Diabetic retinopathy : economic evaluation and cellular functions

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This thesis reports an investigation from the “bedside” back to the “bench”. That is, from the economic evaluation of a medical intervention to basic research and development of a contractility assay. The underlying theme of this thesis is cellular contractility, which was stimulated from our laboratory’s work in the microvascular complications of Diabetic Retinopathy (DR). The health economic perspective of this thesis evaluates the cost effectiveness and cost utility of DR prognosis using the prog-DR test. This novel prognostic test developed in our laboratory relies on the contractile response of blood vessels to detect subjects with high risk of developing DR. Markov modeling based on information in the literature was used to estimate the outcomes of a hypothetical population. The costs, health and utility outcomes of DR were compared to the potential outcomes if the prog-DR test was used. The model show that the prog-DR test can improve the health of the hypothetical population as measured in the number of life years (LY), sight years (SY) and quality-adjusted life years (QALY). The prog-DR test was more cost effective than the benchmark of annual or bi-annual screening and the incremental cost effectiveness ratio (ICER) appears to be at an acceptable level. Scenario and sensitivity analysis also show that the cost effectiveness of the prog-DR test can be improved by (i) better blood glucose management post prog-DR test, (ii) targeted screening (as opposed to population-wide screening) and (iii) reduced costs of both screening and management of DM and DR. The physiological perspective of the thesis aimed to develop a contractility assay for DR that was based on a 3D scaffold, which was affordable, easy to make and mimicked the three dimensional physiological environment of blood vessels. The contractility assay was developed using a 3D, hollow scaffold (PE-PAH capsule) and involved (i) the selection of the optimal core material, (ii) optimisation of the manufacturing process, (iii) characterisation of the scaffold and (iv) ensuring that cells can be grown on it. The cyto-biocompatibility of the candidate polyelectrolyte Poly(Sodium 4-Styrene Sulfonate) (PSS) and Poly(Allylamine Hydrochloride) (PAH) in the thin films format were investigated using three different cell lines and the effects of these thin films were also compared to titanium and titanium nitride thin films. In essence, PSS and PAH are not cytotoxic and was used to develop the contractile scaffold, PE-PAH capsule. This scaffold is relative elastic and the contractile force exerted by the 3T3-L1 cells was calculated based on the deformation of the PE-PAH capsule. The contractility assay was sufficiently sensitive to detect the nano-Newton magnitude of force developed by individual cells and discriminated the change in force due to disruption of the F-actin cytoskeleton by forskolin and cytochalasin D.
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