Date of Award

6-2017

Document type

Thesis

Degree Name

MD (Medical Doctor)

First Supervisor

Dr Garry Duffy

Second Supervisor

Dr Helena Kelly

Third Supervisor

Dr Eduardo Ruiz-Hernandez

Keywords

Cardiovascular Tissue Engineering, Biomaterials, Insulin like Growth Factor 1 (IGF-1), Rat Cardiac Stem Cells, Myocardial Infarction, PLGA [Poly (Lactic-Co-Glycolic Acid)]

Abstract

Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality around the world. Acute myocardial infarction (MI) and ischemic heart disease (IHD) cause progressive myocardial remodelling and left ventricular dysfunction leading to the development of heart failure (HF) in a significant number of patients. Current treatment modalities do not reverse the damage done to the heart after MI. Over the years, regenerative therapy for ischaemic cardiomyopathy has been an extremely active area of research. Stem cell therapy has the potential to attenuate the inflammatory response and left ventricular (LV) remodelling post MI. Cardiac stem cells (CSCs) are a heterogenic group of cells and are concentrated in specific areas of the heart, such as the atria or pericardium. Due to the likelihood to be intrinsically programmed, they represent a reasonable source to exploit in myocardial regeneration. Functional autologous myocardial tissue is the ideal replacement for the damaged myocardium. However, as presently practiced, the isolation and expansion of endogenous cardiac stem cells (eCSCs) for autologous cell transplantation is slow and expensive. Thus, the need arises for the approaches which specifically activate in situ intrinsic cardiac regenerative potential represented by the resident eCSCs. This can be achieved by using combinations of growth factors, cytokines, and drugs, precluding the need for cell transplantation. Poly (lactic-co-glycolic acid) (PLGA) is a copolymer of poly (glycolic acid) (PGA) and poly (lactic acid) (PLA) and is a widely studied synthetic biodegradable polymer for encapsulating and delivering drugs/proteins to various target organs in the body. Because of its high biocompatibility and safety, it is approved by the United States Food and Drug Administration (FDA) and European Medicine Agency (EMA) to be used as a drug delivery vehicle in humans. Herein this thesis, we optimised the process parameters for fabrication of synthetic Insulin like growth factor (PIGF-1) loaded PLGA microparticles and nanoparticles using two different techniques; double emulsion solvent evaporation method or water-in-oil-in-water (W/O/W) method and electrospray. Depending upon the feasibility of process parameters and reproducibility of results, we favoured double emulsion solvent evaporation method over electrospray. Moreover, good encapsulation efficiency (>60%) of PIGF-1 was achieved with PLGA microparticle formulation. We then worked on the scalability of the fabrication process of PIGF-1 loaded PLGA microparticle using W/O/W method. Furthermore, PIGF-1 loaded PLGA microparticles were incorporated into cross linked hyaluronic acid-tyramide (HA-TA) hydrogel with the vision to increase the retention of PLGA microparticles in the noxious environment post MI. We tested various concentrations of PIGF-1 (10 and 25 ng/ml) released from PLGA microparticles itself and from PLGA microparticles in HA-TA gel (MP-HA) to induce a proliferative effect on treated rat cardiac stem cells (rCSCs). Cells exposed to PIGF-1 showed an increase in dsDNA compared to untreated control group, hence confirming the bioactivity of the released PIGF-1. It is envisioned that the HA gel loaded with PIGF-1-PLGA microaprticles (MP-HA) will be delivered to the infarcted region of the heart via minimally invasive technique like transcatheter delivery method. This multimodal delivery of regenerative therapeutics by minimally invasive technique will be more feasible and economical in comparison to the stem cell transplant therapies.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

File Size

5.45 MB

Comments

A thesis submitted for the degree of Doctor of Medicine from the Royal College of Surgeons in Ireland in 2017.

Available for download on Saturday, June 01, 2019

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