce parts suitable for creating a biomimetic. In total, μCT files from three arterial segments (n = 2 high resolution, n = 1 low resolution) were deemed suitably calcified for segmentation, and thus were segmented to produce 3D models. 3D models of the arterial wall, intima and atheromatous calcium deposits from a high-resolution popliteal artery scan were successfully 3D printed at several scales. While this research is at an early stage, it holds great promise. The workflow for segmentation and 3D printing various components of an atheromatous plaque established here is replicable and uses software and equipment which are accessible to research laboratories in both academia and industry. The ability to print detailed models on a desktop 3D printer is unprecedented and can be improved further, which is promising for future development of biomimetics with multi-material detail of both soft tissue and calcified components of a vascular occlusion. Indeed, this workflow provides a solid foundation for future studies of CTO anatomy and the creation of true, multi-material CTO biomimetics. Such biomimetics may enable the development of improved interventional devices, as they would mimic the general in vivo CTO environment. As this method cannot be applied in vivo, we cannot yet produce patient-specific biomimetics, however, these analogues would still be important in device development, which would improve patient outcomes in critical limb ischaemia.
MeSH term(s)	Humans ; Biomimetics ; Plaque, Atherosclerotic ; Chronic Limb-Threatening Ischemia ; X-Ray Microtomography ; Printing, Three-Dimensional ; Treatment Outcome
Language	English
Publishing date	2022-03-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2955-5
ISSN	1469-7580 ; 0021-8782
ISSN (online)	1469-7580
ISSN	0021-8782
DOI	10.1111/joa.13648
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Article ; Online: Monitoring the macrophage response towards biomaterial implants using label-free imaging.

Lu, Chuan-En / Levey, Ruth E / Ghersi, Giulio / Schueller, Nathan / Liebscher, Simone / Layland, Shannon L / Schenke-Layland, Katja / Duffy, Garry P / Marzi, Julia

Materials today. Bio

2023 Volume 21, Page(s) 100696

Abstract: Understanding the immune system's foreign body response (FBR) is essential when developing and validating a biomaterial. Macrophage activation and proliferation are critical events in FBR that can determine the material's biocompatibility and fate in ... ...

Abstract	Understanding the immune system's foreign body response (FBR) is essential when developing and validating a biomaterial. Macrophage activation and proliferation are critical events in FBR that can determine the material's biocompatibility and fate in vivo. In this study, two different macro-encapsulation pouches intended for pancreatic islet transplantation were implanted into streptozotocin-induced diabetes rat models for 15 days. Post-explantation, the fibrotic capsules were analyzed by standard immunohistochemistry as well as non-invasive Raman microspectroscopy to determine the degree of FBR induced by both materials. The potential of Raman microspectroscopy to discern different processes of FBR was investigated and it was shown that Raman microspectroscopy is capable of targeting ECM components of the fibrotic capsule as well as pro and anti-inflammatory macrophage activation states, in a molecular-sensitive and marker-independent manner. In combination with multivariate analysis, spectral shifts reflecting conformational differences in Col I were identified and allowed to discriminate fibrotic and native interstitial connective tissue fibers. Moreover, spectral signatures retrieved from nuclei demonstrated changes in methylation states of nucleic acids in M1 and M2 phenotypes, relevant as indicator for fibrosis progression. This study could successfully implement Raman microspectroscopy as complementary tool to study in vivo immune-compatibility providing insightful information of FBR of biomaterials and medical devices, post-implantation.
Language	English
Publishing date	2023-06-13
Publishing country	England
Document type	Journal Article
ISSN	2590-0064
ISSN (online)	2590-0064
DOI	10.1016/j.mtbio.2023.100696
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